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Which two drugs were compared in the ARISTOTLE Trial?

['METHODS: We analyzed patients from ARISTOTLE, a randomized trial of 18,201 patients with atrial fibrillation comparing the effects of apixaban versus warfarin on the risk of stroke or systemic embolism. ', ' In this study we evaluated the relationship between inflammatory biomarkers at baseline and future risk of cardiovascular events in the Apixaban for Reduction In Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.METHODS: The ARISTOTLE trial randomised 18,201 patients with AF to apixaban or warfarin.', 'Moreover, apixaban was associated with decreased all-cause mortality (RR 0.89, 95% CI 0.81 to 0.99) although this finding was driven by the results of the ARISTOTLE trial.', 'Compared with warfarin, apixaban (in the ARISTOTLE trial) and edoxaban (in the ENGAGE-AF trial) were shown to be superior or non-inferior, respectively, for reduction in stroke or SE risk in patients with AF. ', 'METHODS: A decision-analytic Markov model was constructed to assess the cost-effectiveness of apixaban versus warfarin, based on data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in AF (ARISTOTLE) trial. ', 'The following phase 3 randomized trials with novel oral anticoagulants versus warfarin for stroke prevention in AF have been completed: the Randomized Evaluation of Long-term Anticoagulant therapy (RE-LY) trial with dabigatran, the Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial with rivaroxaban, and the Apixaban for Reduction of Stroke and Other Thromboembolism Events in Atrial Fibrillation (ARISTOTLE) trial with apixaban.', 'The following phase 3 randomized trials with novel oral anticoagulants versus warfarin for stroke prevention in AF have been completed: the Randomized Evaluation of Long-term Anticoagulant therapy (RE-LY) trial with dabigatran, the Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial with rivaroxaban, and the Apixaban for Reduction of Stroke and Other Thromboembolism Events in Atrial Fibrillation (ARISTOTLE) trial with apixaban', 'We sought to compare the efficacy and safety of the 3 new agents based on data from their published warfarin-controlled randomized trials, using the method of adjusted indirect comparisons.We included findings from 44 535 patients enrolled in 3 trials of the efficacy of dabigatran (Randomized Evaluation of Long-Term Anticoagulation Therapy [RELY]), apixaban (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]), and rivaroxaban (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF]), each compared with warfarin.', 'A comparative analysis of three major clinical trials with factor Xa inhibitor oral anticoagulant (XOAC) drugs versus warfarin in atrial fibrillation-Rocket-AF (rivaroxaban), Aristotle (apixaban) and Engage AF Timi 48 (edoxaban; two different doses and sets of data)-was carried out.Data were extracted from the original reports (study level) and a meta-analysis was carried out.When compared with warfarin, XOAC therapy was associated with a decrease in haemorrhagic stroke, with a similar pattern for all regimens and meta-analysis showing a risk ratio of 0.488 (95% CI 0.', 'Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial.', 'Efficacy and safety of apixaban compared with warfarin for stroke prevention in patients with atrial fibrillation from East Asia: a subanalysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.', 'Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial.', 'A comparative analysis of three major clinical trials with factor Xa inhibitor oral anticoagulant (XOAC) drugs versus warfarin in atrial fibrillation-Rocket-AF (rivaroxaban), Aristotle (apixaban) and Engage AF Timi 48 (edoxaban; two different doses and sets of data)-was carried out.Data were extracted from the original reports (study level) and a meta-analysis was carried out.When compared with warfarin, XOAC therapy was associated with a decrease in haemorrhagic stroke, with a similar pattern for all regimens and meta-analysis showing a risk ratio of 0.488 (95% C', 'This study sought to characterize major bleeding on the basis of the components of the major bleeding definition, to explore major bleeding by location, to define 30-day mortality after a major bleeding event, and to identify factors associated with major bleeding.Apixaban was shown to reduce the risk of major hemorrhage among patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial.All patients who received at least 1 dose of a study drug were included.', 'Little is known about patients with 1 dose-reduction criterion who received the 5 mg twice daily dose of apixaban.To determine the frequency of 1 dose-reduction criterion and whether the effects of the 5 mg twice daily dose of apixaban on stroke or systemic embolism and bleeding varied among patients with 1 or no dose-reduction criteria.Among 18 201 patients in the ARISTOTLE trial, 17\u202f322 were included in this analysis.', 'We sought to compare the efficacy and safety of the 3 new agents based on data from their published warfarin-controlled randomized trials, using the method of adjusted indirect comparisons.We included findings from 44 535 patients enrolled in 3 trials of the efficacy of dabigatran (Randomized Evaluation of Long-Term Anticoagulation Therapy [RELY]), apixaban (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]), and rivaroxaban (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial i', 'This study aimed to evaluate the medical cost reductions associated with the use of individual NOACs instead of warfarin from the US payer perspective.Rates for efficacy and safety clinical events for warfarin were estimated as the weighted averages from the RE-LY, ROCKET-AF and ARISTOTLE trials, and event rates for NOACs were determined by applying trial hazard ratios or relative risk ratios to such weighted averages.', 'The ARISTOTLE trial showed apixaban was superior to warfarin for stroke prevention, significantly reduced all major bleeding, and resulted in a significant reduction in all-cause mortality.', 'The following phase 3 randomized trials with novel oral anticoagulants versus warfarin for stroke prevention in AF have been completed: the Randomized Evaluation of Long-term Anticoagulant therapy (RE-LY) trial with dabigatran, the Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial with rivaroxaban, and the Apixaban for Reduction of Stroke and Other Thromboembolism Events in Atrial Fibrillation (ARISTOTLE) trial with apixaban.', 'In the ARISTOTLE trial, apixaban was superior to warfarin in the reduction of stroke or systemic embolism, major bleeding, intracranial hemorrhage, and all-cause mortality, with a similar reduction in the rate of ischemic stroke and better tolerability.', 'The results of the ARISTOTLE trial, which is evaluating apixaban against warfarin in ∼18\u2009000 patients with AF, are expected to be available later this year.', 'The Medco data did not contain information for patients receiving apixaban as it was not on the market at the time of analysis.RESULTS: Stroke and MB rates among RW NVAF patients during warfarin exposure were higher compared with event rates in patients treated with warfarin in ARISTOTLE (stroke: 5.29 vs.', 'In the ARISTOTLE trial, apixaban when compared with warfarin reduced the rate of stroke, death, and bleeding.', 'The ARISTOTLE trial compared apixaban with warfarin in 18 201 patients with AF and ≥ 1 additional risk factor for stroke.', 'Compared with warfarin, apixaban (in the ARISTOTLE trial) and edoxaban (in the ENGAGE-AF trial) were shown to be superior or non-inferior, respectively, for reduction in stroke or SE risk in patients with AF.', 'Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial.', 'Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial.', 'In the ARISTOTLE trial, the rate of stroke or systemic embolism was reduced by apixaban compared with warfarin in patients with atrial fibrillation (AF).']

['Apixaban for Reduction In Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial compared apixaban and warfarin.']

['apixaban', 'warfarin']

What is the effect of ROS on cyclin B1?

['The present study was undertaken to determine whether sulforaphane-derived reactive oxygen species (ROS) might cause growth arrest and apoptosis in human bladder cancer 5637 cells. Our results show that the reduced viability of 5637 cells by sulforaphane is due to mitotic arrest, but not the G2 phase. The sulforaphane-induced mitotic arrest correlated with an induction of cyclin B1 and phosphorylation of Cdk1, as well as a concomitant increased complex between cyclin B1 and Cdk1.', 'Further mechanistic studies revealed that induction of apoptosis is associated with cell cycle arrest at G2/M phase, increased generation of reactive oxygen species (ROS), reduced mitochondrial membrane potential (MMP), release of cytochrome c (Cyto c) and apoptosis inducing factor (AIF) from mitochondria to cytosol, upregulation of Bax, p21 and p53, and down-regulation of Bcl-2, cyclin B1 and cyclin-dependent kinase 1 (CDK1).', 'LDH inhibition by oxamate induced G2/M cell cycle arrest via downregulation of the CDK1/cyclin B1 pathway and promoted apoptosis through enhancement of mitochondrial ROS generation. N-acetylcysteine, a specific scavenger of ROS, significantly blocked the growth inhibition effect induced by oxamate.', 'As well as DICO induced G2/M cell cycle arrest and apoptosis via a ROS-mediated mitochondrial pathway.', 'Meanwhile, the alterations of cyclin A and B1, p-CDK1 and p-cdc25c levels were also observed in response to DICO treatment.', 'Butyrate (> 2 mm) inhibited the expression of cdc2, cdc25C and cyclinB1 mRNAs and reduced the levels of Cdc2, Cdc25C and cyclinB1 proteins in GFs, as determined using RT-PCR and western blotting, respectively. This toxic effect of butyrate was associated with the production of ROS.', 'Furthermore, costunolide induced cell cycle arrest in the G2/M phase via decrease in Cdc2, cyclin B1 and increase in p21WAF1 expression,', 'In addition, costunolide had a slight induced effect on ROS generation.', 'This study suggested that G2/M cell cycle arrest was triggered by ROS/NO productions with regulations of p53, p21, cell division cycle 25C (Cdc25C), Cdc2 and cyclin B1, which were able to be prevented by protein tyrosine kinase (PTK) activity inhibitor genistein or JNK inhibitor SP600125.', 'Other G(2)/M regulatory molecules such as Cdc25C, Cdk1, cyclin B1 were down-regulated by DIM.', 'Blocking ROS generation by N-acetyl cysteine protects the cells from DIM-mediated G(2)/M arrest and apoptosis.', 'Taken together, these findings suggest that emodin mediated oxidative injury (DNA damage) based on ROS production and ER stress based on the levels of GADD153 and GRP78 that acts as an early and upstream change in the cell death cascade to caspase- and mitochondria-dependent signaling pathways, triggers mitochondrial dysfunction from Bcl-2 and Bax modulation, mitochondrial cytochrome c release and caspase activation, consequently leading to apoptosis in SCC-4 cells.', 'In this study, treatment of human tongue cancer SCC-4 cells with various concentrations of emodin led to G2/M arrest through promoted p21 and Chk2 expression but inhibited cyclin B1 and cdc2;', "Further investigation revealed that plumbagin's inhibition of cell growth was also evident in a nude mice model. Blockade of cell cycle was associated with increased levels of p21, and reduced amounts of cyclin B1, cyclin A, Cdc2, and Cdc25C.", 'We also found the generation of ROS is a critical mediator in plumbagin-induced cell growth inhibition.', "IOA exhibited effective cell growth inhibition by inducing cancer cells to undergo G(2)-M phase arrest and apoptosis. Further investigation revealed that IOA's inhibition of cell growth was also evident in a nude mice model. Cell cycle blockade was associated with increased levels of p21 and reduced amounts of cyclin B1, cyclin A, cdc2, and cdc25C.", 'We also found that the generation of reactive oxygen species (ROS) is a critical mediator in IOA-induced cell growth inhibition.']

['Reactive oxygen species (ROS) production is able to cause growth arrest at the G2-M checkpoint of the cell cycle, partly by deregulation of Cyclin B1 expression.']

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What is the outcome of TAF10 interacting with the GATA1 transcription factor?

['TAF10 Interacts with the GATA1 Transcription Factor and Controls Mouse Erythropoiesis.', 'we show that TAF10 interacts directly with GATA1 and that TAF10 is enriched on the GATA1 locus in human fetal erythroid cells', 'TAF10 Interacts with the GATA1 Transcription Factor and Controls Mouse Erythropoiesis']

['TAF10 Interacts with the GATA1 Transcription Factor and Controls Mouse Erythropoiesis.']

['Control of Mouse Erythropoiesis']

What makes telomerase a good drug target?

['Human telomerase is absent in most normal tissues, but is abnormally activated in all major cancer cells. Telomerase enables tumor cells to maintain telomere length, allowing indefinite replicative capacity.', 'telomerase is believed to be necessary for cancer cells to grow without limit', ' Telomerase, a ribonucleoprotein enzyme is considered as a universal therapeutic target of cancer because of its preferential expression in cancer cells and its presence in 90 % of tumors. ', 'Interestingly, almost 100 % of adenocarcinoma, including breast cancer cells, expresses telomerase which makes it a good target for telomerase-related therapy.', 'The observation that the enzyme telomerase is up-regulated in 80-90% of cancer cells isolated from primary human tumors but is absent in neighboring cells of healthy tissue has resulted in significant efforts to validate telomerase as an anticancer drug target and to develop effective approaches toward its inhibition.', 'Telomerase plays an important role in cell proliferation and carcinogenesis and is believed to be a good target for anti-cancer drugs.', 'In contrast to cancer cells, most normal human cells have no or low telomerase levels which makes it an attractive target for anti-cancer drugs.', 'Telomerase activity is repressed in normal human somatic cells, but is activated in most cancers, suggesting that telomerase may be an important target for cancer therapy.', 'Telomerase is expressed in more than 85% of cancer cells, making it a nearly universal cancer marker, while the majority of normal somatic cells are telomerase negative', 'The activity of telomerase is highly associated with carcinogenesis which makes the enzyme an attractive biomarker in cancer diagnosis and treatment', 'The human telomerase reverse transcriptase (hTERT) is expressed in more than 85% of tumor cells but is usually not found in normal cells, which makes hTERT as an ideal tumor-associate antigen (TAA) to develop potential vaccine specifically destroying cancers without impairing normal tissues in human cancer immunotherapy', 'The differential expression of telomerase in cancer cells makes it an attractive therapeutic target', 'The evidence that telomerase is also present in normal B cells at different levels according to their differentiation and activation state makes the study of telomerase activity in B cell tumors particularly interesting', 'Telomerase is up-regulated in the majority of cancer cells and is essential for their survival, making it a potential anti-cancer drug target. ', 'In contrast to cancer cells, most normal human cells have no or low telomerase levels which makes it an attractive target for anti-cancer drugs. ', 'As normal cells have a considerable telomere reserve, even in elderly humans, this makes telomerase an attractive and potentially selective anti-cancer drug target.', 'The expression of telomerase in approximately 85% of cancers and its absence in the majority of normal cells makes it an attractive target for cancer therapy.', 'Moreover, since telomerase is not or slightly expressed in normal cells, it has been postulated that drugs targeting telomerase would induce low toxicity.', 'Telomerase is expressed in most cancer cells, but not in normal somatic cells, suggesting that telomerase is an attractive target for cancer chemotherapy', 'elomerase, a special reverse transcriptase, has been recognized as a common factor in most tumor cells, and in turn a distinctive characteristic with respect to non-malignant cells', 'Telomerase is detected in the majority of prostate cancers, but not in normal or benign prostatic hyperplasia tissue.', 'The catalytic component of telomerase in humans, hTERT, is upregulated in nearly 90% of all cancers, making it the most widely expressed marker of malignancy. With the exception of germ cells and stem cells, hTERT is undetectable in somatic human tissues.', 'he notion that telomerase is reactivated in 80-90% of human cancers has led to the proposal of telomerase as a promising therapeutic target for novel anticancer interventions']

['Human telomerase is absent in most normal tissues, but is abnormally activated in all major cancer cells. Telomerase enables tumor cells to maintain telomere length, allowing indefinite replicative capacity.', 'Telomerase, a ribonucleoprotein enzyme is considered as a universal therapeutic target of cancer because of its preferential expression in cancer cells and its presence in 90 % of tumors. Human telomerase is absent in most normal tissues, but is abnormally activated in all major cancer cells.', ' telomerase, a ribonucleoprotein enzyme is considered as a universal therapeutic target of cancer because of its preferential expression in cancer cells and its presence in 90 % of tumors.', 'Human telomerase is absent in most normal tissues, but is abnormally activated in all major cancer cells. Telomerase enables tumor cells to maintain telomere length, allowing indefinite replicative capacity. telomerase is believed to be necessary for cancer cells to grow without limit', ' Telomerase, a ribonucleoprotein enzyme is considered as a universal therapeutic target of cancer because of its preferential expression in cancer cells and its presence in 90 % of tumors. ']

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What is the role of the E2-conjugating enzyme in the sumoylation pathway?

['["Among the proteins involved in the sumoylation pathway, Ubc9 is the sole E2-conjugating enzyme required for sumoylation and plays a central role by interacting with almost all of the partners required for sumoylation. ", "We also found a marked rise in levels of Ubc9, the only SUMO conjugation enzyme identified so far. ", "Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays an important role in sumoylation-mediated cellular pathways.", "We observed steady-state expression of SUMO1-3, SUMO-conjugated enzyme-UBC9 and deSUMOylating enzymes - SENPs, throughout normal gestation. ", "The small ubiquitin-like modifier (SUMO) pathway in eukaryotes is an essential post-translational modification required for a variety of cellular processes, development and organelle biogenesis. SUMO-conjugating enzyme (Ubc9) is an important conjunction enzyme in the SUMO pathway. ", "Western blot analysis, EMSA, ELISA, confocal microscopy and immunoprecipitation demonstrated that drastic tissue hypoxia, elevated levels of proteins conjugated by small ubiquitin-related modifier-1 (SUMO-1), Ubc9 (the only known conjugating enzyme for the sumoylation pathway) or HIF-1\\u03b1, augmented sumoylation of HIF-1\\u03b1, nucleus-bound translocation and enhanced transcriptional activity of HIF-1\\u03b1 in RVLM neurons took place preferentially during the pro-life phase of experimental brain death. ", "Among the proteins involved in the sumoylation pathway, Ubc9 is the sole E2-conjugating enzyme required for sumoylation and plays a central role by interacting with almost all of the partners required for sumoylation.", "UBC9 is the only E2 conjugating enzyme involved in this process, and loss of UBC9 completely abolishes the SUMOylation pathway.", "Here we have identified host cell proteins involved with the cellular SUMOylation pathway, SUMO-1 (small ubiquitin-like modifier) and UBC9, a SUMO-1 conjugating enzyme that interact with classical swine fever virus (CSFV) Core protein.", "Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays an important role in sumoylation-mediated cellular pathways.", "In this study, we found that the SUMOylation pathway was involved in the DENV life cycle, since DENV replication was reduced by silencing the cellular gene Ubc9, which encodes the sole E2-conjugating enzyme required for SUMOylation.", "Here we demonstrate that the synaptic diffusion of Ubc9, the sole conjugating enzyme of the sumoylation pathway, is regulated by synaptic activity.", "The SUMO pathway parallels the classical ubiquitinylation pathway with three discrete steps: activation involving the enzyme E1, conjugation involving the E2 enzyme UBC9, and substrate modification through the cooperative association of UBC9 and E3 ligases.", "RAP80 interacts with the SUMO-conjugating enzyme UBC9 and is a novel target for sumoylation.", "Among the proteins involved in the sumoylation pathway, Ubc9 is the sole E2-conjugating enzyme required for sumoylation and plays a central role by interacting with almost all of the partners required for sumoylation.", "Although there are multiple E2 enzymes required for ubiquitination, there is only one E2-conjugating enzyme for sumoylation, which is Ubc9.", "Consistent with a role of sumoylation in inhibiting Tec1 activity, specifically increasing sumoylation of Tec1 by fusing it to the sumoylating enzyme Ubc9 leads to a dramatic decrease of Tec1 transcriptional activity.", "Ubc9 is an E2-conjugating enzyme required for sumoylation and has been implicated in regulating several critical cellular pathways.", "We also exposed placental explants to hypoxia to study the effect on the SUMOylation pathway.We observed steady-state expression of SUMO1-3, SUMO-conjugated enzyme-UBC9 and deSUMOylating enzymes - SENPs, throughout normal gestation", "It has been reported that ubiquitin-conjugating enzyme 9 (Ubc9), the unique enzyme2 in the sumoylation pathway, is up-regulated in many cancers", "Among the proteins involved in the sumoylation pathway, Ubc9 is the sole E2-conjugating enzyme required for sum']

The E2-conjugating enzyme in the sumoylation pathway, specifically Ubc9, is required for sumoylation and plays a central role by interacting with almost all of the partners involved in the sumoylation process. Ubc9 is the sole conjugating enzyme for sumoylation and regulates protein function in sumoylation-mediated cellular pathways.

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What is the mechanism of action of eprotirome?

['Eprotirome and Sobetirome are 2 thyromimetics that have selective TRβ1 activity. ', 'Recently, the development of the most promising agent in this class, eprotirome, was halted over toxicology concerns following long-term canine studies. Consequently, the future of contemporary TRβ agonists is unclear. ', 'We designed novel thyromimetics with high receptor (TRβ) and organ (liver) selectivity based on the structure of eprotirome (3) and molecular modeling. ', 'In humans, eprotirome exerts favorable lipid-modulating effects while lacking thyroid hormone-related side-effects and maintaining normal hypothalamic-pituitary-thyroid feedback.', 'This review details recent advances in the development of TRβ subtype- and liver-selective STRM analogs, and presents the results of preliminary clinical trials with one of these compounds, eprotirome (KB-2115; Karo Bio AB).', 'Examples of synthetic analogues are GC-1 (or sobetirome) and KB2115 (or eprotirome) which show ipolipidaemic and antiaterogenic capacities. ', 'METHODS: The history of thyromimetics in atherosclerosis and dyslipidaemia is reviewed as the background to the recent publication of the first human data on a new selective thyromimetic, KB-2115 (eprotirome). ', ' Eprotirome and Sobetirome are 2 thyromimetics that have selective TRβ1 activity.', 'Eprotirome and Sobetirome are 2 thyromimetics that have selective TRβ1 activity', 'We also examined the effects of the TRβ agonist eprotirome on hepatic gene regulation']

['Eprotirome belongs to thyromimetics and has selective TRβ1 activity. It has shown to be effective in dyslipidemia by the lipid-lowering action of TH in the liver and also in obesity.']

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Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?

['SR Ca-transport is mediated by the SR Ca-ATPase (SERCA2a) and its regulatory phosphoprotein, phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA2a and phosphorylation by protein kinase A (PKA) or calcium-calmodulin-dependent protein kinases (CAMKII) relieves these inhibitory effects.', 'SERCA2a activity can be regulated at multiple levels of a signaling cascade comprised of phospholamban', 'Phospholamban (PLN), the reversible inhibitor of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), is a key regulator of myocyte Ca(2+) cycling with a significant role in heart failure.', 'The sarco(endo)plasmic reticulum (SR) Ca(2+) transport ATPase (SERCA2a) and its inhibitor phospholamban (PLN) control the uptake of Ca(2+) by SR membranes during relaxation. ', 'phospholamban (PLN), a muscle-specific SR Ca(2+)-ATPase (SERCA2a) inhibitor', 'Phospholamban (PLB) is a major target of the beta-adrenergic cascade in the heart, and functions as an endogenous inhibitor of Ca-ATPase transport activity.', 'Phospholamban (PLB) inhibits the activity of SERCA2a, the Ca(2+)-ATPase in cardiac sarcoplasmic reticulum, by decreasing the apparent affinity of the enzyme for Ca(2+).', 'Phospholamban has been suggested to be a key regulator of cardiac sarcoplasmic reticulum (SR) Ca cycling and contractility and a potential therapeutic target in restoring the depressed Ca cycling in failing hearts.', 'phospholamban regulation of SERCA2a', 'SERCA2a activity is regulated by phosphorylation of another SR protein: Phospholamban (PLN). Dephosphorylated PLN inhibits SERCA2a. Phosphorylation of PLN by either cAMP or cGMP-dependent protein kinase at Ser16 or the Ca2+-calmodulin-dependent protein kinase (CaMKII), at Thr17, relieves this inhibition, increasing SR Ca2+ uptake and SR Ca2+ load.', 'The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor, phospholamban, rescued the spectrum of phenotypes that resemble human heart failure.', 'The sarco(endo)plasmic reticulum Ca(2+) transport adenosine triphosphatase (SERCA2a) and its regulator phospholamban (PLN) have a central role in modulating Ca(2+) homeostasis and, therefore, cardiac function.']

['SERCA2a activity is regulated by phosphorylation of another SR protein, Phospholamban (PLN). Phospholamban (PLB) inhibits the activity of SERCA2a, the Ca(2+)-ATPase in cardiac sarcoplasmic reticulum, by decreasing the apparent affinity of the enzyme for Ca(2+).']

['Phospholamban', 'PLN', 'plb']

Which pathological conditions are caused by mutations in the CYLD gene?

['We detected a frameshift mutation in the CYLD gene, designated 2253delG, underlying the disorder and were able to show that a single mutation can result in distinct clinical and histologic expression in familial cylindromatosis.', 'Previously, a candidate MTF locus has been mapped to 9p21 while disease gene for familial cylindromatosis, the CYLD gene located on 16q21-13 has been identified', 'Here, we show that mutations in the CYLD gene are also the genetic basis for three different Chinese families with MFT', 'familial trichoepithelioma (MFT) and familial cylindromatosis are two clinically distinct cancer syndromes. MFT patients developed mostly trichoepithelioma in the face while cylindromatosis patients developed cylindromas predominantly (approximately 90%) on the head and neck', 'phenotype of familial cylindromatosis associated with an R758X nonsense mutation in the CYLD tumour suppressor gene', 'We describe a family with cylindromatosis, in which affected individuals have an inherited R758X nonsense mutation of CYLD', 'YLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes', 'We describe a single family with affected members exhibiting either the FC or the MFT phenotypes associated with a mutation in the CYLD gene. ', 'ndividuals with germline mutations in the tumour-suppressor gene CYLD are at high risk of developing disfiguring cutaneous appendageal tumours, the defining tumour being the highly organised cylindroma', 'YLD is a tumor-suppressor gene mutated in the skin appendage tumors cylindromas, trichoepitheliomas, and spiradenomas. ', 'In addition, we have characterized Maspin downregulation in cylindromas, trichoepitheliomas, and spiradenomas carrying functional inactivating mutations of CYLD, also providing an evidence of the correlation between impaired CYLD function and Maspin decreased expression in vivo in human tumors', 'Germ‑line mutation in cylindromatosis (CYLD), a tumor suppressor gene, causes familial cylindromatosis and Brook‑Spiegler syndrome', 'atients carrying heterozygous germline truncating mutations in the CYLD gene develop multiple primary hair follicle-related tumours. A highly patterned tumour, termed cylindroma, and a highly disorganized tumour, termed spiradenoma, may both develop in the same patient.', 'ultiple trichoepitheliomas associated with a novel heterozygous mutation in the CYLD gene as an adjunct to the histopathological diagnosis', 'ultiple trichoepitheliomas (TEs), especially in the familial setting, have been associated with germline heterozygous mutations in the CYLD gene', 'We describe a 35-year-old woman with multiple facial TEs, in whom the molecular genetic analysis revealed a novel heterozygous c.1843delT mutation in the CYLD gene', 'This frameshift mutation was also present in a heterozygous state in the TE tumor cells. The demonstration of a novel CYLD mutation was used as an adjunct to the histopathological diagnosis in this case', 'novel germline mutation in the CYLD gene in a Slovak patient with Brooke-Spiegler syndrome', 'This new germline mutation in the CYLD gene of a Slovak patient with Brooke-Spiegler syndrome extends the catalogue of known CYLD germline mutations in this condition', 'Molecular biologic study of the CYLD gene performed from the peripheral blood identified a novel splice site c.2041+1 G>T mutation', 'Patients with Brooke-Spiegler syndrome have various mutations in the CYLD gene, a tumor-suppressor gene located on chromosome 16q', 'Mutation and loss of heterozygosity of the CYLD gene causes development of cylindromatosis, a benign tumour originating from the skin', 'Our study shows that CYLD expression is dramatically downregulated in basal cell carcinoma (BCC), the most common cancer in humans', 'Although some early studies suggested a role for the PTCH gene on chromosome 9q22.3 in the etiopathogenesis of MFT, recent studies of occasional patients with the MFT clinical phenotype identified mutations in the CYLD gene on chromosome 16q12-q13, a gene responsible for BSS', 'Since loss of CYLD expression can be observed in different types of human cancer, it is now well established that CYLD acts as a tumor suppressor gene', 'mutations in CYLD can be identified in patients affected with Brooke-Spiegler syndrome, (Familial) Cylindromatosis or multiple familial trichoepithelioma', 'we demonstrate that the expression in tumorigenic epidermal cells of a catalytically inactive form of CYLD (CYLD(C/S)) that mimics the identified mutations of cyld in human tumors and competes with the endogenous CYLD results in enhanced cell proliferation and inhibition of apoptosi', 'In contrast with previous studies showing the development of benign tumors by mutations in the CYLD gene, here we provide evidence that the occurrence of mutations in the CYLD gene in tumorigenic epidermal cells (carrying previous mutations) increases the aggressiveness of carcinomas, mainly through enhancement of the expression of angiogenic factors, having therefore a key role in epidermal cancer malignancy', 'By interphase cytogenetics, a (sub)clonal biallelic CYLD deletion was observed by interphase cytogenetics in 1 of 29 primary cHL, whereas signal patterns indicating decreased CYLD copy numbers were observed in a total of 10 of 29 primary cases', 'mutation in the CYLD gene within a family with Brooke-Spiegler syndrome', 'rooke-Spiegler syndrome is a rare, autosomal dominant disease characterized by multiple skin appendage tumors caused by various mutations in the CYLD gene on chromosome 16q12-q13', 'authors report a case of Brooke-Spiegler syndrome (BSS) with a novel germline CYLD mutation and various somatic mutations identified in the lesional tissues', 'he available histopathological material included 24 trichoepitheliomas, 2 large nodular basal cell carcinomas (BCCs), 2 spiradenomas, 1 spiradenocylindroma and 1 trichoblastoma composed of large and small nodules with prominent clear cell differentiation', 'To comprehensively ascertain the extent and severity of clinical features in affected individuals from 2 large families with proven heterozygous mutations in the CYLD locus and to correlate these findings with the 3 appendageal tumor predisposition syndromes (familial cylindromatosis, Brooke-Spiegler syndrome, and multiple familial trichoepitheliomas) known to be associated with such germline mutations', 'In this report, we identified a novel mutation of CYLD gene in a Chinese family with MFT', 'case of Brooke-Spiegler syndrome with a novel germline deep intronic mutation in the CYLD gene leading to intronic exonization, diverse somatic mutations, and unusual histology', 'present a case of Brooke-Spiegler syndrome with a germline deep intronic mutation in the CYLD gene leading to intronic exonization', 'A deep intronic mutation resulting in exonization and a somatic sequence mutations causing exon skipping are hitherto unreported genetic mechanisms involving the CYLD gene in patients with Brooke-Spiegler syndrome', 'novel splicing mutation of the CYLD gene in a Taiwanese family with multiple familial trichoepithelioma', 'Mutations in the CYLD gene, which is also the gene responsible for familial cylindromatosis, have been reported recently', 'We report a novel splicing mutation (IVS12 + 1 G-->A) in the CYLD gene in a Taiwanese pedigree with MFT, and discuss new developments in treatment options', 'new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity', 'rooke-Spiegler syndrome, familial cylindromatosis, and familial trichoepithelioma are autosomal-dominant genetic predispositions for benign tumors of skin appendages caused by mutations in the CYLD gene localized on chromosome 16q12-q13', 'The disease gene was mapped to 16q12-13, and mutations in the CYLD gene were identified in families with BSS', 'By sequence analysis, we identified a recurrent mutation 2272C>T (R758X) of the CYLD gene in the affected individuals of this family, which was previously identified in other ethnic families with familial cylindromatosis']

['Since loss of CYLD expression can be observed in different types of human cancer, it is now well established that CYLD acts as a tumor suppressor gene. Pathogenic mutations in CYLD can be identified in patients affected with Brooke-Spiegler syndrome, (Familial) Cylindromatosis or multiple familial trichoepithelioma. CYLD expression has also been reported to be dramatically downregulated in basal cell carcinoma (BCC), the most common cancer in humans.']

['Brooke-Spiegler syndrome', 'BSS', 'Cylindromatosis', 'Multiple Familial Trichoepithelioma', 'MFT']

How many genera comprise the Flaviviridae family?

['Within a project aimed at discovering new Flaviviridae inhibitors, new variously substituted 2-phenylbenzimidazoles were synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against viruses representatives of the three genera of the Flaviviridae family, i.e.: Pestivirus (BVDV), Flavivirus (YFV) and Hepacivirus (HCV).', 'Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Pestiviruses and Flaviviruses;', 'The RNA-stimulated NTPase activity of this protein from prototypic members of the Pestivirus and Flavivirus genera has recently been established and enzymologically characterized.', 'Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Flaviviruses and Pestiviruses; ii) other RNA virus families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae).', 'Forty-three 2-[(benzotriazol-1/2-yl)methyl]benzimidazoles, bearing either linear (dialkylamino)alkyl- or bulkier (quinolizidin-1-yl)alkyl moieties at position 1, were evaluated in cell-based assays for cytotoxicity and antiviral activity against viruses representative of two of the three genera of the Flaviviridae family, i.e. Flaviviruses (Yellow Fever Virus (YFV)) and Pestiviruses (Bovine Viral Diarrhoea Virus (BVDV)), as Hepaciviruses can hardly be used in routine cell-based assays.', 'Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Flaviviruses and Pestiviruses; ii) other RNA virus families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae).', ': Pestivirus (BVDV), Flavivirus (YFV) and Hepacivirus (HCV).', 'The family Flaviviridae contains three genera of positive-strand RNA viruses, namely, Flavivirus, Hepacivirus (e.g., hepatitis C virus [HCV]), and Pestivirus.']

['The family Flaviviridae is comprised of three genera: Flavivirus, Pestivirus and Hepacivirus.']

['three', '3']

Is ocular melanosis a risk factor for uveal melanoma?

['Ocular/oculodermal (oculo[dermal]) melanocytosis is a congenital periocular pigmentary condition that can lead to the development of uveal melanoma, estimated at 1 in 400 affected patients.', 'Melanosis oculi is often underestimated as a risk factor for uveal melanoma and glaucoma. Ophthalmic surveillance, every 6 or 12 months is important, in patients with ocular melanocytosis for early detection of high risk diseases.', ' One of about 400 patients with ODM followed for life is estimated to develop uveal melanoma. Excessive melanocytes in the uveal tract in ODM may provide the biologic basis for susceptibility to the development of uveal melanoma. Patients with ODM should be monitored ophthalmoscopically, especially during the susceptible period, for the development of uveal melanoma. The authors suggest that a national registry of ODM patients be created and prospective data collected to better assess the risk of developing uveal melanoma.', 'In the white population, an association between oculo(dermal) melanocytosis (ODM) and uveal melanoma is well recognized. ', 'Malignant melanomas may arise in the uveal tract, the conjunctiva, the skin of the eyelid, or the orbit. Risk factors so far identified include pre-existing choroidal naevi for uveal melanomas, primary acquired melanosis (PAM) for conjunctival tumours, and ocular and oculodermal melanocytosis for uveal and orbital lesions. ', 'Risk factors so far identified include pre-existing choroidal naevi for uveal melanomas, primary acquired melanosis (PAM) for conjunctival tumours, and ocular and oculodermal melanocytosis for uveal and orbital lesions.', 'Phacomatosis pigmentovascularis of cesioflammea type in 7 patients: combination of ocular pigmentation (melanocytosis or melanosis) and nevus flammeus with risk for melanoma.', 'In the fourth case the melanoma was detected in a routine examination and we were able to apply a preserving treatment with I125 brachytherapy.DISCUSSION: Melanosis oculi is often underestimated as a risk factor for uveal melanoma and glaucoma.', 'Association of ocular and oculodermal melanocytosis with the rate of uveal melanoma metastasis: analysis of 7872 consecutive eyes.', 'Risk factors so far identified include pre-existing choroidal naevi for uveal melanomas, primary acquired melanosis (PAM) for conjunctival tumours, and ocular and oculodermal melanocytosis for uveal and orbital lesions', 'In the fourth case the melanoma was detected in a routine examination and we were able to apply a preserving treatment with I125 brachytherapy.Melanosis oculi is often underestimated as a risk factor for uveal melanoma and glaucoma', 'In this study, patients with melanocytosis who developed uveal melanoma were found to have double the risk for metastasis compared with those without melanocytosis.To determine the relationship of oculo(dermal) melanocytosis to the prognosis of patients with uveal melanoma.Retrospective chart review of 7872 patients with uveal melanoma treated at the Ocular Oncology Service, Wills Eye Institute, from August 25, 1970, through August 27, 2008.Enucleation, plaque radiotherapy, local resection, or thermotherapy.Metastasis and death.Of 7872 patients with uveal melanoma, oculo(dermal) melanocytosis was present in 230 (3%)', 'By multivariable analysis, the factors predictive of metastasis in patients harboring uveal melanoma associated with oculo(dermal) melanocytosis were increased tumor thickness (P = .001) and the presence of subretinal fluid (P = .05), and the only factor predictive of death was increased tumor thickness (P = .009). ', 'In the fourth case the melanoma was detected in a routine examination and we were able to apply a preserving treatment with I125 brachytherapy.Melanosis oculi is often underestimated as a risk factor for uveal melanoma and glaucoma.', 'Risk factors so far identified include pre-existing choroidal naevi for uveal melanomas, primary acquired melanosis (PAM) for conjunctival tumours, and ocular and oculodermal melanocytosis for uveal and orbital lesions.', 'CONCLUSIONS AND RELEVANCE Patients with uveal melanoma associated with oculo(dermal) melanocytosis have double the risk for metastasis compared with those with no melanocytosis.', 'By multivariable analysis, the factors predictive of metastasis in patients harboring uveal melanoma associated with oculo(dermal) melanocytosis were increased tumor thickness (P = .001) and the presence of subretinal fluid (P = .05), and the only factor predictive of death was increased tumor thickness (P = .009).', 'CONCLUSIONS AND RELEVANCE Patients with uveal melanoma associated with oculo(dermal) melanocytosis have double the risk for metastasis compared with those with no melanocytosis.']

['Yes, ocular melanosis (melanosis oculi) is a risk factor for uveal melanoma.']

['yes']

Could Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) cause sudden cardiac death?

['Two siblings died suddenly at the ages of 9 and 10\xa0years', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a type of cardiac arrhythmia that occurs in people with a structurally normal heart. Stress or anxiety-induced release of endogenous catecholamines causes a dysfunction in the myocytic calcium-ion channel, leading to ventricular arrhythmias that can cause dizziness, syncope, or sudden cardiac death. ', 'During a follow-up of 48±94 months, arrhythmia events (sudden cardiac death and aborted cardiac arrest) associated with noncompliance occurred in 2 patients. ', 'We report a family with repeat events of sudden cardiac death and recurrent ventricular fibrillation in a teenage girl, where autopsy data and clinical investigations were inconclusive. The diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) was established only following finding a gene mutation in the cardiac ryanodine receptor. ', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. ', 'catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS), leave no evidence to be found at autopsy', 'a spectrum of sudden cardiac death (SCD)-predisposing heritable cardiac arrhythmia syndromes, including long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). ', 'CPVT is a familial arrhythmogenic syndrome characterized by abnormal calcium (Ca(2+)) handling, ventricular arrhythmias, and sudden cardiac death', 'Mutations in RyR2 are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT) and sudden cardiac death.', 'Patients with CPVT often present with exercise- or emotion induced syncope, the first presentation can also be sudden cardiac death.', 'Among the five major arrhythmogenic disorders occurring in the absence of a structural heart disease is catecholaminergic polymorphic ventricular tachycardia (CPVT), which is a highly lethal form of inherited arrhythmias. ', 'Patients with CPVT are at high risk of developing life-threatening ventricular arrhythmias when untreated. ', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by VT induced by adrenergic stress in the absence of structural heart disease and high incidence of sudden cardiac death. ', 'CPVT is an inherited arrhythmia syndrome caused by gene mutations that destabilize cardiac ryanodine receptor Ca(2+) release channels. Sudden cardiac death is incompletely prevented by conventional drug therapy with β-blockers with or without Ca(2+) channel blockers. ', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease that can cause sudden cardiac death due to ventricular fibrillation (VF).', 'Important potential causes of sudden cardiac deaths in the absence of heart disease are primary electrical diseases such as Brugada syndrome, long QT syndrome (LQTS), short QT syndrome and catecholaminergic polymorphic ventricular tachyarrhythmias. ', 'catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) are primary inherited arrhythmia syndromes that may cause syncope and sudden cardiac death in young individuals. ', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac channelopathy characterized by altered intracellular calcium handling resulting in ventricular arrhythmias and high risk of cardiac sudden death in young cases with normal structural hearts. ', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder that causes syncopal episodes related with stress or emotion and even sudden cardiac deaths.', 'Catecholaminergic polymorphic ventricular tachycardia caused by mutations in the RyR2 gene manifests as severe arrhythmias, and may provide a candidate for sudden cardiac deaths.', 'Patients diagnosed with an electrical cardiomyopathy have an increased risk of syncope and sudden cardiac death (SCD). ', 'Patients with CPVT present with exercise-induced syncope and sudden cardiac death but normal resting electrocardiograms. ', 'Over 80% of SCD occurs in patients with organic heart disease. However, approximately 10-15% of SCD occurs in the presence of structurally normal heart and the majority of those patients are young. In this group of patients, changes in genes encoding cardiac ion channels produce modification of the function of the channel resulting in an electrophysiological substrate of VA and SCD. Collectively these disorders are referred to as Cardiac Ion Channelopathies. The 4 major syndromes in this group are: The Long QT Syndrome (LQTS), the Brugada Syndrome (BrS), the Short QT Syndrome (SQTS), and the Catecholaminergic Polymorphic VT (CPVT). ', 'Important potential causes of sudden cardiac deaths in the absence of heart disease are primary electrical diseases such as Brugada syndrome, long QT syndrome (LQTS), short QT syndrome (SQTS), and catecholaminergic polymorphic ventricular tachyarrhythmias (CPVT). ', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial cardiac arrhythmia that is related to RYR2 or CASQ2 gene mutation. It occurs in patients with structurally normal heart and causes exercise-emotion-triggered syncope and sudden cardiac death.', 'Potentially lethal ion channel disorders (channelopathies) such as the long QT syndromes (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT)', 'Aberrant spontaneous, diastolic Ca2+ leak from the SR due to dysfunctional RyR2 contributes to the formation of delayed after-depolarisations, which are thought to underlie the fatal arrhythmia that occurs in both heart failure (HF) and in catecholaminergic polymorphic ventricular tachycardia (CPVT). ', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon heritable disease presenting with syncope or sudden cardiac death.', 'Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]).', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a heritable arrhythmia unmasked by exertion or stress, characterized by triggered activity and sudden cardiac death in affected patients.', 'families that exhibit CPVT (catecholaminergic polymorphic ventricular tachycardia), a condition in which physical or emotional stress can trigger severe tachyarrhythmias that can lead to sudden cardiac death.', 'that often leads to sudden death in HF and in CPVT.', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by adrenergically mediated polymorphic ventricular tachycardia leading to syncope and sudden cardiac death.', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an autosomal dominant inherited disorder characterized by adrenergic induced polymorphic ventricular tachycardias and associated with sudden cardiac death. ', 'These data suggest that "leaky" RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT.', 'Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare arrhythmogenic disorder characterized by syncopal events and sudden cardiac death at a young age during physical stress or emotion, in the absence of structural heart disease. ', ' catecholaminergic polymorphic ventricular tachycardia (CPVT), idiopathic ventricular fibrillation (VF), and arrhythmogenic right ventricular cardiomyopathy (ARVC) account for a relevant proportion of sudden cardiac death cases in young patients cohorts. ', 'has recently been shown to be involved in at least two forms of sudden cardiac death (SCD): (1) Catecholaminergic polymorphic ventricular tachycardia (CPVT) ']

['Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) can cause sudden cardiac death.']

['yes']

Tumor-treating fields are effective for treatment of which cancers?

['Alternating electric fields (tumor-treating fields therapy) can improve chemotherapy treatment efficacy in non-small cell lung cancer both in vitro and in vivo.', 'e evaluated the effects of combining TTFields with standard chemotherapeutic agents on several NSCLC cell lines, both in vitro and in vivo. Frequency titration curves demonstrated that the inhibitory effects of TTFields were maximal at 150 kHz for all NSCLC cell lines tested, and that the addition of TTFields to chemotherapy resulted in enhanced treatment efficacy across all cell lines. ', 'Together, these findings suggest that combining TTFields therapy with chemotherapy may provide an additive efficacy benefit in the management of NSCLC.', 'Response patterns of recurrent glioblastomas treated with tumor-treating fields.', 'NovoTTF Therapy is a novel and US Food and Drug Administration (FDA)-approved antimitotic treatment for recurrent GBM with potential benefits compared with other options. Recurrent GBM patients from two prior trials with demonstrated radiologic tumor response to single-agent NovoTTF Therapy were analyzed to better characterize tumor response patterns and evaluate the associations between response, compliance, and OS. In addition, a compartmental tumor growth model was developed and evaluated for its ability to predict GBM response to tumor-treating fields (TTFields). The overall response rate across both trials was 15% (4% complete responses): 14% in the phase III trial (14/120) and 20% (2/10) in a pilot study. Tumor responses to NovoTTF Therapy developed slowly (median time to response, 5.2 months) but were durable (median duration, 12.9 months).', 'NovoTTF Therapy is a novel antimitotic treatment for recurrent GBM associated with slowly developing but durable tumor responses in approximately 15% of patients.', 'The effect of field strength on glioblastoma multiforme response in patients treated with the NovoTTF™-100A system.', ' An ongoing trial is assessing its efficacy for newly diagnosed glioblastoma multiforme (GBM) and it has been FDA-approved for recurrent GBM.', 'We present three patients with GBM in whom the fields were adjusted at recurrence and the effects of each adjustment.', 'The first patient underwent subtotal resection, radiotherapy with temozolomide (TMZ), and then began NovoTTF Therapy with metronomic TMZ. ', ' A second patient underwent two resections followed by radiotherapy/TMZ and NovoTTF Therapy/TMZ. Six months later, two new distal lesions were noted, and he underwent further resection with adjustment of his fields. He remained stable over the subsequent year on NovoTTF Therapy and bevacizumab. A third patient on NovoTTF Therapy/TMZ remained stable for two years but developed a small, slow growing enhancing lesion, which was resected, and his fields were adjusted accordingly. ', 'A phase I/II trial of Tumor Treating Fields (TTFields) therapy in combination with pemetrexed for advanced non-small cell lung cancer.', 'Promising preclinical data have led to a single arm phase I/II trial in NSCLC patients.METHODS: Forty-two inoperable stage IIIB (with pleural effusion) and IV NSCLC patients who had had tumor progression received pemetrexed 500 mg/m(2) iv q3w together with daily TTFields therapy until disease progression.', 'The median time to in-field progression was 28 weeks and the median time to systemic progression was 22 weeks.', 'CONCLUSIONS: The combination of TTFields and pemetrexed as a second line therapy for NSCLC is safe and potentially more effective than pemetrexed alone. TTFields improved disease control within the treatment field and a phase III study is planned to further investigate its role as a novel treatment in NSCLC.', 'Tumor treating fields (TTFields) is a noninvasive, regional antimitotic treatment modality that has been approved for the treatment of recurrent glioblastoma by the U.S. FDA and has a CE mark in Europe. ', 'The antimitotic effect of TTFields therapy has been demonstrated in multiple cell lines when the appropriate frequency was utilized. A phase III trial of TTFields monotherapy compared to active chemotherapy in recurrent glioblastoma patients established that TTFields therapy is associated with minimal toxicity, better quality of life, and comparable efficacy to chemotherapy. Ongoing and future trials will evaluate TTFields in newly diagnosed glioblastoma, solid tumor brain metastases, nonsmall cell lung cancer, and ovarian and pancreatic cancers.', 'The U.S. Food and Drug Administration has approved the first device, the NovoTTF-100A™, that uses this technology and is indicated for use in progressive glioblastoma multiforme after standard therapies have failed. Promising clinical trial results will likely lead to expanded uses in primary brain tumors and other cancer types. ', 'Long-term survival of patients suffering from glioblastoma multiforme treated with tumor-treating fields.', 'Tumor-treating fields (TTField) therapy is a novel treatment technique that has recently received CE and FDA approval for the treatment of RGBM, and is based on the principle that low intensity, intermediate frequency electric fields (100 to 300 kHz) may induce apoptosis in specific cell types. Our center was the first to apply TTField treatment to histologically proven GBM in a small pilot study of 20 individuals in 2004 and 2005, and four of those original 20 patients are still alive today. We report two cases of GBM and two cases of RGBM treated by TTField therapy, all in good health and no longer receiving any treatment more than seven years after initiating TTField therapy, with no clinical or radiological evidence of recurrence.', 'Tumor treating fields (TTFields) are low intensity (1 ? 2 V/cm), intermediate frequency (100 ? 200 kHz) alternating electric fields administered using insulated electrodes placed on the skin surrounding the region of a malignant tumor. ', 'Furthermore, it summarizes the clinical experience with TTFields, mainly in two indications: one in recurrent glioblastoma multiforme: in a large prospective randomized Phase III trial TTFields was compared with best standard care (including chemotherapy): TTFields significantly improved median overall survival (OS) compared with standard therapy (7.8 vs 6.1 months) for the patients treated per protocol.', 'The second indication was a Phase II study in second-line non-small cell lung cancer, where TTFields was administered concomitantly with pemetrexed. ', 'EXPERT OPINION: The proof of concept of TTFields has been well demonstrated in the preclinical setting, and the clinical data seem promising in various tumor types. ', 'CONCLUSIONS: The results indicate that TTFields alone and in combination with paclitaxel and doxorubicin effectively reduce the viability of both wild type and MDR cell sub-lines and thus can potentially be used as an effective treatment of drug resistant tumors.', 'Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs.', 'Tumor treating fields (TTFields) are low intensity, intermediate frequency, alternating electric fields used to treat cancerous tumors. This novel treatment modality effectively inhibits the growth of solid tumors in vivo and has shown promise in pilot clinical trials in patients with advanced stage solid tumors.', 'BACKGROUND: The present study explores the efficacy and toxicity of combining a new, non-toxic, cancer treatment modality, termed Tumor Treating Fields (TTFields), with chemotherapeutic treatment in-vitro, in-vivo and in a pilot clinical trial.', 'In addition, we studied the effects of combining chemotherapy with TTFields in an animal tumor model and in a pilot clinical trial in recurrent and newly diagnosed GBM patients.RESULTS: The efficacy of TTFields-chemotherapy combination in-vitro was found to be additive with a tendency towards synergism for all drugs and cell lines tested (combination index', 'A pilot study with very low-intensity, intermediate-frequency electric fields in patients with locally advanced and/or metastatic solid tumors.', 'PATIENTS AND METHODS: This open, prospective pilot study was designed to evaluate the safety, tolerability, and efficacy profile of TTFields treatment in patients with locally advanced and/or metastatic solid tumors using the NovoTTF100A(TM) device.', 'Outcomes showed 1 partial response of a treated skin metastasis from a primary breast cancer, 3 cases where tumor growth was arrested during treatment, and 1 case of disease progression. One mesothelioma patient experienced lesion regression near TTFields with simultaneous tumor stability or progression in distal areas.CONCLUSION: Although the number of patients in this study is small, the lack of therapy toxicity and the efficacy observed in data gathered to date indicate the potential of TTFields as a new treatment modality for solid tumors, definitely warranting further investigation.', 'Mitotic disruption and reduced clonogenicity of pancreatic cancer cells in vitro and in vivo by tumor treating fields.', 'OBJECTIVES: Tumor Treating Fields (TTFields) are a non-invasive cancer treatment modality approved for the treatment of patients with recurrent glioblastoma. The present study determined the efficacy and mechanism of action of TTFields in preclinical models of pancreatic cancer.', 'RESULTS: Application of TTFields in vitro showed a significant decrease in cell count, an increase in cell volume and reduced clonogenicity. Further analysis demonstrated significant increase in the number of abnormal mitotic figures, as well as a decrease in G2-M cell population. In hamsters with orthotopic pancreatic tumors, TTFields significantly reduced tumor volume accompanied by an increase in the frequency of abnormal mitotic events. TTFields efficacy was enhanced both in vitro and in vivo when combined with chemotherapy.CONCLUSIONS: These results provide the first evidence that TTFields serve as an effective antimitotic treatment in preclinical pancreatic cancer models and have a long term negative effect on cancer cell survival. These results make TTFields an attractive candidate for testing in the treatment of patients with pancreatic cancer.', 'Tumor Treating Fields (TTFields) are a non-invasive cancer treatment modality approved for the treatment of patients with recurrent glioblastoma.', 'In addition, a compartmental tumor growth model was developed and evaluated for its ability to predict GBM response to tumor-treating fields (TTFields).', 'Tumor-treating fields (TTField) therapy is a novel treatment technique that has recently received CE and FDA approval for the treatment of RGBM, and is based on the principle that low intensity, intermediate frequency electric fields (100 to 300 kHz) may induce apoptosis in specific cell types.', 'Tumor treating fields (TTFields) is a noninvasive, regional antimitotic treatment modality that has been approved for the treatment of recurrent glioblastoma by the U.S. FDA and has a CE mark in Europe.', 'Tumor-treating fields (TTField) therapy is a novel treatment technique that has recently received CE and FDA approval for the treatment of RGBM, and is based on the principle that low intensity, intermediate frequency electric fields (100 to 300 kHz) may induce apoptosis in specific cell types. ', 'In addition, a compartmental tumor growth model was developed and evaluated for its ability to predict GBM response to tumor-treating fields (TTFields). ', 'OBJECTIVES: Tumor Treating Fields (TTFields) are a non-invasive cancer treatment modality approved for the treatment of patients with recurrent glioblastoma. ', 'Tumor Treating Fields (TTFields) are a non-invasive cancer treatment modality approved for the treatment of patients with recurrent glioblastoma.']

['Clinical trials have shown that Tumor-treating fields are effective for treatment of non-small cell lung cancer and glioblastoma. Ongoing and future trials will evaluate TTFields in solid tumor brain metastases, and ovarian, pancreatic cancers and multidrug resistance cancer cells.']

['non-small cell lung cancer', 'glioblastoma']

Which enzyme is inhibited by niraparib?

['While olaparib is the first PARP inhibitor to receive approval for ovarian cancer treatment, others including rucaparib and niraparib are clearly effective in this disease and, within the next year or two, the results of ongoing randomised trials will clarify their respective roles. ', 'Similar trials with other PARP inhibitors (rucaparib, niraparib and veliparib) are in progress and include non-BRCA-mutated ovarian cancer.', 'We report here that while the activities of the four human sirtuin isoforms SIRT1, SIRT2, SIRT3 and SIRT6 are blocked by sirtuin inhibitor Ex527 in vitro, they are unaffected by the seven clinical and commonly used PARP inhibitors niraparib, olaparib, rucaparib, talazoparib, veliparib, PJ34, and XAV939. ', 'Results from a phase III trial indicate that maintenance therapy with the PARP inhibitor niraparib is more effective than placebo in slowing the progression of recurrent platinum-sensitive ovarian cancer.', 'In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma.', 'OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo.', 'There are a number of other PARP inhibitors in late phase clinical development in ovarian cancer including rucaparib, niraparib, veliparib, and talazoparib. ', 'Background Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer.', 'Treatment with the PARP inhibitor, niraparib, sensitizes colorectal cancer cell lines to irinotecan regardless of MSI/MSS status.', 'METHODS: Here we examine the response to niraparib, a potent PARP-1/PARP-2 inhibitor currently under clinical evaluation, in MSI versus microsatellite stable (MSS) CRC cell lines in vitro and in vivo. ', 'Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. ', 'Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination.', 'We describe the rationale for this approach and the design and discovery of niraparib, a potent PARP-1/2 inhibitor with good cell based activity, selectivity for cancer over normal cells, and oral bioavailability. ', 'Niraparib (50 mg/kg) inhibited PARP1 activity in vivo and extended survival of mice with orthotopic pHGA xenografts, when administered before IR (20 Gy, fractionated), relative to control mice (40 vs. 25 days)', 'Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells.', 'The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial.', 'Niraparib was characterized in a number of preclinical models before moving to phase I clinical trials, where it showed excellent human pharmacokinetics suitable for once a day oral dosing, achieved its pharmacodynamic target for PARP inhibition, and had promising activity in cancer patients. ', 'The aim of this study was to assess niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase (PARP) inhibitor, for its ability to radiosensitize human tumor cells. ', 'Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. ', 'Moreover, the potency in trapping PARP differed markedly among inhibitors with niraparib (MK-4827) > olaparib (AZD-2281) >> veliparib (ABT-888), a pattern not correlated with the catalytic inhibitory properties for each drug. ', 'Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity.', 'These results indicate that human tumor cells are significantly radiosensitized by the potent and selective PARP-1 inhibitor, niraparib, in the in vitro setting.', 'Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function.', 'Moreover, the potency in trapping PARP differed markedly among inhibitors with niraparib (MK-4827)>olaparib (AZD-2281)>>veliparib (ABT-888), a pattern not correlated with the catalytic inhibitory properties for each drug.', 'Niraparib (50 mg/kg) inhibited PARP1 activity in vivo and extended survival of mice with orthotopic pHGA xenografts, when administered before IR (20 Gy, fractionated), relative to control mice (40 vs.', 'Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination.', 'Treatment with the PARP inhibitor, niraparib, sensitizes colorectal cancer cell lines to irinotecan regardless of MSI/MSS status.', 'Other PARP inhibitors under clinical trials include rucaparib, niraparib, veliparib, and the "PARP-trapping" BMN-673.', 'The high-throughput screens identified multiple clinical poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors, such as olaparib (AZD-2281), niraparib (MK-4827) and BMN 673, as being selective for ERCC1 deficiency.', 'Inhibition of Poly(ADP-ribose) Polymerase1 (PARP1) impairs DNA damage repair, and early generation PARP1/2 inhibitors (olaparib, niraparib, etc.) have demonstrated clinical proof of concept for cancer treatment.', 'Moreover, the potency in trapping PARP differed markedly among inhibitors with niraparib (MK-4827) > olaparib (AZD-2281) >> veliparib (ABT-888), a pattern not correlated with the catalytic inhibitory properties for each drug.']

['Niraparib is a Poly(ADP-ribose) Polymerase (PARP) Inhibitor. It is used for ovarian cancer treatment.']

['Poly(ADP-ribose) Polymerase']

Matuzumab has been tested for treatment of which cancers?

[' Matuzumab and panitumumab have also been studied in phase II trials.', 'A phase I pharmacokinetic study of matuzumab in combination with paclitaxel in patients with EGFR-expressing advanced non-small cell lung cancer.', 'This phase I study investigated the tolerability, safety and pharmacokinetics (PK) of matuzumab in combination with paclitaxel in patients with EGFR-expressing advanced non-small cell lung cancer (NSCLC). ', 'Matuzumab combined with paclitaxel was generally well tolerated in patients with advanced NSCLC. ', 'This article focuses on anti-Her-2 therapy, specifically trastuzumab, as well as other epidermal growth factor receptor antagonists such as cetuximab, panitumub, matuzumab, nimotzumab, gefitinib, and erlotinib.', 'Phase I study of matuzumab in combination with 5-fluorouracil, leucovorin and cisplatin (PLF) in patients with advanced gastric and esophagogastric adenocarcinomas.', 'BACKGROUND: To evaluate the safety and tolerability of two different weekly doses of the fully humanized epidermal growth factor receptor (EGFR)-targeting monoclonal antibody matuzumab combined with high-dose 5-fluorouracil, leucovorin and cisplatin (PLF) in the first-line treatment of patients with EGFR-positive advanced gastric and esophagogastric adenocarcinomas.', 'Matuzumab and panitumumab have also been evaluated in phase II trials. ', 'Pemetrexed with or without matuzumab as second-line treatment for patients with stage IIIB/IV non-small cell lung cancer.', 'INTRODUCTION: This randomized phase II study investigated pemetrexed in combination with the epidermal growth factor receptor (EGFR)-targeting monoclonal antibody matuzumab compared with pemetrexed alone as second-line therapy for patients with advanced non-small cell lung cancer. ', 'Matuzumab plus epirubicin, cisplatin and capecitabine (ECX) compared with epirubicin, cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophago-gastric cancer: a randomised, multicentre open-label phase II study.', 'BACKGROUND: Clinical data showed promising antitumour activity with feasible tolerability for matuzumab plus epirubicin, cisplatin and capecitabine (ECX) chemotherapy in untreated advanced oesophago-gastric (OG) cancer. ', ' CONCLUSION: Matuzumab 800 mg weekly combined with ECX chemotherapy does not increase response or survival for patients with advanced OG cancer.', 'In all studies, the patients had different types of advanced carcinoma - mainly colon, rectal and pancreatic cancer. They received matuzumab as multiple 1-hour intravenous infusions in a wide range of dosing regimens (development dataset: from 400 mg every 3 weeks to 2000 mg in the first week followed by 1600 mg weekly; evaluation dataset: from 100 mg weekly to 800 mg weekly). ', ' Other anti-EGFR monoclonal antibodies, such as panitumumab, matuzumab, nimotuzumab, and ch806, are in different stages of development for the treatment of advanced NSCLC.', 'Molecular determinants of response to matuzumab in combination with paclitaxel for patients with advanced non-small cell lung cancer.', 'Antibodies targeting epidermal growth factor receptor (EGFR) have proven to be effective in patients with non-small cell lung cancer (NSCLC) that express EGFR. We recently published a phase I study of weekly matuzumab plus paclitaxel.', 'Our data suggest that EGFR expression and KRAS mutation status is predictive for clinical response to matuzumab +/- paclitaxel in patients with advanced NSCLC.', 'Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer.', 'To evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of the humanised antiepidermal growth factor receptor monoclonal antibody matuzumab combined with epirubicin, cisplatin and capecitabine (ECX) in patients as first-line treatment for advanced oesophagogastric cancer that express epidermal growth factor receptor (EGFR). ', 'Therefore, these first successes led to the development of several drugs including monoclonal antibodies (trastuzumab, panitumumab, matuzumab), TK inhibitors targeting one receptor as well as TK pan-inhibitors (lapatinib, HKI 272, PKI 166, EKB-569, AEE-788), currently assessed through clinical trials worldwide.', 'Antibodies to the epidermal growth factor receptor in non small cell lung cancer: current status of matuzumab and panitumumab.', 'Matuzumab and panitumumab are antibodies against the epidermal growth factor receptor (EGFR) that are being evaluated in several malignancies including non-small cell lung cancer (NSCLC). In phase I trials of single-agent matuzumab in patients with EGFR-positive cancer, three tumor responses were documented in esophageal squamous cell carcinoma as well as colorectal carcinoma.', 'A phase II trial of EMD72000 (matuzumab), a humanized anti-EGFR monoclonal antibody, in patients with platinum-resistant ovarian and primary peritoneal malignancies.', 'CONCLUSIONS: Matuzumab at the dose and schedule selected is well tolerated. In this population of very heavily pretreated patients with epithelial ovarian and primary peritoneal malignancies, there was no evidence of significant clinical activity when matuzumab was administered as monotherapy.', 'Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer.', ' Three groups of chemotherapy-naive advanced pancreatic adenocarcinoma patients (n=17) received escalating doses of matuzumab (400 mg weekly, 800 mg biweekly, or 800 mg weekly) and gemcitabine (1000 mg m-2 weekly in weeks 1-3 of each 4-week cycle). ', 'A phase I study of the humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody EMD 72000 (matuzumab) in combination with paclitaxel in patients with EGFR-positive advanced non-small-cell lung cancer (NSCLC).', 'This phase I study assessed the tolerability, pharmacokinetics and efficacy of the combination of matuzumab and paclitaxel in patients with advanced NSCLC.', 'Other anti-EGFR monoclonal antibodies (panitunumab, matuzumab) are currently evaluated. ', 'It is the target for a class of agents at the forefront of development for the treatment of colorectal cancer, ie, the anti-EGFR monoclonal antibodies, which include cetuximab, panitumumab, and matuzumab. ', 'Two other monoclonal antibodies, matuzumab (EMD 72000) and panitumumab (ABG-EGF), also have shown activity against EGFR-expressing CRC but are still in the early stage of clinical development.', 'Matuzumab is currently undergoing phase II clinical trials for gastric, cervical, pancreatic and ovarian cancers.']

['Matuzumab has been tested for treatment of non-small cell lung, gastric, esophageal, colorectal, primary peritoneal, pancreatic, ovarian and cervical cancers.']

['non-small cell lung', 'gastric', 'esophageal', 'colorectal', 'primary peritoneal', 'pancreatic', 'ovarian', 'cervical']

What is the association between moon cycle and rupture risk of intracranial aneurysms?

['An incidence peak for aneurysm rupture (28 patients) was seen during the phase of new moon, which was statistically significant (p < 0.001)', 'The lunar cycle seems to affect the incidence of intracranial aneurysm rupture, with the new moon being associated with an increased risk of aneurysmal SAH.']

['The lunar cycle seems to affect the incidence of intracranial aneurysm rupture, with the new moon being associated with an increased risk of aneurysmal SAH.']

[]

What is oprozomib?

['Carfilzomib and ONX 0912 inhibit cell survival and tumor growth of head and neck cancer and their activities are enhanced by suppression of Mcl-1 or autophagy.', 'ONX 0912 (oprozomib) is an orally bioavailable derivative. ', 'Carfilzomib and ONX 0912 potently induced apoptosis in HNSCC cell lines via upregulation of pro-apoptotic Bik. Upregulation of Mcl-1 by these agents served to dampen their efficacies. Carfilzomib and ONX 0912 also induced autophagy, mediated, in part, by activation of the UPR pathway involving upregulation of ATF4 transcription factor. Autophagy induction served a prosurvival role. Oral administration of ONX 0912 inhibited the growth of HNSCC xenograft tumors in a dose-dependent manner.', 'These results show that carfilzomib and ONX 0912 are potently active against HNSCC cells, and the activities of these agents can be enhanced via suppression of Mcl-1 or inhibition of autophagy. Oral ONX 0912 exhibits in vivo activity against HNSCC tumors and may represent a useful therapeutic agent for this malignancy.', 'The next generation proteasome inhibitors carfilzomib and oprozomib activate prosurvival autophagy via induction of the unfolded protein response and ATF4.', 'We recently reported the impact and mechanisms of carfilzomib and oprozomib, second-in-class proteasome inhibitors with higher specificities and reduced toxicities, against head and neck squamous cell carcinoma (HNSCC). Carfilzomib and oprozomib potently inhibit HNSCC cell survival and the growth of HNSCC tumors. Both compounds promote upregulation of proapoptotic BIK and antiapoptotic MCL1, which serves to mediate and attenuate, respectively, the killing activities of these proteasome inhibitors. Both compounds also induce complete autophagic flux that is partially dependent on activation of the unfolded protein response (UPR) and upregulation of ATF4. Carfilzomib- and oprozomib-induced autophagy acts to promote HNSCC cell survival. Our study indicates that the therapeutic benefit of these promising proteasome inhibitors may be improved by inhibiting MCL1 expression or autophagy.', 'Carfilzomib and its orally bioavailable analog oprozomib, effectively decreased MM cell viability following continual or transient treatment mimicking in vivo pharmacokinetics. ', 'At clinically relevant concentrations, carfilzomib and oprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Accordingly, carfilzomib and oprozomib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice. Finally, in mouse models of disseminated MM, the epoxyketone-based PIs decreased murine 5TGM1 and human RPMI-8226 tumor burden and prevented bone loss. These data demonstrate that, in addition to anti-myeloma properties, carfilzomib and oprozomib effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM.', 'Finally, we found that DC incubation with the drug(s) enhanced IκB expression and that oprozomib inhibited NF-κB expression. We concluded that based on its activity and oral bioavailability, oprozomib merits further investigation in an animal GvHD prevention model. ', 'Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors.', 'Carfilzomib and its orally bioavailable structural analog oprozomib are second-generation, highly-selective, proteasome inhibitors.', 'In addition, novel drug classes have shown promising activity in RR MM, including the orally-administered proteasome inhibitors ixazomib and oprozomib; monoclonal antibodies such as the anti-CS1 monoclonal antibody elotuzumab and anti-CD38 monoclonal antibody daratumumab; and histone deacetylase inhibitors such as panobinostat and rocilinostat.', 'Carfilzomib- and oprozomib-induced autophagy acts to promote HNSCC cell survival.', 'Further, new orally administered second-generation PI oprozomib is being investigated.', 'Carfilzomib and its orally bioavailable structural analog oprozomib are second-generation, highly-selective, proteasome inhibitors.', 'Accordingly, carfilzomib and oprozomib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice.', 'Carfilzomib and its orally bioavailable analog oprozomib, effectively decreased MM cell viability following continual or transient treatment mimicking in vivo pharmacokinetics.', 'Finally, we found that DC incubation with the drug(s) enhanced IκB expression and that oprozomib inhibited NF-κB expression.', 'Carfilzomib and oprozomib potently inhibit HNSCC cell survival and the growth of HNSCC tumors.', 'The next generation proteasome inhibitors carfilzomib and oprozomib activate prosurvival autophagy via induction of the unfolded protein response and ATF4', 'The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects', 'Further, new orally administered second-generation PI oprozomib is being investigated', 'In addition, novel drug classes have shown promising activity in RR MM, including the orally-administered proteasome inhibitors ixazomib and oprozomib; monoclonal antibodies such as the anti-CS1 monoclonal antibody elotuzumab and anti-CD38 monoclonal antibody daratumumab; and histone deacetylase inhibitors such as panobinostat and rocilinostat', 'The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects.', 'We recently reported the impact and mechanisms of carfilzomib and oprozomib, second-in-class proteasome inhibitors with higher specificities and reduced toxicities, against head and neck squamous cell carcinoma (HNSCC). Carfilzomib and oprozomib potently inhibit HNSCC cell survival and the growth of HNSCC tumors. ', 'Accordingly, carfilzomib and oprozomib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice. ', 'At clinically relevant concentrations, carfilzomib and oprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. ', 'Carfilzomib and oprozomib potently inhibit HNSCC cell survival and the growth of HNSCC tumors. ', 'Carfilzomib and its orally bioavailable structural analog oprozomib are second-generation, highly-selective, proteasome inhibitors. ', 'Carfilzomib- and oprozomib-induced autophagy acts to promote HNSCC cell survival. ', 'Carfilzomib and its orally bioavailable structural analog oprozomib are second-generation, highly-selective, proteasome inhibitors. However, the mechanisms of acquired resistance to carfilzomib and oprozomib are incompletely understood, and effective strategies for overcoming this resistance are needed.', 'Finally, we found that DC incubation with the drug(s) enhanced IκB expression and that oprozomib inhibited NF-κB expression. We concluded that based on its activity and oral bioavailability, oprozomib merits further investigation in an animal GvHD prevention model.', 'At clinically relevant concentrations, carfilzomib and oprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Accordingly, carfilzomib and oprozomib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice.', 'We recently reported the impact and mechanisms of carfilzomib and oprozomib, second-in-class proteasome inhibitors with higher specificities and reduced toxicities, against head and neck squamous cell carcinoma (HNSCC). Carfilzomib and oprozomib potently inhibit HNSCC cell survival and the growth of HNSCC tumors.', 'Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials.']

['Oprozomib is a second-generation, highly-selective, orally administered proteasome inhibitor with promising activity against multiple myeloma.\nOprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Oprozomib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice. Consequently, oprozomib seems to be able to effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM.\nOprozomib effectively decreases multiple myeloma cell viability.\nOprozomib potently inhibit cell survival and induce apoptosis in HNSCC cell lines via upregulation of pro-apoptotic Bik. Upregulation of Mcl-1 by these agents served to dampen their efficacies. Oprozomib also induced autophagy, mediated, in part, by activation of the UPR pathway involving upregulation of ATF4 transcription factor. Autophagy induction served a prosurvival role. Oral administration of ONX 0912 inhibited the growth of HNSCC xenograft tumors in a dose-dependent manner.\nOprozomib inhibited NF-κB expression.']

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Have hESC been tested for the treatment of age-related macular degeneration?

['Development of human embryonic stem cell therapies for age-related macular degeneration', 'In this review, we describe recent approaches to develop cell-based therapies for the treatment of AMD. Recent research has focused on replacing the retinal pigment epithelium (RPE), a monolayer of cells vital to photoreceptor cell health. We discuss the various methods used to differentiate and purify RPE from human embryonic stem cells (HESC), and describe the surgical approaches being used to transplant these cells in existing and forthcoming clinical trials.', 'Age-related macular degeneration (AMD) is characterized by the loss or dysfunction of retinal pigment epithelium (RPE) and is the most common cause of vision loss among the elderly. Stem-cell-based strategies, using human embryonic stem cells (hESCs) or human-induced pluripotent stem cells (hiPSCs), may provide an abundant donor source for generating RPE cells in cell replacement therapies.', 'This study contributes to our understanding of the utility of hESC/hiPSC-derived RPE in AMD therapy.', 'Two important early potential hESC applications are the use of retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration and Stargardt disease, an untreatable form of macular dystrophy that leads to early-onset blindness.', 'Human embryonic stem cells (hESCs) are a promising source of retinal pigment epithelium (RPE) cells: cells that can be used for the treatment of common and incurable forms of blindness, such as age-related macular degeneration.', 'A potential application of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) is the generation of retinal pigmented epithelium (RPE) to treat age-related macular degeneration (AMD), a common but incurable retinal disease.', 'Human embryonic stem cells (hESCs) are a promising source of retinal pigment epithelium (RPE) cells: cells that can be used for the treatment of common and incurable forms of blindness, such as age-related macular degeneration', 'A potential application of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) is the generation of retinal pigmented epithelium (RPE) to treat age-related macular degeneration (AMD), a common but incurable retinal disease', 'Assessments of safety and efficacy are crucial before human ESC (hESC) therapies can move into the clinic. Two important early potential hESC applications are the use of retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration and Stargardt disease, an untreatable form of macular dystrophy that leads to early-onset blindness.', 'A potential application of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) is the generation of retinal pigmented epithelium (RPE) to treat age-related macular degeneration (AMD), a common but incurable retinal disease. RPE cells derived from hESCs (hESC-RPEs) and iPSCs (iPSC-RPEs) express essential RPE markers and can rescue visual function in animal models.', 'Two important early potential hESC applications are the use of retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration and Stargardt disease, an untreatable form of macular dystrophy that leads to early-onset blindness. Here we show long-term functional rescue using hESC-derived RPE in both the RCS rat and Elov14 mouse, which are animal models of retinal degeneration and Stargardt, respectively.']

['Yes, human embryonic stem cell (hESC) therapies are being assessed for age-related macular degeneration (AMD).']

['yes']

Oxantel is used for periodontitis treatment. How does it work?

['Oxantel disrupts polymicrobial biofilm development of periodontal pathogens', 'he anthelmintic drug oxantel has been shown to inhibit fumarate reductase (Frd) activity in some pathogenic bacteria and inhibit P. gingivalis homotypic biofilm formation.', 'Oxantel, a cholinergic anthelmintic and fumarate reductase inhibitor, significantly inhibited biofilm formation by P. gingivalis and disrupted established biofilms at concentrations below its MIC against planktonic cells.']

['Oxantel, a cholinergic anthelmintic and fumarate reductase inhibitor, significantly inhibited biofilm formation by P. gingivalis and disrupted established biofilms.']

['Oxantel disrupts polymicrobial biofilm']

List symptoms of Hakim Triad.

['Triad of Hakim--Adams is well known for normal pressure hydrocephalus (NPH): dementia, gait disturbances and urinary incontinence.', 'Normal pressure hydrocephalus (NPH) is a clinical triad of gait disturbance, dementia, and urinary incontinence combined with radiographic findings of ventriculomegaly and laboratory findings of normal cerebrospinal fluid pressures. Although it was first described by Hakim and Adams in 1965, there is no formal definition of NPH, causing discrepancy in its incidence in various studies. ', 'INTRODUCTION: Normal-pressure hydrocephalus (NPH) is a chronic neurological disorder characterized by enlarged ventricles and a triad of clinical symptoms affecting gait, cognition, and urinary continence. Salomón Hakim first identified the syndrome in 1957 at the Hospital San Juan de Dios in Bogotá, Colombia. ', 'Although several reports of cases with the characteristic clinical manifestations of normal pressure hydrocephalus--progressive dementia, gait difficulty and urinary incontinence--have been published earlier, it was Adams and Hakim who emphasized the clinical triad and the effect of shunting the cerebrospinal fluid as a means of treatment.', 'Although several reports of cases with the characteristic clinical manifestations of normal pressure hydrocephalus--progressive dementia, gait difficulty and urinary incontinence--have been published earlier, it was Adams and Hakim who emphasized the clinical triad and the effect of shunting the cerebrospinal fluid as a means of treatment.', "Chronic (normotensive or low pressure) hydrocephalus is characterized clinically by gait disturbance, cognitive and urinary impairment, known as Hakim's triad.", 'Triad of Hakim--Adams is well known for normal pressure hydrocephalus (NPH): dementia, gait disturbances and urinary incontinence', 'Although several reports of cases with the characteristic clinical manifestations of normal pressure hydrocephalus--progressive dementia, gait difficulty and urinary incontinence--have been published earlier, it was Adams and Hakim who emphasized the clinical triad and the effect of shunting the cerebrospinal fluid as a means of treatment', "BACKGROUND: Chronic (normotensive or low pressure) hydrocephalus is characterized clinically by gait disturbance, cognitive and urinary impairment, known as Hakim's triad. "]

['Triad of Hakim--Adams is well known for normal pressure hydrocephalus (NPH): dementia, gait disturbances and urinary incontinence.']

['dementia', 'gait disturbances', 'urinary incontinence']

Which are the additions of the JASPAR 2016 open-access database of transcription factor binding profiles?

['For this 2016 release, we expanded the JASPAR CORE collection with 494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and updated 59 profiles (58 in vertebrates and 1 in fungi). The introduced profiles represent an 83% expansion and 10% update when compared to the previous release. We updated the structural annotation of the TF DNA binding domains (DBDs) following a published hierarchical structural classification. In addition, we introduced 130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites. This new JASPAR release is accompanied by a new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence. Moreover, we provide the users with a Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles. Finally, we provide the JASPAR2016 R/Bioconductor data package with the data of this release']

['Compared to the JASPAR CORE collection, JASPAR 2016 has been expanded with 494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and 59 profiles (58 in vertebrates and 1 in fungi) have been updated. The introduced profiles represent an 83% expansion and 10% update when compared to the previous release. The structural annotation of the TF DNA binding domains (DBDs) has been updated following a published hierarchical structural classification. In addition, 130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites were introduced . The new JASPAR release is accompanied by a new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence. Moreover, users are provided with a Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles. JASPAR2016 R/Bioconductor data package is also provided with the data of this release.']

['494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and updated 59 profiles (58 in vertebrates and 1 in fungi)', 'Updated structural annotation of the TF DNA binding domains (DBDs) following a published hierarchical structural classification', '130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites', 'A new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence', 'A Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles', 'JASPAR2016 R/Bioconductor data package']

What is the benserazide's mechanism of function when co-administered with L-DOPA in patients with Parkinson's Disease?

["Recent human and animal biochemical investigations clearly confirm and extend previous findings indicating that benserazide is much more potent than carbidopa as peripheral decarboxylase inhibitor. L-DOPA in combination with benserazide or carbidopa constitutes the best available therapy for Parkinson's disease (PD). To reduce peaks and rapid fluctuations of L-DOPA plasma levels (possibly responsible for peak-dose dyskinesias and end-of-dose deterioration) a slow-release formulation of L-DOPA in combination with benserazide or with benserazide plus catechol-O-methyltransferase inhibitors should be developed. ", "In an open label study 63 patients with idiopathic Parkinson's disease suffering from end-of-dose akinesia were switched from a treatment with a L-DOPA standard formulation to a combined therapy of L-DOPA standard in the morning and L-DOPA slow release (levodopa, benserazide, Madopar Depot) at the remaining single doses.", 'In the present study, L-dopa and benserazide were loaded by poly (lactic-co-glycolic acid) microspheres (LBM), which can release levodopa and benserazide in a sustained manner in order to continuous stimulate dopaminergic receptors.']

["Benserazide is a peripheral decarboxylase inhibitor. Benserazide in combination with L-DOPA constitutes a slow-release formulation of L-DOPA in patients with Parkinson's disease (PD), it reduces peaks and rapid fluctuations of L-DOPA plasma levels (possibly responsible for peak-dose dyskinesias and end-of-dose deterioration) and considered as the best available therapy."]

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Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?

['α- and β-spectrin by LC-MS/MS identifies Cys in these antiparallel chains', 'antiparallel spectrin heterodimers', 'alpha- and beta-spectrins are stable as monomeric forms but occur physiologically as alpha,beta-heterodimers', 'human erythroid alpha-spectrin repeats 13 and 14 (HEalpha13,14) and human erythroid beta-spectrin repeats 8 and 9 (HEbeta8,9), are located opposite each other on antiparallel spectrin dimers.', 'Spectrins comprise α- and β-subunits made up predominantly of a series of homologous repeating units of about 106 amino acids; the α- and β-chains form antiparallel dimers by lateral association', 'The spectrin heterodimer is formed by the antiparallel lateral association of an alpha and a beta subunit', 'Two of the less stably folded fragments, human erythroid alpha-spectrin repeats 13 and 14 (HEalpha13,14) and human erythroid beta-spectrin repeats 8 and 9 (HEbeta8,9), are located opposite each other on antiparallel spectrin dimers.', 'Influence of lateral association on forced unfolding of antiparallel spectrin heterodimers.', 'The antiparallel side-to-side association of spectrin alpha and beta monomers is a two-step process which occurs in seconds even at 0 degrees C and at low concentrations.', 'The spectrin heterodimer is formed by the antiparallel lateral association of an alpha and a beta subunit, each of which comprises largely a series of homologous triple-helical motifs.', 'Human erythrocyte spectrin is an antiparallel heterodimer comprised of a 280 kDa alpha subunit and a 246 kDa beta subunit which further associates into tetramers in the red cell membrane cytoskeleton', 'The spectrin heterodimer is formed by the antiparallel lateral association of an alpha and a beta subunit, each of which comprises largely a series of homologous triple-helical motifs', 'The basic unit of spectrin is an antiparallel heterodimer composed of two homologous chains, beta and alpha']

['Alpha and beta spectrin subunits form antiparallel spectrin heterodimers by lateral association.']

['antiparallel']

Which databases exist for experimentally determined topologies of α-helical transmembrane proteins ?

['ExTopoDB: a database of experimentally derived topological models of transmembrane proteins', 'ExTopoDB is a publicly accessible database of experimentally derived topological models of transmembrane proteins. It contains information collected from studies in the literature that report the use of biochemical methods for the determination of the topology of α-helical transmembrane proteins. Transmembrane protein topology is highly important in order to understand their function and ExTopoDB provides an up to date, complete and comprehensive dataset of experimentally determined topologies of α-helical transmembrane proteins. Topological information is combined with transmembrane topology prediction resulting in more reliable topological models. AVAILABILITY: http://bioinformatics.biol.uoa.gr/ExTopoDB', 'TMPDB: a database of experimentally-characterized transmembrane topologies', 'TMPDB is a database of experimentally-characterized transmembrane (TM) topologies. TMPDB release 6.2 contains a total of 302 TM protein sequences, in which 276 are alpha-helical sequences, 17 beta-stranded, and 9 alpha-helical sequences with short pore-forming helices buried in the membrane. The TM topologies in TMPDB were determined experimentally by means of X-ray crystallography, NMR, gene fusion technique, substituted cysteine accessibility method, N-linked glycosylation experiment and other biochemical methods. TMPDB would be useful as a test and/or training dataset in improving the proposed TM topology prediction methods or developing novel methods with higher performance, and as a guide for both the bioinformaticians and biologists to better understand TM proteins. TMPDB and its subsets are freely available at the following web site: http://bioinfo.si.hirosaki-u.ac.jp/~TMPDB/', 'Transmembrane protein topology is highly important in order to understand their function and ExTopoDB provides an up to date, complete and comprehensive dataset of experimentally determined topologies of ж┴-helical transmembrane proteins.', 'TMPDB: a database of experimentally-characterized transmembrane topologies.', 'TMPDB is a database of experimentally-characterized transmembrane (TM) topologies.', 'The TM topologies in TMPDB were determined experimentally by means of X-ray crystallography, NMR, gene fusion technique, substituted cysteine accessibility method, N-linked glycosylation experiment and other biochemical methods.', 'Transmembrane protein topology is highly important in order to understand their function and ExTopoDB provides an up to date, complete and comprehensive dataset of experimentally determined topologies of α-helical transmembrane proteins.', 'Transmembrane protein topology is highly important in order to understand their function and ExTopoDB provides an up to date, complete and comprehensive dataset of experimentally determined topologies of �-helical transmembrane proteins.', 'UNLABELLED: ExTopoDB is a publicly accessible database of experimentally derived topological models of transmembrane proteins.', 'The TM topologies in TMPDB were determined experimentally by means of X-ray crystallography, NMR, gene fusion technique, substituted cysteine accessibility method, N-linked glycosylation experiment and other biochemical methods.', 'Transmembrane protein topology is highly important in order to understand their function and ExTopoDB provides an up to date, complete and comprehensive dataset of experimentally determined topologies of α-helical transmembrane proteins', 'The TM topologies in TMPDB were determined experimentally by means of X-ray crystallography, NMR, gene fusion technique, substituted cysteine accessibility method, N-linked glycosylation experiment and other biochemical methods', 'TMPDB is a database of experimentally-characterized transmembrane (TM) topologies', 'ExTopoDB: a database of experimentally derived topological models of transmembrane proteins.', 'ExTopoDB is a publicly accessible database of experimentally derived topological models of transmembrane proteins']

['ExTopoDB and TMPDB.']

['ExTopoDB', 'TMPDB']

Are epigenetic modifications implicated in cardiovascular development and disease?

['Gene expression regulation through the interplay of DNA methylation and histone modifications is well-established, although the knowledge about the function of epigenetic signatures in cardiovascular disease is still largely unexplored.', 'The study of epigenetic markers is, therefore, a very promising frontier of science which may aid in a deeper understanding of molecular mechanisms underlying the modulation of gene expression in the biomolecule pathways linked to cardiovascular diseases.', 'This review highlights our current knowledge of epigenetic gene regulation and the evidence that chromatin remodeling and histone modifications play key roles in the pathogenesis of cardiovascular disease through (re)programming of cardiovascular (stem) cells commitment, identity and function.', 'Notably, multiple subunits of switching defective/sucrose non-fermenting (SWI/SNF) chromatin-remodeling complexes have been identified as strong candidates underlying these defects because they physically and functionally interact with cardiogenic transcription factors critical to cardiac development, such as TBX5, GATA-4, and NKX2-5. While these studies indicate a critical role of SWI/SNF complexes in cardiac development and congenital heart disease, many exciting new discoveries have identified their critical role in the adult heart in both physiological and pathological conditions involving multiple cell types in the heart, including cardiomyocytes, vascular endothelial cells, pericytes, and neural crest cells.', 'Recent studies have greatly expanded our understanding of the regulation of cardiovascular development at the chromatin level, including the remodeling of chromatin and the modification of histones. Chromatin-level regulation integrates multiple inputs and coordinates broad gene expression programs. Thus, understanding chromatin-level regulation will allow for a better appreciation of gene regulation as a whole and may set a fundamental basis for cardiovascular disease.', 'Genetic and epigenetic factors are of great importance in cardiovascular biology and disease. Tobacco-smoking, one of the most important cardiovascular risk factors, is itself partially determined by genetic background and is associated with altered epigenetic patterns.', 'Epigenetic modifications, including DNA methylation, histone modification (acetylation, methylation and phosphorylation) and miRNA, are critical for regulating developmental events. However, aberrant epigenetic mechanisms may lead to pathological consequences such as cardiovascular disease (CAD), neurodegenerative disease, obesity, metabolic disorder, bone and skeletal diseases and various cancers.', 'Cardiovascular disease pathways are now being approached from the epigenetic perspective, including those associated with atherosclerosis, angiogenesis, ischemia-reperfusion damage, and the cardiovascular response to hypoxia and shear stress, among many others. With increasing interest and expanding partnerships in the field, we can expect new insights to emerge from epigenetic perspectives of cardiovascular health.', 'Epigenetic modifications are heritable alterations of the genome, which can govern gene expression without altering the DNA sequence. The purpose of this review is to render an overview of the possible mechanisms of epigenetic regulation of gene expression in response to environmental pollutants leading to cardiovascular diseases (CVD).', 'From varied study approaches directed either toward the general understanding of the key pathway regulatory genes, or sampling population cohorts for global and gene-specific changes, it has been possible to identify several epigenetic signatures of environmental exposure relevant to CVD.', 'An understanding of chromatin remodelling in response to environmental stimuli conducive to CVD is emerging, with the promise of novel diagnostic and therapeutic candidates.', 'Consolidated knowledge is accumulating as to the role of epigenetic regulatory mechanisms in the physiology of vascular development and vascular tone as well as in the pathogenesis of cardiovascular disease. The modulation of gene expression through modification of the epigenome by structural changes of the chromatin architecture without alterations of the associated genomic DNA sequence is part of the cellular response to environmental changes. Such environmental conditions, which are finally being translated into adaptations of the cardiovascular system, also comprise pathological conditions such as atherosclerosis or myocardial infarction. ', 'Emerging data suggest that these epigenetic modifications also impact on the development of cardiovascular disease. Histone modifications lead to the modulation of the expression of genetic information through modification of DNA accessibility. In addition, RNA-based mechanisms (e.g., microRNAs and long non-coding RNAs) influence the development of disease.', 'We here outline the recent work pertaining to epigenetic changes in a cardiovascular disease setting.', 'Epigenetics may represent one of the possible scientific explanations of the impact of such intrauterine risk factors for the subsequent development of cardiovascular disease (CVD) during adulthood.', 'Epigenetic mechanisms include DNA methylation, histone modification, and microRNA alterations, which collectively enable the cell to respond quickly to environmental changes. A number of CVD risk factors, such as nutrition, smoking, pollution, stress, and the circadian rhythm, have been associated with modification of epigenetic marks. Further examination of these mechanisms may lead to earlier prevention and novel therapy for CVD.', ' Emerging data suggest that these epigenetic modifications also impact on the development of cardiovascular disease.', 'Emerging data suggest that these epigenetic modifications also impact on the development of cardiovascular disease.', 'Epigenetic alterations are associated with inflammation and cardiovascular disease in patients with chronic kidney disease.', 'Emerging data suggest that these epigenetic modifications also impact on the development of cardiovascular disease', 'Epigenetic mechanisms that underpin metabolic and cardiovascular diseases.', 'Epigenetic regulation of cardiovascular differentiation.', 'Epigenetic control mechanisms play a key role in the regulation of embryonic development and tissue homeostasis and modulate cardiovascular diseases.']

['Genetic and epigenetic factors are of great importance in cardiovascular biology and disease. Aberrant epigenetic mechanisms may lead to pathological consequences such as cardiovascular disease (CAD).Recent studies have greatly expanded our understanding of the regulation of cardiovascular development at the chromatin level, including the remodeling of chromatin and the modification of histones. Thus, understanding chromatin-level regulation will allow for a better appreciation of gene regulation as a whole and may set a fundamental basis for cardiovascular disease.']

['yes']

Which types of bacterial microflora are associated with the progression of peri-implantitis?

[' Later, the specific plaque hypothesis established the role of some microorganisms such as A. actinomycetemcomitans, P. gingivalis, T. forsythensis, T. denticola, P. intermedia and F. nucleatum in different forms of periodontal diseases', 'The microbiological analysis revealed that the total bacterial load increased during the period following ligature removal and established an anaerobic Gram-negative microflora.', 'Most periodontal pathogens are common saprophytes of the oral cavity, expressing their virulence only in a susceptible host or when some changes come about in the oral environment', 'Overall, the types and relative proportions of putative periodontal pathogens in plaque associated with ligature-induced peri-implantitis and ligature-induced periodontitis were similar. Only levels of anaerobic Actinomyces and spirochetes were significantly different between both sites']

['Bacteria such as A. actinomycetemcomitans, P. gingivalis, T. forsythensis, T. denticola, P. intermedia and F. nucleatum are associated with the progression of peri-implantitis.']

['A. actinomycetemcomitans', 'P. gingivalis', 'T. denticola', 'T. forsythia', 'P. intermedia', 'F. nucleatum']

Which factors play a role in promoter proximal pausing of RNA polymerase II?

['Among the factors we describe are the pausing factors--NELF (negative elongation factor) and DSIF (DRB sensitivity-inducing factor)', 'BMP target gene expression requires the pause-inducing negative elongation factor (NELF) complex', 'NA polymerase II (Pol II) and the pausing complex, NELF and DSIF, are detected near the transcription start site (TSS) of many active and silent genes', 'pausing complex NELF/DSIF', 'knockdown of the pause-inducing factor NELF leads to broadly attenuated immune gene activation', 'pausing factors NELF and DSIF', 'pausing factors NELF and DSIF', 'pausing factor DSIF (DRB sensitivity-inducing factor)', '(NELF) and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole sensitivity-inducing factor (DSIF) are involved in pausing RNA Polymerase II (Pol II) in the promoter-proximal region', 'Pausing and resumption of the elongation of transcripts is under the control of transcription elongation factors. Three of them, P-TEFb, DSIF, and NELF have been well characterized ', 'NELF-mediated stalling of RNAPII ', 'At several eukaryotic promoters, DSIF, together with NELF (negative elongation factor), leads to promoter-proximal pausing of RNA polymerase II', 'negative transcription elongation factor NELF', '(DSIF), is involved in regulating the processivity of RNA polymerase II. DSIF plays also a role in transcriptional activation, and in concert with the negative elongation factor NELF causes promoter proximal pausing of RNA polymerase II', 'NELF causes Pol II to pause in the promoter-proximal region', '(DSIF) regulates RNA polymerase II (RNAPII) processivity by promoting, in concert with negative elongation factor (NELF), promoter-proximal pausing of RNAPI', '(DSIF) and negative elongation factor (NELF) negatively regulate transcription elongation by RNA polymerase II (RNAPII) in vitro.', 'pausing caused by NELF ', 'ELF and DSIF collaborate to inhibit elongation by RNA polymerase IIa', 'The presence of DSIF reduced pausing,']

['NELF (negative elongator factor) and DSIF (DRB Sensitivity Inducing Factor)']

['NELF', 'DSIF']

Is olaparib effective for prostate cancer?

['We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. ', 'CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. ', " In addition, phase III trials in breast, gastric and pancreatic cancer are underway/planned, and phase I/II investigation is being conducted in other malignancies, including prostate cancer, non-small cell lung cancer, Ewing's sarcoma and advanced cancer. ", 'In a phase II study, researchers found that the PARP inhibitor olaparib led to stable disease or tumor regressions in patients with advanced breast, ovarian, pancreatic, and prostate cancers who had germline mutations in BRCA1 or BRCA2.', 'Eligibility included ovarian cancer resistant to prior platinum; breast cancer with ≥ three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy. ', 'The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers, respectively. Stable disease ≥ 8 weeks was observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreatic, or prostate cancer, respectively. ', 'It is increasingly clear that there are molecularly distinct subtypes of various common cancers, with different therapeutic approaches required for each subtype, for example, the use of the monoclonal antibodies (trastuzumab and cetuximab) in HER2-positive breast cancer and wild-type KRAS colorectal cancer; tyrosine kinase inhibitors (imatinib, gefitinib, erlotinib and crizotinib) in chronic myeloid leukaemia, gastrointestinal stromal tumours and non-small-cell lung cancer and intracellular agents (vemurafenib and olaparib) in metastatic malignant melanoma and ovarian, breast and prostate cancer.', 'Olaparib, one of the most studied PARPis, has demonstrated activity in BRCA1/2(MUT+) and BRCA-like sporadic ovarian and breast cancers, and looks promising in prostate and pancreatic cancers.', 'Prostate cancer cells cotreated with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) and the PARPi, olaparib, demonstrated a synergistic decrease in cell viability compared with single-agent treatment (combination index<0.9), whereas normal prostatic cells did not.', 'CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate.', 'Olaparib, one of the most studied PARPis, has demonstrated activity in BRCA1/2(MUT+) and BRCA-like sporadic ovarian and breast cancers, and looks promising in prostate and pancreatic cancers. ', 'DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.', 'Prostate cancer cells cotreated with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) and the PARPi, olaparib, demonstrated a synergistic decrease in cell viability compared with single-agent treatment (combination index < 0.9), whereas normal prostatic cells did not.', 'We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.', 'A phase II study of the PARP inhibitor olaparib (AstraZeneca) for cancer patients with inherited BRCA1 and BRCA2 gene mutations confirmed earlier results showing clinical benefit for advanced breast and ovarian cancers, and demonstrated evidence of effectiveness against pancreatic and prostate cancers.', 'BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. ', 'Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.', 'Silencing RAD51 sensitized prostate cancer cells to SAHA and olaparib alone. Collectively, cotreatment with HDACi and PARPi downregulated HR-related protein expression and concomitantly increased DNA damage, resulting in prostate cancer cell death.', 'Prostate cancer cells cotreated with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) and the PARPi, olaparib, demonstrated a synergistic decrease in cell viability compared with single-agent treatment (combination index<0.9), whereas normal prostatic cells did not. ', 'The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. ', 'Prostate cancer cells cotreated with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) and the PARPi, olaparib, demonstrated a synergistic decrease in cell viability compared with single-agent treatment (combination index &lt; 0.9), whereas normal prostatic cells did not.', "In addition, phase III trials in breast, gastric and pancreatic cancer are underway/planned, and phase I/II investigation is being conducted in other malignancies, including prostate cancer, non-small cell lung cancer, Ewing's sarcoma and advanced cancer. "]

['Yes, olaparib was shown to be effective for treatment of prostate cancer. Olaparib led to stable disease or tumor regressions of prostate cancer patients.', 'Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate.']

['yes']

Which type of lung cancer is afatinib used for?

['Afatinib is a novel irreversible inhibitor of the ErbB family members EGFR, tyrosine kinase-type cell surface receptors HER2 and HER4. It shows preclinical efficacy in NSCLC with common EGFR-activating mutations and the T790M mutation typically associated with EGFR TKI resistance', 'At present, only first-generation EGFR-tyrosine kinase inhibitors (TKIs) (erlotinib and gefitinib) are available for clinical use. Second-generation irreversible EGFR-TKIs, such as afatinib, are still in clinical trials. In current clinical practice, EGFR-TKI is the first-line treatment of choice for metastatic NSCLC patients with tumor EGFR mutation or as salvage therapy in NSCLC patients who received systemic chemotherapy previously', 'Afatinib is a small molecule covalently binding and inhibiting the EGFR, HER2 and HER4 receptor tyrosine kinases. In preclinical studies, afatinib not only inhibited the growth of models with common activating EGFR mutations, but was also active in lung cancer models harboring wild-type EGFR or the EGFR L858R/T790M double mutant. Clinical efficacy of afatinib has been extensively studied in the LUX-Lung study program. These trials showed promising efficacy in patients with EGFR-mutant NSCLC or enriched for clinical benefit from EGFR tyrosine kinase inhibitors gefitinib or erlotinib', 'BIBW2992 is an irreversible EGFR TKI that also inhibits HER2 and vascular epidermal growth factor receptors', 'In vitro work shows that this compound inhibits wild-type EGFR, EGFR exon 19 deletion, EGFR L858R, and EGFR T790M, the mutation associated with acquired resistance', 'Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms', 'Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial.', 'Phase I study of continuous afatinib (BIBW 2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitinib (LUX-Lung 4).', 'The LUX-Lung clinical trial program of afatinib for non-small-cell lung cancer.']

['Afatinib is a small molecule covalently binding and inhibiting the EGFR, HER2 and HER4 receptor tyrosine kinases. Trials showed promising efficacy in patients with EGFR-mutant NSCLC or enriched for clinical benefit from EGFR tyrosine kinase inhibitors gefitinib or erlotinib.', 'Afatinib is a novel irreversible inhibitor of the ErbB family members EGFR, tyrosine kinase-type cell surface receptors HER2 and HER4. It shows preclinical efficacy in NSCLC with common EGFR-activating mutations and the T790M mutation typically associated with EGFR TKI resistanceBIBW2992 is an irreversible EGFR TKI that also inhibits HER2 and vascular epidermal growth factor receptors']

['EGFR-mutant non small cell lung carcinoma', 'EGFR-mutant NSCLC']

How are ultraconserved elements called when they form clusters?

['We were wondering whether this approach could provide insights about utlraconserved non-coding elements (UCNEs). These elements are organized as large clusters, so-called gene regulatory blocks (GRBs) around key developmental genes. Their molecular functions and the reasons for their high degree of conservation remain enigmatic', "This 'winner-takes-all' pattern suggests that UCNEs of a GRB function in a highly cooperative manner. We propose that the multitude of interactions between UCNEs is the reason for their extreme sequence conservation", 'UCNEbase--a database of ultraconserved non-coding elements and genomic regulatory blocks', 'The majority of UCNEs are supposed to be transcriptional regulators of key developmental genes. As most of them occur as clusters near potential target genes, the database is organized along two hierarchical levels: individual UCNEs and ultra-conserved genomic regulatory blocks (UGRBs)', 'These elements are organized as large clusters, so-called gene regulatory blocks (GRBs) around key developmental genes.', 'As most of them occur as clusters near potential target genes, the database is organized along two hierarchical levels: individual UCNEs and ultra-conserved genomic regulatory blocks (UGRBs).', 'These elements are organized as large clusters, so-called gene regulatory blocks (GRBs) around key developmental genes']

['Ultraconserved non-coding elements (UCNEs) are organized as large clusters, so-called gene regulatory blocks (GRBs) around key developmental genes. Their molecular functions and the reasons for their high degree of conservation remain enigmatic.']

['gene regulatory blocks (GRBs)']

Which antibodies cause Riedel thyroiditis?

['LEARNING POINTS: There are potential clinical applications of identifying subsets of patients with IgG4 thyroiditis (FVHT and Riedel thyroiditis).', 'The importance of IgG4 in the predictive model of thyroiditis.', 'Increased lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related thyroid disease).', 'The present study describes in depth a case of Riedel thyroiditis (RT) to clarify its pathogenesis and its putative inclusion in the spectrum of IgG4-related disease. ', 'Our findings support the inclusion of RT within the spectrum of IgG4-related thyroid disease (IgG4-RTD). Although the etiology and physiopathology of IgG4-RTD still remain elusive, the results obtained in the present case suggest the participation of lymphatic vessels in the pathogenesis of RT.', 'More than 80 % of the left thyroid lobe was effaced by fibrosis and inflammation (lymphocytes, 57 IgG4+ plasma cells per 1 high-power field, an IgG4/IgG ratio of 0.67, and eosinophils) with extension into the surrounding tissues and occlusive phlebitis. ', 'Diagnosed early as Riedel disease, the high serum IgG4, immunohistopathology and decreased fibrosis with corticosteroid therapy, finally confirm for the first time, the origin of IgG4-RSD fibrosis of the thyroid.', ' While IgG4-RSD is well documented in the pancreas and other organs, it is poorly characterized in the thyroid gland. ', 'He was careful to distinguish this from Riedel thyroiditis but it has become clear that fibrosis and atrophy of the thyroid are indeed components of Hashimoto thyroiditis, and in rare cases IgG4-related sclerosing disease may be an outcome. ', 'The relationship between HT and Riedel thyroiditis remains unclear; however, recent evidence seems to suggest that it may also be part of the spectrum of Ig4-related sclerosing disease. ', ' One patient with advanced thyroid fibrosis associated with Riedel thyroiditis and a history of disease in multiple other organ systems did not have improvement in the thyroid gland, but the disease did not progress to involve new organs. ', "IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz's disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor.", 'Increased lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related thyroid disease)', 'The present study describes in depth a case of Riedel thyroiditis (RT) to clarify its pathogenesis and its putative inclusion in the spectrum of IgG4-related disease', 'The present study describes in depth a case of Riedel thyroiditis (RT) to clarify its pathogenesis and its putative inclusion in the spectrum of IgG4-related disease.']

['Riedel thyroiditis (Immunoglobulin G4-related thyroid disease) is caused by IgG4 antibodies. It is part of the spectrum of Ig4-related sclerosing disease.\nIt is associated with fibrosis and inflammation of the thyroid gland.']

['IgG4']

Which genes have been proposed as potential candidates for gene therapy of heart failure?

['The molecular abnormalities underlying HF are discussed along with potential targets for gene therapy, focusing on SERCA2a.', 'The aim of this study was to improve cardiac function in chronic HF by overexpressing constitutively active inhibitor-1 (I-1c) ', 'In summary, I-1c overexpression using BNP116 improves cardiac function in a clinically relevant model of ischemic HF.', 'therapeutic activation of YAP or its downstream targets, potentially through AAV-mediated gene therapy, may be a strategy to improve outcome after MI', 'calcium up-regulation by AAV1/SERCA2a gene therapy is safe and of potential benefit in advanced heart failure patients. ', 'Survivin gene therapy can attenuate the progression of LV systolic dysfunction in doxorubicin cardiomyopathy.', 'Heart failure-inducible molecular targeting of PP1β has potential as a novel therapeutic strategy for heart failure.', 'The recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a), along with the start of more recent phase 1 trials, opens a new era for gene therapy for the treatment of heart failure.', 'Our results present a strong rationale for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure.', 'S100A1, a positive inotropic regulator of myocardial contractility, becomes depleted in failing cardiomyocytes in humans and animals, and myocardial-targeted S100A1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium (Ca(2+)) handling in acutely and chronically failing hearts in small animal models.', 'Use of gene therapy for heart failure is gaining momentum as a result of the recent successful completion of phase II of the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial, which showed clinical safety and efficacy of an adeno-associated viral vector expressing sarco-endoplasmic reticulum calcium ATPase (SERCA2a).', 'The recent successful and safe completion of a phase 2 trial targeting the cardiac sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump (SERCA2a) has the potential to open a new era for gene therapy for heart failure.', 'The recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) has the potential to open a new era for gene therapy in the treatment of heart failure.', 'AIMS: Impaired myocardial sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) activity is a hallmark of failing hearts, and SERCA2a gene therapy improves cardiac function in animals and patients with heart failure (HF).']

['There are at least 6 genes which have been proposed as potential candidates of gene therapy in heart failure.\n1. Cardiac Sarco-Endoplasmic Reticulum Calcium ATPase 2A (SERCA2A)\n2. Inhibitor 1 (I-1) of Protein Phosphatase 1B\n3. Protein Phosphatase 1B (PP1B)\n4. Yes Associated Protein (YAP)\n5. Survivin\n6. S100A1']

['Sarco-Endoplasmic Reticulum Calcium ATPase 2A', '(SERCA2A)', 'Inhibitor 1 of Protein Phosphatase 1B', '(I-1)', 'Protein Phosphatase 1B', '(PP1B)', 'Yes Associated Protein', '(YAP)', 'Survivin', 'S100A1']

What is hyperosmia

['Hyperosmia is suspected in pregnancy; however, no empirical study using validated measures of olfactory function has clearly confirmed the anecdotal reports of this phenomenon.', 'subjective hyperosmia is associated with primarily negative odor-related experiences.', 'Hyperosmia is increased olfactory acuity']

['Hyperosmia is increased olfactory acuity ', 'increased olfactory acuity']

['increased olfactory acuity']

What is the mechanism of action of trichostatin A (TSA) as an antitumoral agent?

['histone deacetylase inhibitor trichostatin A (TSA), an agent that also targets cancer cells and tumor vasculature', 'Histone deacetylase (HDAC) inhibitors are promising antitumoral drugs.', ' trichostatin A and FK901228 showed higher potency', 'istone deacetylase inhibitors (HDACi) show promise as a novel class of antitumoral agents and have shown the ability to induce apoptosis of tumor cells. ', 'we conducted a functional gene screen approach named suppression of mortality by antisense rescue technique to identify the key genes responsible for the tumor-selective killing trichostatin A', 'ydroxamic acid (HA)-based histone deacetylase (HDAC) inhibitors, with trichostatin A (TSA) as the reference compound, are potential antitumoral drugs and show promise in the creation of long-term primary cell cultures', 'Trichostatin A (TSA), a histone deacetylase inhibitor with promising antifibrotic and antitumoral properties', 'Trichostatin A (TSA) is a classic histone deacetylases inhibitor (HDACi) that specifically inhibits the biochemical functions of HDAC and is demonstrated to be an active anticancer drug.', 'Histone deacetylase inhibitors (HDACi) are anticancer agents targeting epigenetic regulation of gene expression', 'ive MM cell lines were treated with trichostatin A', 'novel potential anticancer drug histone deacetylase (HDAC) and inhibitor trichostatin A (TSA) ', 'Histone deacetylase (HDAC) inhibitors represent a promising class of potential anticancer agents for treatment of human malignancies. In this study, we investigated the effect of trichostatin A (TSA), one such HDAC inhibitor', 'Trichostatin A (TSA) is a potent histone deacetylase inhibitor and widely used as a promising anticancer agent', 'we found that a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), inhibited cell proliferation and invasion', 'e reported a novel potential anticancer strategy by using histone deacetylase (HDAC) inhibitor to enhance the action of endocrine therapy in ERα-positive breast cancer cell. The well-described HDAC inhibitor, trichostatin A (TSA', 'We determined whether the HDAC inhibitor, Tricostatin A (TSA) in combination with curcumin would produce greater antiproliferative ', 'trichostatin A (TSA) exert antitumor activity as histone deacetylase inhibitors, ', 'anticancer activity of anticancer agent trichostatin A (the histone deacetylase inhibitor)', 'One of the advantages of the use of histone deacetylase inhibitors, such as TSA, is that its effects have been found to be more potent toward cancer cells compared to normal cells.', ' the HDAC inhibitor trichostatin A (TSA). However, only combined treatment with TSA/paclitaxel caused synergistic inhibition of cell growth.', 'a histone deacetylase inhibitor, trichostatin A (TSA), was proven to be a chemo-sensitizer on human erythroleukemia cells', 'we demonstrated that the HDIs butyrate and trichostatin A (TSA) directly repress c-Src proto-oncogene expression in many cancer cell lines.', 'istone deacetylase inhibitors (HDIs) induce cell cycle arrest, differentiation and/or apoptosis in numerous cancer cell types', 'The results suggest that TSA inhibits bladder carcinoma cell growth', 'istone deacetylase inhibitors (HDACis) are emerging as a promising new class of anticancer agents displaying growth-inhibitory activity and low toxicity in vivo. In this study, we examined the effect of sodium butyrate (NaB) and trichostatin A (TSA', 'the in vitro effects of HDAC inhibitors, such as trichostatin A (TSA), sodium butyrate, depsipeptide (FR901228, FK228), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA), and the demethylating agent, 5-aza-CdR used alone and in combination treatment of human cancer cells']

['Trichostatin A (TSA) exerts antitumoral activity as a histone deacetylase inhibitor']

[]

Is there any link between the aurora B kinase and the polycomb protein ring1B?

['The aurora B kinase and the polycomb protein ring1B combine to regulate active promoters in quiescent lymphocytes.', 'We show that the Aurora B kinase and the polycomb protein Ring1B have essential roles in regulating transcriptionally active genes in quiescent lymphocytes. Ring1B and Aurora B bind to a wide range of active promoters in resting B and T\xa0cells. Conditional knockout of either protein results in reduced transcription and binding of RNA Pol II to promoter regions and decreased cell viability. Aurora B phosphorylates histone H3S28 at active promoters in resting B cells as well as inhibiting Ring1B-mediated ubiquitination of histone H2A and enhancing binding and activity of the USP16 deubiquitinase at transcribed genes. Our results identify a mechanism for regulating transcription in quiescent cells that has implications for epigenetic regulation of the choice between proliferation and quiescence.', 'We show that the Aurora B kinase and the polycomb protein Ring1B have essential roles in regulating transcriptionally active genes in quiescent lymphocytes.', 'We show that the Aurora B kinase and the polycomb protein Ring1B have essential roles in regulating transcriptionally active genes in quiescent lymphocytes. Ring1B and Aurora B bind to a wide range of active promoters in resting B and T\xa0cells. Conditional knockout of either protein results in reduced transcription and binding of RNA Pol II to promoter regions and decreased cell viability. ', 'We show that the Aurora B kinase and the polycomb protein Ring1B have essential roles in regulating transcriptionally active genes in quiescent lymphocytes. Ring1B and Aurora B bind to a wide range of active promoters in resting B and T\xa0cells.']

['Yes. The aurora B kinase and the polycomb protein ring1B combine to regulate active promoters in quiescent lymphocytes.']

['yes']

Is macitentan an ET agonist?

['Administration of an ET receptor antagonist, either bosentan or macitentan, markedly attenuated PD-induced MMT, fibrosis, angiogenesis, and peritoneal functional decline. ', 'Macitentan is an oral, once-daily, dual endothelin (ET)A and ETB receptor antagonist with high affinity and sustained receptor binding that was approved in the USA, Europe, Canada, and Switzerland for the treatment of PAH.', 'Macitentan (Opsumit®) is a novel dual endothelin receptor antagonist (ERA) with sustained receptor binding properties developed by Actelion Pharmaceuticals Ltd.', "Macitentan, also called Actelion-1 or ACT-064992 [N-[5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-N'-propylaminosulfonamide], is a new dual ET(A)/ET(B) endothelin (ET) receptor antagonist designed for tissue targeting. Selection of macitentan was based on inhibitory potency on both ET receptors and optimization of physicochemical properties to achieve high affinity for lipophilic milieu. In vivo, macitentan is metabolized into a major and pharmacologically active metabolite, ACT-132577. ", 'Macitentan and its metabolite antagonized the specific binding of ET-1 on membranes of cells overexpressing ET(A) and ET(B) receptors and blunted ET-1-induced calcium mobilization in various natural cell lines, with inhibitory constants within the nanomolar range. In functional assays, macitentan and ACT-132577 inhibited ET-1-induced contractions in isolated endothelium-denuded rat aorta (ET(A) receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ET(B) receptors). In rats with pulmonary hypertension, macitentan prevented both the increase of pulmonary pressure and the right ventricle hypertrophy, and it markedly improved survival. ', 'In conclusion, macitentan, by its tissue-targeting properties and dual antagonism of ET receptors, protects against end-organ damage in diabetes and improves survival in pulmonary hypertensive rats. This profile makes macitentan a new agent to treat cardiovascular disorders associated with chronic tissue ET system activation.', 'Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist.', 'Renal, retinal and cardiac changes in type 2 diabetes are attenuated by macitentan, a dual endothelin receptor antagonist.', 'Here we investigated the effects of macitentan, an orally-active, tissue-targeting dual ET receptor antagonist on chronic complications in type 2 diabetes.MAIN METHODS: db/db mice and their age- and sex-matched controls were examined after 2 and 4 months of diabetes. ', 'Macitentan is a novel dual ETA/ETB receptor antagonist with enhanced tissue distribution and sustained receptor binding properties designed to achieve a more efficacious ET receptor blockade. ', 'Recently oral prostacyclin receptor agonists have shown encouraging results. Many clinical studies targeting the vasoconstrictor ET-1 pathway with receptor antagonists like bosentan and ambrisentan have shown strong results, even more optimism coming from macitentan, the newest drug.']

['No, macitentan is anendothelin receptor antagonist.']

['no']

What are the side effects during statins administration in patients with atherosclerosis?

['A history of side effects was reported by 40 (19.5%) of the patients, and mainly consisted of muscle complaints and gastrointestinal symptoms. ', 'Treatment Options for Statin-Associated Muscle Symptoms.', 'Muscle symptoms are a clinically relevant side effect of statin treatment.', 'At least 5% of patients taking statins have statin-associated muscle symptoms (SAMS). ', 'Muscle problems and other adverse symptoms associated with statin use are frequent reasons for non-adherence and discontinuation of statin therapy, which results in inadequate control of hyperlipidemia and increased cardiovascular risk. ', 'It was estimated that rosuvastatin-associated absolute hazards of muscle-, liver- and renal-related adverse effects are lower than the corresponding vascular benefits in moderate vascular risk individuals. ', 'Rosuvastatin-induced proteinuria appears to be of tubular origin, not relating to kidney injury. Rosuvastatin increases the risk of new-onset diabetes by dose-dependently impairing insulin sensitivity. ', 'Statins are associated with myopathy, transaminase elevations, and an increased risk of incident diabetes mellitus among some patients; connections between statins and other processes, such as renal and neurologic function, have also been studied with mixed results. ', 'Muscle symptoms are a clinically relevant side effect of statin treatment.This review is based on pertinent publications retrieved by a selective literature search, and on the current recommendations of the European Atherosclerosis Society.At least 5% of patients taking statins have statin-associated muscle symptoms (SAMS).', 'Nevertheless, patients may develop side effects such as muscle pain and weakness years after starting statin therapy; however, the absolute number of patients affected by statin myopathy increases with treatment duration.', "Better understanding of the molecular mechanisms involved in statin-induced myopathy may help identify patient groups susceptible to statins' side effects, thereby increasing their safety.."]

['The side effects during statins administration in patients with atherosclerosis are:\n1) Myopathy\n2) Transaminase elevations\n3) Diabetes mellitus \n4) Renal and neurologic adverse effects.']

['Myopathy', 'Transaminase elevations', 'Diabetes mellitus', 'Renal adverse effects', 'Neurologic adverse effects']

Which inherited disorder is known to be caused by mutations in the NEMO gene?

['Incontinentia pigmenti (IP) is a rare neurocutaneous disorder with a frequency of 1 in 50,000 newborn, and is associated with mutations in IKBKG gene (NEMO) in Xq28, inherited as an X-linked dominant trait', 'Mutations in the NEMO gene give rise to a heterogeneous group of disorders, including the X-linked dominant disorder incontinentia pigmenti', 'De novo NEMO gene deletion (delta4-10)--a cause of incontinentia pigmenti in a female infant', 'Incontinentia pigmenti (IP) is a rare, inherited, multisystem genodermatosis. It is transmitted as an X-linked dominant trait. The disorder is a consequence of mutations in the NEMO gene (Xq28) that completely abolish expression of the NF-kappaB essential modulator', 'Incontinentia pigmenti (IP) is a rare inherited multisystem disorder characterized by a distinctive swirling pattern of the skin; defects of teeth, hair, and nails; and ophthalmic, central nervous system, and musculoskeletal abnormalities. It progresses through several well-defined stages. IP is transmitted as a dominant X-linked trait with variable expressivity, but many--if not most--cases are sporadic. IP has been shown to result from mutations in the NEMO gene that completely abolish expression of NF-kappaB essential modulator', 'Incontinentia pigmenti (IP; MIM308310) is a rare neurocutaneous X-dominant inherited disorder. Besides skin and neurological abnormalities, there is also ophthalmologic and dental involvement', 'The disorder is observed almost exclusively in girls, but diseased boys are more seriously affected. The IP gene is localised on chromosome Xq28. Mutations in the NEMO-gene are responsible for IP. This gene codes for the nuclear factor-KB essential modulator protein (NEMO; synonym: inhibitor kappaB kinase (IKK)y)', 'Incontinentia pigmenti (IP) is an X-linked-dominant Mendelian disorder caused by mutation in the IKBKG/NEMO gene, encoding for NEMO/IKKgamma, a regulatory protein of nuclear factor kappaB (NF-kB) signaling.', 'Mutations in the NEMO gene give rise to a heterogeneous group of disorders, including the X-linked dominant disorder incontinentia pigmenti.', 'In patients with incontinenia pigmenti, mutations in the NEMO gene are found.', 'Mutations in the NEMO gene have been reported in association with hypohidrotic ectodermal dysplasia with immunodeficiency (HED-ID), OL-HED-ID, and incontinentia pigmenti.', 'IKBKG/NEMO gene mutations cause an X-linked, dominant neuroectodermal disorder named Incontinentia Pigmenti (IP).', '[NEMO Delta 4-10 deletion of NEMO gene in Chinese incontinentia pigmenti cases].', 'In patients with incontinenia pigmenti, mutations in the NEMO gene are found', 'Amorphic mutations in the NF- kappa B essential modulator (NEMO) cause X-dominant incontinentia pigmenti, which is lethal in males in utero, whereas hypomorphic mutations cause X-recessive anhidrotic ectodermal dysplasia with immunodeficiency, a complex developmental disorder and life-threatening primary immunodeficiency. ', 'NEMO gene mutations in Chinese patients with incontinentia pigmenti.', 'De novo NEMO gene deletion (delta4-10)--a cause of incontinentia pigmenti in a female infant: a case report.', 'Mutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), also called nuclear factor-kappaB (NF-kB) essential modulator (NEMO), gene are the most common single cause of incontinentia pigmenti (IP) in females and anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males.', 'NEMO/IKK gamma-deficient mice model incontinentia pigmenti.', 'Germline mutations in two genes, NEMO and CYBB, have long been known to cause other human diseases-incontinentia pigmenti (IP) and anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (NEMO/IKKG), and X-linked chronic granulomatous disease (CGD) (CYBB)-but specific mutations in either of these two genes have recently been shown to cause XR-MSMD.', 'Mutations in the NEMO gene give rise to a heterogeneous group of disorders, including the X-linked dominant disorder incontinentia pigmenti.', 'IKBKG/NEMO gene mutations cause an X-linked, dominant neuroectodermal disorder named Incontinentia Pigmenti (IP).']

['Incontinentia pigmenti (IP) is a rare neurocutaneous disorder with a frequency of 1 in 50,000 newborn, and is associated with mutations in IKBKG gene (NEMO) in Xq28, inherited as an X-linked dominant trait', 'Incontinentia pigmenti (IP) or Bloch-Sulzberger syndrome (BSS) is a rare neurocutaneous disorder with a frequency of 1 in 50,000 newborn, and is associated with mutations in IKBKG gene (NEMO) in Xq28, inherited as an X-linked dominant trait.']

['Incontinentia pigmenti or Bloch-Sulzberger syndrome']

What is the role of mismatched uracil glycosylase (Mug) in DNA repair?

['XDG activity is attributable to MUG', 'xanthine DNA glycosylase (XDG) activity in E. coli', 'The wild type MUG possesses more robust activity against xanthine than uracil and is active against all xanthine-containing DNA', 'The gene for the mismatch-specific uracil DNA glycosylase (MUG) was identified in the Escherichia coli genome as a sequence homolog of the human thymine DNA glycosylase with activity against mismatched uracil base pairs.', 'The bacterial mismatch-specific uracil-DNA glycosylase (MUG) and eukaryotic thymine-DNA glycosylase (TDG) enzymes form a homologous family of DNA glycosylases that initiate base-excision repair of G:U/T mismatches.', 'the principal role of Mug in E. coli may be to help repair damage to DNA caused by exogenous chemical agents such as chloroacetaldehyde', 'excise epsilonC. The latter activity is missing in extracts from mug cells, suggesting that Mug may be the only enzyme in E. coli that can remove this mutagenic adduct. ', 'Base-excision of a self-complementary oligonucleotide with central G:T mismatches by the G:T/U-specific mismatch DNA glycosylase (MUG)', 'Mug does not repair U.G or T.G mismatches in vivo.', 'remove 3,N(4)-ethenocytosine (epsilonC) from epsilonC.G mismatches', 'The human thymine-DNA glycosylase has a sequence homolog in Escherichia coli that is described to excise uracils from U.G mismatches', 'The structure of this complex explains the preference for G:U over G:T mispairs, and reveals an essentially non-specific pyrimidine-binding pocket that allows MUG/TDG enzymes to excise the alkylated base, 3, N(4)-ethenocytosine.', 'One member of the uracil-DNA glycosylase family of repair enzymes, Escherichia coli mismatch-specific uracil-DNA glycosylase (Mug), is reported to distinguish U:G mispairs from U:A base pairs based upon specific contacts with the mispaired guanine after flipping the target uracil out of the duplex.', 'T transition in the ung mug double mutant as compared to the single ung mutant suggest that MUG may be a back-up repair enzyme to the classic uracil-DNA glycosylase.', 'The human thymine-DNA glycosylase has a sequence homolog in Escherichia coli that is described to excise uracils from U.G mismatches (Gallinari, P., and Jiricny, J. (1996) Nature 383, 735-738) and is named mismatched uracil glycosylase (Mug).', 'Because uracil-DNA glycosylase (Ung) and Vsr are known to repair U.G and T.G mismatches, respectively, we conclude that Mug does not repair U.G or T.G mismatches in vivo.', 'Mismatch uracil DNA glycosylase (Mug) from Escherichia coli is an initiating enzyme in the base-excision repair pathway.', 'Role of mismatch-specific uracil-DNA glycosylase in repair of 3,N4-ethenocytosine in vivo.', 'Thus, the principal role of Mug in E. coli may be to help repair damage to DNA caused by exogenous chemical agents such as chloroacetaldehyde.', 'The role of the Escherichia coli mug protein in the removal of uracil and 3,N(4)-ethenocytosine from DNA.', 'The bacterial mismatch-specific uracil-DNA glycosylase (MUG) and eukaryotic thymine-DNA glycosylase (TDG) enzymes form a homologous family of DNA glycosylases that initiate base-excision repair of G:U/T mismatches', 'The gene for the mismatch-specific uracil DNA glycosylase (MUG) was identified in the Escherichia coli genome as a sequence homolog of the human thymine DNA glycosylase with activity against mismatched uracil base pairs', 'One member of the uracil-DNA glycosylase family of repair enzymes, Escherichia coli mismatch-specific uracil-DNA glycosylase (Mug), is reported to distinguish U:G mispairs from U:A base pairs based upon specific contacts with the mispaired guanine after flipping the target uracil out of the duplex', 'Mismatch uracil DNA glycosylase (Mug) from Escherichia coli is an initiating enzyme in the base-excision repair pathway', 'Because uracil-DNA glycosylase (Ung) and Vsr are known to repair U.G and T.G mismatches, respectively, we conclude that Mug does not repair U.G or T.G mismatches in vivo']

['The mismatch-specific uracil DNA glycosylase (MUG) belongs to a homologous family of DNA glycosylases that initiate base-excision repair of G:U/T mismatches. The crystal structure of the Mug repair complex points to a preference of Mug for G:U over G:T mispairs. Nonetheless, Mug does not repair U:G or T:G mismatches in vivo. Mug possesses xanthine DNA glycosylase (XDG) activity in E.coli. The repair activity of Mug is more robust against xanthine than uracil. Furthermore, Mug excises the alkylated base, 3, N(4)-ethenocytosine (epsilonC) from epsilonC:G mismatches, and may be the only enzyme in E.coli that can remove this mutagenic adduct. Thus, the principal role of Mug may be the repair of DNA damages caused by exogenous chemical agents such as chloroacetaldehyde.']

[]

Can venlafaxine block NET and SERT?

['Treatment for 14 days with 70 mg/kg per day venlafaxine, which inhibits both the NET and SERT, or 10 mg/kg per day phenelzine, a monoamine oxidase inhibitor, produced antidepressant-like effects on behavior without altering NET or SERT expression.', 'Venlafaxine blocks both serotonin and norepinephrine transporters (SERT and NET), with higher affinity for SERT.', 'Chronic venlafaxine treatment affected SERT and NET binding differently from paroxetine or desipramine.', 'Venlafaxine blocks both serotonin and norepinephrine transporters (SERT and NET), with higher affinity for SERT', 'Paroxetine and venlafaxine are potent serotonin transporter (SERT) antagonists and weaker norepinephrine transporter (NET) antagonists', 'Using a novel blood assay that estimates CNS transporter occupancy we estimated the relative SERT and NET occupancy of paroxetine and venlafaxine in human subjects to assess the relative magnitude of SERT and NET inhibition', 'Treatment for 14 days with 70 mg/kg per day venlafaxine, which inhibits both the NET and SERT, or 10 mg/kg per day phenelzine, a monoamine oxidase inhibitor, produced antidepressant-like effects on behavior without altering NET or SERT expression', 'We then performed the first reported investigation of epistasis between the SERT gene and norepinephrine transporter gene (SLC6A2, alias NET) in AN, as an earlier study suggested that atypical AN responds to the dual serotonin-norepinephrine reuptake inhibitor venlafaxine', 'Of particular interest were the findings that paroxetine, generally thought of as a selective SERT antagonist, possesses moderately high affinity for the NET and that venlafaxine, which has been described as a &quot;dual uptake inhibitor&quot;, possesses weak affinity for the NET', 'The ratios of measured occupancy ED(50) values (doses at which 50% occupancy occurs) among SERT, NET and DAT sites for duloxetine, venlafaxine, nomifensine, indatraline, DOV 21,947 and DOV 216,303 were consistent with the ratios of the in vitro affinities between these target binding sites', 'SERT and NET occupancy by venlafaxine and milnacipran in nonhuman primates: a PET study', 'In this study in nonhuman primates, we aimed to investigate the relationship between SERT and NET affinity by measuring the in vivo occupancy at both transporters of venlafaxine and milnacipran', 'We hypothesized that venlafaxine would affect monoamine transporters dose-dependently, with low doses causing selective reduction of SERT binding sites and higher doses reducing both SERT and NET binding sites', 'Comparative studies with clinically used antidepressants showed that venlafaxine possessed a profile similar to S33005 but was less potent. Clomipramine likewise interacted with SERTs and NETs but also with several other receptors types, while citalopram and reboxetine were preferential ligands of SERTs and NETs, respectively. In conclusion, S33005 interacts potently with SERTs and, less markedly, with NETs. ', 'Venlafaxine blocks both serotonin and norepinephrine transporters (SERT and NET), with higher affinity for SERT. Serotonergic effects occur with lower doses, whereas both serotonergic and noradrenergic effects occur with higher doses of venlafaxine.', 'Taken together, the results from this study indicate that the low dose of venlafaxine blocked selectively the reuptake of 5-HT, whereas the high dose blocked the reuptake of both 5-HT and NE. Moreover, an enhancement of serotonergic neurotransmission by venlafaxine was only achieved under conditions whereby the desensitization of the terminal 5-HT(1B) autoreceptor is appended to that of the somatodendritic 5-HT(1A) receptor.']

['Yes, venlafaxine inhibits both the NET and SERT.']

['yes']

Is avanafil indicated for treatment of erectile dysfunction?

['CONTEXT: Avanafil (AVA) is used in the treatment of erectile dysfunction, but is reported for its poor aqueous solubility. ', 'BACKGROUND: Phosphodiesterase 5 inhibitors (PDE5-Is) sildenafil, vardenafil, tadalafil and the recently approved avanafil represent the first-line choice for both on-demand and chronic treatment of erectile dysfunction (ED). ', 'A survey on the experience of 136 Italian urologists in the treatment of erectile dysfunction with PDE5 inhibitors and recommendations for the use of Avanafil in the clinical practice.', 'Efficacy of Avanafil 15 Minutes after Dosing in Men with Erectile Dysfunction: A Randomized, Double-Blind, Placebo Controlled Study.', 'PURPOSE: We examined the therapeutic effects of avanafil 15 minutes after dosing in men with mild to severe erectile dysfunction.', 'Sildenafil, vardenafil, tadalafil and avanafil are FDA approved drugs in market as PDE5 inhibitors for treating erectile dysfunction.', "CONCLUSION: Avanafil along with the other PDE5Is has shown to be a safe and effective oral treatment for ED, with avanafil's possible place in therapy for patients who want an on-demand option or as an alternative in patients who experience visual disturbances with the other agents.", 'Avanafil (STENDRA™, SPEDRA™, Zepeeed™) is an oral phosphodiesterase type 5 inhibitor indicated for the treatment of erectile dysfunction.', 'In a 12-week, randomized, double-blind, placebo-controlled, multicentre trial in patients with erectile dysfunction, avanafil 50, 100 and 200 mg recipients had significantly greater improvements from baseline than placebo recipients in mean international index of erectile dysfunction-erectile function domain scores and in successful vaginal penetration and sexual intercourse attempts (coprimary endpoints).', 'Avanafil for the treatment of erectile dysfunction. An updated review.', 'Selectivity of avanafil, a PDE5 inhibitor for the treatment of erectile dysfunction: implications for clinical safety and improved tolerability.', 'A randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of avanafil in subjects with erectile dysfunction.', 'Avanafil, a potent and highly selective phosphodiesterase-5 inhibitor for erectile dysfunction.', 'Avanafil, a highly selective phosphodiesterase type 5 inhibitor for erectile dysfunction, shows good safety profiles for retinal function and hemodynamics in anesthetized dogs.', 'Cumulative data suggest that avanafil has a promising pharmacological profile for erectile dysfunction.', 'These findings suggest that intracavernosal administration of avanafil might be beneficial for the treatment of erectile dysfunction in patients with T2DM.', 'An open-label, long-term evaluation of the safety, efficacy and tolerability of avanafil in male patients with mild to severe erectile dysfunction.', 'The effect of intracavernosal avanafil, a newer phosphodiesterase-5 inhibitor, on neonatal type 2 diabetic rats with erectile dysfunction.', 'A phase 3, placebo controlled study of the safety and efficacy of avanafil for the treatment of erectile dysfunction after nerve sparing radical prostatectomy.', 'Avanafil is a potent selective phosphodiesterase type 5 (PDE5) inhibitor newly developed for treating erectile dysfunction (ED).', 'Adverse events most commonly reported with avanafil treatment were headache, nasopharyngitis, flushing, and sinus congestion.Avanafil was safe and effective for treating erectile dysfunction in men with diabetes and was effective as early as 15 minutes and more than 6 hours after dosing', 'Avanafil (STENDRA™, SPEDRA™, Zepeeed™) is an oral phosphodiesterase type 5 inhibitor indicated for the treatment of erectile dysfunction', 'Avanafil is rapidly absorbed after oral administration, with a median time to maximum plasma concentration of 30 to 45 min. In a 12-week, randomized, double-blind, placebo-controlled, multicentre trial in patients with erectile dysfunction, avanafil 50, 100 and 200 mg recipients had significantly greater improvements from baseline than placebo recipients in mean international index of erectile dysfunction-erectile function domain scores and in successful vaginal penetration and sexual intercourse attempts (coprimary endpoints)', 'A phase II, single-blind, randomized, crossover evaluation of the safety and efficacy of avanafil using visual sexual stimulation in patients with mild to moderate erectile dysfunction', 'To evaluate the safety, efficacy and time course of three doses of avanafil (50 mg, 100 mg and 200 mg) compared with sildenafil 50 mg or placebo, given in conjunction with visual sexual stimulation (VSS) videos in men with mild to moderate erectile dysfunction (ED).Male patients, 35-70 years of age, with mild to moderate ED of ≥6 months duration, were included in the study', 'Avanafil for erectile dysfunction', 'To review the pharmacology, pharmacokinetics, safety, and efficacy of avanafil and evaluate relevant clinical trial data.A MEDLINE, International Pharmaceutical Abstracts, ClinicalTrials.gov, and Google Scholar searches (1966 to July 2013) were conducted using the key words: avanafil, erectile dysfunction, and phosphodiesterase type 5 (PDE5) inhibitor.Articles evaluating avanafil for erectile dysfunction (ED) published in English and using human subjects were selected', 'In trials in patients with erectile dysfunction in association with diabetes mellitus, and after nerve-sparing radical prostatectomy, avanafil 100 or 200 mg was significantly more efficacious than placebo for primary and most secondary endpoints', 'However, the potentiating effect of avanafil at 1 mg/kg was significantly weaker than that of sildenafil (p &lt;0.05).Data suggest that avanafil has a favorable safety profile for erectile dysfunction, which is attributable to its high inhibitory selectivity for phosphodiesterase type 5 against type 6 (retina) and 1 (vessels, etc), respectively, and its short acting pharmacodynamic property.<CopyrightInformation>Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.</', 'Avanafil for the treatment of erectile dysfunction: a multicenter, randomized, double-blind study in men with diabetes mellitus.', 'The discovery of avanafil for the treatment of erectile dysfunction: a novel pyrimidine-5-carboxamide derivative as a potent and highly selective phosphodiesterase 5 inhibitor.', 'Efficacy and safety of avanafil for treating erectile dysfunction: results of a multicentre, randomized, double-blind, placebo-controlled trial.', 'Phosphodiesterase 5 inhibitors (PDE5-Is) sildenafil, vardenafil, tadalafil and the recently approved avanafil represent the first-line choice for both on-demand and chronic treatment of erectile dysfunction (ED).', 'The phosphodiesterese-5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), tadalafil (Cialis™) and avanafil (Stendra™) have been developed for the treatment of erectile dysfunction.', 'To compare the efficacy and safety between different dosages of avanafil for the treatment of erectile dysfunction (ED).PubMed, Cochrane Library, and Embase were searched to identify randomized controlled trials which compared avanafil with placebo, or compared different dosages of avanafil for ED.', 'We evaluated the safety and efficacy of 100 and 200 mg avanafil for the treatment of adult males with erectile dysfunction after bilateral nerve sparing radical prostatectomy.This was a double-blind, placebo controlled, parallel group, phase 3 study in males age 18 to 70 years with a history of erectile dysfunction of 6 months or more after bilateral nerve sparing radical prostatectomy.', 'To determine the effect of avanafil, a novel phosphodiesterase-5 inhibitor, on the treatment of erectile dysfunction associated with type 2 diabetes mellitus (T2DM).In 2-day-old rats, T2DM was induced by single intraperitoneal injection of 90 mg/kg of streptozotocin (STZ; i.p.).', 'These findings suggest that intracavernosal administration of avanafil might be beneficial for the treatment of erectile dysfunction in patients with T2DM.<CopyrightInformation>Copyright © 2014 Elsevier Inc. All rights reserved.</C', 'Avanafil, a potent new selective phosphodiesterase type 5 (PDE5) inhibitor, has been developed for the treatment of erectile dysfunction (ED).', 'Adverse events most commonly reported with avanafil treatment were headache, nasopharyngitis, flushing, and sinus congestion.Avanafil was safe and effective for treating erectile dysfunction in men with diabetes and was effective as early as 15 minutes and more than 6 hours after dosing.', "Coprimary end points assessed changes in the percentage of sexual attempts in which men were able to maintain an erection of sufficient duration to have successful intercourse (Sexual Encounter Profile [SEP] 3), percentage of sexual attempts in which men were able to insert the penis into the partner's vagina (SEP 2), and International Index of Erectile Function erectile function domain score.RESULTS: Compared with placebo, least-squares mean change from baseline to study end in SEP 3, SEP 2, and International Index of Erectile Function erectile function domain score were significantly improved with both avanafil, 100 mg (P?.002), and avanafil, 200 mg (P<.001).", 'Adverse events most commonly reported with avanafil treatment were headache, nasopharyngitis, flushing, and sinus congestion.CONCLUSION: Avanafil was safe and effective for treating erectile dysfunction in men with diabetes and was effective as early as 15 minutes and more than 6 hours after dosing.', 'Avanafil for the treatment of erectile dysfunction. An updated review.', 'Avanafil for erectile dysfunction.', 'Avanafil for the treatment of erectile dysfunction: a multicenter, randomized, double-blind study in men with diabetes mellitus.', 'To compare the efficacy and safety between different dosages of avanafil for the treatment of erectile dysfunction (ED).', 'Selectivity of avanafil, a PDE5 inhibitor for the treatment of erectile dysfunction: implications for clinical safety and improved tolerability.', 'A phase 3, placebo controlled study of the safety and efficacy of avanafil for the treatment of erectile dysfunction after nerve sparing radical prostatectomy.', 'We evaluated the safety and efficacy of 100 and 200 mg avanafil for the treatment of adult males with erectile dysfunction after bilateral nerve sparing radical prostatectomy.']

['Yes, avanafil is indicated for treatment of erectile dysfunction.']

['yes']

How many genes does the human hoxD cluster contain?

['Both children are heterozygous for a deletion that eliminates at least eight (HOXD3-HOXD13) of the nine genes in the HOXD cluster']

["The human HOXD complex contains nine genes: HOXD1, HOXD3, HOXD4, HOXD8, HOXD9, HOXD10, HOXD11, HOXD12 and HOXD13, which are clustered from 3′ to 5′ in an approximately 100-kb stretch on chromosome 2q31.1 with HOXD1 at the 3' end and HOXD13 the 5′ end."]

['9']

Are proteasome inhibitors good candidates for treatment of leukemia and solid tumors?

['We show that treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model. Our results show that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target', 'We further found that ATO targets AME via both myelodysplastic syndrome 1 (MDS1) and EVI1 moieties and degrades EVI1 via the ubiquitin-proteasome pathway and MDS1 in a proteasome-independent manner. Our results suggest that ATO could be used as a part of targeted therapy for AME-, AML1/MDS1-, MDS1/EVI1-, and EVI1-positive human cancers.', 'Previously we had shown the synergic effect of bortezomib and thiostrepton in breast cancer cells in vitro, where sub-apoptotic concentrations of both proteasome inhibitors resulted in synergic increase in cell death when combined as a treatment. Here, we administered such a combination to MDA-MB-231 xenograft tumors in vivo, and found that the effect of complementary proteasome inhibitors reduced tumor growth rates more efficiently than compared with when administered alone.', 'Addition of a proteasome inhibitor to anti-hormonal therapy resulted in a clinical benefit rate of 22% in a limited number of patients with endocrine resistant and progressive metastatic breast cancer.', 'Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications.', 'Bortezomib has minimal activity as a single-agent in the treatment of recurrent platinum-sensitive EOC/PPC', 'Our study indicates a molecular mechanism by which the sensitivity of thyroid cancer cells is regulated by the level of GRP78 as well as preferential induction of GRP78 or CHOP upon treatment with proteasome inhibitors. Our experiments therefore suggest a novel approach toward sensitization of thyroid cancer cells to proteasome inhibitors.', 'Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity.', 'The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib.', 'Given the results of this trial, it is safe and reasonable to recommend treatment with PS341 on the schedule used in this trial at 1.56 mg/m2/dose in Phase II trials. Particular care should be taken with patients with preexisting neuropathy', 'The successes of proteasome inhibitors in MM are now being translated to other hematologic malignancies, including acute leukemia', 'Such efforts have led to bortezomib, the first FDA approved proteasome inhibitor now used as a frontline treatment for newly diagnosed multiple myeloma (MM), relapsed/refractory MM and mantle cell lymphoma', 'We recently reported the impact and mechanisms of carfilzomib and oprozomib, second-in-class proteasome inhibitors with higher specificities and reduced toxicities, against head and neck squamous cell carcinoma (HNSCC). Carfilzomib and oprozomib potently inhibit HNSCC cell survival and the growth of HNSCC tumors']

['Yes, several compounds that inhibit different members of the proteasome pathway (for example Bortezomib) are on trial for treatment of leukemia and solid tumors. It seems that a combination with other drugs may be a useful therapy for solid tumors.']

['yes']

Which autophagy pathway is trigered by the KFERQ motif of cytosolic proteins?

['Chaperone-mediated autophagy (CMA) is a selective form of lysosomal degradation targeting proteins carrying the KFERQ motif.', 'The significance of the receptor glycoprotein lamp2a in the chaperone-mediated autophagy of cytosolic proteins with KFERQ motif has been described in details as well as the chaperone protein Hsc73 and other chaperones involved in this process.', 'We investigated chaperone-mediated autophagy, a lysosomal import pathway that depends on the 73-kDa heat shock cognate protein and allows the degradation of proteins containing a specific lysosomal import consensus sequence (KFERQ motif). ', 'The significance of the receptor glycoprotein lamp2a in the chaperone-mediated autophagy of cytosolic proteins with KFERQ motif has been described in details as well as the chaperone protein Hsc73 and other chaperones involved in this process.', 'We investigated chaperone-mediated autophagy, a lysosomal import pathway that depends on the 73-kDa heat shock cognate protein and allows the degradation of proteins containing a specific lysosomal import consensus sequence (KFERQ motif).', 'Chaperone-mediated autophagy (CMA) is a selective form of lysosomal degradation targeting proteins carrying the KFERQ motif.', 'Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of soluble cytosolic proteins bearing the sequence KFERQ.', 'The abundance of proteins containing that chaperone-mediated autophagy KFERQ signal motif increased 38% and individual KFERQ containing proteins [e.', 'Furthermore, four annexins containing KFERQ-like sequences, annexins I, II, IV, and VI, are enriched in lysosomes with high chaperone-mediated autophagy activity as expected for substrate proteins.', 'Using isolated lysosomes, only the annexins containing KFERQ-like sequences are degraded by chaperone mediated-autophagy.', 'Macroautophagy is followed by chaperone-mediated autophagy (CMA), in which Hsc70 (Heat shock cognate 70) selectively binds proteins with exposed KFERQ motifs and pushes them inside lysosomes through the LAMP-2A (Lysosome-associated membrane protein type 2A) receptor.', 'Macroautophagy is followed by chaperone-mediated autophagy (CMA), in which Hsc70 (Heat shock cognate 70) selectively binds proteins with exposed KFERQ motifs and pushes them inside lysosomes through the LAMP-2A (Lysosome-associated membrane protein type 2A) receptor.', 'AIMS: Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of soluble cytosolic proteins bearing the sequence KFERQ.', 'We investigated chaperone-mediated autophagy, a lysosomal import pathway that depends on the 73-kDa heat shock cognate protein and allows the degradation of proteins containing a specific lysosomal import consensus sequence (KFERQ motif).', 'The significance of the receptor glycoprotein lamp2a in the chaperone-mediated autophagy of cytosolic proteins with KFERQ motif has been described in details as well as the chaperone protein Hsc73 and other chaperones involved in this process', 'Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of soluble cytosolic proteins bearing the sequence KFERQ', 'In cell culture, growth factors suppress the lysosomal pathway of chaperone-mediated autophagy leading to the accumulation of specific cytoplasmic proteins containing KFERQ motifs', 'We investigated chaperone-mediated autophagy, a lysosomal import pathway that depends on the 73-kDa heat shock cognate protein and allows the degradation of proteins containing a specific lysosomal import consensus sequence (KFERQ motif)', 'The abundance of proteins containing that chaperone-mediated autophagy KFERQ signal motif increased 38% and individual KFERQ containing proteins [e.g., M2 pyruvate kinase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pax2] were more abundant', 'These results provide striking evidence for the importance of KFERQ motifs in substrates of chaperone-mediated autophagy.', 'Macroautophagy is followed by chaperone-mediated autophagy (CMA), in which Hsc70 (Heat shock cognate 70) selectively binds proteins with exposed KFERQ motifs and pushes them inside lysosomes through the LAMP-2A (Lysosome-associated membrane protein type 2A) receptor']

['Cytosolic proteins carrying the KFERQ motif (a specific lysosomal import consensus sequence) are directed to a selective form of lysosomal degradation, called chaperone-mediated autophagy (CMA), as chaperone protein Hsc73 and other chaperones are involved in this process.']

['chaperone-mediated autophagy (CMA)']

Is the PTPN22 gene a biomarker for Rheumatoid Arthritis?

['Combined longitudinal analysis of the 2 cohorts suggests further association of several loci with Larsen score (KIF5A, PTPN22, AFF3, TAGAP) and therefore a significant accumulation of RA severity markers among RA susceptibility markers (p = 0.016)', 'A non-intronic marker at TNFAIP3, GIN1/C5orf30, STAT4, ANKRD55/IL6ST, BLK and PTPN22 showed association with RA susceptibility, irrespective of the serological status, the latter three markers remaining significantly associated with anti-CCP negative RA, after correction for multiple testing', 'A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease', 'In addition, how the overall activity of PTPN22 is regulated and how the R-to-W conversion contributes to rheumatoid arthritis is still poorly understood', 'Our data depict a model that can reconcile the conflicting observations on the functional impact of the C1858T SNP and also suggest that PTPN22.6 is a novel biomarker of rheumatoid arthritis.', 'Lack of association of common variants in PTPN22 with RA in Han Chinese was confirmed', 'This study identifies MMEL1 and CTLA4 as RA susceptibility genes, provides suggestive evidence of association for a further six loci in the Han Chinese population and confirms lack of PTPN22 association in Asian populations', 'PTPN22 R620W genotype-phenotype correlation analysis and gene-environment interaction study in early rheumatoid arthritis: results from the ESPOIR cohort', ' PTPN22 620W risk allele was associated with ACPA production [odds ratio (OR)\u2009=\u20092.21, 95% CI 1.4, 3.4, P\u2009<\u20090.0001]', 'Hormonal treatment exposition and smoking were found to act with a protective effect against ACPA production (OR\u2009=\u20090.44, 95% CI 0.3, 0.7, P\u2009=\u20090.001) and early bone erosion (OR\u2009=\u20090.56, 95% CI 0.4-0.8, P\u2009=\u20090.003), respectively, and independently of HLADR and PTPN22 status', ' RA patients (n=333) and controls (n=490) from the Cree/Ojibway NAN population in Central Canada were HLA-DRB1 typed and tested for 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL', 'Several other genes, including PTPN22 and PADI4, show modest association with RA', 'Other variants in potentially pathogenic genes located in non-MHC regions have been implicated by recently performed genome wide analysis studies. These genes include PTPN22, TRAF1-C5, PADI4, STAT4', 'Among these genes, PTPN22 plays an outstanding role. CD40, STAT4, PRM1, and TNFAIP3 also seem to be of relevance.', 'HLA-DRB1 and the R620W single-nucleotide polymorphism of PTPN22 were genotyped', 'In addition, evidence of a significant interaction between the shared epitope and the risk allele of PTPN22 was observed only in these patients', 'Although SNPs in PADI4 had similar allele frequency among three groups [maximal difference 11%; (P >0.05)], the other three loci revealed statistically significant allele frequency differences (maximal difference 39% (P <0.00001), 13% (P <0.00001), and 8% (P <0.00001) in SLC22A4, PDCD1, and PTPN22, respectively)', "Several multiple, large-scale, genetic studies on autoimmune-disease-associated SNPs have been reported recently: peptidylarginine deiminase type 4 (PADI4) in rheumatoid arthritis (RA); solute carrier family 22 members 4 and 5 (SLC22A4 and 5) in RA and Crohn's disease (CD); programmed cell death 1 (PDCD1) in systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), and RA; and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in T1D, RA, and SLE", ' Recently a number of convincing candidate genes have begun to emerge and an update has been provided for three of these: PTPN22, CTLA-4 and MIF.', 'Association studies support a role for several genes, including TNFR2, PADI4, SLC22A4, RUNX1, and PTPN22', 'Analyses of families with multiple autoimmune disorders have revealed a functional polymorphism, 620W, in the intracellular tyrosine phosphatase gene PTPN22 as a predisposing factor for type 1 diabetes, seropositive rheumatoid arthritis, systemic lupus erythematosus, and Hashimoto thyroiditis, and the presence of the PTPN22 protein appears to herald the development of autoantibodies in these disorders', 'Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4.', 'We found strong evidence of an association of PTPN22 with the development of anti-citrulline antibody-positive RA (odds ratio [OR] 1.49; P=.00002), using previously untested EIRA samples.', ' Exploration of our data set with clinically relevant subsets of RA reveals that PTPN22 is associated with an earlier age at disease onset (P=.004) and that PTPN22 has a stronger effect in males than in females (P=.03)', ' Given the strong statistical power to replicate a true-positive association in this study, our results provide support for PTPN22, CTLA4, and PADI4 as RA susceptibility genes and demonstrate novel associations with clinically relevant subsets of RA', 'In logistic regression analysis, ACPA predicted RA-development independent of PTPN22, while the PTPN22 polymorphism had no independent effect.', 'Risk of progression from undifferentiated arthritis to rheumatoid arthritis: the effect of the PTPN22 1858T-allele in anti-citrullinated peptide antibody positive patients', 'Anti-citrullinated peptide antibodies (ACPA) and the C1858T missense single-nucleotide polymorphism (SNP) in the PTPN22 gene are both associated with the development of rheumatoid arthritis (RA)', 'Associations between human leukocyte antigen, PTPN22, CTLA4 genotypes and rheumatoid arthritis phenotypes of autoantibody status, age at diagnosis and erosions in a large cohort study', 'HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA)', 'Auto-antibodies, HLA and PTPN22: susceptibility markers for rheumatoid arthritis', 'The combination of the PTPN22 1858T variant and anti-CCP antibodies gave a high specificity for the disease, and was significantly associated with RA (P = 8.86 x 10(-5), OR 10.05, 95% CI 1.88-53.73)', 'The combination of the T variant of the 1858 polymorphism of the PTPN22 gene in combination with the presence of anti-CCP antibodies, preferentially in a SE-positive individual, is associated with the development of RA', 'No association of the PTPN22 gene with mortality was detected', 'Cox proportional hazards regression models were used to assess the association of the HLA-DRB1 (including the shared epitope [SE]) and PTPN22 genes with the risk of death from all causes and from cardiovascular disease (CVD) and to assess the interactions between SE, smoking, and anti-cyclic citrullinated peptide (anti-CCP) status, adjusted by age at symptom onset and sex', "The disease association of the common 1858C>T Arg620Trp (rs2476601) nonsynonymous single nucleotide polymorphism (SNP) of protein tyrosine phosphatase; nonreceptor type 22 (PTPN22) on chromosome 1p13 has been confirmed in type 1 diabetes and also in other autoimmune diseases, including rheumatoid arthritis and Graves' disease", 'To evaluate the predictive values for disease progression of various antibodies against citrullinated peptide proteins (ACPA) and their relation to PTPN22 1858C/T polymorphism and HLA-DRB1 alleles in early rheumatoid arthritis (RA)', 'PTPN22, PADI-4, and CTLA-4 have been associated with risk for rheumatoid arthritis (RA)', 'A significant multiplicative interaction between PTPN22 and smoking for more than 10 pack-years was observed (P = 0.04)', 'No gene-gene interaction was observed between PTPN22 and HLA-SE', 'After adjusting for smoking and reproductive factors, PTPN22 was associated with RA risk among Caucasian women in these cohorts. We found both additive and multiplicative interactions between PTPN22 and heavy cigarette smoking.', 'Weak evidence for an effect at the PTPN22 locus was also observed', 'Association of the PTPN22 gene (-1123G > C) polymorphism with rheumatoid arthritis in Chinese patients', 'These data suggest, the CC genotype and C allele of the -1123G > C in the PTPN22 gene are associated with an increased risk for RA in Chinese population', 'Therefore, the CC genotype and C allele of the -1123G > C in the PTPN22 gene may be used as a genetic marker for the predisposition of RA in Chines', 'A longer duration of breastfeeding increased the risk of developing RA, especially among individuals seropositive for ACPA or IgM-RF or carrying the PTPN22 1858T variant', 'In a multiple logistic regression analysis, increasing time of breastfeeding (OR 9.5, 95% CI 2.14-42.43 for ≥ 17 months), seropositivity for ACPAs (OR 19.5, 95% CI 4.47-84.81), and carriage of the PTPN22 1858T variant (OR 3.2, 95% CI 1.36-7.54) remained significant predictors of RA', 'After quality control, 3209 patients and 3692 controls were included in the study. Eight markers (ie, rs1160542 (AFF3), rs1678542 (KIF5A), rs2476601 (PTPN22), rs3087243 (CTLA4), rs4810485 (CD40), rs5029937 (6q23), rs10760130 (TRAF1/C5) and rs7574865 (STAT4)) were significantly associated with RA by meta-analysis', 'Recent genome-wide association studies (GWAS) on RA identified known and novel susceptibility genes like HLA-DRB1, PTPN22, STAT4, TRAF1/C5, OLIG3/TNFAIP3, CD40, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, IL2RB, and KIF5A-PIP4K2C', 'In the total RA inception cohort, the HLA-DRB1 shared epitope (per-allele odds ratio (OR) = 2.1, trend P < 0.0001), PTPN22 (per-allele OR = 1.5, trend P < 0.0001), OLIG3/TNFAIP3 locus (per-allele OR = 1.2, trend P = 0.009) and TRAF1/C5 locus (per-allele OR = 1.1, trend P = 0.04) were associated with RA', 'Progress has been made in determining the relative contributions and the interaction of the shared epitope, PTPN22 and smoking in conferring the risk of anticitrullinated protein antibodies-positive and negative RA', 'Homozygous and heterozygous carriers of the PTPN22 1858T allele had a decreased probability of remission', 'Our analyses have confirmed previous findings for genes PTPN22 and C5', 'Fifty-five percent of the FDRs had > or =1 copy of the shared epitope, 20% had > or =1 copy of the PTPN22 polymorphism, and approximately 16% were positive for rheumatoid factor (RF; including isotypes) and/or anti-cyclic citrullinated peptide antibody', 'As an effect several new genes have been recognized as an HLA-independent genetic risk factors of RA. PTPN22 gene polymorphism, C5/TRAF1 genes region polymorphism and TNFAIP3-OLIG3 genes region polymorphism(s) are among newly identified and already confirmed genetic risk factors, whereas STAT 4, CTLA4, PADI4 and IRF5 genes polymorphisms are listed among probable RA development genetic risk factors', 'Patients were analysed for anti-MCV and anti-cyclic citrullinated peptide (CCP), and were genotyped for human leukocyte antigen (HLA)-DRB1 "shared epitope" (SE) and protein tyrosine phosphatase, non-receptor type 22 (PTPN22) 1858T', 'As well as the major susceptibility gene HLA-DRB1, recent genome-wide and candidate-gene studies reported additional evidence for association of single nucleotide polymorphism (SNP) markers in the PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5 loci with RA', 'However, we were able to replicate the association signals between RA and HLA-DRB1 alleles, STAT4 (rs7574865), PTPN22 (rs2476601) and OLIG3/TNFAIP3 (rs10499194 and rs6920220)', 'Additionally, SNPs rs7574865STAT4 (P = 9.2*10-6; OR = 1.71, 95% CI = 1.35 - 2.18) and rs2476601PTPN22 (P = 9.5*10-4; OR = 1.67, 95% CI = 1.23 - 2.26) were associated with susceptibility to RA, whereas after permutation testing OLIG3/TNFAIP3 SNPs rs10499194 and rs6920220 missed our criteria for significance (Pcorr = 0.114 and Pcorr = 0.180, respectively', 'In our Slovak population, HLA-DRB1 alleles as well as SNPs in STAT4 and PTPN22 genes showed a strong association with RA', 'Currently, 5 loci (HLA, PTPN22, TRAF1/C5, TNFAIP3, and STAT4) have been consistently reported, whereas others have been observed less systematically', 'Genetic markers such as shared epitope alleles and PTPN22 1858T variant increase the relative risk for disease development', 'Particularly, ACPAs in combination with human leukocyte antigen-shared epitope alleles and PTPN22 1858T carriage increased the relative risks of developing RA compared with not having these factors', 'However, inconsistent results of the contributions of non-HLA susceptibility genes have been described, with the exception of a few genes repeatedly associated with RA-susceptibility, such as PTPN22 gene in populations of European ancestry and PADI4 gene in populations of Asian ancestry, revealing the presence of genetic heterogeneity in RA', 'Functional polymorphisms of PTPN22 and FcgR genes in Tunisian patients with rheumatoid arthritis', 'We found strong evidence of an association of PTPN22 620W allele and RA', 'In conclusion, we have confirmed that PTPN22 620W allele is associated with Tunisian RA but does not constitute a factor influencing clinical manifestations', 'The C1858T allele of the PTPN22 gene has been reported to confer risk for RA', 'Similarly, the presence or absence of the HLA-DRB1 shared epitope or the RA-associated PTPN22 allele had no influence on this association', 'Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability', 'Lastly, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential', 'Contribution of PTPN22 1858T, TNFRII 196R and HLA-shared epitope alleles with rheumatoid factor and anti-citrullinated protein antibodies to very early rheumatoid arthritis diagnosis', 'PTPN22 1858T, TNFRII 196R and HLA-SE alleles do not improve the predictive value of RF and ACPA for RA diagnosis in our cohort, and do not contribute to an earlier diagnosis in undifferentiated patients initially negative for RF and ACPA']

['The PTPN22 gene has been repeatedly associated with RA-susceptibility in populations of European ancestry.']

['yes']

Are messenger RNA molecules epigenetically methylated?

['The most abundant mRNA post-transcriptional modification is N(6)-methyladenosine (m(6)A), which has broad roles in RNA biology.', 'N(6)-methyladenosine (m6A) is the most abundant modified base in eukaryotic mRNA and has been linked to diverse effects on mRNA fate.', " Recently, methylation patterns have also been revealed in mRNA. Surprisingly, the two most commonly studied methylation states in mRNA (m6A and m5C) are found to be enriched in 3'-UTRs (untranslated regions), the target site for the majority of miRNAs.", 'MeT-DB: a database of transcriptome methylation in mammalian cells', 'Methyltranscriptome is an exciting new area that studies the mechanisms and functions of methylation in transcripts. The MethylTranscriptome DataBase (MeT-DB, http://compgenomics.utsa.edu/methylation/) is the first comprehensive resource for N6-methyladenosine (m(6)A) in mammalian transcriptome.', 'Mammalian messenger RNA (mRNA) and long noncoding RNA (lncRNA) contain tens of thousands of posttranscriptional chemical modifications. Among these, the N(6)-methyl-adenosine (m(6)A) modification is the most abundant and can be removed by specific mammalian enzymes.', 'Recent discoveries of reversible N(6)-methyladenosine (m(6)A) methylation on messenger RNA (mRNA) and mapping of m(6)A methylomes in mammals and yeast have revealed potential regulatory functions of this RNA modification.', "There are several identified methylation modifications in eukaryotic messenger RNA (mRNA), such as N(7)-methylguanosine (m(7)G) at the cap, N(6)-methyl-2'-O-methyladenosine (m(6)Am), 2'-O-methylation (Nm) within the cap and the internal positions, and internal N(6)-methyladenosine (m(6)A) and 5-methylcytosine (m(5)C)."]

['Yes, methyltranscriptome is an exciting new area that studies the mechanisms and functions of methylation in transcripts.']

['yes']

What is enCHIP?

['Identification of telomere-associated molecules by engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP).', 'Here, we report isolation of telomeres by engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) using a transcription activator-like (TAL) protein recognizing telomere repeats. Telomeres recognized by the tagged TAL protein were immunoprecipitated with an antibody against the tag and subjected to identification of telomere-binding molecules. enChIP-mass spectrometry (enChIP-MS) targeting telomeres identified known and novel telomere-binding proteins.', 'Efficient isolation of specific genomic regions and identification of associated proteins by engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) using CRISPR.', 'Here, we established a novel method, engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP), for purification of specific genomic regions retaining molecular interactions. We showed that enChIP using the CRISPR system efficiently isolates specific genomic regions. In this form of enChIP, specific genomic regions are immunoprecipitated with antibody against a tag(s), which is fused to a catalytically inactive form of Cas9 (dCas9), which is co-expressed with a guide RNA (gRNA) and recognizes endogenous DNA sequence in the genomic regions of interest. enChIP-mass spectrometry (enChIP-MS) targeting endogenous loci identified associated proteins. enChIP using the CRISPR system would be a convenient and useful tool for dissecting chromatin structure of genomic regions of interest.', 'Recently, we developed the engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) technology for purification of specific genomic regions.', 'Here, we established a novel method, engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP), for purification of specific genomic regions retaining molecular interactions. ', 'Recently, we developed the engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) technology for purification of specific genomic regions.', 'Here, we established a novel method, engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP), for purification of specific genomic regions retaining molecular interactions.', 'In this form of enChIP, specific genomic regions are immunoprecipitated with antibody against a tag(s), which is fused to a catalytically inactive form of Cas9 (dCas9), which is co-expressed with a guide RNA (gRNA) and recognizes endogenous DNA sequence in the genomic regions of interest. enChIP-mass spectrometry (enChIP-MS) targeting endogenous loci identified associated proteins.', 'Recently, we developed the engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) technology for purification of specific genomic regions. Here, we developed a retroviral expression system for enChIP using CRISPR.', 'Here, we established a novel method, engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP), for purification of specific genomic regions retaining molecular interactions. We showed that enChIP using the CRISPR system efficiently isolates specific genomic regions.']

['Engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) is a novel method for purification of specific genomic regions retaining molecular interactions. EnChIP using the CRISPR system efficiently isolates specific genomic regions. In this form of enChIP, specific genomic regions are immunoprecipitated with antibody against a tag(s), which is fused to a catalytically inactive form of Cas9 (dCas9), which is co-expressed with a guide RNA (gRNA) and recognizes endogenous DNA sequence in the genomic regions of interest. enChIP-mass spectrometry (enChIP-MS) targeting endogenous loci identified associated proteins. enChIP using the CRISPR system would be a convenient and useful tool for dissecting chromatin structure of genomic regions of interest.']

[]

How does Vildagliptin compare to other DPP-4 inhibitors in reaching HbA1c <7% in type 2 diabetes patients?

[' controlled trials (RCTs) of DPP-4 inhibitors and metformin as initial combination therapy or as monotherapy in patients with T2DM by the end of December 2012, using the key words \'alogliptin\', \'dutogliptin\', \'linagliptin\', \'saxagliptin\', \'sitagliptin\', \'vildagliptin\' and \'metformin\'. ", "Sitagliptin (MK- 0431), Saxagliptin, Melogliptin, Linagliptin (BI-1356), Dutogliptin, Carmegliptin, Alogliptin and Vildagliptin (LAF237). ", "Aim of the present meta-analysis is the systematic collection and synthesis of information on treatment-emergent cases of acute heart failure described in randomized clinical trials with DPP4.DATA SOURCES: An extensive Medline, Embase, and Cochrane Database search for \\"vildagliptin\\", \\"sitagliptin\\", \\"saxagliptin\\", \\"alogliptin\\", \\"linagliptin\\", and \\"dutogliptin\\" was performed, collecting all randomized clinical trials on humans up to October 1st, 2013. ", "Quantitative model of the relationship between dipeptidyl peptidase-4 (DPP-4) inhibition and response: meta-analysis of alogliptin, saxagliptin, sitagliptin, and vildagliptin efficacy results.", "The dipeptidyl peptidase-4 (DPP-4) inhibitors linagliptin, sitagliptin, saxagliptin, vildagliptin and alogliptin are being developed and have been approved for the treatment of type-2 diabetes. ", "The objective of this model-based meta-analysis was to describe the time course of HbA1c response after dosing with alogliptin (ALOG), saxagliptin (SAXA), sitagliptin (SITA), or vildagliptin (VILD). ", "Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on linagliptin and alogliptin.", "The dipeptidylpeptidase-IV inhibitors sitagliptin, vildagliptin and saxagliptin do not impair innate and adaptive immune responses.", "In conclusion, BI 1356 inhibited DPP-4 more effectively than vildagliptin, sitagliptin, saxagliptin, and alogliptin and has the potential to become the first truly once-a-day DPP-4 inhibitor for the treatment of type 2 diabetes.", "Highly potent DPP-4 inhibitors have been identified by hybrid compound design based on linagliptin and alogliptin. ", "AIM: We assessed the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin, sitagliptin, saxagliptin and alogliptin to reach the haemoglobin HbA1c target of <7% in people with type 2 diabetes. ", "Whether the DPP-IV inhibitors sitagliptin, vildagliptin or saxagliptin impair immune responses is, however, currently unknown. ", "OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibitors, including sitagliptin, saxagliptin, vildagliptin, and linagliptin, in type 2 diabetes. ", "Given as monotherapy, linagliptin, sitagliptin, and vildagliptin (but not saxagliptin) met the equivalence criterion when compared with one another.", "Given in combination with metformin, linagliptin, saxagliptin, sitagliptin, and vildagliptin showed an equivalent effect whereas alogliptin did not satisfy the equivalence criterion.", "an extensive Medline, Embase and Cochrane Database search for \'vildagliptin\', \'sitagliptin\', \'saxagliptin\', \'alogliptin\', \'linagliptin\' and \'dutogliptin\' was performed up to 1 March 2013.", "An extensive Medline and Embase search for \'vildagliptin\', \'sitagliptin\', \'saxagliptin\', \'alogliptin\', \'linagliptin\', and \'dutogliptin\' was performed, collecting all randomized clinical trials on humans up to March 1, 2011.", "An extensive Medline, Embase, and Cochrane Database search for \\"vildagliptin\\", \\"sitagliptin\\", \\"saxagliptin\\", \\"alogliptin\\", \\"linagliptin\\", and \\"dutogliptin\\" was performed, collecting all randomized clinical trials on humans', ' controlled trials (RCTs) of DPP-4 inhibitors and metformin as initial combination therapy or as monotherapy in patients with T2DM by the end of December 2012, using the key words \'alogliptin\', \'dutogliptin\', \'linagliptin\', \'saxagliptin\', \'sitagliptin\', \'vildagliptin\' and \'metformin\'. ", "Sitagliptin (MK- 0431), Saxagliptin, Melogliptin, Linagliptin (BI-1356), Dutogliptin, Carmegliptin, Alogliptin and Vildagliptin (LAF237). ", "Aim of the present meta-analysis is the systematic collection and synthesis of information on treatment-emergent cases of acute heart failure described in randomized clinical trials with DPP4.DATA SOURCES: An extensive Medline, Embase, and Cochrane Database search for \\"vildagliptin\\", \\"sitagliptin\\", \\"saxagliptin\\", \\"alogliptin\\", \\"linagliptin\\", and \\"dutogliptin\\" was performed, collecting all randomized clinical trials on humans up to October 1st, 2013. ", "Quantitative model of the relationship between dipeptidyl peptidase-4 (DPP-4) inhibition and response: meta-analysis of alogliptin, saxagliptin, sitagliptin, and vildagliptin efficacy results.", "The dipeptidyl peptidase-4 (DPP-4) inhibitors linagliptin, sitagliptin, saxagliptin, vildagliptin and alogliptin are being developed and have been approved for the treatment of type-2 diabetes. ", "The objective of this model-based meta-analysis was to describe the time course of HbA1c response after dosing with alogliptin (ALOG), saxagliptin (SAXA), sitagliptin (SITA), or vildagliptin (VILD). ", "Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on linagliptin and alogliptin.", "The dipeptidylpeptidase-IV inhibitors sitagliptin, vildagliptin and saxagliptin do not impair innate and adaptive immune responses.", "In conclusion, BI 1356 inhibited DPP-4 more effectively than vildagliptin, sitagliptin, saxagliptin, and alogliptin and has the potential to become the first truly once-a-day DPP-4 inhibitor for the treatment of type 2 diabetes.", "Highly potent DPP-4 inhibitors have been identified by hybrid compound design based on linagliptin and alogliptin. ", "AIM: We assessed the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin, sitagliptin, saxagliptin and alogliptin to reach the haemoglobin HbA1c target of <7% in people with type 2 diabetes. ", "Whether the DPP-IV inhibitors sitagliptin, vildagliptin or saxagliptin impair immune responses is, however, currently unknown. ", "OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibitors, including sitagliptin, saxagliptin, vildagliptin, and linagliptin, in type 2 diabetes. ", "Given as monotherapy, linagliptin, sitagliptin, and vildagliptin (but not saxagliptin) met the equivalence criterion when compared with one another.", "Given in combination with metformin, linagliptin, saxagliptin, sitagliptin, and vildagliptin showed an equivalent effect whereas alogliptin did not satisfy the equivalence criterion.", "an extensive Medline, Embase and Cochrane Database search for \'vildagliptin\', \'sitagliptin\', \'saxagliptin\', \'alogliptin\', \'linagliptin\' and \'dutogliptin\' was performed up to 1 March 2013.", "An extensive Medline and Embase search for \'vildagliptin\', \'sitagliptin\', \'saxagliptin\', \'alogliptin\', \'linagliptin\', and \'dutogliptin\' was performed, collecting all randomized clinical trials on humans up to March 1, 2011.", "An extensive Medline, Embase, and Cochrane Database search for \\"vildagliptin\\", \\"sitagliptin\\", \\"saxagliptin\\", \\"alogliptin\\", \\"linagliptin\\", and \\"dutogliptin\\" was performed, collecting all randomized clinical trials on humans']

In conclusion, BI 1356 inhibited DPP-4 more effectively than vildagliptin, sitagliptin, saxagliptin, and alogliptin and has the potential to become the first truly once-a-day DPP-4 inhibitor for the treatment of type 2 diabetes.

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Which are the available biomedical text mining tools for the detection of protein-protein interactions?

['In this study, we propose a novel algorithm for extracting PPIs from literature which consists of two phases. First, we automatically categorize the data into subsets based on its semantic properties and extract candidate PPI pairs from these subsets. Second, we apply support vector machines (SVMs) to classify candidate PPI pairs using features specific for each subset.', 'The source code and scripts used in this article are available for academic use at http://staff.science.uva.nl/~bui/PPIs.zip', 'We describe a system for the detection of mentions of protein-protein interactions in the biomedical scientific literature. The original system was developed as a part of the OntoGene project', 'Extracting Protein-Protein Interactions from MEDLINE using the Hidden Vector State model', 'We have constructed an information extraction system based on the Hidden Vector State (HVS) model for protein-protein interactions.', 'When applied in extracting protein-protein interactions, we found that it performed better than other established statistical methods', 'The developed BioMap system allows discovering implicit P-P interactions from large quantity of biomedical literature data.', 'In this paper we examine if P-P interactions in regenerating tissues and cells of the anuran Xenopus laevis can be discovered from biomedical literature using computational and literature mining techniques. Using literature mining techniques, we have identified a set of implicitly interacting proteins in regenerating tissues and cells of Xenopus laevis that may interact with Cdc2 to control cell division.', 'P-P interactions that are implicitly appearing in literature can be effectively discovered using literature mining techniques.']

['Protein-protein interactions (PPI) can be extracted from biomedical literature using text mining approaches. These approaches have been classified into two categories, the statistical calculation of the co-occurrence of proteins and the computational linguistic method. Moreover, bioinformatics methods based on sequence, structural, or evolutionary information have been developed to predict protein-protein interactions. The available state-of-the-art biomedical text mining tools are: eFIP (Extracting Functional Impact of Phosphorylation), a system for text mining of protein interaction networks of phosphorylated proteins; GeneView, a suite of state-of-the-art text-mining tools designed for the automated identification of protein–protein interactions; PPI finder, a text mining tool for human protein-protein interactions based on computational linguistic methods. PPI Finder system consists of the Information Retrieval module and Information Extraction module; PreBIND and Textomy are two components of a biomedical literature-mining system optimized to discover protein-protein interactions using a support vector machine; BioMap system is optimized for the identification of protein-protein interactions from large biomedical literature datasets; Protopia searches for and integrates protein-protein interactions and the information about them contained in five different Protein Interaction Web Databases; STRING uses Natural Language Processing to extract a subset of semantically specified known and predicted protein-protein interactions.', 'Several tools have been developed to detect protein-protein interactions (PPIs) by text mining the biomedical literature. Two main computational approaches used for this task are co-occurrence-based methods and Natural Language Processing methods. Biomedical text mining tools for PPI identification are the following (in alphabetical order): BioCreative Meta Server, BioMap, eFIP, Extracting Functional Impact of Phosphorylation, GeneView, HAPPI, Hidden Vector State model, iHop, LAITOR, OntoGene, OpenDMAP, PIE (Protein interaction information extraction system), PPI finder (Paired-PPI Finder), PPInterFinder, PPIs, PolySearch, PreBind and Textomy, Protopia, STRING, TafTalent.']

['BioCreative Meta Server', 'Hidden Vector State model', 'iHop', 'LAITOR', 'OntoGene', 'PIE', 'Protein interaction information extraction system', 'PPInterFinder', 'PPIs', 'TafTalent', 'PolySearch', 'OpenDMAP', 'HAPPI', 'GeneView', 'PPI finder', 'Paired-PPI Finder', 'PreBind', 'PreBIND', 'Textomy', 'BioMap', 'eFIP', 'Extracting Functional Impact of Phosphorylation', 'Protopia', 'STRING']

Have 5q35 microdeletions been implicated in Sotos syndrome development?

['Loss-of-function mutations of NSD1 and 5q35 microdeletions encompassing NSD1 are a major cause of Sotos syndrome (Sos), which is characterized by overgrowth, macrocephaly, characteristic facies, and variable intellectual disability (ID)', 'We observed a novel 3.5 Mb 5q subtelomeric deletion in a 3-year-old girl with developmental delay, hypotonia and multiple minor anomalies. Comparison of her phenotype with the few published patients with terminal 5q35 deletions revealed several overlapping features, but also showed remarkable differences such as shortness of stature versus macrosomia. After the report of 5q35.3 microdeletions in Sotos syndrome we integrated the published BACs into the public draft sequence and exactly mapped the deletion size in our patient by FISH analysis with 15 BAC probes. We demonstrated that the deletion in our patient is immediately adjacent to the reported Sotos syndrome deletion site', 'Switch in FGFR3 and -4 expression profile during human renal development may account for transient hypercalcemia in patients with Sotos syndrome due to 5q35 microdeletions.', 'Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome.', 'After the report of 5q35.3 microdeletions in Sotos syndrome we integrated the published BACs into the public draft sequence and exactly mapped the deletion size in our patient by FISH analysis with 15 BAC probes.', 'Clinical and genetic spectrum of 18 unrelated Korean patients with Sotos syndrome: frequent 5q35 microdeletion and identification of four novel NSD1 mutations.', 'Here we describe a new case of Sotos syndrome with a 5q35 microdeletion, affecting the fibroblast growth factor receptor 4 (FGFR4) gene, presenting with infantile hypercalcemia.', 'Microdeletions at 5q35.3, encompassing NSD1, are responsible for approximately 10% of non-Japanese cases of Sotos.', 'Alu-related 5q35 microdeletions in Sotos syndrome.', 'Most cases of Sotos syndrome are caused by intragenic NSD1 mutations or 5q35 microdeletions.', 'Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome', 'Clinical and genetic spectrum of 18 unrelated Korean patients with Sotos syndrome: frequent 5q35 microdeletion and identification of four novel NSD1 mutations', 'Microdeletions at 5q35.3, encompassing NSD1, are responsible for approximately 10% of non-Japanese cases of Sotos', 'A case of Sotos syndrome with 5q35 microdeletion and novel clinical findings.', 'Here we describe a new case of Sotos syndrome with a 5q35 microdeletion, affecting the fibroblast growth factor receptor 4 (FGFR4) gene, presenting with infantile hypercalcemia. ', 'There are two types of mutations that cause NSD1 haploinsufficiency: mutations within the NSD1 gene (mutation type) and a 5q35 submicroscopic deletion encompassing the entire NSD1 gene (deletion type). ', 'aCGH and metaphase FISH are useful for rapid diagnosis of 5q35 microdeletion associated with Sotos syndrome.', 'Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome.', 'Switch in FGFR3 and -4 expression profile during human renal development may account for transient hypercalcemia in patients with Sotos syndrome due to 5q35 microdeletions.', 'A case of Sotos syndrome with 5q35 microdeletion and novel clinical findings.', 'Most cases of Sotos syndrome are caused by intragenic NSD1 mutations or 5q35 microdeletions.', 'aCGH and metaphase FISH are useful for rapid diagnosis of 5q35 microdeletion associated with Sotos syndrome.', 'Alu-related 5q35 microdeletions in Sotos syndrome.']

['Loss-of-function mutations of NSD1 and 5q35 microdeletions encompassing NSD1 are a major cause of Sotos syndrome (Sos), which is characterized by overgrowth, macrocephaly, characteristic facies, and variable intellectual disability (ID).', 'Loss-of-function mutations of NSD1 and 5q35 microdeletions encompassing NSD1 are a major cause of Sotos syndrome (Sos), which is characterized by overgrowth, macrocephaly, characteristic facies, and variable intellectual disability (ID)']

['yes']

What is the Pfam database?

['The Pfam database is an important tool in genome annotation, since it provides a collection of curated protein families.', 'Protein domains are the common currency of protein structure and function. Over 10,000 such protein families have now been collected in the Pfam database. ']

['The Pfam database provides a collection of curated protein families.']

['The Pfam database is a collection of curated protein families.']

What is Behçet's disease

["Behçet's disease (BD) is a complex chronic relapsing inflammatory disorder of unknown etiology. ", ' Behçet disease is a systemic disease of young adults characterized by venous occlusion in both the deep venous and retinal circulations. In severe ocular disease, blindness may occur despite immunosuppressive treatment', 'Behçet disease is a chronic relapsing inflammatory disease affecting many different organs. ', "Behçet's disease is a multisystem disease featuring mucocutaneous, ocular, articular, vascular, intestinal, urogenital, and neurologic involvement and occurs with a high prevalence in the Mediterranean including Turkey. ", 'Behçet syndrome is a chronic disease hallmarked by inflammation of the blood vessels that is related to an autoimmune reaction caused by inherited susceptibility due to specific genes and environmental factors, probably components of infectious microorganisms, which turn on or get going the disease in genetically susceptible subjects', 'Behçet disease (BD) is a rare relapsing, multisystem vasculitis characterised by recurrent oral and genital ulcers, and uveitis.', "Behçet's disease, also known as the Silk Road Disease, is a rare systemic vasculitis disorder of unknown etiology. Recurrent attacks of acute inflammation characterize Behçet's disease. ", "Behçet's disease is a chronic multisystem vasculitis of unknown etiology that involves skin, mucous membranes, eyes, blood vessels, joints, central nervous system, digestive system, and occasionally other organs.", "Behcet's disease is a multisystem inflammatory disorder, and its etiology has not been defined clearly yet. ", "Behçet's disease is a systemic inflammatory disease presented with recurrent oral aphtha, cutaneous manifestations, uveitis, and genital ulcer. ", "ehçet's disease is a systemic immunoinflammatory disease of young adults characterized by systemic vasculitis of arteries and veins."]

["Behet's disease (BD) is a complex chronic relapsing inflammatory disorder of unknown etiology.", "Behçet's disease (BD) is a complex chronic relapsing inflammatory disorder of unknown etiology.", "Behçet's disease (BD) is a complex chronic relapsing inflammatory disorder of unknown etiology. ", "behçet's disease (bd) is a complex chronic relapsing inflammatory disorder of unknown etiology."]

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Which translocation is harbored in the Askin tumor cells?

['The Ewing sarcoma family of tumors includes osseous Ewing sarcoma, extraskeletal Ewing sarcoma, primitive neuroectodermal tumor, and Askin tumor. They share a karyotype abnormality with translocation involving chromosomes 11 and 22', 'Ewing tumor family consists of Ewing tumor of bone, extraosseous Ewing tumor, primitive neurectodermal tumor and Askin tumor. All of them share genetic abnormality, reciprocal translocation (11; 22) (q24; q12), and originate from the same primordial stem cell', "Chromosomal analysis of the neoplastic cells revealed translocation (11;22)(q24;q12), which is often found in Ewing's sarcoma and Askin tumor", 'Malignant small cell tumor of the thoracopulmonary region (MSCT) was first described in 1979 and has been referred to as the Askin tumor', "MSCT and PPNET have a common reciprocal cytogenetic translocation [t(11;22)q(24;q12)], which is shared with Ewing's sarcoma", "The Askin tumor, a primitive malignant small-cell tumor of the chest wall, is mostly seen among children and adolescents. It is closely related to Ewing's sarcoma of the same location, both tumors showing a chromosomal translocation t(11;22)", "Chromosomal analysis of the neoplastic cells revealed translocation (11;22)(q24;q12), which is often found in Ewing's sarcoma and Askin tumor.", "Chromosomal analysis of the neoplastic cells revealed translocation (11;22)(q24;q12), which is often found in Ewing's sarcoma and Askin tumor.", "In Ewing's sarcoma (a tumor of unknown histogenesis), and in peripheral neuroepithelioma and Askin's tumor (tumors with evidence of neural origin), we have observed an indistinguishable t(11;22) translocation.", "Reciprocal translocations of chromosomes 11 and 22 are the most common cytogenetic abnormalities in Ewing's sarcoma and the related Askin's tumor", 'The t(11;22)(q24;q12) and t(21;22)(q22;q12) are specific chromosomal translocations found in the Ewing family of tumors including ES, PNET and Askin tumors']

["The Askin tumor is a primitive malignant small-cell tumor of the chest wall mostly seen among children and adolescents. It is closely related to Ewing's sarcoma of the same location, with both tumors harboring reciprocal translocation t(11;22) (q24;q12)."]

['reciprocal translocation t(11;22) (q24;q12)']

Is the toxin produced by Clostridium botulinum always deadly?

['Animals treated with trace elements recovered. It appears that intestinal microbiota dysbiosis and trace element deficiency could explain the extensive emergence of chronic Botulism.', 'The patient was treated with human botulism immune globulin and had rapid recovery in weakness. A stool sample from the patient was positive for Type A Clostridium botulinum toxin eventually confirming the diagnosis of infant botulism', 'The botulism immunoglobulin was administered, and a diagnosis was confirmed with positive botulinum toxin in the stool samples. Full recovery was made by the infant', 'Botulinum neurotoxin (BoNT) serotype B (BoNT/B) is one of the serotypes of BoNT that causes deadly human botulism, though it is used clinically for treatment of many neuromuscular diseases.', 'Foodborne botulism is a rare and sometimes fatal illness caused by consuming foods containing botulinum neurotoxin', 'To assess the effectiveness and safety of botulinum toxin in treating MPS, excluding MPS in neck and head muscles.', 'Botulinum toxin (BTX) is one of the most potent bacterial toxins known and its effectiveness in the treatment of some pain syndromes is well known.', ' An emerging treatment option to address these issues is the use of a paralyzing material such as botulinum toxin A (Botox) to decrease the appearance of the wrinkles, which yields a more esthetic and youthful facial appearanc', 'lthough BoNT is an extremely toxic molecule, it is now increasingly used for the treatment of disorders related to muscle hyperactivity and glandular hyperactivity.']

['There are numerous examples where children and animals survived infection with clostridium botulinum.']

['no']

Describe the known functions for the prothymosin alpha c-terminal peptide?

['The C-terminal decapeptide of prothymosin α is responsible for its stimulatory effect on the functions of human neutrophils in vitro', 'In this study, we investigated the ability of the immunoreactive fragment of the polypeptide prothymosin alpha (proTα), i.e., the decapeptide proTα(100-109), to enhance the functions of neutrophils isolated from the peripheral blood of breast cancer patients in comparison with those from healthy donors.', 'Our results suggest that proTα(100-109) activates neutrophils, particularly those derived from breast cancer patients', 'The Ca²(+)-dependent interaction between ProTα and S100A13 was found to require the C-terminal peptide sequences of both proteins.', 'When cells were administered apoptogenic compounds, ProTα was cleaved by caspase-3 to generate a C-terminal peptide-deficient fragment, which lacks the nuclear localization signal (NLS).', 'Prothymosin alpha immunoactive carboxyl-terminal peptide TKKQKTDEDD stimulates lymphocyte reactions, induces dendritic cell maturation', 'Prothymosin alpha (ProTalpha) is a small acidic polypeptide with important immunostimulatory properties, which we have previously shown to be exerted by its carboxyl (C)-terminus', "Here, we assayed the activity of synthetic peptides homologous to ProTalpha's C-terminus to stimulate lymphocyte functions, in particular natural killer cell cytotoxicity of peripheral blood mononuclear cells isolated from healthy donors. A synthetic decapeptide TKKQKTDEDD was identified as the most potent lymphocyte stimulator. The activity of this peptide was sequence-specific and comparable to that of the intact molecule, suggesting that ProTalpha's immunoactive segment encompasses the nuclear localization signal sequence of the polypeptide.", 'These data, in conjunction with reports showing that the peptide TKKQKTDEDD is generated in vivo upon caspase-cleavage of ProTalpha during apoptosis, strengthen our hypothesis that immune response stimulation by ProTalpha is in principle exerted via its bioactive C-terminal decapaptide, which can acquire a sequence-specific beta-sheet conformation and induce DC maturation.', 'Ability to stimulate p53-dependent transcription was lost by C-terminal mutants of prothymosin alpha with impaired nuclear accumulation, but not by N-terminal deletion mutants and by the double mutant of prothymosin alpha with impaired ability to bind Keap1, suggesting that prothymosinalpha-Keap1 interaction is dispensable for p53 response.', 'We found that zinc binding causes partial folding of the C-terminal half of ProTalpha, especially the Glu-rich region', 'The immunologically active site of prothymosin alpha is located at the carboxy-terminus of the polypeptide.', ". ProTalpha(89-102) and proTalpha(103-109) significantly fortified healthy donor-lymphocytes' immune responses to levels comparable to those induced by intact proTalpha. These effects were more pronounced in cancer patients, where peptides proTalpha(89-102) and proTalpha(103-109) partly, however significantly, restored the depressed AMLR and cytolytic ability of PBMC, by simulating the biological activity exerted by intact proTalpha.", "This is the first report showing that proTalpha's immunomodulating activity can be substituted by its C-terminal peptide(s)", 'The peptide (1-88) of calf prothymosin alpha is shown not to accumulate in the Xenopus nucleus, demonstrating that the C-terminal 21 residues, which include a KKQK sequence, are required for nuclear migration.', 'fProt-alpha contains 28 aspartic and 25 glutamic acid residues and presents the typical basic KKQK amino acid sequence in the close carboxyl terminal region', "This is the first report showing that proTalpha's immunomodulating activity can be substituted by its C-terminal peptide(s)."]

['Prothymosin alpha (ProTα) (encoded in human by the PTMA gene) is a ubiquitous, highly acidic nuclear polypeptide. During early apoptosis, proTα is cleaved by activated caspase-3, with a primary attach site being D99, close to its carboxyl-terminus. The role of the cleaved decapeptide -- proTα(100-109) -- is not fully understood. proTα(100-109), which contains the nuclear localization signal (NLS) for ProTα, has been demonstrated to have immunostimulatory properties, such as to stimulate lymphocytes and neutrophils and induce dendritic cell maturation.']

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Is COL5A2 gene associated to ischemic heart disease?

['Analysis of a gene co-expression network establishes robust association between Col5a2 and ischemic heart disease', 'Col5a2, a gene previously not specifically linked to MI response but responsible for the classic type of Ehlers-Danlos syndrome, was found to have many and strong co-expression associations within this community', 'Col5a2 shows predictive potential in MI, and in principle may represent a novel candidate marker for the identification and treatment of ischemic cardiovascular disease', 'Analysis of a gene co-expression network establishes robust association between Col5a2 and ischemic heart disease.']

['Analysis of a gene co-expression network establishes robust association between Col5a2 and ischemic heart disease ', 'In a gene co-expression network from microarray data originating from a mouse model of myocardial infraction, Col5a2 shows predictive potential, and in principle may represent a novel candidate marker for the identification and treatment of ischemic cardiovascular disease.']

['yes']

Is the SDHAF2 gene encoding a protein necessary for flavination of SDHA?

['the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5)', 'SDHAF2, required for flavination of SDHA', 'Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. ', 'At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes.', 'Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA.', 'In a recent issue of Science, Rutter and coworkers showed that SDH5 is required for the flavination of SDHA, which is necessary for SDH assembly and function.', 'At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes', 'Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA', 'CONTEXT: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. ', 'This gene is co-expressed with a number of genes encoding mitochondrial proteins, including SDH1-1, and has low partial sequence similarity to human SDHAF2, a protein required for flavin-adenine dinucleotide (FAD) insertion into SDH. ']

['Yes, SDHAF2 or hSDH5, is the gene encoding the enzyme responsible for the flavination of SDHA.', 'Yes, SDHAF2 is required for flavination of SDHA.']

['yes']

Which driver mutations have been identified for Diffuse Intrinsic Pontine Glioma (DIPG)?

['We found conservation of heterozygous K27M mutations in H3F3A (n\u2009=\u20094) or HIST1H3B (n\u2009=\u20093) across all primary, contiguous, and metastatic tumor sites in all DIPGs', 'ACVR1 (n\u2009=\u20092), PIK3CA (n\u2009=\u20092), FGFR1 (n\u2009=\u20092), and MET (n\u2009=\u20091) were also intra-tumorally conserved', ' TP53 aberrations (n\u2009=\u20093 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved.', 'Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis.', 'These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). ', 'Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78\xa0% of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36\xa0% of non-brainstem gliomas carrying either K27M or G34R/V mutations.', 'Moreover, in diffuse intrinsic pontine gliomas (DIPG), recurrent somatic mutations of ACVR1 were found in association with HIST1H3B mutations', 'Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78\xa0% of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36\xa0% of non-brainstem gliomas carrying either K27M or G34R/V mutations', 'K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.', 'Recurrent mutations within the histone H3 genes H3F3A and HIST1H3B that convert K27 to methionine (H3K27M) and disrupt the global H3K27 methylation landscape and PRC2-dependent silencing, have recently been identified in pediatric high-grade gliomas including Diffuse Intrinsic Pontine Glioma (DIPG) and Glioblastoma multiforme (GBM; Type IV glioma).', 'Sequencing analysis showed c.83A>T mutations in the H3F3A or HIST1H3B gene in 77\xa0% of our DIPG cohort.', 'Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78\xa0% of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36\xa0% of non-brainstem gliomas carrying either K27M or G34R/V mutations.', 'K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.']

['We found conservation of heterozygous K27M mutations in H3F3A (n\u2009=\u20094) or HIST1H3B (n\u2009=\u20093) across all primary, contiguous, and metastatic tumor sites in all DIPGs', 'found conservation of heterozygous k27m mutations in h3f3a (n\u2009=\u20094) or hist1h3b (n\u2009=\u20093) across all primary , contiguous , and metastatic tumor sites in all dipgs . h3k27m ubiquitously-associated mutations involve alterations in tp53 cell-cycle (tp53/ppm1d) or specific growth factor pathways (acvr1/pik3r1) . reconstruction indicates histone 3 (h3) k27m--including h3.2k27m--mutations potentially arise first and are invariably associated with specific , high-fidelity obligate partners throughout the tumour and its spread , from diagnosis to end-stage disease , suggesting mutual need for tumorigenesis. . aberrations (n\u2009=\u20093 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved. . ', 'We found conservation of heterozygous K27M mutations in H3F3A (nâ\x80\x89=â\x80\x894) or HIST1H3B (nâ\x80\x89=â\x80\x893) across all primary, contiguous, and metastatic tumor sites in all DIPGs. Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1).', 'We found conservation of heterozygous K27M mutations in H3F3A (n=4) or HIST1H3B (n=3) across all primary, contiguous, and metastatic tumor sites in all DIPGs. ACVR1 (n=2), PIK3CA (n=2), FGFR1 (n=2), and MET (n=1) were also intra-tumorally conserved. TP53 aberrations (n=3 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved. Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). ', 'Recurrent mutations within the histone H3 genes H3F3A and HIST1H3B that convert K27 to methionine (H3K27M) and disrupt the global H3K27 methylation landscape and PRC2-dependent silencing, have recently been identified in pediatric high-grade gliomas including Diffuse Intrinsic Pontine Glioma (DIPG) and Glioblastoma multiforme (GBM; Type IV glioma). The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships. TP53 aberrations (n\u2009=\u20093 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved.Spatial conservation of prognostically-relevant and therapeutically-targetable somatic mutations in DIPG and mHGG contrasts the significant heterogeneity of driver mutations seen in adult HGG and supports uniform implementation of diagnostic biopsy in DIPG and mHGG to classify molecular risk groups and guide therapeutic strategy. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Sequencing analysis showed c.83A>T mutations in the H3F3A or HIST1H3B gene in 77\xa0% of our DIPG cohort. Protein profiling identified 2,305 unique proteins indicating distinct DIPG protein expression patterns compared to other pediatric brain tumors. Two distinct subgroups of DIPG were identified.', 'We found conservation of heterozygous K27M mutations in H3F3A (n\u2009=\u20094) or HIST1H3B (n\u2009=\u20093) across all primary, contiguous, and metastatic tumor sites in all DIPGs ACVR1 (n\u2009=\u20092), PIK3CA (n\u2009=\u20092), FGFR1 (n\u2009=\u20092), and MET (n\u2009=\u20091) were also intra-tumorally conserved TP53 aberrations (n\u2009=\u20093 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved.', 'Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. Conservation of heterozygous K27M mutations in H3F3A (n\u2009=\u20094) or HIST1H3B (n\u2009=\u20093) was observed across all primary, contiguous, and metastatic tumor sites in all DIPGs. ACVR1 (n\u2009=\u20092), PIK3CA (n\u2009=\u20092), FGFR1 (n\u2009=\u20092), and MET (n\u2009=\u20091) were also intra-tumorally conserved. TP53 aberrations (n\u2009=\u20093 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved.', 'We found conservation of heterozygous K27M mutations in H3F3A (n\u2009=\u20094) or HIST1H3B (n\u2009=\u20093) across all primary, contiguous, and metastatic tumor sites in all DIPGs TP53 aberrations (n\u2009=\u20093 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1).', 'We found conservation of heterozygous K27M mutations in H3F3A (n=4) or HIST1H3B (n=3) across all primary, contiguous, and metastatic tumor sites in all DIPGs. Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). TP53 aberrations (n=3 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved. ACVR1 (n=2), PIK3CA (n=2), FGFR1 (n=2), and MET (n=1) were also intra-tumorally conserved. ', 'We found conservation of heterozygous K27M mutations in H3F3A (n\u2009=\u20094) or HIST1H3B (n\u2009=\u20093) across all primary, contiguous, and metastatic tumor sites in all DIPGs These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). ']

['K27M in H3F3A', 'HIST1H3B']

How does TGF-beta affect myofibroblast phenotype in wound healing and cardiac repair?

['["Transforming growth factor (TGF)-beta plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition.", "We then performed a chemical screen and identified several small molecules that increase or reduce cardiomyocyte proliferation during heart development. These compounds act via Hedgehog, Insulin-like growth factor or Transforming growth factor \\u03b2 signaling pathways. Direct examination of heart regeneration after mechanical or genetic ablation injuries indicated that these pathways are activated in regenerating cardiomyocytes and that they can be pharmacologically manipulated to inhibit or enhance cardiomyocyte proliferation during adult heart regeneration. ", "Transforming growth factor beta, bone morphogenic protein and Wnt pathways interact to form a complex signaling network that is critical in regulating the fate choices of both stromal and tissue-specific resident stem cells (TSCs), determining whether functional regeneration or the formation of scar tissue follows an injury. ", "In the adult heart under pressure overload, Notch inhibited the development of cardiomyocyte hypertrophy and transforming growth factor-\\u03b2/connective tissue growth factor-mediated cardiac fibrosis.", "EMT and CSps formation is enhanced in the presence of transforming growth factor \\u03b21 (TGF\\u03b21) and drastically blocked by the type I TGF\\u03b2-receptor inhibitor SB431452, indicating that TGF\\u03b2-dependent EMT is essential for the formation of these niche-like 3D-multicellular clusters. Since TGF\\u03b2 is activated in the myocardium in response to injury, our data suggest that CSps formation mimics an adaptive mechanism that could potentially be enhanced to increase in vivo or ex vivo regenerative potential of adult CPCs.", "During the proliferative phase of healing, infarct fibroblasts undergo myofibroblast transdifferentiation forming stress fibers and expressing contractile proteins (such as \\u03b1-smooth muscle actin). Mechanical stress, transforming growth factor (TGF)-\\u03b2/Smad3 signaling and alterations in the composition of the extracellular matrix induce acquisition of the myofibroblast phenotype. ", "Collectively, this data strongly suggests Wnt3a promotes the formation of a myofibroblast-like phenotype in cultured fibroblasts, in part, by upregulating TGF-\\u03b2 signaling through SMAD2 in a \\u03b2-catenin-dependent mechanism. As myofibroblasts are critical regulators of wound healing responses, these findings may have important implications for our understanding of normal and aberrant injury and repair events.", "Conversely, exogenous addition of TGF-beta to the wound increased VIC activation, proliferation, wound closure rate, and stress fibers. Thus, wounding activates VICs, and TGF-beta signaling modulates VIC response to injury."]', '["Transforming growth factor (TGF)-beta plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition.", "We then performed a chemical screen and identified several small molecules that increase or reduce cardiomyocyte proliferation during heart development. These compounds act via Hedgehog, Insulin-like growth factor or Transforming growth factor \\u03b2 signaling pathways. Direct examination of heart regeneration after mechanical or genetic ablation injuries indicated that these pathways are activated in regenerating cardiomyocytes and that they can be pharmacologically manipulated to inhibit or enhance cardiomyocyte proliferation during adult heart regeneration. ", "Transforming growth factor beta, bone morphogenic protein and Wnt pathways interact to form a complex signaling network that is critical in regulating the fate choices of both stromal and tissue-specific resident stem cells (TSCs), determining whether functional regeneration or the formation of scar tissue follows an injury. ", "In the adult heart under pressure overload, Notch inhibited the development of cardiomyocyte hypertrophy and transforming growth factor-\\u03b2/connective tissue growth factor-mediated cardiac fibrosis.", "EMT and CSps formation is enhanced in the presence of transforming growth factor \\u03b21 (TGF\\u03b21) and drastically blocked by the type I TGF\\u03b2-receptor inhibitor SB431452, indicating that TGF\\u03b2-dependent EMT is essential for the formation of these niche-like 3D-multicellular clusters. Since TGF\\u03b2 is activated in the myocardium in response to injury, our data suggest that CSps formation mimics an adaptive mechanism that could potentially be enhanced to increase in vivo or ex vivo regenerative potential of adult CPCs.", "During the proliferative phase of healing, infarct fibroblasts undergo myofibroblast transdifferentiation forming stress fibers and expressing contractile proteins (such as \\u03b1-smooth muscle actin). Mechanical stress, transforming growth factor (TGF)-\\u03b2/Smad3 signaling and alterations in the composition of the extracellular matrix induce acquisition of the myofibroblast phenotype. ", "Collectively, this data strongly suggests Wnt3a promotes the formation of a myofibroblast-like phenotype in cultured fibroblasts, in part, by upregulating TGF-\\u03b2 signaling through SMAD2 in a \\u03b2-catenin-dependent mechanism. As myofibroblasts are critical regulators of wound healing responses, these findings may have important implications for our understanding of normal and aberrant injury and repair events.", "Conversely, exogenous addition of TGF-beta to the wound increased VIC activation, proliferation, wound closure rate, and stress fibers. Thus, wounding activates VICs, and TGF-beta signaling modulates VIC response to injury."]']

TGF-beta affects myofibroblast phenotype in wound healing and cardiac repair by promoting myofibroblast phenotypic modulation and extracellular matrix deposition in cardiac repair, and inducing acquisition of the myofibroblast phenotype in wound healing through signaling pathways like TGF-β/Smad3.

[]

Is the mouse Sry gene locus free of repetitive sequences?

['We demonstrate that the presence of long inverted repeats (IR) flanking the mouse Sry gene leads to the formation of the Sry circular transcript in cultured cells', 'Circularization requires the presence of both IR. As few as 400 complementary nt are necessary for this process', 'The presence of the IR does not significantly stimulate intermolecular annealing and trans-splicing in vivo', 'We have found that in an in vitro assay, the SRY protein binds to several sites of the Sry gene and especially to a (CA)25 sequence and to a (CAG)30 repeat', 'The Q-rich domain of the mouse sex determining gene, Sry, is encoded by an in-frame insertion of a repetitive sequence composed of mostly CAG repeats.', 'Inverted repeat structure of the Sry locus in mice.', 'We performed separate amplifications of DXZ4 repetitive satellite sequences on the X chromosome, and SRY gene - testis determined factor on the Y chromosome, using nested PCR', 'Detailed analysis of the Sry genomic locus reveals a further difference in that the mouse Sry open reading frame lies within 2.8 kilobases of unique sequence at the center of a large inverted repeat. ', 'Detailed analysis of the Sry genomic locus reveals a further difference in that the mouse Sry open reading frame lies within 2.8 kilobases of unique sequence at the center of a large inverted repeat.', 'The mouse genomic Sry locus is characterized by two arms of a large inverted repeat, flanking a unique region that, between an acceptor and a donor splice site, contains a single exon encoding the Sry protein.', 'Recombination involving the repeat region may have led to an 11-kilobase deletion, precisely excising Sry in a line of XY female mice.', 'Repetitive element analysis revealed numerous LINE-L1 elements at regions where conservation is lost among the Sry copies.', 'Inverted repeat structure of the Sry locus in mice.']

['We demonstrate that the presence of long inverted repeats (IR) flanking the mouse Sry gene leads to the formation of the Sry circular transcript in cultured cells. We have found that in an in vitro assay, the SRY protein binds to several sites of the Sry gene and especially to a (CA)25 sequence and to a (CAG)30 repeat.', 'The presence of long inverted repeats (IR) flanking the mouse Sry gene leads to the formation of the Sry circular transcript in cultured cells.', 'We demonstrate that the presence of long inverted repeats (IR) flanking the mouse Sry gene leads to the formation of the Sry circular transcript in cultured cells Circularization requires the presence of both IR.', 'We demonstrate that the presence of long inverted repeats (IR) flanking the mouse Sry gene leads to the formation of the Sry circular transcript in cultured cells We have found that in an in vitro assay, the SRY protein binds to several sites of the Sry gene and especially to a (CA)25 sequence and to a (CAG)30 repeat', 'We demonstrate that the presence of long inverted repeats (IR) flanking the mouse Sry gene leads to the formation of the Sry circular transcript in cultured cells']

['no']

What is SCENAR therapy used for?

['SCENAR therapy to patients with localized suppurative peritonitis in the postoperative period', 'post-herpetic neuralgia using a bioelectronical device (SCENAR)', 'All patients experienced substantial relief of pain from the first treatment.', 'An electronic biofeedback device (SCENAR) may be successfully utilized in the management of post-herpetic neuralgia.', 'A new technique of low-frequency modulated electric current therapy, SCENAR therapy, was used in treatment of 103 patients with duodenal ulcer (DU).', 'Addition of SCENAR therapy to the complex conventional pharmacotherapy fastened ulcer healing, increased the effectiveness of Helicobacter pylori eradication, and improved the condition of the gastroduodenal mucosa.', 'SCENAR) as effective in the treatment of neurogenic dysfunction of the bladder in children with nocturnal enuresis. ']

['all patients experienced substantial relief of pain from the first treatment. an electronic biofeedback device (scenar) may be successfully utilized in the management of post-herpetic neuralgia. scenar) as effective in the treatment of neurogenic dysfunction of the bladder in children with nocturnal enuresis. post-herpetic neuralgia using a bioelectronical device (scenar). addition of scenar therapy to the complex conventional pharmacotherapy fastened ulcer healing, increased the effectiveness of helicobacter pylori eradication, and improved the condition of the gastroduodenal mucosa. scenar therapy to patients with localized suppurative peritonitis in the postoperative period. a new technique of low-frequency modulated electric current therapy, scenar therapy, was used in treatment of 103 patients with duodenal ulcer (du). ', 'localized suppurative peritonitis in the postoperative period\nmanagement of post-herpetic neuralgia\ntreatment of 103 patients with duodenal ulcer\ntreatment of neurogenic dysfunction of the bladder in children with nocturnal enuresis']

['peritonitis postoperative', 'pain in postherpetic neuralgia', 'duodenal ulcer', 'nocturnal enuresis']

Which technique led to the elucidation of the role of HOXD10 in regulating lymphatic endothelial responses to VEGF-C?

['DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C', 'DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C.', 'DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C.']

['DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C.', 'DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C', 'DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C. ']

['DeepCAGE']

Name triad of Wernicke encephalopathy.

['In the classical form it is characterized by a typical triad (confusion, oculomotor disturbance and ataxia), however, in the majority of the cases only confusion is present. ', "Wernicke's encephalopathy is an acute neurological disorder characterized by mental confusion, oculomotor dysfunction, and ataxia. ", 'The classic triad consists of encephalopathy, oculomotor dysfunction and gait ataxia but is not seen in a majority of patients.', 'After frequent vomiting, he presented with mental status changes, ocular abnormalities, and truncal ataxia (the classic triad).', "Wernicke's encephalopathy is a triad of ophthalmoplegia, ataxia and confusion seen in alcoholics with dietary vitamin B1 (thiamine) deficiency.", 'Wernicke encephalopathy is caused by thiamine deficiency in the central nervous system, and is defined by the triad of confusional symptoms, ocular alterations and ataxia.', 'The classical triad of clinical symptoms described by Wernicke (gait ataxia, ophthalmoplegia, and confusion) are found in only a third of patients upon initial examination.', "It was found that only 0.4% of the population studied had the classical triad of Wernicke's encephalopathy, namely confusion, ophthalmoplegia, and ataxia.", "The triad of Wernicke's encephalopathy--global confusional state, ophthalmoplegia and nystagmus, and ataxia--is occasionally seen in chronic alcoholics and is often attenuated by immediate thiamine treatment.", "Only six presented with the Wernicke's encephalopathy clinical triad (mental status changes, ocular signs, and ataxia) at neurologic onset; nine eventually demonstrated this triad.", "Wernicke's encephalopathy is a well-described syndrome characterized by the classic triad of confusion, ataxia, and ophthalmoplegia.", 'Wernicke&apos;s encephalopathy is a triad of ophthalmoplegia, ataxia and confusion seen in alcoholics with dietary vitamin B1 (thiamine) deficiency', 'Wernicke encephalopathy (WE) is an acute neurologic disorder characterized by a triad of ophthalmoplegia, ataxia, and mental confusion', 'Wernicke&apos;s encephalopathy is a metabolic disorder caused by deficiency of thiamine (vitamin B1) seen in alcoholics and even in nonalcoholic patients, classically presenting with a triad of ataxia, ophthalmoplegia, and altered mental status', 'Wernicke&apos;s encephalopathy is an acute neurological syndrome due to thiamine deficiency, which is characterized by a typical triad of mental status changes, oculomotor dysfunction and ataxia', 'The triad of Wernicke&apos;s encephalopathy--global confusional state, ophthalmoplegia and nystagmus, and ataxia--is occasionally seen in chronic alcoholics and is often attenuated by immediate thiamine treatment', 'In 25/73 (35%) of the patients the classic triad of Wernicke&apos;s encephalopathy with ocular symptoms, ataxia and confusion, was found', 'It was found that only 0.4% of the population studied had the classical triad of Wernicke&apos;s encephalopathy, namely confusion, ophthalmoplegia, and ataxia', 'Wernicke&apos;s encephalopathy (WE) is a serious, potentially fatal, neurologic disorder caused by thiamine deficiency (vitamin B(1)), classically described as presenting with a triad of ocular abnormalities, ataxia, and confusion', 'Only six presented with the Wernicke&apos;s encephalopathy clinical triad (mental status changes, ocular signs, and ataxia) at neurologic onset; nine eventually demonstrated this triad. The high rate of patients diagnosed only at postmortem examination (41.9%) confirms that Wernicke&apos;s encephalopathy is underdiagnosed in children.']

["Wernicke's encephalopathy is a triad of ophthalmoplegia, ataxia and confusion seen in alcoholics with dietary vitamin B1 (thiamine) deficiency."]

['ophthalmoplegia', 'ataxia', 'confusion']

Which agents are included in the FLAMSA chemotherapy regimen?

['After 3 days of rest, RIC was carried out, consisting of 4 Gy total body irradiation, antithymocyte globulin (ATG-Fresenius), and cyclophosphamide (fludarabine, amsacrine, and cytarabine (FLAMSA)-RIC protocol).', 'We report a retrospective single center analysis of aplasia-inducing chemotherapy using fludarabine, cytarabine, and amsacrine (FLAMSA) followed by reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (HCT) in 62 consecutive primary refractory or relapsed AML patients.', 'A sequential regimen of cytoreductive chemotherapy (fludarabine, high-dose AraC, amsacrine) followed by reduced intensity conditioning (FLAMSA-RIC), was uniformly used for conditioning.', 'Between November 2003 and June 2010, 30 patients (20 high-risk MDS, 10 sAML) received fludarabine (4 × 30 mg/m(2)), amsacrine (4 × 100 mg/m(2)), and Ara-C (4 × 2 g/m(2), FLAMSA). ', 'The preparative regimen consisted of fludarabine, Ara-C and amsacrine (FLAMSA) chemotherapy, followed by reduced intensity conditioning (RIC) 3 days later. ', 'Fifteen patients received fludarabine 30 mg/m(2), cytarabine 2000 mg/m(2), amsacrine 100 mg/m(2) on days -10, -9, -8 and -7, anti-thymocyte globulin (ATG-Fresenius) 20 mg/kg body weight on days -6, -5 and -4 and fractionated total body irradiation 2 x 2 Gy on days -3, -2 and -1 (FLAMSA-ATG-TBI) before allogeneic hematopoietic stem cell transplantation. ', 'The goal of this analysis was to define the role of the moderate-intensity fludarabin Ara-C amsacrin (FLAMSA)-reduced intensity conditioning (RIC) regimen for patients with high-risk AML undergoing allogeneic SCT (alloSCT) in first CR1. ', 'The goal of this analysis was to define the role of the moderate-intensity fludarabin Ara-C amsacrin (FLAMSA)-reduced intensity conditioning (RIC) regimen for patients with high-risk AML undergoing allogeneic SCT (alloSCT) in first CR1', 'The preparative regimen consisted of fludarabine, Ara-C and amsacrine (FLAMSA) chemotherapy, followed by reduced intensity conditioning (RIC) 3 days later', 'A sequential regimen of cytoreductive chemotherapy (fludarabine, high-dose AraC, amsacrine) followed by reduced intensity conditioning (FLAMSA-RIC), was uniformly used for conditioning', 'A sequential regimen of cytoreductive chemotherapy (fludarabine, high-dose AraC, amsacrine) followed by reduced intensity conditioning (FLAMSA-RIC), was uniformly used for conditioning', 'We report a retrospective single center analysis of aplasia-inducing chemotherapy using fludarabine, cytarabine, and amsacrine (FLAMSA) followed by reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (HCT) in 62 consecutive primary refractory or relapsed AML patients', 'The preparative regimen consisted of fludarabine, Ara-C and amsacrine (FLAMSA) chemotherapy, followed by reduced intensity conditioning (RIC) 3 days later']

['Fludarabine, cytarabine and amsacrine are included in the FLAMSA chemotherapy regimen.']

['fludarabine', 'cytarabine', 'amsacrine']

Which are the side effects during tacrine administration in patients with Alzheimer's Disease?

['Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity.', 'Tacrine and its analogues impair mitochondrial function and bioenergetics: a lipidomic analysis in rat brain.', 'However, its low therapeutic efficiency and a high incidence of side effects have limited its clinical use. ', 'Tacrine induced significant perturbations in the mitochondrial PL profile, which were detected by means of changes in the relative abundance of phosphatidylcholine (PC), PE, phosphatidylinositol (PI) and CL and by the presence of oxidized phosphatidylserines.', 'These results indicate that tacrine and its analogues impair mitochondrial function and bioenergetics, thus compromising the activity of brain cells.', 'Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. ', 'The antidementives are well tolerated and undesired effects are rare; except hepatotoxicity of tacrine and gastrointestinal side effects of donepezil, rivastigmine, galantamin and tacrine that result from acetylcholinesterase inhibition. Nausea, diarrhea, vomiting, and weight loss are the most common side effects of the acetylcholinesterase inhibitors. ', 'Raised serum liver enzymes was the major reason for withdrawal. ', 'Gastrointestinal side effects (diarrhoea, anorexia, dyspepsia and abdominal pain) were the other major cause of adverse events and for withdrawal, and the odds ratio for withdrawal was also significantly different from one in favour of the control group (OR 3.8; 95%CI 2.8-5.1).', "To determine the clinical efficacy of tacrine for the symptoms of Alzheimer's disease.", "In Alzheimer's disease, cognition now responds to several drugs. Anticholinesterases target the acetylcholine deficit. In mild-to-moderate Alzheimer's disease, they all provide significant benefit versus placebo on the Alzheimer's Disease Assessment ScheduleCognitive Section (ADAS-Cog), Side effects, in 5% to 15% of cases, include nausea, vomiting, diarrhea, anorexia, and dizziness. Tacrine, the leading anticholinesterase, caused frequent hepatic enzyme elevation and was withdrawn", 'This 12-week randomised, double-blind, placebo-controlled study was undertaken to evaluate the ability of silymarin to antagonise or prevent the hepatotoxic effects of tacrine and to analyse its action on tacrine efficacy and tolerability.METHODS: Outpatients suffering from mild-to-moderate dementia of the Alzheimer type were randomly assigned to two treatment groups: tacrine + silymarin and tacrine + placebo.', 'Hepatotoxic effects of tacrine administration in patients with Alzheimers disease', "Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease.", 'Tremulous jaw movements produced by acute tacrine administration: possible relation to parkinsonian side effects.', "Administration of tacrine (THA) for the treatment of Alzheimer's disease results in a reversible hepatotoxicity in 30-50% of patients, as indicated by an increase in transaminase levels.", "Tacrine, the first drug marketed for Alzheimer's disease (AD), induces an elevation of serum liver transaminase prohibiting an effective dosage in many patients. This 12-week randomised, double-blind, placebo-controlled study was undertaken to evaluate the ability of silymarin to antagonise or prevent the hepatotoxic effects of tacrine and to analyse its action on tacrine efficacy and tolerability.METHODS: Outpatients suffering from mild-to-moderate dementia of the Alzheimer type were randomly assigned to two treatment groups: tacrine + silymarin and tacrine + placebo.", "BACKGROUND: Silymarin is a well-known hepatoprotective agent. Tacrine, the first drug marketed for Alzheimer's disease (AD), induces an elevation of serum liver transaminase prohibiting an effective dosage in many patients. This 12-week randomised, double-blind, placebo-controlled study was undertaken to evaluate the ability of silymarin to antagonise or prevent the hepatotoxic effects of tacrine and to analyse its action on tacrine efficacy and tolerability.METHODS: Outpatients suffering from mild-to-moderate dementia of the Alzheimer type were randomly assigned to two treatment groups: tacrine + silymarin and tacrine + placebo.", "Tacrine, the first drug marketed for Alzheimer's disease (AD), induces an elevation of serum liver transaminase prohibiting an effective dosage in many patients. This 12-week randomised, double-blind, placebo-controlled study was undertaken to evaluate the ability of silymarin to antagonise or prevent the hepatotoxic effects of tacrine and to analyse its action on tacrine efficacy and tolerability.METHODS: Outpatients suffering from mild-to-moderate dementia of the Alzheimer type were randomly assigned to two treatment groups: tacrine + silymarin and tacrine + placebo. The study was double-blind for silymarin and open for tacrine and was conducted in 22 French neurology and geriatric centres.", "Tacrine, the first drug marketed for Alzheimer's disease (AD), induces an elevation of serum liver transaminase prohibiting an effective dosage in many patients.", "Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease."]

["The side effects during tacrine administration in patients with Alzheimer's Disease are:\r\n1) Hepatotoxicity\r\n2) Gastrointestinal (diarrhea, anorexia, dyspepsia, abdominal pain, nausea, vomiting)\r\n3) Mitochondrial impairement"]

['Hepatotoxicity', 'Gastrointestinal', 'diarrhea', 'anorexia', 'dyspepsia', 'abdominal pain', 'nausea', 'vomiting', 'anorexia', 'Mitochondrial impairement']

Is Hirschsprung disease one of the characteristics of the Mowat-Wilson syndrome?

['Mowat-Wilson syndrome is a genetic disease caused by heterozygous mutations or deletions of the zinc finger E-box-binding homeobox 2 (ZEB2) gene. The syndrome is characterized by typical facial features, moderate-to-severe mental retardation, epilepsy and variable congenital malformations, including Hirschsprung disease, genital anomalies, congenital heart disease, agenesis of the corpus callosum, and eye defects', "Mowat-Wilson syndrome (MWS) is a rare genetic condition where variable and multiple congenital anomalies including Hirschsprung's disease, intellectual disability, and prominent facial features are present", 'Individuals with Mowat-Wilson syndrome (MWS; OMIM#235730) have characteristic facial features, a variety of congenital anomalies such as Hirschsprung disease, and intellectual disabilities caused by mutation or deletion of ZEB2 gene', 'Mowat-Wilson syndrome is a genetic disease characterized by typical facial features, Hirschsprung disease and multiple congenital abnormalities', 'Mowat-Wilson syndrome (MWS) is a severe intellectual disability (ID)-distinctive facial gestalt-multiple congenital anomaly syndrome, commonly associating microcephaly, epilepsy, corpus callosum agenesis, conotruncal heart defects, urogenital malformations and Hirschsprung disease (HSCR)', ' The prevalence of Mowat-Wilson syndrome is currently unknown, but it seems that Mowat-Wilson syndrome is underdiagnosed, particularly in patients without Hirschsprung disease.', 'Mowat-Wilson syndrome is a mental retardation-multiple congenital anomaly syndrome characterized by a typical facies, developmental delay, epilepsy, and variable congenital malformations, including Hirschsprung disease, urogenital anomalies, congenital heart disease, and agenesis of the corpus callosum.', '"Mowat-Wilson" syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene.', 'Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation; a multiple congenital anomaly syndrome characterised by a typical facial gestalt, Hirschsprung disease or severe constipation, genitourinary anomaly, congenital heart defects, agenesis of corpus callosum and eye defects.', 'We report a girl who had Hirschsprung disease in association with distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation (Mowat-Wilson syndrome).', 'Mowat-Wilson syndrome (MWS) is characterized by severe mental retardation with seizures, specific facial dysmorphism, Hirschsprung disease, anomalies of the corpus callosum, and genitourinary and cardiac malformations.', 'BACKGROUND/PURPOSE: Patients with zinc finger homeo box 1B (ZFHX1B) mutations or deletions develop multiple congenital anomalies including Hirschsprung disease, known as Mowat-Wilson syndrome (MWS).', 'Severe clinical course of Hirschsprung disease in a Mowat-Wilson syndrome patient.', 'Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype (high forehead, frontal bossing, large eyebrows, medially flaring and sparse in the middle part, hypertelorism, deep set but large eyes, large and uplifted ear lobes, with a central depression, saddle nose with prominent rounded nasal tip, prominent columella, open mouth, with M-shaped upper lip, frequent smiling, and a prominent but narrow and triangular pointed chin), moderate-to-severe intellectual deficiency, epilepsy and variable congenital malformations including Hirschsprung disease (HSCR), genitourinary anomalies (in particular hypospadias in males), congenital heart defects, agenesis of the corpus callosum and eye anomalies.', 'Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype, Hirschsprung disease, microcephaly and mental retardation.', 'Mowat-Wilson syndrome is a genetic disease characterized by typical facial features, Hirschsprung disease and multiple congenital abnormalities.', 'Supernumerary intestinal muscle coat in a patient with Hirschsprung disease/Mowat-Wilson syndrome.', 'We present the 1st case report of an additional enteric smooth muscle layer in a patient with Mowat-Wilson syndrome and Hirschsprung disease.', 'Mowat-Wilson" syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene.', 'Mowat-Wilson syndrome (MWS) is an autosomal dominant intellectual disability syndrome characterised by unique facial features and congenital anomalies such as Hirschsprung disease, congenital heart defects, corpus callosum agenesis and urinary tract anomalies.', 'Mowat-Wilson syndrome (MWS) is a mental retardation syndrome associated with distinctive facial features, microcephaly, epilepsy, and a variable spectrum of congenital anomalies, including Hirschsprung disease (HSCR), agenesis of the corpus callosum, genitourinary abnormalities, and congenital heart disease.', 'Mowat-Wilson syndrome is a mental retardation-multiple congenital anomaly syndrome characterized by a typical facies, developmental delay, epilepsy, and variable congenital malformations, including Hirschsprung disease, urogenital anomalies, congenital heart disease, and agenesis of the corpus callosum', 'Mowat-Wilson syndrome is a genetic disorder characterized by a distinct facial appearance, moderate-to-severe mental retardation, microcephaly, agenesis of the corpus callosum, Hirschsprung disease, congenital heart disease, and genital anomalies', 'We present the 1st case report of an additional enteric smooth muscle layer in a patient with Mowat-Wilson syndrome and Hirschsprung disease', 'Mowat-Wilson syndrome (MWS) is an autosomal dominant intellectual disability syndrome characterised by unique facial features and congenital anomalies such as Hirschsprung disease, congenital heart defects, corpus callosum agenesis and urinary tract anomalies', 'Mowat-Wilson syndrome (MWS) is characterized by severe mental retardation with seizures, specific facial dysmorphism, Hirschsprung disease, anomalies of the corpus callosum, and genitourinary and cardiac malformations', 'zfhz1b is the causative gene for Mowat-Wilson syndrome, in which patients demonstrate developmental delay and Hirschsprung disease, as well as other anomalies.', 'Mowat-Wilson syndrome (MWS) is a mental retardation syndrome associated with distinctive facial features, microcephaly, epilepsy, and a variable spectrum of congenital anomalies, including Hirschsprung disease (HSCR), agenesis of the corpus callosum, genitourinary abnormalities, and congenital heart disease', "Outcomes of Hirschsprung's disease associated with Mowat-Wilson syndrome.", 'Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype, Hirschsprung disease, microcephaly and mental retardation']

['Mowat-Wilson syndrome is characterized by typical facial features, moderate-to-severe mental retardation, epilepsy and variable congenital malformations, including Hirschsprung disease, genital anomalies, congenital heart disease, agenesis of the corpus callosum, and eye defects.', 'Mowat-Wilson syndrome (MWS) is a rare genetic condition where variable and multiple congenital anomalies including Hirschsprung s disease, intellectual disability, and prominent facial features are present ', 'Yes. Mowat-Wilson syndrome (MWS) is a rare genetic condition where variable and multiple congenital anomalies including Hirschsprungs disease, intellectual disability, and prominent facial features are present']

['yes']

Is Prochlorococcus the most abundant photosynthetic organism?

['The marine cyanobacterium Prochlorococcus is the smallest and most abundant photosynthetic organism on Earth.', 'The marine cyanobacterium Prochlorococcus is the numerically dominant photosynthetic organism in the oligotrophic oceans, and a model system in marine microbial ecology.', 'The marine cyanobacterium Prochlorococcus is the most abundant photosynthetic organism in oligotrophic regions of the oceans.', 'The oceanic picoplankton Prochlorococcus - probably the most abundant photosynthetic organism on our planet - can grow at great depths where light intensity is very low.']

['Yes, the marine cyanobacterium Prochlorococcus is the smallest and most abundant photosynthetic organism on Earth.']

['yes']

Which genes are involved in patient response to warfarin?

['We identified ORM1 as another polymorphic gene affecting warfarin dose requirements. ORM1 *S carriers require lower maintenance doses to achieve and maintain an optimal level of anticoagulation.', 'Detecting genetic polymorphism of CYP2C9 and VKORC1 could guide clinical use of warfarin to reduce the risk of adverse reactions including bleeding in patients receiving chronic anticoagulation therapy', 'The genes encoding for cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are the major genetic determinants of warfarin pharmacokinetics and pharmacodynamics, respectively.', 'Numerous studies have demonstrated significant contributions of these genes to warfarin dose requirements. The CYP2C9 gene has also been associated with bleeding risk with warfarin. The CYP4F2 gene influences vitamin K availability and makes minor contributions to warfarin dose requirements', 'There are other genetic polymorphisms that may further explain the response to warfarin. The VKORC1 genotype is an important determinant of response to warfarin in Chinese, but some genetic variants found in other ethnic groups that have a large effect on warfarin response and dosing are not commonly found in Chinese', 'the alleles rs1799853 (*2) and rs1057910 (*3) of the CYP2C9 gene, as well as rs9923231 of the VKORC1 gene were associated with warfarin dose required to achieve anticoagulation with INR of 2-3.', 'Polymorphisms in the genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and the vitamin K epoxide reductase (VKORC1) are known to contribute to variability in sensitivity to coumarins.', 'VKORC1 and CYP2C9 polymorphisms are important factors that influence warfarin dose response in Sudanese patients', 'he response to the anticoagulant drug warfarin is greatly affected by genetic polymorphisms in the VKORC1 and CYP2C9 genes.', 'The HDA-based assays demonstrated a clinically acceptable performance for genotyping the VKORC1 -1639G>A SNP and two SNPs (430C>T and 1075A>C) for the CYP2C9 enzyme (CYP2C9*2 and CYP2C9*3), all of which are relevant in warfarin pharmacogenentics.', 'Genetic variability in the VKORC1 and CYP2C9 genes is associated with increased warfarin sensitivity', 'CYP2C9 and VKORC1 polymorphisms known to affect warfarin response', 'genetic variants of VKORC1, CYP2C9, CYP4F2, and EPHX1 were found to be significant predictor variables for the maintenance dose of warfarin, explaining 26.6% of dose variability.', 'CYP2C9 was the most important gene determining initial anticoagulant control, whereas VKORC1 was more important for stable anticoagulation. Novel associations with some clinical outcomes were found with single nucleotide polymorphisms in the cytochrome 450 genes CYP2C18 and CYP2C19, which were independent of the associations observed with CYP2C9 and in genes encoding CYP3A5, protein S and clotting factor V, although the variability explained by these genes was small.', 'VKORC1 -1639 G>A polymorphism, body weight, age, and serum albumin were found to affect the inter-individual variabilit', 'the CYP2C9 and VKORC1 genes have been demonstrated to be determinants of warfarin response.', 'On the basis of these observations, the Food and Drug Administration (FDA) approved a labeling change for warfarin that includes the genetic information of VKORC1 and CYP2C9 as factors influencing interindividual variability in warfarin dosing. T', 'the two key genes of interest, the cytochrome P450 2C9 gene, CYP2C9, and the vitamin K epoxide reductase complex 1 gene, VKORC1, on warfarin response', 'The influence of CYP2C9 and VKORC1 genotypes on warfarin dose requirements has been consistently demonstrated in diverse racial and ethnic patient groups in observational studies and randomized clinical trials.', 'genetic factors influencing drug pharmacokinetics (CYP2C9) and pharmacodynamic response (VKORC1). In particular, the discovery of polymorphisms in the VKORC1 gene that strongly impact oral anticoagulant dose has heightened expectations that genetic testing', 'Our data suggest that CYP2C9 genotype, age and body size are important determinants of warfarin dose requirements in African-Americans. Our data further suggest that the VKORC1 G6853C polymorphism alone may not be useful for predicting warfarin dose requirements in this racial group.', 'A strong association was found between genetic polymorphisms in six genes, including VKORC1, CYP2C9, PROC, EPHX1, GGCX, and ORM1, and interindividual variability in the anticoagulant effect of warfarin; the strongest predictors were VKORC1 and CYP2C9.', 'Three of six VKORC1 SNPs were found to be very strongly associated with the average warfarin dose required to achieve the target international normalised ratio (INR; p<0.0001)', "These results are of considerable clinical interest and confirm recently published results regarding the role of these two genes in modifying warfarin metabolism and maintenance dosage. The consistent findings regarding the role of VKORC1 and CYP2C9 in warfarin metabolism and maintenance dosage represent a clinically useful proof of principal for the use of pharmacogenomic information in medicine and may lead to improved understanding of warfarin's actions.", 'Clinical studies showed an increased plasma level of S-warfarin, decreased clearance of S-warfarin, increased frequency of bleeding, and prolongation of hospitalization in patients with variant CYP2C9 alleles.']

['The following genes have been associated with patient response to warfarin: CYP2C9, VKORC1, ORM1, CYP4F2, EPHX1, CYP2C18, CYP2C19, CYP3A5, protein S, clotting factor V, PROC, GGCX.']

['CYP2C9', 'VKORC1', 'ORM1', 'CYP4F2', 'EPHX1', 'CYP2C18', 'CYP2C19', 'CYP3A5', 'protein S', 'clotting factor V', 'PROC', 'GGCX']

Is treatment resistant depression related to vitamin B9?

['Suboptimal serum and red blood cell folate levels have been associated with a poorer response to antidepressant therapy, a greater severity of symptoms, later onset of clinical improvement, and overall treatment resistance. This article reviews the evidence for L-methylfolate and folic acid as antidepressive agents in depression and discusses their clinical use', 'Although further randomized controlled trials in this area appear warranted, SAMe and L-methylfolate may represent a useful addition to the AD armamentarium.', 'Patients with depression have consistently been found to have lower levels of serum and red blood cell folate than normal or nondepressed psychiatric patients. Decreased folate levels have been associated with lowered response rates to standard antidepressant pharmacotherapy. Recent studies have shown that augmentation with a folate supplement increases medication response in both treatment-naïve and treatment-resistant depressed patients irrespective of whether there is folate deficiency.', 'Depressed patients with both low and normal folate levels may benefit from augmenting a primary antidepressant medication either initially, at the onset of treatment, or later after some degree of treatment resistance has been recognized.', 'The results of this study suggest that intake of vitamin B9 may modulate the total score of Center for Epidemiological Studies Depression Scale (CES-D) and two subscales of the CES-D including depressive affect and interpersonal difficulties.', 'The results of this study suggest that intake of vitamin B9 may modulate the total score of Center for Epidemiological Studies Depression Scale (CES-D) and two subscales of the CES-D including depressive affect and interpersonal difficulties. ', 'This article reviews the metabolic and clinical importance of folate, vitamin B12, and SAMe, as well as clinical trials in relation to depression and dementia', 'In particular, vitamins B1, B3, B6, B9 and B12 are essential for neuronal function and deficiencies have been linked to depression.']

['Treatment with SAMe, as well as with various formulations of folates and analogues, appears to be efficacious and well tolerated in reducing depressive symptoms in treatment resistant depression.']

['yes']

Can FOXOs modulate longevity?

['Forkhead box O (FOXO) transcription factors have a conserved function in regulating metazoan lifespan.', 'In contrast to FoxO1, FoxO3a and FoxO6 were specifically diminished in the CNS of HFD animals possibly contributing to the reduced lifespan observed in these animals.', 'Interestingly, many target proteins of AMPK are so-called longevity factors, e.g., SIRT1, p53, and FoxOs, which not only can increase the stress resistance and extend the lifespan of many organisms but also inhibit the inflammatory responses. ', 'Components of anti-ageing and autophagy include SirTs and FoxOs.', 'Since Sirts and FoxOs are reliable markers of longevity, the results appear to suggest that Longevinex induces longevity after prolonged feeding via induction of autophagy, while it converts death signals into survival signals and provides cardioprotection within a relatively shorter period of time.', 'Forkhead box O (FOXO) transcription factors are involved in various cellular processes, including cell proliferation, stress resistance, metabolism, and longevity', 'In this respect, members of the mammalian forkhead transcription factors of the O class (FoxOs) that include FoxO1, FoxO3, FoxO4 and FoxO6 are increasingly being recognized as exciting prospects for multiple disorders. These transcription factors govern development, proliferation, survival and longevity during multiple cellular environments that can involve oxidative stress. ', 'Here we discuss the fascinating but complex role of FoxOs during cellular injury and oxidative stress, progenitor cell development, fertility, angiogenesis, cardiovascular function, cellular metabolism and diabetes, cell longevity, immune surveillance and cancer.', 'Many longevity genes, e.g. FoxOs and SIRT1, are inhibitors of NF-kappaB signaling. ', 'Interestingly, several longevity genes such as SIRT1, SIRT6, and FoxOs can clearly suppress NF-kappaB signaling and in this way delay the aging process and extend lifespan.', 'Yet, FoxOs also can significantly affect normal cell survival and longevity, requiring new treatments for neoplastic growth to modulate novel pathways that integrate cell proliferation, metabolism, inflammation and survival.', 'These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems. Furthermore, these findings have implications for aging in higher organisms and in malignant stem cell biology, and suggest that FoxOs may play an important role in the maintenance and integrity of stem cell compartments in a broad spectrum of tissues.', 'Forkhead box O (FoxO) transcription factors are important downstream targets of the PI3K/Akt signaling pathway and crucial regulators of cell fate. This function of FoxOs relies on their ability to control diverse cellular functions, including proliferation, differentiation, apoptosis, DNA repair, defense against oxidative stress and ageing.', 'This brief review focuses on the molecular mechanisms, cellular effects and resulting organismal phenotypes generated by differentially regulated FoxO proteins and discusses our current understanding of the role of FoxOs in disease and ageing processes.', 'In this review, we focus on the several interactions of aging-associated signaling cascades regulated either by Sirtuins and FoxOs or NF-kappaB signaling pathways. We provide evidence that signaling via the longevity factors of FoxOs and SIRT1 can inhibit NF-kappaB signaling and simultaneously protect against inflamm-aging process.', 'In diverse species transcription factors belonging to the forkhead/winged helix box gene, group O (FOXO) subfamily have been found to be crucial in downstream suppression of the life-shortening effects of insulin/insulin-like growth factor-I receptor signalling pathways that, when upregulated, accelerate ageing by suppression of FOXO. ', 'In humans, FOXO3a, as well as FOXO1 and -4, and their downstream effectors, could hold the key to counteracting ageing and common diseases.', 'FOXO transcription factors have important roles in metabolism, cellular proliferation, stress tolerance, and aging. ']

['FOXOs are reliable markers of longevity.']

['yes']

What is the ubiquitin proteome?

['Mass spectrometry now allows high throughput approaches for the identification of the thousands of ubiquitinated proteins and of their ubiquitination sites.', 'we used Tandem repeated Ubiquitin Binding Entities (TUBEs) under non-denaturing conditions followed by mass spectrometry analysis to study global ubiquitylation events that may lead to the identification of potential drug targets.', 'To study the ubiquitin proteome we have established an immunoaffinity purification method for the proteomic analysis of endogenously ubiquitinated protein complexes.']

['The ubiquitin proteome is the entire set ubiquitinated proteins and of their respective ubiquitination sites.']

['The ubiquitin proteome is the entire set ubiquitinated proteins and of their respective ubiquitination sites.']

For the treatment of which conditions can atypical neuroleptic drugs be used?

['Further clinical implications are described (capability of learning the therapeutic strategies, deliverability in broader clinical settings, acceptability by patients, combination with atypical neuroleptic drugs,and treatment of choice in risk populations).', 'Intervention strategies are a multimodal psychological programme for the intervention in early prodromal stages and a combination of psychotherapy with atypical neuroleptic drugs in the late prodromal stages. ', 'Atypical neuroleptic drugs have enriched our treatment programs, especially in childhood and adolescent schizophrenia. Reviewed here is the use of atypical neuroleptics in children and adolescents with a schizophrenic disorder. ', 'o prove whether weight gain is a relevant side effect of atypical neuroleptics, the charts of all patients admitted with DSM-III-R diagnoses of schizophrenia, schizoaffective disorder, or delusional disorder in the years 1991 to 1995 were evaluated.', 'The handwriting of 18 schizophrenic patients before and during treatment with typical (haloperidol, haloperidol decanoate) and atypical (clozapine, risperidone) neuroleptic drugs was examined.', 'Atypical and typical neuroleptics, when administered chronically, can bring about profound but contrasting changes in schizophrenic symptoms and motor activation and dramatically modulate brain neurochemistry', 'Recent studies suggest that clozapine is more effective than typical neuroleptics for patients with treatment-resistant schizophrenia.', 'Acute and late onset movement disorders frequently complicate the treatment of psychosis with typical neuroleptic drugs like haloperidol, but not with atypical neuroleptic drugs like clozapine. ', 'Only the group of boys presented other comorbidities such as negativism and conduct disorders; approximately 25% of them required treatment with atypical neuroleptic drugs.', 'Atypical neuroleptic drugs are the preferred treatment for symptoms such as delusions, hallucinations, agitation and aggressive behaviour.', 'Monotherapeutic treatment with new atypical neuroleptic drugs had a more positive effect on the mental health related quality of life (MCS) in comparison to treatment with polypharmacological treatment but not with oral conventional antipsychotics. ']

['Atypical neuroloeptic drugs are antipsychotics used in patients with schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorders, psychotic relapse in neuroleptic malignant syndrome and attention deficit hyperactivity disorder when presenting with negativism and conduct disorder.']

['schizophrenia', 'schizophrenia psychosis', 'schizoaffective disorder', 'delusional disorder', 'psychotic relapse in neuroleptic malignant syndrome', 'attention deficit hyperactivity disorder (ADHD) with negativism or conduct disorders', 'psychotic disorders']

Galassi classification is used for which disorder?

[' All these patients were divided into three subgroups according to Galassi classification. ', 'We are led to conclude that Fenestration is suitable for cysts of types I and II (Galassi classification), cysto-peritoneal shunting is better for cysts of type III.', 'According to Galassi classification they were subdivided into 3 groups.', 'According to Galassi classification they were subdivided in three groups.', 'On follow-up CT scan and MRI, cysts of types I and II (Galassi classification) exhibited a steady tendency to reduction or obliteration.', 'All cysts were type II according to Galassi classification.', 'Chronic subdural hemorrhage into a giant arachnoidal cyst (Galassi classification type III).', 'The authors present CT and MRI of a patient with an extremely large arachnoidal cyst (Galassi classification type III). ', 'The authors present CT and MRI of a patient with an extremely large arachnoidal cyst (Galassi classification type III).', 'Unusual volume reduction of Galassi grade III arachnoid cyst following head trauma.', 'The authors present CT and MRI of a patient with an extremely large arachnoidal cyst (Galassi classification type III).']

['Galassi classification system is used to classify arachnoid cysts.']

['arachnoid cyst']

Have C12orf65 mutations been associated with axonal neuropathy and optic atrophy?

['Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy', 'Charcot-Marie Tooth disease (CMT) forms a clinically and genetically heterogeneous group of disorders. Although a number of disease genes have been identified for CMT, the gene discovery for some complex form of CMT has lagged behind. The association of neuropathy and optic atrophy (also known as CMT type 6) has been described with autosomaldominant, recessive and X-linked modes of inheritance. Mutations in Mitofusin 2 have been found to cause dominant forms of CMT6. Phosphoribosylpyrophosphate synthetase-I mutations cause X-linked CMT6, but until now, mutations in the recessive forms of disease have never been identified.METHODS: We here describe a family with three affected individuals who inherited in an autosomal recessive fashion a childhood onset neuropathy and optic atrophy. Using homozygosity mapping in the family and exome sequencing in two affected individuals we identified a novel protein-truncating mutation in the C12orf65 gene, which encodes for a protein involved in mitochondrial translation', 'Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy.', 'Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features.', 'C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families.', 'A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55).', 'Optic atrophy and a Leigh-like syndrome due to mutations in the c12orf65 gene: report of a novel mutation and review of the literature.', 'Recently, we identified the causative gene, C12orf65, that was reported the gene for Leigh syndrome, for autosomal recessive spastic paraplegia with optic atrophy and neuropathy (SPG55).', 'We describe 2 siblings with compound heterozygous mutations in the recently identified C12orf65 gene who presented with optic atrophy and mild developmental delays and subsequently developed bilateral, symmetric lesions in the brainstem reminiscent of Leigh syndrome.', 'C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families', 'Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features', 'CONCLUSIONS: This work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy.', 'C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families. ', 'Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. ', 'We described a large consanguineous family with neuropathy and optic atrophy carrying a loss of function mutation in the C12orf65 gene.', 'In these patients, we identified a homozygous splice mutation, g.21043\u2009T>A (c.282+2\u2009T>A) which leads to skipping of exon 2. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features.', 'This work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy.', 'Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features.', 'Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy.', 'This work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy.', 'A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55).', 'C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families.']

['Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy', 'The association of neuropathy and optic atrophy (also known as Charcot-Marie-Tooth [CMT] disease type 6) has been described with autosomal dominant, recessive and X-linked modes of inheritance. Mutations in Mitofusin 2 have been found to cause dominant forms of CMT6. Phosphoribosylpyrophosphate synthetase-I mutations cause X-linked CMT6, whereas a protein-truncating mutation in the C12orf65 gene, which codes for a protein involved in mitochondrial translation, was found to be the cause of an autosomal recessive form of the disease, with childhood onset neuropathy and optic atrophy.']

['yes']

What systems have been developed for the numbering of antibody residues?

['IMGT is a high quality integrated knowledge resource specialized in immunoglobulins (IG), T cell receptors (TR), major histocompatibility complex (MHC) of human and other vertebrates, and related proteins of the immune system (RPI) of any species which belong to the immunoglobulin superfamily (IgSF) and to the MHC superfamily (MhcSF). IMGT consists of five databases, ten on-line tools and more than 8,000 HTML pages of Web resources. IMGT provides a common access to standardized data from genome, genetics, proteome and three-dimensional structures. ', 'amino acid positions according to the IMGT unique numbering (NUMEROTATION) that are used in IMGT/3Dstructure-DB cards, results of contact analysis and renumbered flat files.', 'Standardized sequence and structure analysis of antibody using IMGT(®) databases and tools allows one to bridge, for the first time, the gap between antibody sequences and three-dimensional (3D) structures. This is achieved through the IMGT Scientific chart rules, based on the IMGT-ONTOLOGY concepts of classification (IMGT gene and allele nomenclature), description (IMGT standardized labels), and numerotation (IMGT unique numbering and IMGT Colliers de Perles). ', 'Kabat Database was initially started in 1970 to determine the combining site of antibodies based on the available amino acid sequences at that time.', 'comparative analysis of the main-chain conformation of the L1, L2, L3, H1 and H2 hypervariable regions in 17 immunoglobulin structures that have been accurately determined at high resolution is described. This involves 79 hypervariable regions in all. We also analysed a part of the H3 region in 12 of the 15 VH domains considered here. On the basis of the residues at key sites the 79 hypervariable regions can be assigned to one of 18 different canonical structures. We show that 71 of these hypervariable regions have a conformation that is very close to what can be defined as a "standard" conformation of each canonical structure. These standard conformations are described in detail. The other eight hypervariable regions have small deviations from the standard conformations that, in six cases, involve only the rotation of a single peptide group', 'the basis of comparative studies of known antibody structures and sequences it has been argued that there is a small repertoire of main-chain conformations for at least five of the six hypervariable regions of antibodies, and that the particular conformation adopted is determined by a few key conserved residues.']

['The most prevalent antibody numbering systems are the Kabat system, the Chothia system as well as the IMGT numbering system.']

[]

Is zyxin a focal adhesion protein?

[' zyxin from FAs', 'zyxin relocation from focal adhesions ', '. Here we systematically examined the expression, localization, and function of zyxin, a focal adhesion protein', 'focal adhesion protein zyxin', 'Focal adhesions formed in the absence of α-actinins are delayed in their maturation, exhibit altered morphology, have decreased amounts of Zyxin and VASP, and reduced adhesiveness to extracellular matrix', 'one focal adhesion protein (zyxin)', 'Zyxin is a focal adhesion protein that has been implicated in the modulation of cell adhesion and motility', ' focal adhesion proteins (vinculin, talin, zyxin, FAK, and paxilin)', 'Such paxillin-positive complexes mature into focal adhesions by tyrosine phosphorylation and recruitment of zyxin. ', 'Zyxin concentrates at focal adhesions ', 'zyxin, a focal adhesion protein,', 'Focal adhesion proteins Zyxin and Vinculin are co-distributed at tubulobulbar complexes.', ' Here we explore the prediction that zyxin, a focal adhesion protein known to be present at podosomes, also is present at apical TBCs', 'the association of zyxin with focal adhesions is force-dependent, smaller zyxin-positive adhesion as well as its higher turnover rate suggests that the traction force in focal adhesion on 350 nm topography is decreased.', '. Zyxin is a focal adhesion protein that responds to external mechanical forces;', 'Vinculin and zyxin in focal adhesions but not integrins are seen to bridge ligand gaps. ', 'The focal adhesion protein zyxin', '. To explore how this response is regulated by focal adhesion-associated proteins the expression levels of paxillin, focal adhesion kinase (FAK), and zyxin were knocked down using gene silencing techniques', ' Zyxin is an adaptor protein at focal adhesion plaque', 'ocked localization of zyxin at focal adhesion sites']

['Yes, zyxin is a focal adhesion protein.']

['yes']

Which histone modifications are associated with constitutive heterochromatin?

['Remarkably, in mammalian somatic cells, H3S10P initiates in the pericentromeric heterochromatin during the late G2 phase, and phosphorylation spreads throughout the chromosomes arms in prophase, being maintained until the onset of anaphase when it gets dephosphorylated', 'Based on these findings, we believe that H3S10P is a good marker of pericentromeric heterochromatin, especially in the late 1- and 2-cell stages as it labels both parental genomes and that it can be used to further investigate epigenetic regulation and heterochromatin mechanisms in early preimplantation embryos', '3S10 phosphorylation marks constitutive heterochromatin during interphase in early mouse embryos until the 4-cell stage', 'H3 trimethylation at lysine 36 is associated with constitutive and facultative heterochromatin', 'We show here that the maternally inherited Snurf-Snrpn 3-Mb region, which is silenced by a potent transcription repressive mechanism, is uniformly enriched in histone methylation marks usually found in constitutive heterochromatin, such as H4K20me3, H3K9me3, and H3K79me3', 'We show that H3K36me3 deposition within this large heterochromatin domain does not correlate with transcription events, suggesting the existence of an alternative pathway for the deposition of this histone modification', 'In addition, we demonstrate that H3K36me3 is markedly enriched at the level of pericentromeric heterochromatin in mouse embryonic stem cells and fibroblasts', 'This result indicates that H3K36me3 is associated with both facultative and constitutive heterochromatin', 'Our data suggest that H3K36me3 function is not restricted to actively transcribed regions only and may contribute to the composition of heterochromatin, in combination with other histone modifications.', 'accumulation of histone H3.3 and euchromatic histone modifications in pericentromeric heterochromatin in response to a decrease in DNA methylation levels', 'In this study, we show that inhibition of DNA methylation in mouse fibroblast cells affects histone modification and the subnuclear localization of histone H3.3 in a cell cycle-dependent manner', 'Moreover, we found that histone H3.3 was deposited on the pericentromeric heterochromatin prior to the accumulation of the euchromatic histone modifications', 'Classical histone modifications associated with heterochromatin, including H3K9me2, H3K27me1 and H3K27me2, were distributed throughout both A and B chromosomes', 'However, H3K27me2 showed a reduced level on the B chromosome compared with the A chromosomes and was not associated with some classes of constitutive heterochromatin', 'Recently analyzed H3K9 methyltransferases (HMTases) as SUV39H1, Clr4p, DIM-5, Su(var)3-9 or SUVH2 are responsible for the establishment of histone H3 lysine 9 methylation (H3K9me), which is intimately connected with heterochromatinization', 'heterochromatic histone H3K9 methyltransferases left its marks behind', 'Compilation and parsimony analysis reveal that histone H3K9 methylation is, next to histone deacetylation, the evolutionary most stable heterochromatic mark, which is established by at least two subfamilies of specialized heterochromatic HMTases in almost all studied eukaryote', 'Trimethylated H3(K9) marks pericentromeric constitutive heterochromatin and the male Y chromosome, while H2A.Z is dramatically reduced at these chromosomal locations', 'Of eight tested antibodies, the one for histone H4 acetylated at lysine 4, 8, 12, or 16 was best for distinguishing constitutive heterochromatin from unexpressed euchromatin, but differences in the extent of immunoprecipitation of these two types of chromatin were only modest, although highly reproducible', 'In addition, immunocytochemical analysis was done with an antibody to heterochromatin protein 1alpha (HP1alpha), whose preferential binding to heterochromatin has been linked to trimethylation of H3 at lysine 9', 'Our combined ChIP and immunocytochemical results suggest that factors other than hypoacetylation of the N-terminal tails of H4 and hypermethylation of H3 at lysine 9 can play an important role in determining whether a chromatin sequence in mammalian cells is constitutively heterochromatic', 'To test for the putative heterochromatinization, we quantitated chromatin immunoprecipitation with an antibody for acetylated histone H4 that discriminates between constitutive heterochromatin and unexpressed euchromatin', 'high methylation of H3 lysine 9 is dispensable for constitutive heterochromatin', 'Strong methylation at H3 lysine 4 was restricted to euchromatin, while strong methylation at H3 lysine 9 occurred preferentially in heterochromatic chromocenters of Arabidopsis nuclei']

['Strong methylation at H3 lysine 9 occurred preferentially in heterochromatic chromocenters of Arabidopsis nuclei. In general, heterochromatin has been linked to trimethylation of H3 at lysine 9 and parsimony analysis reveal that histone H3K9 methylation is, next to histone deacetylation, the evolutionary most stable heterochromatic mark. Classical histone modifications associated with heterochromatin also include H3K27me1 and H3K27me2. H3K36me3 function is not restricted to actively transcribed regions only and may contribute to the composition of heterochromatin. Other histone methylation marks usually found in constitutive heterochromatin are H4K20me3, H3K9me3, and H3K79me3. H3S10P is a good marker of pericentromeric heterochromatin.', 'H3K9 methylation\nH3S10 phosphorylation\nH3K79 and H4K20 methylation']

['H3K9Me1', 'H3K9Me2', 'H3K9me3', 'H3K9 trimethylation', 'H3K27me1', 'H3K27me2', 'H4K20me3', 'H4K20 trimethylation', 'H3K79me3', 'H3K79 methylation', 'H3S10', 'H3S10 phosphorylation']

Which R package is used for the detection of chromosomal abnormalities from microarray data?

['CAFE: an R package for the detection of gross chromosomal abnormalities from gene expression microarray data', 'CAFE: an R package for the detection of gross chromosomal abnormalities from gene expression microarray data.', 'It is implemented as an R package that analyzes Affymetrix *.CEL files and comes with flexible plotting functions, easing visualization of chromosomal abnormalities.CAFE is available from https://bitbucket.org/cob87icW6z/cafe/ as both source and compiled packages for Linux and Windows.', 'SUMMARY: The current methods available to detect chromosomal abnormalities from DNA microarray expression data are cumbersome and inflexible. CAFE has been developed to alleviate these issues. It is implemented as an R package that analyzes Affymetrix *.CEL files and comes with flexible plotting functions, easing visualization of chromosomal abnormalities.AVAILABILITY AND IMPLEMENTATION: CAFE is available from https://bitbucket.org/cob87icW6z/cafe/ as both source and compiled packages for Linux and Windows.', 'SUMMARY: The current methods available to detect chromosomal abnormalities from DNA microarray expression data are cumbersome and inflexible. CAFE has been developed to alleviate these issues.', 'CAFE: an R package for the detection of gross chromosomal abnormalities from gene expression microarray data.']

['CAFE is an R package for the detection of gross chromosomal abnormalities from gene expression microarray data.']

['CAFE']

Where is the TAZ (G4.5) is located in humans?

['Tafazzin (EC 2.3.1.23) is a Phospholipid Transacylase involved in Cardiolipin remodeling on mitochondrial membrane and coded by TAZ gene (Cytogenetic Location: Xq28) in human.', 'Barth syndrome is an X-linked cardiomyopathy with neutropenia and 3-methylglutaconic aciduria. Recently, mutations in the G4.5 gene, located in Xq28, have been described in four probands with Barth syndrome. ', 'The disorder is caused by mutations in the tafazzin (TAZ/G4.5) gene located on Xq28.', 'Disabling mutations or deletions of the tafazzin (TAZ) gene, located at Xq28, cause the disorder by reducing remodeling of cardiolipin, a principal phospholipid of the inner mitochondrial membrane', 'The tafazzin gene (TAZ) is located at Xq28 and encodes a protein involved in the transacylation of cardiolipin, an essential mitochondrial phospholipid', 'The disorder is caused by mutations in the tafazzin (TAZ/G4.5) gene located on Xq28', 'The disorder is caused by mutations in the tafazzin (TAZ/G4.5) gene located on Xq28.', 'Recently, mutations in the G4.5 gene, located in Xq28, have been described in four probands with Barth syndrome.']

['TAZ gene (G4.5) is located on Xq28 in humans.']

['Xq28']

What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?

['CR-ABL-targeted TKI that inhibits BCR-ABL with greater potency compared with imatinib', 'reciprocal translocation between chromosomes 9 and 22 [t(9;22)(q34;q11), Philadelphia chromosome] creates a BCR-ABL1 fusion protein', 'A novel tyrosine kinase inhibitor (TKI), imatinib, has been confirmed as an effective targeted treatment in most CML patients', 'The availability of tyrosine kinase inhibitors (TKIs) has considerably changed the management of Philadelphia chromosome positive leukemia. The BCR-ABL inhibitor imatinib i', 'The BCR/ABL fusion tyrosine kinase is expressed in chronic myeloid leukemia and Philadelphia-positive (Ph+) acute lymphoblastic leukemia cells, and its inhibition by the clinically used tyrosine kinase inhibitors imatinib ', 'Chronic myeloid leukemia (CML) is a clonal malignant myeloproliferative disorder characterized by the expansion of hematopoietic cells carrying the Philadelphia chromosome', 'Patients received imatinib after diagnosis and underwent regular laboratory monitoring (quantification of BCR-ABL ratio', 'CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. ', 'tyrosine kinase inhibitors (TKIs), imatinib', 'Characterized by a translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, small-molecule tyrosine kinase inhibitors (TKIs) targeted against the oncogenic BCR-ABL fusion protein', 'Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the t(9;22), which fuses BCR to ABL ', 'ABL-kinase inhibitors (AKIs) Imatinib', 'hiladelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by constitutively activated BCR-ABL', ' BCR-ABL tyrosine kinase inhibitor imatinib ', 'matinib was the first BCR-ABL tyrosine kinase inhibitor', 'CML) is a pluripotent hematopoietic disorder that is currently considered incurable. The tyrosine kinase product of the Philadelphia chromosome, P210 BCR-ABL, ', 'Imatinib mesylate, an orally available BCR-ABL kinase inhibitor', 'Since the initial approval of imatinib much has been learned about its resistance mechanisms, and efforts have continued to improve upon BCR-ABL tyrosine kinase inhibitor therapy.', 'CML) originates from a hematopoietic stem cell carrying the Philadelphia (Ph) chromosome and oncogenic BCR-ABL1 fusion gene. The first tyrosine-kinase inhibitor (TKI) imatinib ', 'chronic myeloid leukemia (CML) patients ', 'Philadelphia chromosome and/or BCR-ABL positive, received first-line treatment with imatinib', 'matinib mesylate is the sole BCR-ABL tyrosine kinase inhibitor approved as first-line treatment of accelerated-phase (AP) chronic myeloid leukemia (CML', 'Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase', 'Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor, has revolutionized the treatment of Bcr-Abl positive chronic myeloid leukemia ', 'The development of first-generation (imatinib) and second-generation (dasatinib and nilotinib) tyrosine kinase inhibitors (TKIs) that target the BCR-ABL1 fusion protein produced by the Ph chromosome revolutionized the treatment of chronic myelogenous leukemia (CML).', 'The cytogenetic characteristic of Chronic Myeloid Leukemia (CML) is the formation of the Philadelphia chromosome gene product, BCR-ABL. Given that BCR-ABL is the specific target of Gleevec in CML treatment, ', 'chronic myeloid leukemia (CML), BCR-ABL-mediated oncogenic signaling can be successfully targeted with the BCRABL- inhibitors imatinib', 'matinib mesylate (STI 571; Gleevec; Novartis Pharmaceuticals, Basel, Switzerland) is an orally available tyrosine kinase inhibitor that targets a constitutively activated BCR-ABL tyrosine kinase', 'Philadelphia chromosome positive chronic myelogenous leukemia (CML) ', 'CML) is caused by the BCR-ABL oncogene. The Philadelphia chromosome (Ph) from a reciprocal translocation, t(9;22) (q34;q11) causes a fusion gene, BCR-ABL, that encodes a constitutively active tyrosine kinase. Treatment of CML by imatinib', 'BCR-ABL levels', 'Imatinib induces a durable response in most patients with Philadelphia chromosome-positive chronic myeloid leukemia,', 'CML is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome or the BCR-ABL fusion oncogene', 'imatinib therapy', 'The discovery of targeted tyrosine kinase inhibition of BCR-ABL kinase dramatically changed the treatment of CML. Imatinib, the first TKI approved for treatment of patients with Philadelphia chromosome--positive CML', 'CML) is a genetically associated malignancy of haematopoietic stem cells, characterized by a t(9;22) translocation that forms the Philadelphia chromosome and creates a novel fusion gene, BCR-ABL. Treatment with molecular-targeted therapy is usually initiated with imatinib', 'imatinib, a selective BCR-ABL tyrosine kinase inhibitor (TKI), was started but Ph-positive chromosomes remained', 'CML is induced by the BCR-ABL oncogene, whose gene product is a BCR-ABL tyrosine kinase. Currently, inhibition of BCR-ABL kinase activity by its kinase inhibitor such as imatinib mesylate (Gleevec)', 'The Bcr-Abl tyrosine kinase inhibitor imatinib represented a major advance over conventional CML therapy', 'Imatinib (Glivec, Gleevec), a specific small molecule inhibitor of Bcr-Abl, has become the standard drug therapy for CML,', 'Imatinib blocks proliferation and induces apoptosis of BCR-ABL-expression in CML', 'CML is the presence of a balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11.2), which is known as the Philadelphia (Ph) chromosome. This translocation results in the formation of the bcr-abl fusion gene,', 'emergence of imatinib', 'matinib mesylate, binding to the inactive conformation of Bcr-Abl tyrosine kinase and suppressing the Ph chromosome positive clone, has revolutionized the treatment of chronic myeloid leukaemia (CML) patients.', 'Ph) chromosome is the cytogenetic hallmark of chronic myeloid leukemia (CML). The translocation forms a chimeric gene, bcr-abl, which generates BCR-ABL. This fusion protein constitutively activate ABL tyrosine kinase and causes CML. Imatinib mesylate is a selective tyrosine kinase inhibitor on ABL', 'CML) is characterized by the presence of a BCR-ABL fusion gene, which is the result of a reciprocal translocation between chromosomes 9 and 22, and is cytogenetically visible as a shortened chromosome 22 (Philadelphia)', 'imatinib mesylate was introduced into the treatment regimen for CML', 'matinib was developed as the first molecularly targeted therapy to specifically inhibit the BCR-ABL kinase in Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML)', 'hronic myelogenous leukemia is characterized by the Philadelphia-chromosome, a shortened chromosome 22 which is the result of a reciprocal translocation between chromosome 9 and 22. The fusion gene is called BCR-ABL. ', 'Imatinib mesylate (Glivec) ', ' BCR-ABL transcripts in the peripheral blood of patients with CML who were treated with imatinib mesylate (Glivec, Novartis)', 'Imatinib was the first small molecule developed to inhibit BCR-ABL tyrosine kinase ', 'hronic myeloid leukemia cells contain a BCR-ABL oncoprotein', 'Imatinib mesylate, a tyrosine kinase inhibitor with specific activity against the breakpoint cluster region--Abelson murine leukemia (BCR-ABL) tyrosine kinase has been developed for treatment of chronic myelogenous leukemia (CML).', 'The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph), which results in the synthesis of the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) fusion oncoprotein, a constitutively active tyrosine kinase. The introduction of imatinib, a tyrosine kinase inhibitor (TKI) that is specific for BCR-ABL, was a major breakthrough in CML therapy', 'original TKI, imatinib', 'CML were the discovery of the Philadelphia chromosome in 1960, and of the (9;22) translocation in 1973. There followed definition of the breakpoint cluster region on chromosome 22 in 1984 and the demonstration of the BCR-ABL transcript in CM', 'Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor, has proved to be most effective therapy of Philadelphia chromosome-positive chronic myelogenous leukemia. ', 'The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph) that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase (TK). The introduction of imatinib, a TK inhibitor (TKI) specific for BCR-ABL, was a major breakthrough in CML therapy', 'CML has enabled the development of Abl-specific tyrosine kinase inhibitors, such as imatinib mesylate', 'CML) arises as a consequence of a chromosomal translocation giving rise to the Philadelphia chromosome and Bcr-Abl oncogene.', 'CML) is a paradigm for neoplasias that are defined by a unique genetic aberration, the BCR-ABL1 fusion gene', 'protein tyrosine kinase inhibitor, imatinib,', 'BCR-ABL fusion gene represents the hallmark of chronic myelogenous leukemia (CML) and is derived from a translocation between chromosome 9 and 22.', 'CML patients with imatinib treatment', 'CML) is characterized by the presence of the Philadelphia chromosome (Ph), a genetic aberration that codes for bcrabl, which plays a key role in disease pathophysiology. The first oral inhibitor of Brc-Abl was imatinib', 'CML) is characterized by the presence of the Philadelphia (Ph) chromosome, which results from a reciprocal translocation between the long arms of the chromosomes 9 and 22 t(9;22)(q34;q11). This translocation creates two new genes, BCR-ABL on the 22q- (Ph chromosome) and the reciprocal ABL-BCR on 9q-. ', 'tyrosine kinase inhibitor (TKI), introduced into clinical practice in 1998, was imatinib mesylate', 'BCR-ABL tyrosine kinase is the critical pathogenetic event in CML and an ideal target for therapy. This was confirmed in clinical trials of imatinib', 'CML) is characterized by the presence of a constitutively active Abl kinase, which is the product of a chimeric BCR-ABL gene, caused by the genetic translocation known as the Philadelphia chromosome. Imatinib, a selective inhibitor of the Bcr-Abl tyrosine kinase, ', 'CML) is the first human malignancy for which the promise of targeted therapy has come true. CML is invariably associated with a specific genetic lesion--the t(9;22) chromosomal translocation. As a consequence of this translocation, a BCR-ABL fusion gene', 'Imatinib mesylate, an orally available tyrosine kinase inhibitor that targets Bcr-Abl,', 'CR-ABL tyrosine kinase inhibitors, such as imatinib (Gleevec) are highly effective in treating human Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML) ', 'Chronic myeloid leukemia (CML) is a hematopoietic stem cell cancer driven by the BCR-ABL fusion protein that arises from the translocation of chromosomes 9 and 22', 'BCR-ABL inhibitors, such as imatinib', 'TKIs (tyrosine kinase inhibitors), including IM (imatinib mesylate),', 'chronic myeloid leukaemia) is a myeloproliferative disease that originates in an HSC (haemopoietic stem cell) as a result of the t(9;22) translocation, giving rise to the Ph (Philadelphia chromosome) and bcr-abl oncoprotein', 'CML) was the first human malignant disease to be linked to a single, acquired genetic abnormality. Identification of the Bcr-Abl kinase fusion protein and its pivotal role in the pathogenesis of CML provided new opportunities to develop molecular-targeted therapies. Imatinib mesylate', ' identification of the Philadelphia chromosome in cells from individuals with chronic myelogenous leukemia (CML) led to the recognition that the BCR-ABL tyrosine kinase causes CML. This in turn led to the development of imatinib mesylate, a clinically successful inhibitor of the BCR-ABL kinase', 'CML) was the first human malignancy to be associated with a single genetic abnormality, characterized by a reciprocal translocation involving chromosomes 9 and 22 (the Philadelphia chromosome). The fusion gene that results (BCR-ABL) produces a constitutively activated tyrosine kinase that exists in different isoforms depending on BCR break-points. Imatinib mesylate is a highly selective inhibitor of this kinase,', 'CML) is characterized by the presence of the Philadelphia chromosome, which is associated with a balanced translocation involving chromosomes 9 and 22 to produce a fusion gene (bcr-abl) that gives rise to a constitutively activated Abl tyrosine kinase. This kinase led to the discovery of several small-molecule inhibitors, imatinib', 'matinib mesylate was designed as an inhibitor targeting the BCR-ABL tyrosine kinase, the molecular counterpart of the Philadelphia translocation t(9;22)(q34;q11).', 'CML) is a clonal hematopoietic disorder caused by the reciprocal translocation between chromosome 9 and 22. As a result of this translocation, a novel fusion gene, BCR-ABL, is created on Philadelphia (Ph) chromosome, and the constitutive activity of the BCR-ABL protein tyrosine kinase plays a critical role in the disease pathogenesis. Imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor', 'CML was the first human cancer demonstrated to be strongly associated to the presence of a recurrent chromosomal translocation (the t(9;22)(q34;q11) that creates the Philadelphia (Ph)-chromosome) and to a specific molecular defect, the formation of a hybrid BCR-ABL gene ', 'imatinib, (Glivec, Gleevec, Novartis), a potent tyrosine kinase inhibitor of the Bcr-Abl protein', 'matinib mesylate is a new drug that can inhibit the tyrosine kinase activity of Bcr-Abl, the receptors for platelet-derived growth factor receptor(PDGF) and stem cell factor, or c-kit. Chronic myeloid leukemia (CML) is distinguished by the presence of a reciprocal translocation between chromosomes 9 and 22 that results in a shortened chromosome 22, termed the Philadelphia(Ph) chromosome.', 'IM) binds to the BCR-ABL protein', 'Philadelphia chromosome found in leukemia cells of chronic myelogenous leukemia (CML) patients is produced by translocation between chromosomes 9 and 22, resulting in expression of a chimera protein of Bcr and Abl kinase', 'Abl kinase inhibitors were synthesized. STI571 (imatinib mesylate', 'CML) is characterized by the Philadelphia translocation that fuses BCR sequences from chromosome 22 upstream of the ABL gene on chromosome 9.', 'Imatinib, an ATP-competitive selective inhibitor of Bcr-Abl', 'Imatinib mesylate is a tyrosine kinase inhibitor with high affinity for the BCR-ABL fusion protein expressed by the hematopoietic cells in chronic myelogenous leukemia (CML).', 'BCR/ABL, encodes an activated tyrosine kinase that can act alone to induce a CML-like syndrome ', 'The kinase inhibitor imatinib mesylate (Gleevec)', 'hiladelphia chromosome translocation (t(9;22)) results in the molecular juxtaposition of two genes, BCR and ABL, to form an aberrant BCR-ABL gene on chromosome 22. BCR-ABL is critical to the pathogenesis of chronic myelogenous leukemia', 'imatinib mesylate (Gleevec,', 'matinib mesylate (Glivec) is a selective inhibitor of bcr-abl tyrosine kinase, the product of the Philadelphia chromosome, which is the hallmark of chronic myeloid leukaemia (CML)', 'matinib mesylate (STI571, Glivec, Gleevec) is a powerful inhibitor of the tyrosine kinase activity of Bcr-Abl, the oncoprotein responsible for chronic myeloid leukemia (CML)', 'CML) is characterized by the presence of a Bcr-Abl fusion protein with deregulated tyrosine kinase activity that is required for maintaining the malignant phenotype. Imatinib, a selective inhibitor of Bcr-Abl', 'Imatinib is an orally administered, potent inhibitor of the Bcr-Abl tyrosine kinase.', 'Imatinib mesylate (STI571), a selective inhibitor of the Bcr-Abl tyrosine kinase, has significant activity in AP CML.', 'Chronic myelogenous leukemia (CML) is characterized by a molecular aberration, a fusion BCR-ABL gene encoding for aberrant tyrosine kinase activity, which is crucial in the pathogenesis of CML. In vitro, inhibition of BCR-ABL protein tyrosine kinase activity by a tyrosine kinase inhibitor, Imatinib mesylate', 'CML) is characterised by the occurrence of the Philadelphia (Ph) chromosome (9/22 translocation) and the formation of a fusion protein--the BCR-ABL transcript with constitutive activation of the BCR-ABL tyrosine kinase and consequent changes in the intracellular signal transduction, which is responsible for the deregulated myeloid cell proliferation. STI571 (signal transduction inhibition number 571) is a potent and selective inhibitor of the BCR-ABL tyrosine kinase', 'Imatinib mesylate (STI571), a specific Bcr-Abl tyrosine-kinase signal-transduction inhibitor, has shown encouraging activity in phase I and II studies of CML', 'Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase.', 'CML) is a clonal hematopoietic stem cell disorder characterized by Philadelphia chromosome and resultant production of the constitutively activated BCR-ABL tyrosine kinase. Imatinib (STI571), selective inhibitor of the ABL-tyrosine kinase,']

['The fusion protein BCR-ABL']

['BCR-ABL']

Is the protein lefty an inhibitor of nodal?

['The expression of lefty, an inhibitor of nodal is often reduced in tumor cells.', ' Nodal, and an inhibitor, Lefty.', 'as well as the expression of Lefty, an inhibitor of nodal signaling,', 'he Nodal inhibitor lefty', 'The morphogen Nodal was proposed to form a long-range signaling gradient via a reaction-diffusion system, on the basis of differential diffusion rates of Nodal and its antagonist Lefty.']

['Yes, lefty is an inhibitor of nodal.']

['yes']

List types of avoided words in bacterial genomes

['Avoidance of palindromic words in bacterial and archaeal genomes: a close connection with restriction enzymes.', 'Short palindromic sequences (4, 5 and 6 bp palindromes) are avoided at a statistically significant level in the genomes of several bacteria, including the completely sequenced Haemophilus influenzae and Synechocystis sp. genomes and in the complete genome of the archaeon Methanococcus jannaschii.', 'Palindromes corresponding to sites for restriction enzymes from other species are also avoided, albeit less significantly, suggesting that in the course of evolution bacterial DNA has been exposed to a wide spectrum of restriction enzymes, probably as the result of lateral transfer mediated by mobile genetic elements, such as plasmids and prophages', 'Palindromic words appear to accumulate in DNA once it becomes isolated from restriction-modification systems, as demonstrated by the case of organellar genomes', 'In certain cases, a comparison of avoided palindromic words in taxonomically related bacteria shows a pattern of relatedness of their R-M systems.', 'Recognition sites for type II restriction and modification enzymes in genomes of several bacteria are recognized as semi-palindromic motifs and are avoided at a significant degree.', 'On the basis of the set of most avoided words, and in accordance to the IUPAC coding standards, suggestions are made regarding potential recognition sequences. In certain cases, a comparison of avoided palindromic words in taxonomically related bacteria shows a pattern of relatedness of their R-M systems.']

['Short palindromic sequences (4, 5 and 6 bp palindromes) are avoided at a statistically significant level in the genomes of several bacteria, including the completely sequenced Haemophilus influenzae and Synechocystis sp. genomes and in the complete genome of the archaeon Methanococcus jannaschii. Palindromes corresponding to sites for restriction enzymes from other species are also avoided, albeit less significantly, suggesting that in the course of evolution bacterial DNA has been exposed to a wide spectrum of restriction enzymes, probably as the result of lateral transfer mediated by mobile genetic elements, such as plasmids and prophages. Palindromic words appear to accumulate in DNA once it becomes isolated from restriction-modification systems, as demonstrated by the case of organellar genomes.']

['Short palindromic sequences (4, 5 and 6 bp palindromes)', 'Palindromes corresponding to sites for restriction enzymes from other species']

Are deletions of chromosomal regulatory boundaries associated with congenital disease?

['Deletions of chromosomal regulatory boundaries are associated with congenital disease.', 'Our results suggest that enhancer adoption caused by deletions of regulatory boundaries may contribute to a substantial minority of copy-number variation phenotypes and should thus be taken into account in their medical interpretation', 'Deletions of chromosomal regulatory boundaries are associated with congenital disease', 'Deletions of chromosomal regulatory boundaries are associated with congenital disease.']

['Yes. Enhancer adoption caused by deletions of regulatory boundaries may contribute to a substantial minority of copy-number variation phenotypes and should thus be taken into account in their medical interpretation.']

['yes']

Which drug is benserazide usually co-administered with?

['The present study utilizes in vivo amperometry to investigate the impact from unilateral 6-hydroxydopamine lesions and l-DOPA (4 mg/kg, including benserazide 15 mg/kg) -induced dyskinetic behavior on striatal basal extracellular glutamate concentration and potassium-evoked glutamate release in urethane-anesthetized rats. ', 'Co-administration of L-Dopa with peripheral DDC inhibitors (carbidopa or benserazide) is the most effective symptomatic treatment for PD.', 'In experiment 1, l-DOPA-primed rats were pre-treated with Vehicle (0.9% NaCl), various doses of the partial 5-HT(1A) agonist, buspirone (0.25, 1.0 or 2.5 mg/kg, ip) or buspirone (2.5 mg/kg, ip)+the 5-HT(1A) antagonist, WAY100635 (0.5 mg/kg, ip) 5 min prior to l-DOPA (12 mg/kg+15 mg/kg benserazide, ip). R', 'L-DOPA induced hyperalgesia occurred after conversion to dopamine because co-administration of benserazide, a DOPA decarboxylase inhibitor, completely abolished the L-DOPA-induced hyperalgesia. ', 'First, animals were treated with levodopa (50 mg/kg with benserazide 12.5 mg/kg, twice daily), intraperitoneally (i.p.) for 22 days. ', 'Chronic L-DOPA-treated rats received the D1 receptor antagonist SCH23390 (0.01, 0.1, and 1.0 mg/kg; i.p.), the D2 receptor antagonist Eticlopride (0.01, 0.1, and 1.0 mg/kg; i.p.), a mixture of both antagonists (0.01, 0.1, 1.0 mg/kg each; i.p.), or vehicle 30 min prior to L-DOPA (6 mg/kg; i.p.)+Benserazide (15 mg/kg; i.p.).', 'Nociceptive behaviors in mice after an intrathecal (i.t.) administration of substance P were evaluated. L-DOPA (i.t.) dose-dependently attenuated the substance P-induced nociceptive behaviors. Co-administration of benserazide (i.t.), a DOPA decarboxylase inhibitor, abolished the antinociceptive effect of L-DOPA.', 'They were injected subcutaneously (s.c.) with L-DOPA methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-DOPA/benserazide) alone or in combination with (-)-OSU6162 (1.0, 3.0, 6.0 or 10 mg/kg, s.c.)', 'They were injected subcutaneously (s.c.) with L-Dopa methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-Dopa/benserazide) alone or in combination with JL-18 (at the doses of 0.1, 0.3, or 0.9 mg/kg, s.c.).', 'The administration of L-dopa (20 and 60 mg/kg p.o.) + benserazide (15 mg/kg p.o.) resulted in dose-dependent increase of dialysate levels of L-dopa and 3-O-methyl-DOPA. Tolcapone (30 mg/kg p.o.), given as adjunct to both doses of L-dopa, markedly enhanced the elevation or extracellular L-dopa, while it completely prevented the formation of 3-O-methyl-DOPA. In another experiment, the administration of L-dopa + benserazide (30 + 15 mg/kg p.o.) resulted in increased extracellular levels of dopamine, DOPAC, HVA and 3-methoxytyramine.', 'In healthy subjects and in patients with parkinsonism plasma ALAAD level fell after administration of L-dopa + benserazide, but returned to previous levels within 90 min.', 'In a cross-sectional study blood was obtained, 2 h after dosing, from 104 patients with idiopathic parkinsonism, divided into four groups: no L-dopa treatment (group 1), L-dopa alone (group 2), L-dopa + benserazide (Madopar) (group 3) and L-dopa + carbidopa (Sinemet) (group 4).']

['Co-administration of L-Dopa with carbidopa or benserazide is the most effective symptomatic treatment for Parkinson Disease (PD).']

['L-Dopa']

Is there an association between serum interleukin-6 concentrations and outcomes of stroke patients?

[' In addition, IL-6 concentrations affect clinical outcomes in ischemic stroke.', 'After appropriate adjustment, the odds ratios for the association of markers and poor outcome (comparing the upper and the lower third) were interleukin-6, 3.1 (95% CI: 1.9-5.0); C-reactive protein, 1.9 (95% CI: 1.2-3.1); fibrinogen, 1.5 (95% CI: 1.0-2.36); white cell count, 2.1 (95% CI: 1.3-3.4); and glucose 1.3 (95% CI: 0.8-2.1). The results for interleukin-6 were similar to other studies. ', '-6 and IL-10 levels were higher in patients with poor outcome. On logistic regression analysis, higher values of IL-6 were significantly associated with clinical outcome at 1 month (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.02-1.54). ', 'In hemorrhagic stroke, high levels of IL-6 in the early phase indicated a poor neurological outcome.', 'Initially elevated levels of hs-IL-6 at presentation further correlated with unfavorable clinical outcomes (by NIHSS and mRs) at both time points. Analysis of variance in the different quartiles identified an hs-IL-6 gradient-dependent correlation at both time points, such that the higher the initial hs-IL-6 concentration, the higher the elevation in inflammatory biomarkers and the poorer the neurological state at both time points (p<0.001 for NIHSS and p=0.001 for mRs, for trend across quartiles). CONCLUSIONS: This study demonstrates the potential of employing hs-IL-6 as an early stage biomarker for the prognosis of acute ischemic stroke. ', 'Another negative correlation was found between IL-6 and CNS scores (r = -0.451, p = 0.000).', 'In addition, increased levels of IL-6 and reduced levels of protein C and protein S may play a role in acute ischemic stroke severity.', 'Variables that are predictors of adverse stroke outcome include erythrocyte sedimentation rate, and levels of C-reactive protein (CRP), interleukin-6, tumour necrosis factor-alpha and intercellular adhesion molecule-1. ']

['Yes. Greater serum interleukin-6 concentrations are associated with worse outcomes in ischemic and hemmorhagic stroke patients']

['yes']

Which packages are used for performing overlap analysis of genomic regions in R/bioconductor?

['At the core of the infrastructure are three packages: IRanges, GenomicRanges, and GenomicFeatures. These packages provide scalable data structures for representing annotated ranges on the genome, with special support for transcript structures, read alignments and coverage vectors. Computational facilities include efficient algorithms for overlap and nearest neighbor detection, coverage calculation and other range operations. This infrastructure directly supports more than 80 other Bioconductor packages, including those for sequence analysis, differential expression analysis and visualization.']

['IRanges, GenomicRanges, and GenomicFeatures provide scalable data structures for representing annotated ranges on the genome, with special support for transcript structures, read alignments and coverage vectors. Computational facilities include efficient algorithms for overlap and nearest neighbor detection, coverage calculation and other range operations. This infrastructure directly supports more than 80 other Bioconductor packages, including those for sequence analysis, differential expression analysis and visualization.', 'At the core of the infrastructure are three packages: IRanges, GenomicRanges, and GenomicFeatures. These packages provide scalable data structures for representing annotated ranges on the genome, with special support for transcript structures, read alignments and coverage vectors. Computational facilities include efficient algorithms for overlap and nearest neighbor detection, coverage calculation and other range operations. This infrastructure directly supports more than 80 other Bioconductor packages, including those for sequence analysis, differential expression analysis and visualization.']

['IRanges', 'GenomicRanges', 'GenomicFeatures']

What is clinical presentation of the Gardner-Diamond syndrome?

["Antidepressants were prescribed by the psychiatrist that not only cured the depression with time but also the bleeding episodes which were actually related to child's depression (Gardner-Diamond syndrome or psychogenic purpura). ", 'Psychogenic Purpura (Gardner-Diamond Syndrome).', 'Psychogenic purpura, also known as Gardner-Diamond syndrome or autoerythrocyte sensitization syndrome, is a rare condition characterized by spontaneous development of painful edematous skin lesions progressing to ecchymosis over the next 24 hours. Severe stress and emotional trauma always precede the skin lesions. ', 'Gardner Diamond syndrome is a rare condition characterized with painful ecchymoses in different parts of the body and cutaneous and mucosal hemorrhages. The etiology is not known fully and psychogenic factors are thought to be involved. ', 'Psychogenic purpura, also known as Gardner-Diamond syndrome, is a rare, distinctive, localized cutaneous reaction pattern mostly affecting psychologically disturbed adult women. Repeated crops of tender, ill-defined ecchymotic lesions on the extremities and external bleeding from other sites characterize the condition. ', 'PPDDM includes impulse control disorders, obsessive-compulsive disorders, factitious disorder, factitious disorder by proxy, self-mutilation, delusions of parasitosis, psychogenic purpura/Gardner-Diamond syndrome, and cutaneous sensory disorders.', 'Psychogenic purpura (Gardner-Diamond syndrome) is the occurrence and spontaneous recurrence of painful ecchymosis following emotional stress and minor trauma. ', 'We describe the clinical presentation and course of a patient with autoerythrocyte sensitization (Gardner-Diamond) syndrome, and review the literature for similar cases.', 'Gardner-Diamond syndrome (GDS) is also known as psychogenic purpura, autoerythrocyte sensitization syndrome and painful bruising syndrome.', 'Autoerythrocyte sensitization (Gardner-Diamond) syndrome mimicking compartment syndrome.', 'Autoerythrocyte sensitization syndrome (Gardner-Diamond syndrome): review of the literature.', 'We report a case with an unusual manifestation of autoerythrocyte sensitization syndrome (Gardner-Diamond syndrome).', 'The Gardner-Diamond syndrome is a disorder characterized by recurrent spontaneous painful bruising in patients with underlying psychosis and neurosis.', 'A 54-year old anorectic patient with painful bruising syndrome (Gardner-Diamond syndrome) suffered from various gastrointestinal and psychologic complaints.', 'This paper presents a 26-year-old woman with the characteristic features of Gardner-Diamond syndrome: recurrent painful bruises reproducible by intradermal injection of autologous red blood cells, and a "hysterical" personality pattern together with nonspecific multisystem complaints.', "Gardner-Diamond's syndrome, or autoerythrocyte sensitization, is a disorder of spontaneous, painful ecchymoses whose pathogenesis is unresolved.", 'Autoerythrocyte sensitization (Gardner-Diamond) syndrome mimicking compartment syndrome.', 'Autoerythrocyte sensitization (Gardner-Diamond) syndrome.', 'Autoerythrocyte sensitization syndrome (Gardner-Diamond syndrome) associated with cutaneous vasculitis.', 'Gardner-Diamond syndrome (GDS) is an uncommon disease clinically characterized by a wide spectrum of psycho-emotive symptoms associated with painful ecchymoses/purpuric lesions and positivity of auto-erythrocyte sensitization skin test.']

['Psychogenic purpura, also known as Gardner-Diamond syndrome, is a rare, distinctive, localized cutaneous reaction pattern mostly affecting psychologically disturbed adult women. Repeated crops of tender, ill-defined ecchymotic lesions on the extremities and external bleeding from other sites characterize the condition.']

[]

List co-morbidities that may occur together with "Stiff man Syndrome"

["To report an association between two autoimmune conditions, Graves' disease and stiff-person (stiff-man) syndrome, and discuss the relevant literature.", "This case illustrates the association between TRAB-positive Graves' disease and stiff-person syndrome and the improvement of Graves' disease with immunosuppressive therapy.", 'HCV may be the etiologic virus of progressive encephalomyelitis with rigidity; a rare disorder similar to stiff-man syndrome although different because it is progressive and fatal.', 'The triad of stiff-man syndrome, breast cancer, and autoantibodies against amphiphysin identifies a new autoimmune paraneoplastic syndrome of the CNS.', 'GAD has been suggested as an autoantigen in insulin-dependent diabetes mellitus and stiff-man syndrome', 'Stiff-man syndrome (SMS) is a rare disorder of the central nervous system of probable autoimmune origin.', 'Patients with SMS often have other autoimmune diseases, in particular type I (insulin-dependent) diabetes mellitus (IDDM).', 'GAD-65 is a dominant autoantigen in stiff-man syndrome and insulin-dependent diabetes mellitus.', 'In this group, there is a striking association of the stiff-man syndrome with organ-specific autoimmune diseases, primarily insulin-dependent diabetes mellitus.', 'We studied three women with the stiff-man syndrome and breast cancer,', 'RESULTS: Autoantibodies directed against a 128-kd brain protein were found in two of the women with the stiff-man syndrome and breast cancer. These results led to a search for breast cancer in the third patient with the stiff-man syndrome, who also had autoantibodies. A small invasive ductal carcinoma was detected by ultrasonography and removed.', 'CONCLUSIONS: In a subgroup of patients with the stiff-man syndrome, the condition is likely to have an autoimmune paraneoplastic origin. The detection of autoantibodies against the 128-kd antigen in patients with this syndrome should be considered an indication to search for an occult breast cancer.', 'We have previously reported the presence of autoantibodies against glutamic acid decarboxylase (GAD) in a patient with stiff-man syndrome, epilepsy, and insulin-dependent diabetes mellitus.', 'These findings support the hypothesis that stiff-man syndrome is an autoimmune disease and suggest that GAD is the primary autoantigen involved in stiff-man syndrome and the associated insulin-dependent diabetes mellitus.', 'An elderly man with progressive dementia and concomitant development of stiff-man syndrome is described. He had not had stiff-man syndrome one year earlier, when he had only mild dementia. An association between stiff-man syndrome and dementia has not been previously described.', 'It is possible that this patient represents an exaggerated form of such motor disturbances in dementia, and that clinical and electromyographic features of stiff-man syndrome may be present with increased incidence in patients with dementia.']

["SMS (Stiff man Syndrome) is is a rare disorder of the central nervous system of probable autoimmune origin and as such is associated with other autoimmune diseases, such as Insulin Dependent Diabetes Mellitus . GAD-65 is a dominant auto-antigen that is found both in in stiff-man syndrome and insulin-dependent diabetes mellitus. TRAB -positive Graves' disease has been reported to occur together with SMS. \nIn a subgroup of patients with the stiff-man syndrome, the condition is likely to have an autoimmune paraneoplastic origin. The detection of autoantibodies against the 128-kd antigen in patients with this syndrome should be considered an indication to search for an occult breast cancer.\n\nHCV may be the etiologic virus of progressive encephalomyelitis with rigidity; a rare disorder similar to stiff-man syndrome although different because it is progressive and fatal.\nIt is possible that the reported case of association of progressive dementia with concomitant development of stiff-man syndrome in an elderly man represents an exaggerated form of such motor disturbances in dementia, and that clinical and electromyographic features of stiff-man syndrome may be present with increased incidence in patients with dementia."]

['Insulin Dependent Diabetes Mellitus', 'type I (insulin-dependent) diabetes mellitus (IDDM)', "Grave's disease", 'Breast Cancer', 'Dementia']

List non-surgical treatment modalities that are included in the Stupp protocol.

['OBJECTIVE: It is now accepted that the concomitant administration of temozolomide with radiotherapy (Stupp regime), in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM), significantly improves survival and this practice has been adopted locally since 2004.', 'BACKGROUND: The introduction of ALA-Fluorescence-guided surgery (FGS) followed by concomitant radiochemotherapy according to the Stupp-protocol is representative of the major changes in glioblastoma therapy in the past years.', 'CONCLUSIONS: FGS and radiochemotherapy according to the Stupp protocol have induced an impressive improvement in overall survival in glioblastoma patients. ', 'Current treatment strategies in patients with newly-diagnosed glioblastoma include surgical resection with post-operative radiotherapy and concomitant/adjuvant temozolomide (the "Stupp protocol") or resection with implantation of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) wafers in the surgical cavity followed by radiotherapy. ', 'The standard treatment today is maximal surgical resection followed by concomitant chemo-radiation therapy followed by adjuvant TMZ according to Stupp protocol. ', 'PATIENTS AND METHODS: A total of 191 patients with primary GBM were postoperatively treated with either radiation and concomitant TMZ, followed by adjuvant TMZ (Stupp protocol) (n = 154), or radiation followed by adjuvant TMZ (n = 37).', 'Afterward, patients received concomitant radiochemotherapy according to the Stupp protocol. ', 'The treatment of glioblastoma includes surgery followed by chemoradiation with the protocol of Stupp et al. ', "Since the publication of a study by Stupp et al in 2005, which used a protocol of conventional fractionated irradiation with concomitant TMZ followed by standard TMZ for six cycles, many clinical studies in the People's Republic of China have demonstrated that such a treatment strategy has significantly improved efficacy with limited side effects for newly diagnosed glioblastoma after surgery as compared with strategies that do not contain TMZ.", 'Standard chemoradiotherapy as per the Stupp protocol, together with multimodal rehabilitation, resulted in substantial functional improvement within 6 weeks of initiation.', 'BACKGROUND: Patients with glioblastoma treated with BCNU wafer implantation for recurrence frequently receive frontline chemoradiotherapy with temozolomide as part of the Stupp protocol.', 'This is followed by concurrent radio-chemotherapy with temozolomide (TMZ) according to the Stupp protocol. ', 'CONCLUSIONS: MGMT promoter methylation status and low MGMT expression both were identified as positive prognosticators in patients with newly diagnosed glioblastoma who underwent surgical resection and received Gliadel wafer implants followed by adjuvant radiotherapy and concomitant oral TMZ chemotherapy (the Stupp protocol).', "INTRODUCTION: To evaluate the incidence and impact of early post-chemoradiation (cRT) 'pseudoprogression' (PsPD) amongst glioblastoma multiforme (GBM) patients treated with the current standard of care - 60 Gy conformal radiotherapy with concurrent low-dose temozolomide, followed by six cycles of high-dose temozolomide (the 'Stupp protocol'). ", "In patients with glioblastoma multiforme (GBM), there is no consensus on the sequential use of two existing regimens: post-operative Gliadel implantation into the surgical cavity and concomitant temozolomide with radiotherapy followed by adjuvant temozolomide ('Stupp protocol'). ", 'We also screened for associations between the level of methylation of CpG sites and overall survival in a cohort of 50 patients uniformly treated by surgery, radiotherapy and chemotherapy with concomitant and adjuvant temozolomide (STUPP protocol). ', 'Surprisingly, less than half the patients having surgery received concomitant radiochemotherapy according to the Stupp protocol. ', 'We analyzed MGMT methylation by methylation-specific PCR in 90 GBM patients from four Portuguese hospitals, uniformly treated with radiotherapy combined with concomitant and adjuvant temozolomide (Stupp protocol).', 'The current care standards for newly diagnosed glioblastoma consist, when feasible, in surgical resection, radiotherapy, and chemotherapy, as described in the Stupp protocol. ', 'Moreover, there are no data concerning the effect of concomitant radiochemotherapy according to the STUPP protocol on the course ofMS in patients with coexisting glioblastoma. ', 'Current treatment strategies in patients with newly-diagnosed glioblastoma include surgical resection with post-operative radiotherapy and concomitant/adjuvant temozolomide (the "Stupp protocol") or resection with implantation of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) wafers in the surgical cavity followed by radiotherapy', 'Current treatment strategies in patients with newly-diagnosed glioblastoma include surgical resection with post-operative radiotherapy and concomitant/adjuvant temozolomide (the "Stupp protocol") or resection with implantation of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) wafers in the surgical cavity followed by radiotherapy', 'The standard treatment today is maximal surgical resection followed by concomitant chemo-radiation therapy followed by adjuvant TMZ according to Stupp protocol']

['Radiotherapy and chemotherapy are non-surgical treatment modalities that are included in the Stupp protocol. This protocol is widely used for treatment of glioblastoma.']

['radiotherapy', 'chemotherapy']

Can valproic acid prolong survival of glioblastoma patients?

['For patients who presented with epilepsy, the use of the antiepileptic drug VPA did not associate with survival when compared with patients who did not receive VPA treatment.', 'This prognostic effect is not solely explained by early diagnosis, and survival is not associated with VPA treatment.', 'Several in vivo and in vitro studies have indicated that VPA has radiosensitizing effects for gliomas and radioprotective influence on normal brain tissue or hippocampal neurons. The results of several retrospective studies have also indicated potential benefit to improve survival of patients with GBM. Moreover, the promising treatment results of a phase 2 trial of concurrent radiation therapy, temozolomide, and VPA for patients with GBM have been recently reported. ', 'While there have not been any novel anti-GBM therapeutics approved for many years, there has been the gradual accumulation of clinical data suggesting that the widely used anti-convulsant agent, valproic acid (VPA) may significantly prolong survival in GBM patients.', ' Additionally, VPA may result in improved outcomes compared to historical data and merits further study.', 'Several retrospective studies in seizure patients with glioblastoma treated with chemotherapy have provided evidence for a moderately improved survival with the use of valproic acid, possibly due to inhibition of histone deacetylase', 'Several clinical studies have reported that valproic acid could prolong survival of GBM patients', 'While there have not been any novel anti-GBM therapeutics approved for many years, there has been the gradual accumulation of clinical data suggesting that the widely used anti-convulsant agent, valproic acid (VPA) may significantly prolong survival in GBM patients', 'Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma', 'Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma.', 'Valproic acid use during radiation therapy for glioblastoma associated with improved survival.', 'Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24-0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53-0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49-0.93). ', 'Several retrospective studies in seizure patients with glioblastoma treated with chemotherapy have provided evidence for a moderately improved survival with the use of valproic acid, possibly due to inhibition of histone deacetylase.', 'Several uncontrolled retrospective case series and a post hoc analysis of the registration trial for temozolomide indicated an association between valproic acid (VPA) use and improved survival outcomes in patients with newly diagnosed glioblastoma.To confirm the hypothesis suggested above, a combined analysis of survival association of antiepileptic drug use at the start of chemoradiotherapy with temozolomide was performed in the pooled patient cohort (n = 1,869) of four contemporary randomized clinical trials in newly diagnosed glioblastoma: AVAGlio (Avastin in Glioblastoma; NCT00943826), CENTRIC (Cilengitide, Temozolomide, and Radiation T', 'Several clinical studies have reported that valproic acid could prolong survival of GBM patients.', 'Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24-0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53-0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49-0.93).VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy.', 'The combination of radiotherapy, temozolomide and valproic acid (VPA) has shown some promise in retrospective analyses of patients with glioblastoma, although their mechanisms of action remain unknown.We investigated the in vitro and in vivo effects of pretreating glioma cells with temozolomide and VPA as an immunization strategy to boost an adaptive immune response in a syngeneic mouse model.Temozolomide and VPA induced autophagy in GL261 glioma cells, and caused tumor antigen-specific T-cells to become activated effector T-cells.', 'Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma.']

['Yes, there is evidence to suggest that valproic acid (VPA) is associated with prolonged survival of glioblastoma patients. Several studies have indicated that VPA has radiosensitizing effects for gliomas and radioprotective influence on normal brain tissue or hippocampal neurons.']

['yes']

Which types of cancer can be recognized and treated by the use of immunotherapy?

['omising expansion of antigen-specific T cells, the clinical responses following vaccination have been limited, indicating that further improvements of DC vaccine potency are necessary. Pre-clinical studies suggest that vaccination with combination of primary DC subsets, such as myeloid and plasmacytoid blood DCs (mDCs and pDCs, respectively), may result in stronger clinical responses. However, it is a challenge to obtain high enough numbers of primary DCs for immunotherapy, since their frequency in blood is very low. We therefore explored the possibility to generate them from hematopoietic progenitor cells (HPCs). Here, we show that by inhibiting the aryl hydrocarbon receptor with its antagonist StemRegenin 1 (SR1), clinical-scale numbers of functional BDCA2(+)BDCA4(+) pDCs, BDCA1(+) mDCs, and BDCA3(+)DNGR1(+) mDCs can be efficiently generated from human CD34(+) HPCs. The ex vivo-generated DCs were phenotypically and functionally comparable to peripheral blood DCs. They secreted high levels of pro-inflammatory cytokines such as interferon (IFN)-α, interleukin (IL)-12, and tumor necrosis factor (TNF)-α and upregulated co-stimulatory molecules and maturation markers following stimulation with Toll-like receptor (TLR) ligands. Further, the', 'odent models of prostate cancer have served as valuable preclinical models to evaluate novel treatments and understand malignant disease progression. In particular, a transgenic rat autochthonous model of prostate cancer using the SV40 large T antigen expressed under a prostate-specific probasin promoter was previously developed as a model of androgen-dependent prostate cancer (TRAP). In the current report, we backcrossed this strain to the Lewis strain, an inbred rat strain better characterized for immunological analyses. We demonstrate that Lewis transgenic rats (Lew-TRAP) developed prostate adenocarcinomas with 100% penetrance by 25 weeks of age. Tumors were predominantly androgen-dependent, as castration prevented tumor growth in the majority of animals. Finally, we demonstrate that Lew-TRAP rats could be immunized with a DNA vaccine encoding a human prostate tumor antigen (prostatic acid phosphatase) with the development of Lewis strain-specific T-cell responses. We propose', ' we analyzed NY-ESO-1 expression in 222 melanoma specimens, including 16 primary and 206 metastatic tumors. Our results support previous findings showing higher expression of NY-ESO-1 in metastatic (58/206; 28.2%) versus primary (0/16) tumors. In addition, our results show that the epithelioid subtype of melanoma has the highest incidence of NY-ESO-1 expression. These findin', ' Immunotherapy is a highly promising form of cancer treatment, but its efficacy can be severely compromised by an immunosuppressive tumor microenvironment.']

['When normal cells turn into cancer cells, some of the antigens on their surface change. These cells, like many body cells, constantly shed bits of protein from their surface into the circulatory system. Often, tumor antigens are among the shed proteins.\nThese shed antigens prompt action from immune defenders, including cytotoxic T cells, natural killer cells, and macrophages. According to one theory, patrolling cells of the immune system provide continuous bodywide surveillance, catching and eliminating cells that undergo malignant transformation. Tumors develop when this immune surveillance breaks down or is overwhelmed.\nA new approach to cancer therapy uses antibodies that have been specially made to recognize specific cancers such as Melanoma, Leukaemia, Lung Cancer, Colorectal Cancer, Breast Cancer, Head Cancer and Pancreatic Cancer.']

['Melanoma', 'Leukaemia', 'Lung Cancer', 'Colorectal Cancer', 'Breast Cancer', 'Head Cancer', 'Pancreatic Cancer', 'Prostate tumor']

Are transcription and splicing connected?

[', as splicing is often cotranscriptional, a complex picture emerges in which splicing regulation not only depends on the balance of splicing factor binding to their pre-mRNA target sites but also on transcription-associated features such as protein recruitment to the transcribing machinery and elongation kinetics.', 'recent evidence shows that chromatin structure is another layer of regulation that may act through various mechanisms', 'hese span from regulation of RNA polymerase II elongation, which ultimately determines splicing decisions, to splicing factor recruitment by specific histone marks.', 'Chromatin may not only be involved in alternative splicing regulation but in constitutive exon recognition as well', "Moreover, splicing was found to be necessary for the proper 'writing' of particular chromatin signatures, giving further mechanistic support to functional interconnections between splicing, transcription and chromatin structure.", 'These links between chromatin configuration and splicing raise the intriguing possibility of the existence of a memory for splicing patterns to be inherited through epigenetic modifications.', 'Spliceosome assembly occurs co-transcriptionally, raising the possibility that DNA structure may directly influence alternative splicing.', 'upporting such an association, recent reports have identified distinct histone methylation patterns, elevated nucleosome occupancy and enriched DNA methylation at exons relative to introns', 'Moreover, the rate of transcription elongation has been linked to alternative splicing.', 'ere we provide the first evidence that a DNA-binding protein, CCCTC-binding factor (CTCF), can promote inclusion of weak upstream exons by mediating local RNA polymerase II pausing both in a mammalian model system for alternative splicing, CD45, and genome-wide', 'We recently showed that cotranscriptional splicing occurs efficiently in Drosophila,', 'In recent years it became apparent that splicing is predominantly cotranscriptional', 'To determine the prevalence of cotranscriptional splicing in Drosophila, we sequenced nascent RNA transcripts from Drosophila S2 cells as well as from Drosophila heads. Eighty-seven percent of the introns assayed manifest >50% cotranscriptional splicing. The remaining 13% are cotranscriptionally spliced poorly or slowly, with ∼3% being almost completely retained in nascent pre-mRNA.', 'We estimate that > or =90% of endogenous yeast splicing is posttranscriptional, consistent with an analysis of posttranscriptional snRNP-associated pre-mRNA.', 'Notably, the topoisomerase I inhibitor camptothecin, which stalls elongating Pol II, increased cotranscriptional splicing factor accumulation and splicing in parallel. This provides direct evidence for a kinetic link between transcription, splicing factor recruitment and splicing catalysis.', 'Recent evidence indicates that transcriptional elongation and splicing can be influenced reciprocally: Elongation rates control alternative splicing and splicing factors can, in turn, modulate pol II elongation.', 'The presence of transcription factors in the spliceosome and the existence of proteins, such as the coactivator PGC-1, with dual activities in splicing and transcription can explain the links between both processes and add a new level of complexity to the regulation of gene expression in eukaryotes.']

['Yes. There is strong evidence that splicing and transcription are intimately coupled in metazoans, with genome wide surveys show that most splicing occurs during transcription. Chromatin structure, RNA polymerase dynamics, and recruitment of splicing factors through the transcriptional machinery are factors that explain a role for transcription in the regulation of splicing.']

['yes']

What is the phenotype of people carrying mutations in the gene PRDM12?

['The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception.', 'Here we show that PRDM12 is a key regulator of sensory neuronal specification in Xenopus. Modeling of human PRDM12 mutations that cause hereditary sensory and autonomic neuropathy (HSAN) revealed remarkable conservation of the mutated residues in evolution.', 'Transcriptional regulator PRDM12 is essential for human pain perception.', ' New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. ', ' However, the study of genetic disorders rendering individuals completely unable to feel pain offers hope. All causes of congenital painlessness affect nociceptors, evolutionarily conserved specialist neurons able to sense all type of tissue damage. The discovery of new genes essential for sensing pain (SCN11A, PRDM12, and CLTCL1) has provided unexpected insights into the biological mechanisms that drive distinct stages of nociception.']

['New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families.']

['congenital insensitivity to pain', 'CIP']

Is insulin-like growth factor-I (IGF-I) able to affect tendon protein synthesis in classic Ehlers-Danlos syndrome patients?

['Tendon protein synthesis rate in classic Ehlers-Danlos patients can be stimulated with insulin-like growth factor-I', 'IGF-I injections significantly increased FSR values in cEDS patients but not in controls', 'In conclusion, baseline protein synthesis rates in connective tissue appeared normal in cEDS patients, and the patients responded with an increased tendon protein synthesis rate to IGF-I injections', 'In conclusion, baseline protein synthesis rates in connective tissue appeared normal in cEDS patients, and the patients responded with an increased tendon protein synthesis rate to IGF-I injections', 'IGF-I injections significantly increased FSR values in cEDS patients but not in controls (delta values: cEDS 0']

['Tendon protein synthesis rate in classic Ehlers-Danlos patients can be stimulated with insulin-like growth factor-I ', 'In an experimental setting, baseline protein synthesis rates in connective tissue appeared normal in classic Ehlers-Danlos syndrome patients, and the patients responded with an increased tendon protein synthesis rate to IGF-I injections.']

['yes']

How many and which are the different isoforms for the ryanodine receptor?

['Skeletal (RyR1) and cardiac muscle (RyR2) isoforms of ryanodine receptor calcium channels', 'Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca(2+) from intracellular stores during excitation-contraction coupling in both cardiac and skeletal muscle. RyRs are the largest known ion channels (> 2MDa) and exist as three mammalian isoforms (RyR 1-3),', 'Ryanodine receptors (RyRs) are a family of intracellular calcium release channels that mediate calcium-induced calcium release from the endoplasmic reticulum. Among the three RyR isoforms, RyR3 is preferentially expressed in the brain especially in the hippocampus and striatum.', 'In excitable cells such as skeletal and cardiac myocytes excitation-contraction coupling is an important intermediate step between initiation of the action potential and induction of contraction. This process is predominantly controlled by Ca(2+) release from the sarcoplasmic reticulum via the ryanodine receptor. This very large protein (MW 560 kDa) exists as a homotetramer (~2.2 MDa) and is expressed in three isoforms: RyR1, expressed in skeletal muscle; RyR2, expressed in cardiac muscle; and RyR3, expressed in various cells at lower levels than the other isoforms. ', 'Generally, three ryanodine receptor isoforms (RyR1-RyR3) are known; ', 'Ryanodine receptor (RyR) is a Ca(2+) channel that mediates Ca(2+) release from intracellular stores.', 'There are three RyR isoforms,', 'Ryanodine receptors (RyRs) are intracellular Ca(2+) channels that mediate the release of calcium from internal stores and therefore play an important role in Ca(2+) signaling and homeostasis. Three RyR isoforms have been described thus far,', 'RyR1 and RyR2', 'RyR3', 'Three different isoforms of the SR Ca2+ release channels, or ryanodine receptors (RyRs), have been isolated (RyR1, RyR2, and RyR3).']

['Generally, three ryanodine receptor isoforms (RyR1-RyR3) are known. RyR1, expressed in skeletal muscle; RyR2, expressed in cardiac muscle; and RyR3, expressed in various cells. RyR3 is preferentially expressed in the brain especially in the hippocampus and striatum.']

['Ryanodine Receptor type 1', 'RyR1', 'Ryanodine Receptor type 2', 'RyR2', 'Ryanodine Receptor type 3', 'RyR3']

Which interleukins are inhibited by Dupilumab?

['The world\'s first prospective controlled studies with the biologic human anti-IL4R antibody dupilumab for the indication "atopic dermatitis" were published in 2014. These motivated (1) to extend the studies to dupilumab and (2) to clinically test antagonization of other target molecules of TH2 polarized, atopic inflammation, e.g., IL-13, IL-31, IL-22, TSLP, and CRTH2. A', 'Among the recently developed antiasthma biologic drugs, the monoclonal antibody dupilumab is very promising because of its ability to inhibit the biological effects of both IL-4 and IL-13. Indeed, dupilumab prevents IL-4/13 interactions with the α-subunit of the IL-4 receptor complex. ', 'BACKGROUND: Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. ', ' In early-phase trials, dupilumab, a fully human mAb targeting IL-4 receptor α, markedly improved disease activity, but the effect of IL-4/IL-13 blockade on AD at the molecular level has not been characterized.', 'Examples include the efficacy of omalizumab in patients with severe refractory atopic asthma characterized by raised serum total IgE, mepolizumab, reslizumab, and benralizumab in patients with recurrent eosinophilic exacerbations characterized by blood and sputum eosinophilia despite high doses of corticosteroids, and lebrikizumab, pitrakinra, dupilumab, and tralokinumab that target the IL-4/IL-13 signalling pathways in patients with eosinophilic asthma or raised serum periostin.', 'BACKGROUND: Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels.', 'With respect to immune dysregulation, dupilumab, a fully human monoclonal antibody directed at the IL-4 receptor alpha subunit was recently shown to be effective in treating adults with moderate-to-severe AD.', 'Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels.', 'We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels.', 'Indeed, dupilumab prevents IL-4/13 interactions with the α-subunit of the IL-4 receptor complex.', 'We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels. ', 'BACKGROUND: Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)-mediated inflammation could help in the treatment of related diseases, including atopic dermatitis. ', 'Indeed, dupilumab prevents IL-4/13 interactions with the α-subunit of the IL-4 receptor complex.', 'We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels.', 'Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels.']

['Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels.']

['interleukin-4', 'interleukin-13']

Can desvenlafaxine be used at a dose of 50mg/day?

['Long-term use of desvenlafaxine was safe and well tolerated, with a clinical benefit/risk profile similar to that in other populations.', 'e objective of this study was to evaluate the long-term safety of desvenlafaxine for continuation treatment of major depressive disorder (MDD) in Japanese patients. This was a phase 3, multicenter, 10-month, open-label study with flexible dosing of desvenlafaxine (25, 50, 100 mg/day)', 'n an effort to establish the lowest effective dose of desvenlafaxine (administered as desvenlafaxine succinate), we assessed the efficacy, safety, and tolerability of 10- and 50-mg/day desvenlafaxine vs placebo for the treatment of major depressive disorder', 'Change from baseline to final evaluation in adjusted HAM-D(17) total scores was not significantly different comparing desvenlafaxine 10 mg/day (-9.28) and desvenlafaxine 50 mg/day (-8.92) with placebo (-8.42)', 'Overall rates of treatment-emergent adverse events with both doses were similar to placebo', 'However, in a companion study reported separately, desvenlafaxine 50 mg, but not 25 mg, separated from placebo. Taken together, these studies suggest that 50 mg is the minimum effective dose of desvenlafaxine for the treatment of major depressive disorder. ', 'Desvenlafaxine XR was dosed at 50 mg/day for 10 days.', 'Desvenlafaxine therapy is initiated at the therapeutic dose (50 mg/day) without a need for dose titration.', 'Clinical studies have investigated the efficacy of DVS in doses ranging from 50 to 400 mg/day for the treatment of MDD in adult outpatients. The effects of DVS 50 mg/day have been clearly distinguished from placebo in the reduction of MDD symptoms in such clinical trials. No additional therapeutic benefits were found at doses > 50 mg/day. The recommended dose of DVS ranges from 50 to 100 mg.', 'Adult outpatients with major depressive disorder received desvenlafaxine doses ranging from 50-400 mg/day or placebo for 8 weeks', ' At the recommended therapeutic dose of 50 mg/day, discontinuation due to adverse events was similar to placebo', 'atients received fixed (50, 100, 200, or 400 mg/day; n=1,342) or flexible doses (100-400 mg/day; n=463) of desvenlafaxine or placebo (n=1,108)', 'Desvenlafaxine demonstrated short-term efficacy for treating major depressive disorder across the range of doses studied. No evidence of greater efficacy was observed with doses >50 mg/day; a strong dose-response effect on tolerability was observed.', 'To assess the efficacy, safety, and tolerability of 50- and 100-mg/day doses of desvenlafaxine (administered as desvenlafaxine succinate), a serotonin-norepinephrine reuptake inhibitor, for the treatment of major depressive disorder (MDD)', 'Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) MDD and 17-item Hamilton Rating Scale for Depression (HAM-D(17)) scores > or =20 were randomly assigned to double-blind placebo or desvenlafaxine treatment (fixed dose of 50 mg/day or 100 mg/day) for 8 weeks.', 'Desvenlafaxine 50 mg was associated with a significantly greater adjusted mean change from baseline on the HAM-D(17) (-11.5) compared with placebo (-9.5, p=0.018)', ' These results demonstrate efficacy, safety, and tolerability of desvenlafaxine 50 mg/day for treating MDD. ', 'CONCLUSIONS: Desvenlafaxine at the recommended dose of 50 mg/d was effective in relapse prevention of depression during a 6-month period in patients who demonstrated stable response after 20 weeks of open-label desvenlafaxine treatment.']

['Yes, desvenlafaxine can be at 50mg/day to treat patients with major depressive disorder. Studies suggest that 50 mg is the minimum effective dose of desvenlafaxine for the treatment of major depressive disorder. The recommended dose of DVS ranges from 50 to 100 mg.']

['yes']

In which proteins is the chromodomain present?

['Chromodomain helicase DNA-binding protein 2 affects the repair of X-ray and UV-induced DNA damage.', 'Chromodomain helicase DNA-binding proteins (CHD) belong to a group of highly conserved chromatin remodeling proteins that are implicated in regulation of transcription. In an effort to understand the physiological role of one of the CHD members in a mammalian model system, we developed a mutant mouse model for the Chd2 gene.', 'Crystal structure of the chromodomain helicase DNA-binding protein 1 (Chd1) DNA-binding domain in complex with DNA.', 'Because, in plants, DNA methylation can serve as a signal for H3-lysine9-dimethylation (H3K9me2), and subsequently for non-CG-context DNA methylation, SET-domain histone methyltransferase and chromodomain dna methyltransferase 3 (cmt3) mutations were introgressed. In suvh4 suvh5 suvh6 and cmt3 mutants, H3K9me2 associated with lacO repeats is diminished, but homologous pairing persists.', 'Mutations in CHD7, the gene encoding chromodomain helicase DNA binding protein 7, are present in 60-80% of individuals with the CHARGE syndrome.', 'Chromodomain is present in the integrase structures of blastopia and 412 subgroup LTR-retrotransposons and may facilitate the process of non-specific integration.', 'The CHARGE syndrome is a multiple congenital malformation syndrome that usually results from deletion or heterozygous loss of function mutations of the chromodomain helicase DNA-binding protein 7 (CHD7) gene at 8q12.1.', 'A causative mutation within the chromodomain helicase DNA-binding protein-7 gene, which plays an important role in the embryonic development, is present in 2/3 of affected patients.', 'CHD1 is a subfamily member of the CHD family, which possesses a chromodomain, a helicase domain, and a DNA-binding domain.', 'The chromatin organizer modifier domain (chromodomain) is present in proteins that contribute to chromatin organization and mediates their binding to methylated histone H3.', 'Mass spectrometric analysis revealed serine-42, a conserved amino acid in the chromodomain, as a phosphorylation site of Cbx2. Phosphorylation of the chromodomain of Cbx2 on this residue in vitro resulted in a reduced level of binding to an H3 peptide containing trimethylated lysine-9 as well as an increase in the extent of binding to an H3 peptide containing trimethylated lysine-27, suggesting that such phosphorylation changes the binding specificity of Cbx2 for modified histone H3. Phosphorylation of the chromodomain of Cbx2 may therefore serve as a molecular switch that affects the reading of the histone modification code and thereby controls epigenetic cellular memory.', 'Here we identify the ATP-dependent chromatin remodeling factor chromodomain helicase DNA-binding protein 8 (CHD8) as a novel coregulator of androgen-responsive transcription.', 'Mutations in CHD7, a chromodomain gene, are present in a majority of individuals with CHARGE syndrome, a multiple anomaly disorder characterized by ocular Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital hypoplasia and Ear anomalies.', 'Two new chromodomain-containing proteins that associate with heterochromatin in Sciara coprophila chromosomes.', 'Both proteins, ScoHET1 of 37 kDa and ScoHET2 of 44 kDa, display two chromodomain motifs that contain the conserved residues essential for the recognition of methylated histone H3 at lysine 9.', 'In this study, we present a detailed histomorphologic characterization of mice containing a mutation in the chromodomain helicase DNA-binding protein 2 (Chd2).', 'Specificity of the chromodomain Y chromosome family of chromodomains for lysine-methylated ARK(S/T) motifs.', 'Previous studies have shown two homologous chromodomain modules in the HP1 and Polycomb proteins exhibit discriminatory binding to related methyllysine residues (embedded in ARKS motifs) of the histone H3 tail.', 'In vertebrates, HP1-like chromodomains are also present in the chromodomain Y chromosome (CDY) family of proteins adjacent to a putative catalytic motif. The human genome encodes three CDY family proteins, CDY, CDYL, and CDYL2.', 'The CDY chromodomain exhibits discriminatory binding to lysine-methylated ARK(S/T) motifs, whereas the CDYL2 chromodomain binds with comparable strength to multiple ARK(S/T) motifs. Interestingly, subtle amino acid changes in the CDYL chromodomain prohibit such binding interactions in vitro and in vivo.', 'We assessed mRNA transcript abundance of seven genes that code for proteins with established roles in epigenetically-mediated gene silencing [transcriptional co-repressor SIN3A, DNA (cytosine-5-) methyltransferase 1, methyl CpG binding protein 2, chromodomain helicase DNA binding protein 4, histone binding protein rbbp4, histone deacetylase 1 and nuclear receptor co-repressor 2] using qRT-PCR.', 'CHD7 is a member of the chromodomain helicase DNA binding domain (CHD) family of ATP-dependent chromatin remodelling enzymes.', 'The cysteine-rich CXXC domains of MBD1 bound to Ring1b and the chromodomain of hPc2.', 'Methylation of lysine 9 within histone H3 and the subsequent binding of the chromodomain protein heterochromatin protein 1 (HP1) are thought to initiate heterochromatin formation in vivo and to propagate a heterochromatic state lasting through several cell divisions.', 'Here, we show that the SNF2-like chromodomain helicase protein CHD8 interacts with the insulator binding protein CTCF. C', 'The chromodomain (CD) of the Drosophila Polycomb protein exhibits preferential binding affinity for histone H3 when trimethylated at lysine 27.', 'Despite a high degree of conservation, the Cbx chromodomains display significant differences in binding preferences.', 'Three-dimensional solution structures of the chromodomains of cpSRP43.', 'Recently, three functionally distinct chromodomains (CDs) have been identified in cpSRP43.', 'The C-terminal helical segment typically found in the nuclear chromodomains is absent in CD1.', 'Critical comparison of the structures of the chromodomains of cpSRP43 with those found in nuclear chromodomain proteins revealed that the diverse protein-protein interactions mediated by the CDs appear to stem from the differences that exist in the surface charge potentials of each CD.', 'Characterization and functional analysis of CReMM, a novel chromodomain helicase DNA-binding protein.', 'The present study describes a newly identified protein named CReMM (chromatin-related mesenchymal modulator). The protein was studied by bioinformatic means and classified as a member of the third subfamily of chromodomain helicase DNA-binding proteins (CHD). In silico translation defined CReMM as a multiple domains protein including two chromodomains, SNF2/ATPase, helicase C domain and an A/T-DNA-binding domain (DBD).', 'Identification and analysis of chromodomain-containing proteins encoded in the mouse transcriptome.', 'The chromodomain is 40-50 amino acids in length and is conserved in a wide range of chromatic and regulatory proteins involved in chromatin remodeling. Chromodomain-containing proteins can be classified into families based on their broader characteristics, in particular the presence of other types of domains, and which correlate with different subclasses of the chromodomains themselves.', 'Here we show that the chromodomain of CMT3 can directly interact with the N-terminal tail of histone H3, but only when it is simultaneously methylated at both the H3K9 and H3K27 positions.', 'In addition to the canonical MYST HAT catalytic domain, both TgMYST-A and -B possess an atypical C2HC zinc finger and a chromodomain.', 'Clr7 and Clr8 are required for localization of the Swi6 chromodomain protein and for histone H3 lysine 9 methylation, thereby influencing not only mating-type switching but also transcriptional silencing in all previously characterized heterochromatic regions, chromosome segregation, and meiotic recombination in the mating-type region.', 'MRG15, a novel chromodomain protein, is present in two distinct multiprotein complexes involved in transcriptional activation.', 'MRG15 is a novel chromodomain protein that is a member of a family of genes related to MORF4. MORF4 (mortality factor on chromosome 4) induces senescence in a subset of human tumor cell lines.', 'Analysis of deletion mutants of MRG15 indicated that the leucine zipper at the C-terminal region of MRG15 was important for the protein associations in MAF1 and that the N-terminal chromodomain was required for the assembly of the MAF2 protein complex. Consistent with these data was the fact that a histone acetyltransferase activity associated with MRG15 was lost when the chromodomain was deleted and that both mutant MRG15 proteins failed to activate the B-myb promoter. The various mechanisms by which MRG15 could activate gene transcription are discussed.', 'The chromodomain (CD) is a highly conserved motif present in a variety of animal and plant proteins, and its probable role is to assemble a variety of macromolecular complexes in chromatin.', 'Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail.', 'The chromodomain of the HP1 family of proteins recognizes histone tails with specifically methylated lysines. Here, we present structural, energetic, and mutational analyses of the complex between the Drosophila HP1 chromodomain and the histone H3 tail with a methyllysine at residue 9, a modification associated with epigenetic silencing. The histone tail inserts as a beta strand, completing the beta-sandwich architecture of the chromodomain. The methylammonium group is caged by three aromatic side chains, whereas adjacent residues form discerning contacts with one face of the chromodomain.', 'The MORF4-Related Gene on chromosome 15 (MRG15) is a member of a novel family of genes originally identified in studies to reveal cell senescence-inducing factors. MRG15 contains several predicted protein motifs, including a nuclear localization signal, a helix-loop-helix region, a leucine zipper, and a chromodomain.', 'Four alleles of dMi-2 mutants were further characterized in molecular nature; dMi-2(BL1) was found to have a mutation in the ATP-binding motif of the ATPase domain, dMi-2(BL7) in the core histidine of the first plant homeodomain zinc finger and dMi-2(BL12) in a conserved serine in the chromodomain.', 'These analyses also suggest that the msl-3/MRG15 duplication occurred after the fungus/animal split, while an independent duplication occurred in plants. The proteins encoded by these genes have similar structures, including a putative chromodomain close to their N-terminal end and a putative leucine zipper at their C-terminus.', 'CHD1 interacts with SSRP1 and depends on both its chromodomain and its ATPase/helicase-like domain for proper association with chromatin.', 'Interaction between an integral protein of the nuclear envelope inner membrane and human chromodomain proteins homologous to Drosophila HP1.', 'A mammalian DNA-binding protein that contains a chromodomain and an SNF2/SWI2-like helicase domain.', 'A Southern blot analysis indicated that this protein, which we have named CHD-1, for chromodomain-helicase-DNA-binding protein, is present in most, if not all, mammalian species.', 'Here we show that chromodomain helicase DNA-binding protein 4 (Chd4) forms a complex with Gata3 in Th2 cells that both activates Th2 cytokine transcription and represses the Th1 cytokine IFN-γ.', 'Chromodomain helicase DNA-binding protein 4 (CHD4), the defining subunit of the nucleosome remodeling and deacetylase (NuRD) complex, is a nucleosome-remodeling protein of the SNF2/ISWI2 family, members of which contain two chromo domains and an ATP-dependent helicase module.', 'Among those proteins with >40% regulation were Macrophage Capping protein (CAPG) and Chromodomain Helicase DNA binding protein 4 (CHD4) proteins which were significantly upregulated by pp32r1 and pp32r1Y140H overexpression.', 'This heterochromatin coordinates expression levels by associating with a chromodomain protein Chp1 and an antisilencing factor Epe1.', 'Within NCCs, Brg1 partners with chromatin remodeler Chromodomain-helicase-DNA-binding protein 7 (Chd7) on the PlexinA2 promoter to activate PlexinA2, which encodes a receptor for semaphorin to guide NCCs into the OFT.', 'Chromodomain Helicase DNA binding protein 5 (CHD5) is a tumor suppressor mapping to 1p36, a genomic region that is frequently deleted in human cancer.', 'Here, we identify ENHANCED PHOTOMORPHOGENIC1 (EPP1), previously known as PICKLE (PKL), an ATP-dependent chromatin remodeling factor of the chromodomain/helicase/DNA binding family, as a repressor of photomorphogenesis in Arabidopsis thaliana.', 'Chromodomain on Y-like (CDYL) is a chromodomain protein that has sequence homology to members of the enoyl CoA hydratase family.', 'Our previous structural work demonstrated that a coiled-coil interaction between MBD2 and GATA zinc finger domain containing 2A (GATAD2A/p66α) proteins recruits the chromodomain helicase DNA-binding protein (CHD4/Mi2β) to the NuRD complex and is necessary for MBD2-mediated DNA methylation-dependent gene silencing in vivo (Gnanapragasam, M. N., Scarsdale, J. N., Amaya, M. L., Webb, H. D., Desai, M. A., Walavalkar, N. M., Wang, S. Z., Zu Zhu, S., Ginder, G. D., and Williams, D. C., Jr. (2011) p66α-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex.', 'Sequence analysis showed that NlElp3 contains GNAT-type HAT domain and Radical SAM domain, and NlMof contains chromodomain and MOZ-SAS acetyltransferase domain.', 'We examined requirements for individual domains of chromodomain helicase DNA-binding protein 4 (CHD4), a core catalytic component of NuRD complexes, as well as the NuRD subunit methyl-binding domain protein 2 (MBD2) and methylated DNA, for NuRD function in the context of tissue-specific transcription.', 'OBJECTIVE: Chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1L) is an SNF2-like transcription factor involved in the development of human hepatocellular carcinoma (HCC).', 'Twelve rare copy number variants segregate with talipes equinovarus in multiplex pedigrees, and contain the developmentally expressed transcription factors and transcriptional regulators PITX1, TBX4, HOXC13, UTX, CHD (chromodomain protein)1, and RIPPLY2.', 'OBJECTIVE: Chromodomain helicase DNA-binding protein 5 (CHD5) plays a role in normal neural development and in tumorigenesis of various human cancers.', 'The chromodomain, helicase, DNA-binding protein 5 (CHD5) is a chromatin remodeling enzyme which is implicated in tumor suppression.', 'The methyl-mark determines a highly flexible and very dynamic interaction of the chromodomain of hHP1β with the H3-tail.', 'To test this hypothesis, we performed a comprehensive molecular dynamics study in which we analyzed a crystallographically defined complex that involves the HP1 chromodomain and an H3 tail peptide.', 'Whereas the molecular target of the MRG15 chromodomain (CD) has been suggested to be H3K36me(2/3), the precise molecular target of the Pf1 plant homeodomain 1 (PHD1) has remained elusive.', 'Chp1, a chromodomain (CD) protein, forms the Ago1-containing RNA-induced transcriptional silencing (RITS) complex and recruits siRNA-bound RITS to methylated histone H3 lysine 9 (H3K9me) via its CD.', 'In addition, cells expressing S473A also displayed defective mobilization of the HP1-β chromodomain protein.', 'CHD7 is a chromodomain-containing, ATP dependent helicase protein that is highly expressed in the developing ear and is required for semicircular canal development in both humans and mice.', "Moreover, the LTR retrotransposon fraction in BAC clones harboring genes is disproportionately composed of chromodomain-containing Gypsy LTR retrotransposons ('chromoviruses'), and the majority of the intact chromoviruses contain tandem chromodomain duplications.", 'Stimulated by positively charged residues in the hinge region, RNA competes with methylated histone H3K9 for binding to the chromodomain of HP1(Swi6).', 'CHD7 is one of the nine members of the chromodomain helicase DNA-binding family of ATP-dependent chromatin remodeling enzymes.', 'Therefore, p53, ZNF237, and Chromodomain helicase DNA-binding protein 3 inhibit the function ER Ca²⁺ leak channels to regulate both ER and cytoplasmic Ca²⁺ levels and may potentially control Ca²⁺-signaling function of PS1.', 'We show that chromodomain helicase DNA-binding domain 2 (Chd2), a SNF2 chromatin remodelling enzyme family member, interacts with MyoD and myogenic gene regulatory sequences to specifically mark these loci via deposition of the histone variant H3.3 prior to cell differentiation.', 'Analysis of the Neurospora crassa chromodomain protein CDP-2, a component of a newly characterized HP1-containing complex, reveals a second gene-silencing mechanism and provides insights into the dynamic nature of chromatin domains that possess shared components.', 'We state that the non-tumorogenic potential of bitumen transformant in nude/SCID mice can be attributed to the downregulation of galectin-1, chromodomain helicase DNA-binding protein 1-like gene, and membrane-associated guanylate kinase 2 protein.', 'Mutagenesis of Tf1 integrase revealed that the complete Tf1 integrase protein (excluding its chromodomain) is required for stimulating the Tf1 RT primer removal activity.', 'About 80% of patients with a clinical diagnose, have a mutation or a deletion in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7).', 'Owing to different polyadenylation sites and alternative splicing events, the human CBX2 locus produces two transcripts: a 5-exon transcript that encodes the 532-amino acid CBX2-1 isoform that contains the conserved chromodomain and Pc box and a 4-exon transcript encoding a shorter isoform, CBX2-2, lacking the Pc box but still possessing a chromodomain.', 'Chromodomain helicase DNA-binding protein 4 (Chd4) is the core catalytic subunit of the nucleosome remodeling and deacetylase (NuRD) chromatin remodeling complex.', 'Chromodomain helicase DNA-binding proteins (CHD) belong to a group of highly conserved chromatin remodeling proteins that are implicated in regulation of transcription.', 'Here, we report that chromodomain helicase DNA-binding protein 4 (CHD4) is a novel BRIT1 binding partner that regulates the HR repair process.', 'Here, we report that the chromodomain-containing protein MRG-1 is an important factor for genomic integrity in meiosis in Caenorhabditis elegans.', 'The chromodomain protein, Chromator, can be divided into two main domains, a NH(2)-terminal domain (NTD) containing the chromodomain (ChD) and a COOH-terminal domain (CTD) containing a nuclear localization signal.', 'Chromodomain helicase DNA binding protein 5 (CHD5) is a potent tumor suppressor that serves as a master regulator of a tumor-suppressive network.', 'By high-resolution tiling array CGH, the smallest common deletion targeted just one gene, the chromatin remodeler chromodomain helicase DNA-binding protein 1 (CHD1).', 'Here we report direct evidence for presynaptic pairing activity intrinsic to non-PC regions, which is facilitated by a conserved chromodomain protein, MRG-1.', 'The chromodomain of MPP8 recognizes the dimethylated Dnmt3aK44me2.', 'Members of the chromodomain helicase DNA-binding (CHD) family of proteins are thought to regulate gene expression.', 'It has been shown that the methylation mark of vertebrate histone H1 is specifically recognized by the chromodomain of HP1.', 'To this end, we have performed mutation studies on the Drosophila HP1α chromodomain, which binds H3K9Me(2) and H3K9Me(3) with approximately equal affinities.', 'We are interested in defining which elements of the chromodomain helicase DNA-binding protein 1 (Chd1) remodeler are necessary and sufficient for sliding nucleosomes.', 'Chromatin remodelers are ATP-dependent machines that dynamically alter the chromatin packaging of eukaryotic genomes by assembling, sliding, and displacing nucleosomes.', 'Ocular coloboma, heart malformation, choanal atresia, retardation of growth and/or development, genital hypoplasia, and ear anomalies associated with deafness (CHARGE) syndrome is a rare, usually sporadic, autosomal dominant disorder, caused by mutations within the CHD7 (chromodomain helicase DNA-binding protein 7) gene, in nearly 70% of cases.', 'Here we report that the chromodomain-containing protein CDYL specifically recognizes di- and tri-methylated H3K27 (H3K27me2 and H3K27me3) and directly interacts with EZH2, the catalytic subunit of PRC2.', 'Murine Chd1 (chromodomain helicase DNA-binding protein 1), a chromodomain-containing chromatin remodeling protein, is necessary for embryonic stem (ES) cell pluripotency.', 'Among those genes, zinc finger helicase (ZFH), also termed chromodomain-helicase-DNA-binding protein 3 (Chd3), was one of the highly expressed transcripts in tentative cementoblasts.', 'UNLABELLED: Emerging evidence implicates the chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) as a specific oncogene in human hepatocellular carcinoma (HCC).', 'Here, we investigate the function of chromodomain helicase DNA binding protein 7 (chd7) during zebrafish somitogenesis.', 'Heterozygous mutations in the gene encoding chromodomain-DNA-binding-protein 7 (CHD7) cause CHARGE syndrome, a multiple anomaly condition which includes vestibular dysfunction and hearing loss.', 'BACKGROUND: The CHD5 gene located on 1p36 encodes a protein-chromodomain helicase DNA-binding protein 5. CHD5 has been shown to be a tumor suppressor gene candidate.', 'Because, in plants, DNA methylation can serve as a signal for H3-lysine9-dimethylation (H3K9me2), and subsequently for non-CG-context DNA methylation, SET-domain histone methyltransferase and chromodomain dna methyltransferase 3 (cmt3) mutations were introgressed.', 'Previously, we have shown that the chromodomain protein Chriz and the zinc-finger protein Z4 are essentially required for the maintenance of polytene chromosome structure.', 'In brain, Family with sequence similarity 174 member b (Fam174b) had increased expression in 318 females, whereas Chromodomain helicase DNA binding protein 2 (Chd2-2) had reduced expression in 318 males.', 'RESULTS: Here we demonstrated that chromobox protein homolog 3 (Cbx3) is crucial for SMC differentiation from stem cells and that the chromodomain and chromoshadow domain of Cbx3 are responsible for Cbx3-induced SMC differentiation.', 'Fractionation of the extract identified a single protein, chromodomain helicase DNA binding protein 1 (Chd1), capable of the remodeling activity.', 'Chromodomain helicase DNA-binding protein 5 (CHD5) has been found to be a candidate tumor suppressor gene (TSG) in malignant neural tumors.', 'Similarly, CenH3-GFP distribution was altered in the absence of HP1, the chromodomain protein that binds to H3K9me3.', 'ChIP-Seq reveals that KDM5B is predominantly targeted to intragenic regions and that it is recruited to H3K36me3 via an interaction with the chromodomain protein MRG15.', 'OBJECTIVE: Chromodomain helicase DNA-binding protein (CHD) is a regulator of the chromatin remodelling process.', 'We determined the crystal structure of MPP8 chromodomain in complex with H3K9me3 peptide.', 'On this gene the chromodomain protein HP1γ, frequently defined as a transcriptional repressor, facilitates inclusion of the alternative exons via a mechanism involving decreased RNA polymerase II elongation rate.', 'Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core component of the NuRD complex and contains a nucleosome remodeling ATPase domain along with two chromodomains and two plant homeodomain (PHD) fingers.', 'H3-Lys-9-Me2 interacts with the chromodomain of Swi6/HP1.', 'The chromodomain (CD) of HP1 proteins specifically recognizes the methyl mark on H3 peptides, but the same extent of specificity is not observed within chromatin.', 'We have performed simulations on models of chromodomain helicase DNA-binding protein 1 complexed with a variety of histone H3 modifications.', 'CHARGE syndrome is an autosomal dominant multisystem disorder caused by mutation in the CHD7 gene, encoding chromodomain helicase DNA-binding protein 7. Molecular diagnostic testing for CHD7 mutation has been available in a clinical setting since 2005.', 'In this work we identified Kismet, a chromodomain-containing protein of the SNF2-like family of ATPases, as a novel component of the hedgehog transcriptional repression mechanism in anterior compartment cells.']

['The chromodomain (chromatin organizer modifier domain) is a highly conserved motif, 40-50 amino acids in length, present in a wide range of animal and plant proteins involved in chromatin organization. Chromodomain-containing proteins can be classified into boader families based, particularly, on the presence of other types of domains. Chromodomain is present in: the heterochromatin proteins HP1 alpha and HP1 beta, chromointgrases (e.g. Tf1 integrase) the chromodomain helicase DNA-binding proteins (CHD) and CHD 1-like (CHD1L), CReMM (chromatin-related mesenchymal modulator), dna methyltransferase 3 (cmt3), the chromointegrase of the LTR-retrotransposons, the Polycomb group (PcG) proteins, the mouse Polycomb homologs (Cbx2, Cbx4, Cbx6, Cbx7, Cbx8), the chromodomain Y chromosome (CDY) family of proteins and the CDY-like protein (CDYL), the histone acetyltransferases TgMYST-A and –B, MRG-1 and -15 (MORF4-Related Gene on chromosome 15), ADP/ATP translocase 1, MPP8, MSL3, NlMof, Chp1, Chriz, dMi-2, Corto, cpSRP43, KISMET, PICKLE (PKL), ScoHET1 and ScoHET2.\n']

['HP1 alpha', 'CHD proteins', 'Chromodomain helicase DNA-binding protein', 'CReMM', 'cmt3', 'chromointegrases', 'Polycomb group (PcG) proteins', 'Cbx2', 'TgMYST-A', 'MRG15', 'MSL3', 'Swi6', 'Chp1', 'dMi-2', 'Corto', 'ScoHET1', 'cpSRP43', 'CDY', 'chromodomain Y chromosome', 'transposable elements', 'like heterochromatin protein', 'LHP1', 'ADP/ATP translocase 1', 'CDYL', 'CDY-like protein', 'CHD1L', 'CHD1-like', 'NlMof', 'TIP60', 'Kismet', 'Chriz', 'PICKLE', 'PKL', 'HP1 beta', 'HP1 gamma', 'TgMYST –B', 'Cbx4', 'Cbx6', 'Cbx7', 'Cbx8', 'ScoHET2', 'Cbx3', 'MPP8', 'MRG1']

Is phospholamban a regulatory/inhibitory protein of the Ca ATPase SERCA?

['The membrane protein complex between the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) and phospholamban (PLN) controls Ca(2+) transport in cardiomyocytes, thereby modulating cardiac contractility. β-Adrenergic-stimulated phosphorylation of PLN at Ser-16 enhances SERCA activity via an unknown mechanism.', 'Phospholamban (PLN) is a type II membrane protein that inhibits the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), thereby regulating calcium homeostasis in cardiac muscle. In membranes, PLN forms pentamers that have been proposed to function either as a storage for active monomers or as ion channels.', 'Regulation of the SERCA calcium pump by phospholamban (PLB) is largely due to interactions between their respective transmembrane domains. In spite of numerous mutagenesis and kinetic studies, we still do not have a clear mechanistic picture of how PLB influences the calcium transport cycle of SERCA.', 'Calcium transport across the membrane of the sarcoplasmic reticulum (SR) plays an important role in the regulation of heart muscle contraction and relaxation. The sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA) 2a is responsible for Ca(2+) up-take by this organelle and is inhibited in a reversible manner by phospholamban, another SR membrane protein. Thus, alleviation of phospholamban-mediated inhibition of SERCA2a is a potential therapeutic option for heart failure and cardiomyopathy.', 'Phospholamban has been suggested to be a key regulator of cardiac sarcoplasmic reticulum (SR) Ca cycling and contractility and a potential therapeutic target in restoring the depressed Ca cycling in failing hearts.', 'In larger mammals, a higher fraction of SERCA2a pumps are regulated by phospholamban, and this may influence therapeutic strategies to enhance cardiac contractility and functional cardiac reserve.', 'Phospholamban (PLB) inhibits the sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA), and this inhibition is relieved by Ca(2+) calmodulin-dependent protein kinase II (CaM kinase II) phosphorylation', 'These findings suggest that PLB is an important modulator of gastric antrum smooth muscle contractility by modulation of SR Ca(2+) release and CaM kinase II activity.', 'The function of the SERCA pump is modulated by the endogenous molecules phospholamban (PLB) and sarcolipin (SLN), expressed in cardiac and skeletal muscles. The mechanism of action of PLB on SERCA is well characterized, whereas that of SLN is only beginning to be understood. ', ' Phospholamban (PLB) is an inhibitor of the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA).', 'These results show that alteration of the PLB:SERCA ratio can significantly modulate smooth muscle [Ca2+]i.', 'Phospholamban expressed in cardiac muscle and sarcolipin expressed in skeletal muscle regulate SERCA activity.', 'Phospholamban (PLB) is a 24- to 27-kDa phosphoprotein that modulates activity of the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA). Expression of PLB is reportedly limited to cardiac, slow-twitch skeletal and smooth muscle in which PLB is an important regulator of [Ca2+]i and contractility in these muscles.', 'Regulation of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA 2a) depends on the phosphorylation state of phospholamban (PLB). When PLB is phosphorylated, its inhibitory effect towards SERCA 2a is relieved, leading to an enhanced myocardial performance. ', ' Ca(2+) reuptake occurs via sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA) and is regulated by the inhibitory protein phospholamban (PLB) in many cell types.', 'Phospholamban (PLN) is a small integral membrane protein, which binds and inhibits in a yet unknown fashion the Ca(2+)-ATPase (SERCA) in the sarcoplasmic reticulum.', 'Phospholamban (PLN) is the endogenous inhibitor of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), the integral membrane enzyme responsible for 70�% of the removal of Ca(2+) from the cytosol, inducing cardiac muscle relaxation in humans.', 'Phospholamban (PLB) is an integral membrane protein regulating Ca(2+) transport through inhibitory interaction with sarco(endo)plasmic reticulum calcium ATPase (SERCA).', 'Phosphorylation by protein kinase A and dephosphorylation by protein phosphatase 1 modulate the inhibitory activity of phospholamban (PLN), the endogenous regulator of the sarco(endo)plasmic reticulum calcium Ca(2+) ATPase (SERCA).', 'Phosphorylation by protein kinase A and dephosphorylation by protein phosphatase 1 modulate the inhibitory activity of phospholamban (PLN), the endogenous regulator of the sarco(endo)plasmic reticulum calcium Ca(2+) ATPase (SERCA)', 'We used EPR spectroscopy to probe directly the interaction between phospholamban (PLB) and its regulatory target, the sarcoplasmic reticulum Ca-ATPase (SERCA)']

['Phospholamban (PLB) is a 24- to 27-kDa phosphoprotein that modulates activity of the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA). Expression of PLB is reportedly limited to cardiac, slow-twitch skeletal and smooth muscle in which PLB is an important regulator of [Ca2+]i and contractility in these muscles.The membrane protein complex between the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) and phospholamban (PLN) controls Ca(2+) transport in cardiomyocytes, thereby modulating cardiac contractility. β-Adrenergic-stimulated phosphorylation of PLN at Ser-16 enhances SERCA activity via an unknown mechanism.', 'Phospholamban (PLN) is a type II membrane protein that inhibits the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), thereby regulating calcium homeostasis in cardiac muscle. The sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA) 2a is responsible for Ca(2+) up-take by this organelle and is inhibited in a reversible manner by phospholamban. When PLB is phosphorylated, its inhibitory effect towards SERCA 2a is relieved, leading to an enhanced myocardial performance.Thus, alleviation of phospholamban-mediated inhibition of SERCA2a is a potential therapeutic option for heart failure and cardiomyopathy.']

['yes']

Is phospholamban phosphorylated by Protein kinase A?

['cAMP-dependent protein kinase (PKA) phosphorylation of PLB', 'phosphorylation of PLN, at either Ser(16) by PKA ', 'Activation of cardiac muscle sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) by beta1-agonists involves cAMP- and PKA-dependent phosphorylation of phospholamban (PLB), which relieves the inhibitory effects of PLB on SERCA2a. ', 'Phospholamban (PLB) is a sarcoplasmic reticulum (SR) protein that when phosphorylated at Ser16 by PKA', 'phosphorylation of PLB by the Ca2+-calmodulin-dependent protein kinase (CaMK) and cAMP-dependent protein kinase (PKA). ', 'cAMP-dependent protein kinase (PKA)-mediated phospholamban (PLB) phosphorylation at serine-16', 'Phospholamban (PLB) is a major target of the beta-adrenergic cascade in the heart, functioning to modulate contractile force by altering the rate of calcium re-sequestration by the Ca-ATPase. Functionally, inhibition by PLB binding is manifested by shifts in the calcium dependence of Ca-ATPase activation toward higher calcium levels; phosphorylation of PLB by PKA reverses the inhibitory action of PLB.', 'phosphorylation of both PLB residues (Ser16, PKA site, and Thr17, CaMKII site) ', 'Phosphorylation of Ser(16) by PKA', 'stabilization of the structure of PLB following phosphorylation of Ser(16)', 'Phospholamban (PLB) inhibits the sarcoplasmic reticulum (SR) Ca(2+)-ATPase, and this inhibition is relieved by cAMP-dependent protein kinase (PKA)-mediated phosphorylation. ', 'Two-dimensional tryptic peptide maps of phosphorylated phospholamban indicated that cAMP-dependent protein kinase phosphorylates at a single site, A, and Ca2+-calmodulin-dependent protein kinase phosphorylates at sites C1 and C2 in the low molecular weight form, where A is different from C1 but may be the same as C2.', 'Because SR function is regulated by phosphorylation of phospholamban (PLB), a SR protein phosphorylated by cAMP-dependent protein kinase (PKA) at Ser(16)and Ca(2+)-calmodulin-dependent protein kinase (CaMKII) at Thr(17), the phosphorylation of these residues during ischemia and reperfusion was examined in Langendorff-perfused rat hearts', 'These changes were associated with reduced protein expression of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) and protein kinase A phosphorylated phospholamban (PLB), which was reduced in HF, but essentially abolished in VD-HF', 'The data indicate that 1) phosphorylation of phospholamban at Ser16 by cAMP-dependent protein kinase is the main regulator of beta-adrenergic-induced cardiac relaxation definitely preceding Thr17 phosphorylation and 2) the beta-adrenergic-mediated phosphorylation of Thr17 by Ca2+-calmodulin-dependent protein kinase required influx of Ca2+ through the L-type Ca2+ channel', 'Here we extend this model to explain the reversal of SERCA2a inhibition that occurs after phosphorylation of PLB at Ser(16) by protein kinase A (PKA) and after binding of the anti-PLB monoclonal antibody 2D12, which recognizes residues 7-13 of PLB', 'Phospholamban is phosphorylated in heart by cAMP-dependent protein kinase, cGMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II (CM-kinase-II) and in smooth muscle cells by cGMP-dependent protein kinase', 'Phospholamban, the cardiac sarcoplasmic reticulum proteolipid, is phosphorylated by cAMP-dependent protein kinase, by Ca2+/phospholipid-dependent protein kinase, and by an endogenous Ca2+/calmodulin-dependent protein kinase, the identity of which remains to be defined']

['Phospholamban (PLB) is a sarcoplasmic reticulum (SR) protein that is phosphorylated at Ser16 by PKA. Phosphorylation of PLB by PKA reverses the inhibitory action of PLB.']

['yes']

What disease in Loxapine prominently used for?

['To describe the frequency and trends in the use of antipsychotics for adults with schizophrenia in Canada from 2005 to 2009.', 'Antipsychotic recommendations were estimated using CDTI data in which schizophrenia was listed as the indication. RESULTS: First-generation antipsychotic (FGA) recommendations for adults with schizophrenia increased by 38% between 2005 and 2009, from 329 380 to 454 960 recommendations. There were notable increases in recommendations for chlorpromazine, loxapine, zuclopenthixol, and flupentixol.', 'Loxapine has been prescribed in France since 1980. Its pharmacological profile is close to that of clozapine: it has dopamine (D2), histamine (H1), serotonin (5-HT2) and adrenergic (alpha 1)-blocking activities. Its best indication seems to be paranoid schizophrenia, although some data suggest bipolar action.']

['The best indication of loxapine is paranoid schizophrenia.']

['schizophrenia']