Understanding how antibiotics inhibit bacteria can help to reduce antibiotic use and hence avoid antimicrobial resistance—yet few theoretical models exist for bacterial growth inhibition by a clinically relevant antibiotic treatment regimen. In particular, in the clinic, antibiotic treatment is time-dependent. Here, we use a theoretical model, previously applied to steady-state bacterial growth, to predict the dynamical response of a bacterial cell to a time-dependent dose of ribosome-targeting antibiotic. Our results depend strongly on whether the antibiotic shows reversible transport and/or low-affinity ribosome binding (‘low-affinity antibiotic’) or, in contrast, irreversible transport and/or high affinity ribosome binding (‘high-affinity antibiotic’). For low-affinity antibiotics, our model predicts that growth inhibition depends on the duration of the antibiotic pulse, and can show a transient period of very fast growth following removal of the antibiotic. For high-affinity antibiotics, growth inhibition depends on peak dosage rather than dose duration, and the model predicts a pronounced post-antibiotic effect, due to hysteresis, in which growth can be suppressed for long times after the antibiotic dose has ended. These predictions are experimentally testable and may be of clinical significance. Modern clinical practice relies on the use of antibiotics to combat bacterial infections, yet our knowledge of how antibiotics inhibit bacteria is surprisingly incomplete. In particular, mathematical models are needed to translate known information about the molecular processes that are targeted by antibiotics into predictions for bacterial growth rate as a function of antibiotic concentration. Such models would allow optimisation of dosing regimes –3, and pWe focus here on antibiotics that target bacterial ribosomes. Ribosomes are multi-component, molecular machines which carry out protein synthesis—a function that is crucial for growth. Different ribosome-targeting antibiotics can bind to different components of the bacterial ribosome and inhibit different steps in protein synthesis . In recePharmacokinetic curves describe the time-varying local antibiotic concentration at an infection site during a clinical treatment regime . These cIn this paper, we use the mathematical model of ribosome-targeting antibiotics introduced in  to make aex to which it is exposed. Here, the growth rate is defined by N(t) ~ exp(λt), where N(t) is the number of bacteria at time t. The growth inhibition curve λ(aex) is expected to be a decreasing function, which can be conveniently characterised by the concentration of antibiotic required to halve the growth rate, known as the IC50.We first provide a brief description of the model which was introduced in . The modrb and ru respectively, and the concentration of intracellular antibiotic a. The model consists of the following set of equations for the dynamics of the concentrations: F ≡ kona(ru − rmin) − koffrb describes the antibiotic-ribosome binding / unbinding kinetics. Pin and Pout are rate constants (or permeabilities) for antibiotic transport into and out of the cell (both assumed to be linear processes), and aex(t) is the external antibiotic concentration, which can be controlled in a lab experiment, or is set by the dosing regime in a clinical scenario. The terms −λa, −λru and −λrb describe dilution of the cell contents by growth at rate λ. Finally, s is the rate of synthesis of new ribosomes.As illustrated in s depend on the state of the system To complete the model, we need to describe how the growth rate λ and the ribosome synthesis rate in et al , 21. Thenslation , 23. We s can be deduced from the second‘growth law’ of Scott et al, which states that thetotal ribosome content rtot is linearly related to thegrowth rate  fort > t0 = 3 h, andaex = 0 otherwise. We varied the durationTx, keeping the integrated dose constant:SxTx = 4 ×IC50.In a clinical scenario, the antibiotic concentration in the body decreases graduallyafter a dose, rather than suddenly. The pulse profile shown in Tx), the overshoot is masked by the growth-rate suppression due to the antibiotic.The response to an exponentially-decaying pulse of a high-affinity antibiotic  is also 0. For the low-affinity antibiotic  duration-dependent efficacy for ribosome-targeting antibiotics which bind with low affinity and/or are transported reversibly, (ii) possible growth-rate overshoot for these ‘low-affinity’ antibiotics, (iii) peak intensity-dependent efficacy for ribosome-targeting antibiotics that bind with high affinity and/or are transported irreversibly and (iv) post-antibiotic effect for these ‘high-affinity’ antibiotics, are all independent of the details of the antibiotic dosage protocol.In this paper, we have studied the dynamical response of bacterial growth rate to sustained and transient antibiotic treatment, for ribosome-targeting antibiotics. The model that we have used is simple: it includes only antibiotic-ribosome binding, antibiotic transport, growth, and ribosome synthesis, with the latter two processes being dependent on the state of the system. In previous work , this moHere, we go beyond the steady-state analysis of , to inveet al [Mathematical models that integrate the molecular mechanism of antibiotic action with bacterial physiology are rare, and those that do exist mostly consider only the response to a time-invariant antibiotic concentration , 7–10. Oet al , 12 is crtot ≈ rmax in Are the predictions of our model realistic? Of course many factors have not been included in the model. For example, we have assumed throughout that growth rate is determined solely by the active ribosome abundance, via Enterococcus faecalis populations exposed to a sudden influx of the ribosome-targeting antibiotic tigecycline, which is expected to be in the low-affinity class, does show rapid growth rate suppression followed by slower partial recovery, as predicted by our model 13. At tre 1C of . The latIf confirmed experimentally, the phenomena reported here would be of considerable clinical significance.In particular, our results make a clear prediction for the optimal pharmacodynamic strategy: for low-affinity drugs one should aim to maximise the time of exposure, while for high-affinity drugs, one should aim to maximise the peak dosage. Moreover, the latter are predicted to show a pronounced post-antibiotic effect, meaning that they can be effective for much longer than the actual duration of exposure. Post-antibiotic effects are a widely recognised, but poorly understood, pharmacodynamic phenomenon, and occur for various antibiotics including aminoglycosides –19. Our Appendix


Objectives. Invasion of differentiated thyroid cancer (DTC) into surrounding structures can lead to morbid procedures such as laryngectomy and tracheal resection. In these patients, there is a potential role for neoadjuvant therapy. Methods. We identified three studies involving the treatment of DTC with neoadjuvant chemotherapy: two from Slovenia and one from Japan. Results. These studies demonstrate that in selected situations, neoadjuvant chemotherapy can have a good response and allow for a more complete surgical resection, the treatment of DTC. Additionally, the SELECT trial shows that the targeted therapy lenvatinib is effective in the treatment of DTC and could be useful as neoadjuvant therapy for this disease due to its short time to response. Pazopanib has also demonstrated promise in phase II data. Conclusions. Thus, chemotherapy in the neoadjuvant setting could possibly be useful for managing advanced DTC. Additionally, some of the new tyrosine kinase inhibitors (TKIs) hold promise for use in the neoadjuvant setting in DTC. Neoadjuvant chemotherapy is integrated into the treatment of several cancers, including head and neck squamous cell carcinoma (hnSCC) . In a phWhile the majority of thyroid cancers present as locally resectable tumors with minimal surgical morbidity, occasionally the primary tumor has invaded critical structures, complicating the surgical treatment plan. Direct invasion of the larynx, trachea, pharynx, esophagus, recurrent laryngeal nerve, strap muscles, and/or carotid artery occurs in 7%–16% of patients with thyroid cancer . ExtensiIn this review, we will describe the potential role of neoadjuvant therapy in the treatment of DTC. Chemotherapy generally has a limited role in DTC as it is associated with minimal survival benefit when used as single modality therapy. In the neoadjuvant setting, however, the most important factor for therapy is tumor response. A favorable tumor response may offer the patient and surgeon significant improvement in the ability to provide an oncologic surgical resection. Given that data on neoadjuvant therapy in DTC is extremely limited, we will first discuss chemotherapy in its more established role in the metastatic setting in an effort to assess tumor response rates as they might pertain to neoadjuvant therapy. We will then describe the results of studies demonstrating the efficacy of neoadjuvant chemotherapy in DTC as well as the data for newer, targeted agents in an effort to identify the best possible options for neoadjuvant therapy in DTC.Although a limited number of chemotherapies have been used effectively in the neoadjuvant setting, chemotherapy has not been shown to be particularly effective in the metastatic setting. The only FDA-approved chemotherapy for DTC is doxorubicin, which offers minimal benefit and is associated with toxicity for patients with metastatic DTC. Doxorubicin was initially introduced to clinical practice due to a study by Gottlieb et al., which described 6 case reports of patients with DTC treated with various chemotherapy agents given alone or in combination . Two patGiven the limited efficacy of doxorubicin as monotherapy, other chemotherapy combinations have been evaluated in clinical trials, but also with disappointing results. Williams et al. described a study with 22 patients with advanced thyroid cancer of all histological subtypes treated with doxorubicin and cisplatin . They obWhile these results for both doxorubicin monotherapy and combination chemotherapy are discouraging for the treatment of metastatic DTC this data should be interpreted with caution. Chemotherapy is typically reserved for RAI-refractory cases of DTC, and thus the biology involved in these cases may be different from that seen in the preoperative setting , 32.The following studies, on the other hand, explore the efficacy of doxorubicin as well as various other agents given as neoadjuvant chemotherapy in DTC.We identified three studies involving the treatment of DTC with neoadjuvant chemotherapy: two from Slovenia and one from Japan. Response rates for these three studies are summarized in One of the studies from Slovenia described a retrospective, nonrandomized study of 29 patients with T3 or T4 follicular or Hurthle cell thyroid cancers treated from 1979 to 2004 in which the tumor was considered inoperable . Mean agSimilarly, the same group in Slovenia described a retrospective, nonrandomized study of 16 patients with T3 or T4 papillary thyroid cancer treated from 1988 to 2005 in which the tumor was considered to be inoperable . Mean ag2 for 3 cycles. The tumor size decreased by 45%, and lung metastases disappeared after induction. The patient underwent total thyroidectomy with modified radical neck dissection, and the tumor was completely resected. Lung metastases were identified again 6 months after surgery. The patient received 13 cycles of weekly paclitaxel, but the metastases enlarged gradually. The patient died 21 months after diagnosis and 18 months after surgery. The second patient was a 68-year-old woman with a 4.4 cm thyroid tumor and a single cervical node metastasis, without distant metastases. The patient received induction therapy with weekly paclitaxel (again at 80 mg/m2) for 2 cycles. The tumor size decreased by 15%; this result was evaluated as stable disease (SD). The patient underwent total thyroidectomy and modified neck dissection, and the tumor was completely resected. At the time of publication of this study, the patient was alive 29 months after her diagnosis and 27 months after surgery with no evidence of recurrence. No toxicity was reported for either patient receiving induction therapy.An additional study from Japan evaluated the effect of weekly paclitaxel chemotherapy in 3 patients with papillary thyroid cancer with a squamous cell carcinoma component (a very aggressive tumor with behavior resembling anaplastic thyroid cancer) . Weekly The results from these studies indicate that neoadjuvant chemotherapy may have some effectiveness in DTC and should be considered in select cases. Neoadjuvant regimens consisted mostly of vinblastine, doxorubicin, and/or paclitaxel and offered superior responses compared to doxorubicin alone (or with cisplatin). Of note, patients in these studies were typically older, with mean ages over 60. Thus, neoadjuvant chemotherapy can be both effective and tolerable in this population.Despite these results, the data is limited to these two retrospective studies and two patients from a case series. Interestingly, none of these studies reported toxicity associated with neoadjuvant chemotherapy. While it is possible that neoadjuvant chemotherapy was well tolerated by the patients in these studies, the lack of concrete toxicity data is a significant weakness. Ideally, recommendations for treatment using neoadjuvant therapy would be based on randomized controlled trials (RCTs); however it is unlikely that enough patients could be accrued to power such a study. Consequently, there is a need for more retrospective studies and case reports in order to enhance the current data for this treatment.The studies described thus far in this review have all used cytotoxic chemotherapy, which is relatively indiscriminate in its toxicity. In contrast, newer targeted therapies are based on specific genetic properties of tumors and are generally less toxic as a result. In particular, tyrosine kinase inhibitors (TKIs) have shown promise in the treatment of DTC. In 2013, sorafenib was approved for the treatment of metastatic DTC. Furthermore, lenvatinib was found to extend progression-free survival (PFS) in RAI-resistant DTC in the phase III SELECT trial and was approved for the treatment of metastatic DTC in 2015. Although there are no adjuvant data for these drugs, the phase III trial data is thought provoking for the potential role of targeted therapy in the neoadjuvant setting.The double-blind, randomized, multicenter, phase III DECISION trial examined sorafenib efficacy and safety versus placebo in patients with progressive RAI-refractory DTC . A totalThe multicenter, randomized, placebo-controlled, phase III SELECT trial presented at the American Society of Clinical Oncology (ASCO) 2014 annual meeting examined the efficacy and safety of lenvatinib versus placebo in patients with RAI-refractory DTC . PatientA phase II trial conducted by Bible et al. describes pazopanib as a promising new targeted agent for DTC . Thirty-These data demonstrate that lenvatinib and pazopanib are promising agents for neoadjuvant therapy in DTC. The former has a documented short time to response, and both had good response rates with low toxicity. Furthermore, given that these drugs would be given for a short time period if administered as neoadjuvant therapy, long-term toxicity would also be minimal. However, there exists the theoretical concern of selecting for tumor cell clonality resistant to these new therapies if they are used early in the course of treatment as neoadjuvant therapy. If such a patient were to develop RAI-resistant metastases, the treatment options for the patient would indeed be poor. However, this scenario is very unlikely, and its possibility should not preclude the consideration of targeted agents as neoadjuvant therapy in patients that could benefit from this treatment.Sorafenib, on the other hand, had a relatively low response rate of 12% in a phase III trial, which is consistent with data from prior phase II trials. The different biochemical properties of these drugs may contribute to the considerable differences in response rates between sorafenib and lenvatinib/pazopanib  , 42. HowWhile VEGF is critical for tumor angiogenesis and growth, it is also imperative to wound healing . Thus, aGiven that there is no data regarding the use of antiangiogenic TKIs as neoadjuvant therapy in DTC, it is difficult to speculate as to the possibility of postoperative wound dehiscence or fistula formation. Furthermore, there are no current guidelines for these drugs on how long to wait before surgery. While we believe that, in specific circumstances, neoadjuvant therapy might be a valuable tool in the treatment of DTC, these risks should be deliberated in any treatment plan. The possibility of a waiting period between drug administration and surgery should be considered while considering the risk of tumor regrowth. Given the lack of guidelines or data, these decisions should be made on the basis of the individual patient and tumor. More data need to be collected regarding the possibility of impaired wound healing or fistula formation after treatment with antiangiogenic TKIs in DTC before any recommendations on a waiting period between drug administration and surgery are made. In the opinion of the authors of this paper, an antiangiogenic TKI could be administered for approximately four months (with response first assessed after two months), and surgery could take place 4–6 weeks after stopping the drug. Again, however, additional data is necessary before establishing any guidelines for duration of therapy and the waiting period.Currently, the role for neoadjuvant chemotherapy in DTC is not well established. However, our review shows that in selected situations neoadjuvant chemotherapy can be beneficial in the treatment of DTC. Moreover, the SELECT trial shows that the targeted therapy lenvatinib is effective and safe in the treatment of DTC and could potentially be useful as neoadjuvant therapy for this disease given its high response rate and short time to effect. Pazopanib has also demonstrated promise in phase II data, and sorafenib, while relatively ineffective alone, could possibly be useful in conjunction with other therapies.There are still many unanswered questions regarding neoadjuvant therapy in DTC. There is still limited data on the respective effects of R0, R1, and R2 on prognosis. There are also no clear indications for the use of neoadjuvant therapy in DTC, and this decision would likely be made by the surgeon based on the extent of disease and complexity of the operation for the surgeon. It is unlikely that a sufficiently powered RCT will be conducted for this treatment, and, consequently, treatment recommendations will have to rely on strong retrospective data and case reports and series. Collaboration and cooperative research groups could possibly yield stronger data. Future studies should potentially include combinations of targeted therapies with each other or other cytotoxic chemotherapies to further elucidate the possibilities for neoadjuvant therapy in DTC.


Riedel's thyroiditis (RT) represents one type of IgG4-related thyroid disease (IgG4RTD) and the diagnosis involves quantitative immunohistochemistry showing dense lymphoplasmacellular inflammatory infiltrate consisting of IgG4-positive plasma cells with storiform fibrosis and obliterative phlebitis. We report a case of RT with progressive enlargement of the anterior neck, severe dysphagia, odynophagia, and dyspnea. The patient underwent surgical decompression of the airway, protection tracheotomy, and gastrostomy for nutritional intake 6 months after first symptoms. Complete resolution occurred after surgical treatment combined with prednisolone. Immunostaining revealed IgG4-positive plasma cells 12/HPF (high-power field) and the IgG4/IgG ratio 25%, values that were disproportionate to the intensity of the patient's symptoms. As to this case and the few cases described and analyzed in the literature, our impression is that there is no relation between the intensity of symptoms in RT with the total number of IgG4-positive plasma cells and the IgG4/IgG ratio, but more studies are needed. The German surgeon Bernhard Moritz Carl Ludwig Riedel first described Riedel's thyroiditis in 1883, as a rare disease which changes the thyroid parenchyma texture into an extremely hard lesion with adhesion to the trachea and obstructive symptoms . The morThe differential diagnosis should consider malignant thyroid tumors , includiRiedel's thyroiditis shows several features that justify its inclusion into the spectrum of IgG4 related disease (IgG4-RD). Foremost among them are the fibroinflammatory nature of the infiltrate, the presence of obliterative phlebitis, and its association with other forms of fibrosclerosis including sclerosing cholangitis, as well as retroperitoneal fibrosis, among others. One-third of patients with Riedel's thyroiditis develop fibrosing disorders in other organs. This inclusion was supported by the fact that RT showed elevated numbers of IgG4 positive plasma cells as well as the morphologic features of IgG4 related disease . GlucocoToday RT, the fibrosing variant of Hashimoto's thyroiditis, and a few patients of Graves' orbitopathy represent the types of IgG4-related thyroid disease (IgG4RTD). The diagnosis involves establishing high circulating levels of IgG4 > 135 mg/dL, increased serum IgG4 to IgG ratio of >8%, immunohistochemistry showing dense lymphoplasmacellular inflammatory infiltrate consisting of IgG4-positive plasma cells with storiform fibrosis and obliterative phlebitis, and increased IgG4 positive plasma cell > 10 cells per high-power field when at least three fields are evaluated and the IgG4/IgG ratio of RT is increased by varying degrees , 10.One question not explained in the literature is the relation between the intensity of the thyroiditis, the total number of IgG4-positive plasma cells, and the IgG4/IgG ratio. Immunohistochemistry can show whether IgG-4 plasma cells are increased which could lead to fibrosis in other organs .We present the case of an exuberant manifestation of the disease with dysphagia and dyspnea without a large quantitative manifestation in the immunohistochemical analysis.We describe a 40-year-old woman complaining of a progressive painless enlargement of the anterior neck, dyspnea, dysphagia, odynophagia, and weight loss of 7 Kg in 4 months. The thyroid gland was hard and the ultrasound exam calculated a volume of 70 g. The patient had hypothyroidism and was undergoing hormonal replacement. Fine needle aspiration was suggestive of Riedel's thyroiditis. The CT scan confirmed a large thyroid lesion with esophageal invasion and decreased tracheal lumen of about 50% . BilaterThe patient underwent surgical decompression of the airway , protectThe follow-up was satisfactory using prednisolone 40 mg/day. Her symptoms improved 5 months after surgery and the feeding intake was exclusively oral. Her weight recovered and the tracheal cannula was removed 5 months after the tracheotomy due to the improvement of the vocal folds motion. The prednisolone was discontinued after 2 years and the evolution has been excellent, nowadays only using levothyroxine .We were unable to perform the blood dosage of IgG4 and IgG at the time of the active disease. The hematoxylin and eosin staining of the thyroid lesions revealed lymphoplasmacytic infiltration, severe fibrosis, and phlebitis . The IgGRiedel's thyroiditis is a fibrosclerosing disease whose anatomopathologic aspect is a lymphocytic, plasmocytic, and histiocytic cell infiltration , 3. ThisDyspnea and hoarseness can be found due to tracheal compression or recurrent laryngeal nerve involvement. Furthermore, dysphagia can be the result of pharyngoesophageal involvement and compression . The thyOpen surgical biopsy during the cervicotomy is mandatory in order to confirm the diagnosis. Isthmusectomy is enough in order to perform the diagnosis. Broad resections should be avoided due to the risk of injuring the surrounding structures.An exuberant clinical status with consumption and fast evolution can suggest the undifferentiated carcinoma, such as in the present case reported. The hypothesis of Riedel's thyroiditis was considered because of the FNAB exam. The operation was technically hard to perform, since there was a lack of dissection plane between the thyroid and the trachea, with high risk of injuries to tissues. The patient's weight recovered fast, after starting the use of corticoid. If this treatment is not efficient, other drugs could be employed, such as tamoxifen . Low dosIn spite of being uncommon, Riedel's thyroiditis should be considered a differential diagnosis among the anterior neck masses with fast growth. Severe dysphagia has not been reported as a main symptom.In order to characterize the relationship between RT and IgG4, we performed IgG4 and IgG staining. The total number of IgG4-positive plasma cells was more than 10/HPF, but the IgG4/IgG ratio was less than 40%. IgG4 immunostaining is important for the diagnosis, especially when serum IgG4 is not elevated. Although IgG4 plasma cells per high-power field has an acceptable specificity, an IgG4/IgG plasma cell ratio of greater than 40% is considered more valuable, as some inflammatory lesions have high IgG4 plasma cells . For thiThere is no study associating intensity of the symptoms with the count of inflammatory plasma cells in Riedel's thyroiditis, but in the spectrum of IgG4 related diseases Deshpande et al.  studied As to this case, our impression is that there is no relation between the intensity of the thyroiditis, the total number of IgG4-positive plasma cells and the IgG4/IgG ratio. The guidelines proposed do not supplant careful clinicopathological correlation and sound clinical judgment .Since RT is such a rare disease, immunohistochemical analyses have only been performed in limited cases and long-term investigations are further needed.


Head and neck squamous cell carcinoma (HNSCC) is a highly morbid disease. Recent developments including Food and Drug Administration (FDA) approved molecular targeted agent’s pembrolizumab and cetuximab show promise but did not improve the five-year survival which is currently less than 40%. The hepatocyte growth factor receptor; also known as mesenchymal–epithelial transition factor (c-Met) and its ligand hepatocyte growth factor (HGF) are overexpressed in head and neck squamous cell carcinoma (HNSCC); and regulates tumor progression and response to therapy. The c-Met pathway has been shown to regulate many cellular processes such as cell proliferation, invasion, and angiogenesis. The c-Met pathway is involved in cross-talk, activation, and perpetuation of other signaling pathways, curbing the cogency of a blockade molecule on a single pathway. The receptor and its ligand act on several downstream effectors including phospholipase C gamma (PLCγ), cellular Src kinase (c-Src), phosphotidylinsitol-3-OH kinase (PI3K) alpha serine/threonine-protein kinase (Akt), mitogen activate protein kinase (MAPK), and wingless-related integration site (Wnt) pathways. They are also known to cross-talk with other receptors; namely epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) and specifically contribute to treatment resistance. Clinical trials targeting the c-Met axis in HNSCC have been undertaken because of significant preclinical work demonstrating a relationship between HGF/c-Met signaling and cancer cell survival. Here we focus on HGF/c-Met impact on cellular signaling in HNSCC to potentiate tumor growth and disrupt therapeutic efficacy. Herein we summarize the current understanding of HGF/c-Met signaling and its effects on HNSCC. The intertwining of c-Met signaling with other signaling pathways provides opportunities for more robust and specific therapies, leading to better clinical outcomes. Of all the neoplasms in the head and neck region, roughly 90% are classified as head and neck squamous cell carcinoma (HNSCC) . The estCetuximab, a human/mouse chimeric monoclonal antibody targeting (EGFR), is the only FDA-approved targeted therapy for EGFR in HNSCC . HoweverThe c-Met proto-oncogene is a membrane spanning receptor tyrosine kinase (RTK) whose ligand is the hepatocyte growth factor (HGF) . Its abeHepatocyte growth factor, also then named “Hepatotropin”, was isolated from serum in partially hepatectomized rats and described as a mitogen of liver regeneration in 1984 . HGF wasMet cDNA displayed motogenic and invasive properties when treated with HGF [Scatter factor (SF) was first identified as a protein secreted by fibroblasts and smooth muscle and had properties that dispersed “scattered” uniform epithelial cells in culture by disrupting intracellular junctions ,22,23. Uwith HGF .HGF displayed cytotoxic effects in a few cell lines, deviating from known HGF activity . With thtpr (translocated promoter region) [c-Met, the receptor for HGF, was originally discovered in osteosarcoma cell line that was chemically transformed in 1984 . The che region) ,41,42. T region) .c-Met was shown to be overexpressed in the human gastric cancer line (GTL-16), and later in human thyroid carcinomas, human colorectal cancer, and with many other epithelial tumors in the early 90s ,45,46. PIn normal development and tissue regeneration HGF/c-Met is crucial. HGF/c-Met has physiological roles in cardiovascular remodeling , skeletaLoreto et al. (2010) studied c-Met expression during salivary gland morphogenesis. A sample of 12 human embryonic salivary glands were studied at different stages of development using immunohistochemical staining. While all stages of salivary gland development demonstrated staining for c-Met, there was stronger expression in the earlier stages of development . HGF/c-MThe study of cancer compared to wound healing and tissue regeneration has long been thought as apposite, with many parallels being readily identified. Additionally, many cancer therapies interrupt wound healing . LikewisHGF expression is normally found in the vicinity of epithelial and endothelial cells expressing the c-Met receptor. While much remains to be discovered about HGF formation and secretion, it has been reported that granulocytes (particularly neutrophils) store inactive pro-HGF , and coamet transcript, a 150 kDa polypeptide is produced that is partially glycosylated to become a 170 kDa precursor protein [Mesenchymal epithelial transition factor (c-Met) is a semaphorin, membrane spanning receptor tyrosine kinase that is encoded by the MET proto-oncogene ,90. From protein ,92. The  protein ,94.The α-chain of mature, bivalent HGF binds c-Met β-chain with high affinity at the immunoglobulin-plexin-transcription (IPT) domain. Meanwhile the β-chain of HGF binds c-Met’s Sema domain with low affinity. Engineered proteins mimicking the IPT domains of Met show anti-tumor effects in mice; in vitro display inhibit HGF induced cell growth and invasion . It is wIn physionormative settings, binding of HGF activates c-Met by phosphorylating two intracellular tyrosine residues, inducing catalytic activity . The carAdapter proteins known to interact with the tyrosine residues include: growth factor receptor-bound protein 2 (Grb2), src homology/collagen (SHC), Grb2-associated adaptor protein (Gab1), and CT10 (chicken tumor virus No. 10) regulator of kinase/Crk-like (Crk/CRKL) with signal transducers phosphotidylinsitol-3-OH kinase (PI3K), signal transducer and activator of transcription-3 (Stat3), phospholipase C-γ (PLCγ), Ras guanine nucleotide exchange factor son-of-sevenless (SOS), Src kinase, and Src homology region-2 containing protein tyrosine phosphatase 2 (SHP2) ,104,105.Activation of MAPK will successively activate different protein kinases whose terminal effectors include extracellular signal-regulated kinases (Erk1 and Erk2), Jun amino-terminal kinases  and p38 (a class of Mapk’s). These proteins will activate cell cycle regulators producing cell proliferation and stimulating functional alterations in the cytoskeleton, important to cell migration and invasion. Inactivation of B-cell lymphoma 2 (Bcl-2) antagonist of cell death (BAD) and degradation of the pro-apoptotic protein p53 increases cell survival and apoptotic resistance by activation of the PI3K/AKT pathway . STAT3 aThe plasma membrane proves to be an important area of complex c-Met interaction with other surface proteins, contributing to dynamic c-Met biological responses—EGFR, α6β4 integrin, semaphorins in the plexin B family, and the variant of the hyaluronan receptor cluster of differentiation 44 (CD44) (links intracellular cytoskeleton and the extracellular matrix) ,110.After HGF binding, c-Met is endocytosed via clatherin coated vesicles to early peripheral endosomes. This is facilitated by protein kinase Cε (PKCε), that promotes both the transfer of active Erk to focal adhesions and HGF-induced cell migration. Next, PKCα mediates c-Met travel along the microtubule network towards the late perinuclear compartments. The accumulation of c-Met in endosomal compartments near the nucleus is a determining step of STAT3 activation .Downregulation of c-Met involves trafficking and degradation in the lysosomes. Initiated by juxtamembrane domain site Y1003 association with casitas B-lineage lymphoma (CBL) and endocytic adaptors, c-Met then accumulates in multivesicular bodies that subsequently fuse with lysosomes, which then break down the proteins. Loss of Y1003 residue allows c-Met to evade lysomal degradation and become oncogenic . Alternac-Met downregulation can also occur by its binding to protein tyrosine phosphatases (PTPs), which include receptor-type PTPs density enhanced phosphatase 1 (dEP1) and leukocyte common antigen-related molecule (LAR), and the nonreceptor PTPs PTP1B and T-cell protein tyrosine phosphatase (TCPTP). TCPTP modulates c-Met signaling by dephosphorylating the tyrosines in the kinase domain, and dEP1 downregulates c-Met signaling by dephosphorylating the docking tyrosines ,115.Typical of most tyrosine kinase receptors, c-MET can be activated by one of three mechanisms. First, ligand binding triggers dimerization and transactivation of the receptor. Phosphorylated c-Met (p-Met) is overexpressed in HNSCC patients. Total c-Met is overexpressed in 78% of HNSCC cases, and 66% of HNSCC demonstrate phosphorylation at activating sites Y1230, Y1234, and Y1235. Activating sites in this case refers to tyrosines whose phosphorylation results in the recruitment of signaling molecules that go on to transduce a signal. Thus the phosphorylation of tyrosine results in an activation of a signaling cascade  Figure . Both auMET copy number is present in 16% of HNSCC cases and is associated with c-Met overexpression and poorer outcomes for those individuals [MET mutations have been identified on several domains including the sema, juxtamembrane, and kinase domains. HNSCC metastatic potential increases with Y1230C and Y1235D kinase domain mutations [Second, physical modifications in the receptor can sustain constitutive activation via somatic mutations. In particular, mutations in the kinase domain involving Y1235D and Y1230C are important activators of the c-Met pathway in HNSCC ,121 Fig. Other gividuals . Howeverutations ,121. Y12utations . In HNSCutations . Juxtameutations  -β type II receptor knockout in mice gave rise to prostate and gut epithelial tumors by activating c-Met through paracrine overexpression of HGF by stromal cells . TGF-β iEGFR and c-Met have in common similar downstream pathways: MAPK (RAS/Rapidly accelerating fibrosarcoma (RAF)/ MAP kinase kinases (MEK)/ERK) and PI3K/AKT/mechanistic target of rapamycin (mTOR) ,167,168.The c-Met signaling axis has been implicated in acquired resistance to epidermal growth factor receptor (EGFR) targeting therapies in HNSCC. EGFR, like c-Met, is an RTK that is overexpressed in roughly 90% of HNSCC patients. EGFR overexpression correlates with regional lymph node metastasis and poor outcomes . Acquirec-Met plays a major role in compensating for inhibition of RTK pathways that drive proliferation and metastasis in HNSCC. Therefore, targeting c-Met in conjunction with these pathways may lead to more effective therapeutic strategies. Here we discuss c-Met inhibitors used in combination with other targeted and nontargeted therapies in clinical and preclinical models of HNSCC.Crizotinib is a class Ia small molecule dual inhibitor of c-Met and anaplastic lymphoma kinase (ALK) that was approved for therapeutic use in advanced non-small cell lung cancers positive for either c-ros oncogene 1 (ROS-1) or ALK. Crizotinib inhibits c-Met and ALK by directly binding the activation loop and stabilizing the autoinhibitory conformation of each kinase. Though crizotinib is a potent inhibitor of both kinases, it exhibits greater specificity against c-Met .Preclinical studies using crizotinib alone show potent reduction of proliferation for HNSCC cell lines (cell IC50 4.1–4.7 μM) and a significant inhibition of both wound-closure and invasion in vitro. Crizotinib induced apoptosis and greatly decreased the tumor burden in a patient xenograft in vivo model . In combTo date, capmatinib is the only class Ib small molecule inhibitor of c-Met to be used in clinical trials for HNSCC. This class of inhibitors, like class Ia, interacts with the autoinhibitory loop of c-Met, yet they also take advantage of the smaller ATP-binding site of c-Met to generate greater specificity against this kinase . UnfortuGolvatinib is one of two class II c-Met inhibitors to be used in clinical trials. These inhibitors are large, hydrophobic molecules that occupy the back pocket of c-Met and are usually less specific . As such, golvatinib is a dual inhibitor against c-Met and vascular endothelial growth factor (VEGFR)-2 . In preclinical studies, it inhibited proliferation of a broad range of tumor cell lines (cell IC50 6.2 nM to 4.3 μM) and inhibited HUVEC growth in response to HGF and VEGF as an in vitro model of angiogenesis. Golvatinib also greatly reduced tumor burden in mouse xenograft models and blood vessel density in remaining tumors .Golvatinib has been tested in two clinical trials for HNSCC to date. The first study is a Phase I/II trial targeting EGFR with cetuximab in the presence or absence of golvatinib and is currently recruiting (NCT01332266). The second clinical trial is meant to determine the efficacy of golvatinib treatment in conjunction with cepecitabine and cisplatin (NCT01355302). Unfortunately, this trial did not pass Phase I with five of the seven enrolled patients experiencing serious adverse effects, including supraventricular tachycardia, convulsion, and pulmonary embolism.Foretinib is a class II inhibitor targeting c-Met, VEGFR2, Recepteur d’Origine Nantais (RON), kinase insert domain receptor (KDR), and Fms related tyrosine kinase 1 (Flt-1) with potent inhibition of c-Met kinase activity (enzymatic IC50 1.16 nM) . In HNSCA clinical trial examining the safety and efficacy of foretinib alone in treating recurrent, metastatic HNSCC was terminated after Phase I after none of the enrolled patients presented partial or complete response (NCT00725764). Though this trial did not progress, enrolled patients had a 50% disease stabilization rate, and 6 of the 14 patients showed shrinking tumor size . No clinFiclatuzimab is currently the only biological therapy undergoing trial that targets the c-Met/HGF axis in HNSCC. It is a humanized monoclonal antibody that sequesters HGF, thereby preventing the stimulation of c-Met by HGF. Given its mechanism of action, however, it is important to recognize that ficlatuzumab is unable to inhibit HGF-independent c-Met activation. Ficlatuzumab has been demonstrated to interfere with stromal contributions to proliferation, migration, and invasion in a preclinical in vitro model of HNSCC, as well as epithelial to mesenchymal transition (EMT) . FiclatuOver three decades of research have been spent investigating the HGF/c-Met pathway and its clinical relevance. In HNSCC, c-Met receptor overexpression is commonly associated with poorer outcomes in patients. This is attributable to increased nodal metastases, cellular proliferation, and cell survival. Notably, c-Met contributes to treatment resistance by bypassing traditionally clinically inhibited signals such as EGF. However, Met inhibitors have yet to show marked improvement for patient outcomes. One of the hurdles to overcome is shifting promising multi-signal blockades from preclinical to clinical trials. Further, there is a need to develop c-Met-specific agents and use these in patients with appropriate biomarkers. Understanding the integration between HGF/c-Met axis and other oncogenic signaling pathways may lead to stronger treatment modalities in the near future .


Strigolactones (SLs), being a new class of plant hormones, play regulatory roles against abiotic stresses in plants. There are multiple hormonal response pathways, which are adapted by the plants to overcome these stressful environmental constraints to reduce the negative impact on overall crop plant productivity. Genetic modulation of the SLs could also be applied as a potential approach in this regard. However, endogenous plant hormones play central roles in adaptation to changing environmental conditions, by mediating growth, development, nutrient allocation, and source/sink transitions. In addition, the hormonal interactions can fine-tune the plant response and determine plant architecture in response to environmental stimuli such as nutrient deprivation and canopy shade. Considerable advancements and new insights into SLs biosynthesis, signaling and transport has been unleashed since the initial discovery. In this review we present basic overview of SL biosynthesis and perception with a detailed discussion on our present understanding of SLs and their critical role to tolerate environmental constraints. The SLs and abscisic acid interplay during the abiotic stresses is particularly highlighted.Main Conclusion: More than shoot branching Strigolactones have uttermost capacity to harmonize stress resilience. Striga and Orobanche. Later on, SLs were found to be host-detection and hyphal-branching signals for arbuscular mycorrhizal (AM) fungi (Strigolactones (SLs) were initially known as host-derived germination stimulants for parasitic weeds from the genera M) fungi . In addiM) fungi . This beM) fungi . Here, aFigure 1 for some exemplary structures. Rather wide collections of branching mutants are available in Arabidopsis thaliana [known as more axillary growth (max) mutants], Oryza sativa [dwarf (d) or high-tillering dwarf (htd) mutants], Pisum sativum [ramosus (rms) mutants] and Petunia hybrida [decreased apical dominance (dad) mutants]: their analysis was instrumental to understand and define most of the current assembly of SL biosynthetic  pathways. Based on the observation that plants treated with inhibitors of carotenoid biosynthesis exude fewer SL from their roots, a hypothetical SL-biosynthetic pathway was initially proposed, with β-carotene as a substrate for carotenoid-cleavage dioxygenase (CCD) enzymes  (DWARF27 (D27) and its ortholog in Arabidopsis ATD27, an iron-binding, plastid-localized β-carotene isomerase, works upstream of CCD7 and CCD8 catalyzing the conversion of all-trans-β-carotene into 9-cis-β-carotene (C-40). The latter acts as substrate for CCD7 to cleave cis-configured carotenoids into 9-cis-β-apo-10′-carotenal (C-27) and β-ionone (C-13)  and promotion of seed germination Striga hermonthica , converting CL to carlactonic acid (CLA) then further transformed to methyl carlactonoate (MeCLA) by an unknown enzyme .More than 20 SL and SL-like compounds have been identified so far in the root exudates of several plant species. They all share a conserved tricyclic lactone structure containing rings referred to as ABC rings, linked via an enol-ether bridge to an invariable α,β-unsaturated furanone moiety named D ring. The bioactiphore resides within the region that connects the D-ring to the core; chemical diversity is given by the stereochemistry of the B-C ring junction, the size of the A ring, and the substitution patterns of the A and B rings reviewed by  see Figu enzymes . CCDs sp enzymes . Later oidopsis) . Rice DWe (C-13) . CCD8 the (C-13) . CL act monthica . The genystrigol . MAX1 pun enzyme . The latent-2′-epi-5-deoxystrigol, the presumed precursor of rice SL. A protein encoded by a second MAX1 homolog then catalyzes the conversion of ent-2′-epi-5-deoxystrigol to orobanchol . Presence of both CLA and MeCLA (methyl ester carlactonoate) endogenously in Arabidopsis roots by LC-MS/MS also confirms that CL alone is the target of MAX1. Interestingly exogenous application of both CLA and MeCLA was found to rescue max1 mutant phenotype in Arabidopsis, however, only MeCLA act as substrate to bind with putative SL receptor of Arabidopsis thaliana DWARF14 (AtD14)  is an oxidoreductase-like enzyme of the 2-oxoglutarate and Fe(II)-dependent dioxygenase superfamily, whose expression pattern partially overlaps with that of MAX3. LBO acts on MAX1 products, such as MeCLA or CLA and converts them into an unknown SL-like compound that is hypothesized to be more effective than SL and responsible for branching inhibition  . Elucidaobanchol . More rehibition . For morhibition .In vitro interaction GR24 has been shown to thermally destabilize D14 and for that catalytic triad is necessary. D14 loaded with SL is then recruited to SCFMAX2, which in turn directs further degradation of target proteins  via the proteasome  , SL signaling mechanisms are executed by proteosomal degradation. The SL signaling machinery comprises at present the α/β-fold hydrolase named (At)D14/DAD2/RMS3, the F-box leucine-rich protein MAX2/RMS4/D3, and the D53 a repressor protein, which holds some similarity to class I CIp ATPase enzymes and belongs to a small family of proteins [SMAX1-like (SMXL)] . MAX2, ligure 3) . D14 itsigure 3) . It shouigure 3) ; D53 becigure 3) , but thiSeveral recent reports put forward interesting hypotheses on the evolution of ligand and signaling specificity by members of the wider family of D14 and D14-like proteins. The latter is a closely related protein clade to D14 proteins, some members of which have been characterized as receptors of host-exuded SL by parasitic plants, and would then represent a case of convergent evolution on SL perception with D14 . This laThe discovery of SLs provided new opportunities in the last decade to explore hormonal regulation of plant development and acclimatization to environmental constraints. These research endeavors also identified new instances of hormonal cross talk participating to the orchestration of overall responses in plants.Hormonal cross talk is largely at work to allow an appropriate plant response to environmental stimuli, as well as changes in architecture and acclimatization under challenging conditions such as nutrient starvation and heat/cold/salinity/light stress, by mediating growth, development, nutrient allocation and source/sink transitions.Figure 2). Knowledge of SLs biosynthesis and their physiological role in monitoring the architecture of plants led to well established fact that SLs, need to modulate and interact with many phytohormones – particularly auxins and ABA – to exert their effect.Plastid-derived apocarotenoids produced in response to environmental conditions in plants include several plant growth regulators and signaling molecules besides SLs, such as retinoids and ABA. As mentioned in the Section “Introduction,” SLs have diverse biological functions in addition to regulation of branching phenotype, being important signaling compounds in the rhizosphere  were upregulated by exogenous auxins application  could be in the alteration in biosynthesis, sensitivity, and/or transport of either hormone , cytokinins (CK), gibberellins (GA), ABA have also been explored in some detail . Particu hormone , whose sTrifolium pratense L.) in response to deficiency of various nutrients ; later on, they also tested the effects of N and P deprivation on deoxystrigol levels in sorghum (Sorghum bicolor [L]. Moench) exudates (Solanum lycopersicum L) and alfalfa (Medicago sativa), which only responded to P starvation (T. incarnatum L.]) show increased SL exudation under P deficiency only, while most non-legumes respond to deficiency of both N and P; however, exceptions exist in both groups, as the legume Chinese milk vetch  responds to both (Phosphate (P) and/or Nitrogen (N) deficiency in the soil is a serious abiotic source of stress and commonly encountered by most land plants. The only accessible form of P for plants in soil is inorganic (Pi) . Since texudates . SL quanarvation . As more to both  while th to both . Therefo to both , and are to both , 2013. N to both . Further to both . The ecoD10, D17, D27) of SLs were differentially regulated by P starvation/supplementation; additionally, the transcript encoding PhPRD1, the ABCG transporter responsible for exudation in soil and translocation of SLs from roots to shoot in petunia (Petunia hybrida) also accumulates during P starvation . In general, SLs affect those features of root architecture  controlled by auxins during P starvation , RH elongation, activation of P transporter genes, regulation of phosphate starvation marker genes (PSI), anthocyanin accumulation and reduction in fresh weight of plant , catalyzing the cleavage of 9-cis-epoxycarotenoids to xanthoxin, i.e., the first step in the ABA biosynthetic pathway . Although the initial working hypothesis was that both hormones interact with each other at the biosynthetic level, and that induction of ABA biosynthesis impacts SLs formation and vice versa by substrate competition, recent work has highlighted more subtle interactions.Strigolactones have emerged to be key players in plant physiology under stress such as upon nutrient starvation  but also drought, salinity , and lig pathway . Since tZmNCED1 induced significantly less germination of the parasitic seeds, an effect that may be associated with low levels of SLs (MAX3 and MAX4 transcript accumulation in Arabidopsis (sitiens mutants having only 8% ABA as compared to wild-type, were less susceptible than the latter to AM fungal infection (sitiens deficient in ABA could be the reason of low AM colonization; however, CCD8-silenced transgenic tomato was not significantly affected in AM colonization, indicating that the residual SL production in such lines might be enough to warrant efficient host perception by AM fungi (Root extracts and exudates of ABA-deficient maize plants having null mutations in the ABA-biosynthetic gene s of SLs . In a mobidopsis . These rnfection . Endogennfection . These rnfection . Since Snfection . In suchnfection . The redAM fungi . Also, tAM fungi .max mutants were subjected to drought and salinity stress to investigate the involvement of SLs in abiotic stress resilience. No significant differences in ABA levels could be detected between wild-type and SL mutants in this species, but stressed tissues were not analyzed; this and the previous datasets on tomato and Lotus collectively suggest a general positive influence of SLs on ABA levels under stress, possibly with some species-specific variability. Nonetheless, both SL-deficient and perception mutants of Arabidopsis were reported as more stress-sensitive at different developmental stages in the same work. The positive role of SL in abiotic stress resistance was further proven by exogenous application of SL at the shoot level, which improved performances under stress both of wild-type and of SL-deficient mutants, but not of SL signaling mutants. Interestingly, all SL mutants were partially insensitive to exogenous ABA as compared to wild-type plants, both at germination and seedling developmental stage (max2 in Arabidopsis to abiotic stresses as reported by max3, max4 and max2. On the other hand, max2 displayed hypersensitivity to ABA at pre- and post-germination stages in the work by max2, thus excluding a direct role for the SL metabolites in osmotic stress responses. However, the contribution of SLs in osmotic stress resistance was confirmed in other species, thus supporting the results by Lotus japonicus was more stress-sensitive than its wild-type counterpart; more recently, the same was proven in tomato (A separate analysis should be dedicated to the converse effect – i.e., of SLs on ABA levels – and to the SL-ABA cross-talk under abiotic stresses. In the first report of SL-ABA interaction by al stage . Sensitin tomato . In all If SLs contribute to drought resistance one would expect their levels to increase under stress. This may be true in shoots, where although metabolites remain under the detection threshold, the transcript of biosynthetic genes are more concentrated in dehydrated than unstressed wild-type tissues, both in Arabidopsis and tomato . HoweverThe above-mentioned organ-specific dynamics of SL production during dehydration were investigated into more detail in tomato. The hypothesis of a possible role for the drought-triggered SL decrease at the root level in long-distance signaling of stress to the shoots was tested, by comparing the eco-physiological performances and ABA content of wild-type and SL-depleted plants with those of plants obtained by grafting wild-type shoots on SL-depleted roots, in a drought time-course . This laThe SL-ABA cross-talk has been increasingly spotlighted by research aimed at dissecting and understanding abiotic stress tolerance; interest is escalating because of the theoretical possibility of engineering phytohormonal signaling and metabolism for the improvement of crop performances under natural stress conditions. If we really are to do so, and exploit SL biology to the purpose of sustainable agriculture, the most immediate challenge ahead is to understand the molecular underpinnings of the pervasive SL effects on plant phenotypes under stress, as well as how they may connect physiological strain to appropriate development progression. How do SLs modulate ABA sensitivity? Is their effect linked to altered efficiency or abundance of components in the ABA signaling machinery, and/or to a modulation of ABA transport? Data in Arabidopsis, Lotus and tomato indicate that in the former, ABA transporters are down-regulated in SL-depleted vs. wild-type leaves under drought ; while iWS has compiled the literature and written the manuscript. ZA has initiated and supervised the research. ZA and SN have helped in compilation of manuscript. All three authors have edited and revised the approved manuscript submitted. WS and SN contributed equally in this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A 76-year-old man was incidentally found on a CT scan to have lymphadenopathy and bilateral kidney enlargement suggestive of infiltrative renal disease. He was largely asymptomatic but had bilateral salivary and lacrimal gland enlargement. A grossly elevated serum IgG (>70 g/L) with concomitant suppression of other immunoglobulins, a small IgG restriction, and a parotid biopsy revealing lymphoplasmacytic infiltrate with slight kappa light chain excess all suggested a lymphoproliferative disorder (LPD). The diagnostic workup was further confounded by a normal serum IgG4 concentration. Moreover, bone marrow and renal biopsies did not reveal evidence of LPD. Discussion with the laboratory not only clarified that the markedly increased total IgG could not be accounted for by the small IgG restriction, but also identified a discrepancy in the IgG4 measurement. Repeat analysis of a follow-up sample revealed an elevated IgG4 of 5.94  g/L, which prompted a repeat parotid biopsy that showed predominant IgG4+ lymphocytic infiltrates. Despite the deluding presentations, a final diagnosis of IgG4-related disease (IgG4-RD) was made based on elevated serum IgG4 concentrations and histopathological findings. This case highlights the importance of recognizing limitations of laboratory testing and the benefit of close communications among clinical subspecialties and the laboratory. Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated multisystem disease that is characterized by inflammation and fibrosis of affected organs , 2. SincWe report a case of IgG4-RD diagnosed in a patient who was incidentally found to have lymphadenopathy on a routine CT scan for evaluation of aortic aneurysm repair. His manifestations of IgG4-RD included bilateral painless lacrimal, submandibular and parotid gland enlargement (Mikulicz features), infiltrative renal disease with moderate renal dysfunction, and possibly aortitis leading to further aneurysm extension after repair. The diagnosis was initially confounded by laboratory results that were inconclusive or misleading . Recognition of the limitations of laboratory testing and correlation of clinical findings with immunohistochemistry ultimately confirmed the diagnosis of IgG4-RD.A 76-year-old man was referred by his vascular surgeon to Rheumatology for query connective tissue disease after he was incidentally found to have increased lymphadenopathy and bilateral enlarged kidneys on follow-up CT imaging after thoracic endovascular aortic repair (TEVAR).His surgical history was significant for abdominal aortic aneurysm repaired with stent and type B dissection of thoracoabdominal aortic aneurysm with TEVAR repair three years later. His medical history was significant for hypertension, dyslipidemia, and sinusitis. He had no known drug allergies. His medications included aspirin, ramipril, metoprolol, and atorvastatin.Further history indicated that he had experienced progressive painless swelling in his bilateral cheeks/neck for five years. On review of systems, he also endorsed intermittent sinusitis, dry mouth, multiple dental cavities, and Raynaud's phenomenon. He denied any constitutional symptoms.On examination, he had nontender bilateral parotid gland enlargement and bilateral lacrimal gland hypertrophy. He had chronic perforation of his right tympanic membrane and fragmented decayed dentition. The rest of the examination was unremarkable.Workup for connective tissue disease, including ANA, ENA, ANCA, HIV, hepatitis B and C serology, ESR, CRP, and cryoglobulin screen, was all negative. There was markedly elevated IgG (76.71 g/L) with concomitant suppression of IgA and IgM levels. Serum protein electrophoresis (SPE) suggested an M-protein band of 68 g/L in the beta gamma interzone. Serum immunofixation electrophoresis (IFE), however, identified only a small clonal restriction in IgG while urine IFE identified a very tiny kappa restriction. Serum free light chain assays showed elevated free kappa and lambda concentrations (both >300 mg/L) with a normal ratio. Blood film showed rouleaux, normochromic anemia, mild eosinophilia, few atypical lymphocytes, and slight thrombocytopenia. Chest X-ray showed no hilar adenopathy. Sinus X-ray showed opacification of paranasal sinuses possibly from inflammatory diseases. Initial submandibular gland and lymph node biopsy was nondiagnostic and revealed lymphoplasmacytic infiltrate with slight kappa light chain excess.He was referred to Haematology, as the grossly elevated serum IgG (>70 g/L) with concomitant suppression of other immunoglobulins, small IgG restriction, and biopsy results raised concern for LPD. Imaging for lymphoma protocol was performed. CT scan of the abdomen and pelvis showed multiple lymph nodes and bilateral kidney enlargement with infiltrative and nodular disease. There was also circumferential periaortic wall thickening. MRI brain showed bilateral enlargement of parotid and lacrimal glands as well as chronic sinusitis see .Further discussion with the laboratory revealed that the relative contribution of M-protein was most likely overestimated, since SPE has limited ability to distinguish clonal from polyclonal expansion, especially in the setting of very high total IgG as in this case. Serum and urine IFE were in line with a minor monoclonal gammopathy but were not in keeping with such a marked IgG increase, and the normal free light chain ratio was inconsistent with a large clonal process. Bone marrow biopsy and aspirate showed no evidence of amyloidosis or plasma cell, lymphoproliferative, or myeloproliferative disorder. The patient may have a coincidental monoclonal gammopathy of undetermined significance (MGUS) which may or may not be the result of a reactive immunologic process.2), the patient was also referred to Nephrology for a kidney biopsy which showed atypical interstitial lymphoid infiltrate with some eosinophils and occasional plasma cells but was negative for IgG, IgM, IgA, C3, C1q, lambda, and kappa light chains by immunofluorescence.Given the imaging findings and renal dysfunction . However, the sum of IgG subclasses did not equate to the total IgG concentration reported, and further consultation with a Biochemist led to measurement at a different lab (Lab B) but the result was discrepant see . On furtThe elevated IgG4 level prompted a repeat submandibular excisional biopsy. On this tissue sample, flow cytometry indicated no clonal process and was not supportive of lymphoproliferative disorder. Further, molecular diagnostic studies by PCR did not reveal any evidence of B-cell clonal restriction. However, immunohistochemistry studies showed IgG4 positive plasma cells present in increased numbers (clusters of >100) with IgG4/IgG ratio of >40% see . FurtherA final diagnosis of IgG4-RD was made based on clinical manifestations, elevated IgG4, and histopathologic findings.Immunosuppressive treatment was deferred as the patient was awaiting an extensive dental procedure. He had close follow-ups with Rheumatology and Nephrology. Nearly one year after his diagnosis, he showed significant reductions of his glandular enlargement and stable kidney function. His total IgG dropped from 77 to ~24 g/L while his IgG4 level remained elevated at 6 g/L. Spontaneous resolution of clinical manifestations has been described in IgG4-RD patients who received no treatment. A recent systematic review examining therapeutic approaches to IgG4-RD reported that no therapy (wait-and-see management) was used in 13% of all patients included (264 out of 1952). There were a greater percentage of patients treated without any therapeutic intervention in specific organ involvement: 71% and 35% of those with lymphadenopathy and salivary gland involvement, respectively. Spontaneous resolution was seen in 43% (68 of 159) of patients managed without therapy, although there were higher relapse rates compared to those treated with glucocorticoids. The review concludes that wait-and-see management may be appropriate in asymptomatic patients with lymphadenopathy or mild salivary gland enlargement [After an extensive workup to exclude LPD and malignancy, the patient was diagnosed with IgG4-RD affecting his salivary glands, lacrimal glands, and likely both kidneys. The presence of bilateral renal enlargement with infiltrative hypoattenuating regions provided strong radiographic support for IgG4-related renal disease. The renal biopsy yielded only four glomeruli but demonstrated the presence of an interstitial lymphoid infiltrate with occasional plasma cells. Immunofluorescence was negative for IgG, IgA, IgM, C3, C1q, kappa, and lambda. The pathological features of IgG4-related renal disease can include tubulointerstitial nephritis (TIN) with dense lymphoplasmacytic infiltration, storiform fibrosis, and IgG4-positive plasma cell infiltration . AdditioA clinically significant problem highlighted by this case was the lab-to-lab variability in serum IgG4 measurements and the diagnostic utility of IgG4 levels in IgG4-RD. An IgG4 level of 1.35 g/L evaluated in the diagnosis of autoimmune pancreatitis has been widely accepted as the cut-off level for IgG4-RD , 7. In fIt is important for clinicians to be aware of the limitations of laboratory tests. In this case, the overestimated M-protein in the SPE result and falsely normal initial serum IgG4 level created a diagnostic conundrum and led to possible delays in diagnosis. One likely explanation for the initial falsely negative IgG4 level stems from intrinsic properties of the IgG4 immunoassay, specifically the prozone effect. This phenomenon can occur in the setting of antigen excess , where assays do not provide accurate IgG4 measurements if the sample has not been diluted appropriately , 11. TheThe discrepancies in laboratory measurements in this case were acknowledged and discussed among the various specialists involved, including the Haematologist, Biochemist, and Pathologist, highlighting the importance of open communication among care providers in the face of diagnostic dilemmas.


The aim of this work is to study the influence of the admixture of superplasticizers on the physical properties of cement paste to know the initial and final time, water content and mechanical performance of concrete.In this work we have incorporated an Advanced Superplasticité for Prolonged Slump Retention (ASPPSR402) in the formulation matrix of concrete at different percentages ranging from 0.5% to 5% by weight of cement with a step of 0.5%, while partially substituting the mixing water by the last one to reduce the amount of water used.The obtained results by different prospected formulations show that the admixture of ASPPSR402 in formulations matrix significantly reduces the (Water/Cement “W/C”) ratio. Subsequently, we observed that the initial and final time increases in function of the percentage of ASPPSR402. Similarly, the compressive strength at the young age, median age and long-term has been improved. Specifications TableValue of the data●Evaluation of the W/C ration, setting time and the compressive strength of Portland cement  compared to the cement  based on the various volume of advanced admixtures of superplasticizer for prolonged slump retention.●Estimation of the evolution of the ratio (W/C) and the initial and final time of cement paste as a function of the various percentages of the ASPPSR402 and the amount of water reduced according to the various percentages of ASPPSR402.●Estimation the rate of change compressive strength of ordinary Portland cement as a function of curing time.●Optimization of the curing time to achieve a particular rate of change of compressive strength of using the admixture of ASPPSR402.1The data of the different formulations in a fresh and hardened state presented here are from eleven different cement pastes, mortar or concrete samples fabricated to compare cement pastes, mortar or concrete based of ASPPSR402 with Portland cement based concrete.2To achieve the objective of our study, we made a mortar of reference without additions and ten samples with the ASPPSR402 whose compositions are inspired by that of the normal mortar defined by EN196-1, with a quantity of water adjusted to obtain a paste with a standard consistency. The procedures followed for the preparation of the pastes cement has been done in maintaining fixed consistency standardized of all the formulations produced according to the specification of the standard (EN 196-3 + A1) 3 according to the specification of the standard (NF EN 196-1) To complete our work, we also studied the influence of the ASPPSR402 on the mechanical performance of mortar or concrete by using the compressive strength. The measures of the compressive strength are on standard prismatic standard (4 × 4 × 16) cmThe compositions of the different formulations in a fresh and hardened state are recorded in the , Table 233.1For evaluating the influence the Admixtures of advanced superplasticiser for prolonged slump retention "ASPPSR402", on physical properties of fresh cement paste and mechanical performance  of mortars and /or concretes in the hardened State. We have preceded our work by the characterizing of materials used, to understand the phenomena which occur at the moment of mixing and hardening of concrete.3.1.1The type of cement used in this work is (CMI/42.5) from the plant of Amran in Yemen. The chemical and mineralogical compositions of clinker, gypsum and cement determined by XRF are presented in the 3.1.1.1The physical properties of clinker and cement are gathered at the 3.1.2To prepare our mortar, we used a standard sand conferring to the standard EN 196-1 3.1.3The Advanced superplasticizer for Prolonged Slump Retention "ASPPSR402"), are polymers in liquid form, prepared especially for the cement industry and concrete. They are a basis of salts of sodium or calcium of poly-naphthalene sulfone , salt ofThe ASPPSR402 used in the formulation of mortars and/or concrete of high performance, delivered by the company CONMIX Ltd in Sharjah, United Arab Emirates. They are incorporated during the mixing of the concrete in equal a dose raining from 0.5% to 5% by weight of cement with a step of 0.5% to improve the physical and the mechanical properties of fresh or hardened State.The physical properties of ASPPSR402 are collected at the 3.1.4To waste our mixture, we used tap water (wells). The physical properties of mixing water are assembled at the 3.23.2.1The 3.2.2The 3.3The MC' at different percentages of ASPPSR402.The


Lung remodeling and pulmonary fibrosis are serious, life-threatening conditions resulting from diseases such as chronic severe asthma and idiopathic pulmonary fibrosis (IPF). Preclinical evidence suggests that JNK enzyme function is required for key steps in the pulmonary fibrotic process. However, a selective JNK inhibitor has not been investigated in translational models of lung fibrosis with clinically relevant biomarkers, or in IPF patients.n = 28), with a 4-week, placebo-controlled, double-blind, sequential ascending-dose period  and a 52-week open-label treatment-extension period.The JNK inhibitor CC-930 was evaluated in the house dust mite-induced fibrotic airway mouse model, in a phase I healthy volunteer pharmacodynamic study, and subsequently in a phase II multicenter study of mild/moderate IPF . A total of 13 subjects (46.4 %) experienced adverse events that led to discontinuation of study drug. Nine out of 28 subjects experienced progressive disease in this study. The mean FVC (% predicted) declined after 26–32 weeks at doses of 100 mg QD and 100 mg BID. Changes in MMP-7, SP-D, and tenascin-C significantly correlated with change in FVC (% predicted).These results illustrate JNK enzymatic activity involvement during pulmonary fibrosis, and support systemic biomarker use for tracking disease progression and the potential clinical benefit of this novel intervention in IPF.Trial registration ClinicalTrials.gov NCT01203943The online version of this article (doi:10.1186/s40169-016-0117-2) contains supplementary material, which is available to authorized users. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease of unknown etiology. Primarily occurring in older individuals, IPF is characterized by progressive worsening in dyspnea and pulmonary function . The exaCO) . In each cohort, eligible patients were randomly allocated to receive placebo (two patients) or CC-930 (eight patients) for 4 weeks. The decision to escalate to the next dose level was made after all patients had completed or discontinued prematurely from the preceding dose level, and pharmacokinetic and safety data from the preceding dose level had been reviewed by an external data monitoring committee. Ongoing review of blinded safety data from eight patients receiving CC-930 100 mg BID (cohort 3) revealed increases in liver transaminases that may have been a potential risk to patients if they continued at that dose. This observation led to the issuing of a protocol amendment to decrease the study drug dose in Cohort 3 from 100 mg BID to 100 mg QD (3 of 8 subjects remained on study and were dose-reduced). The data from these 3 subjects were handled on an intent-to-treat basis. All patients who completed the double-blind, ascending-dose phase were eligible to enter the open-label treatment-extension phase and continue on the same dose of CC-930 for 52 weeks. Patients initially allocated to placebo were given the CC-930 dose from their original cohort assignment. The external data monitoring committee regularly reviewed safety results during this phase.The phase II clinical study of CC-930 in IPF patients was a multicenter study, open to enrollment from January 2011 to August 2012, which consisted of a screening period, 4-week blinded sequential ascending-dose phase, a 52-week open-label treatment-extension phase, and a 52-week observational follow-up phase. A total number of 19 clinical sites were activated to recruit subjects (13 sites in the United States and six sites in Canada), out of which 11 sites enrolled subjects (seven sites in the United States and four sites in Canada). The study population was restricted to subjects with an FVC >50 and <90 % of predicted, DLco >25 and <90 % of predicted, and resting saturated oxygen of >92 % on room air at sea level who have findings of usual interstitial pneumonia pattern on HRCT and/or usual interstitial pneumonia pattern on histopathology , and the exclusion of known causes of interstitial lung disease. The primary endpoint of the study was to evaluate the safety , laboratory, or other changes) of CC-930 in the 4-week double-blind treatment phase. Secondary endpoints included: CC-930 pharmacokinetics; evaluation of the long-term safety of CC-930 in the 52-week open-label extension; and disease progression and death rates within the total treatment and follow-up observational period. Exploratory endpoints included: changes in blood biomarkers KL-6, MMP-1, MMP-7, SP-A and SP-D, TIMP-1, CCL-18, CCL-2, PAI-1, and tenascin C; changes in FVC and DLIn the phase I clinical study, healthy male and female volunteers from any race were eligible to participate if they were aged 18–50 years and had Fitzpatrick skin type I or II. Subjects were excluded if they had any serious medical condition or history of major medical condition within 3 years of study, any prescribed systemic or topical medication within 30 days of first dose administration, or any surgical or medical conditions that could affect drug pharmacokinetics.CO of 25–90 % of predicted. Patients were excluded for resting oxygen saturation <92 % on room air at sea level or <88 % at ≥5000 feet2 above sea level; pulmonary arterial hypertension, emphysema, or other significant respiratory disorders; current smoker; connective tissue disorder; significant medical conditions or laboratory abnormalities or history of clinically significant medical conditions that would prevent study participation or put patients at risk; history of serious cardiac conditions within 6 months of study entry; and ECG abnormalities.In the phase II IPF clinical study, patients were eligible to participate if they had confirmed IPF based on American Thoracic Society/European Respiratory Society guidelines, with an FVC of 50–90 % of predicted and a DLIn the phase I clinical study, a small area of skin on the buttocks was exposed to 2 times the minimal erythema dose of UVB at 2 h after dosing on day 6. This exposure to UVB has previously been demonstrated to activate JNK and subsequently increase phosphorylation of its substrate c-Jun . A skin In the phase II IPF clinical study, patients were screened within 5 weeks before the double-blind, ascending-dose phase. Study visits were scheduled at weeks 0 (baseline), 1, 2, and 4 of the double-blind, ascending-dose phase, and at weeks 5, 6, and 8, and every 4 weeks thereafter until the final treatment visit at week 56 or at the early termination visit. Subsequent observational follow-up visits were planned quarterly. Safety assessments, including AEs, vital signs, 12-lead ECGs, and clinical laboratory tests, were performed at each visit. A complete physical examination was done at screening and at the end of each treatment phase; a targeted physical examination was done at all other visits. Holter monitoring was done within 10 days of the first dose of study treatment and at weeks 1, 5, and 16. Chest radiographs were obtained at screening and at the final treatment/early termination visit.CO assessments were made at baseline, every 4 weeks until week 24, and every 8 weeks thereafter. The HRCT/fibrosis score was determined at screening and at the final treatment/early termination visit. Disease progression was defined as death from respiratory failure, progressive sustained decrease in FVC or DLCO, unexplained worsening of hypoxia, or acute exacerbation. Other efficacy parameters, including changes from baseline in FVC, DLCO, and HRCT/fibrosis score, were exploratory endpoints.To monitor the disease course, spirometry and DLBlood was collected at baseline and at weeks 4, 24, and 56 for measurement of MMP-1, MMP-7, TIMP-1, tenascin-C, SP-A, SP-D, CCL-18, KL-6, MCP-1, and PAI-1. All ten biomarkers were assayed using validated enzyme-linked immunosorbent assays or other similar methods by Pacific Biomarkers, Inc . For the pharmacokinetics analysis, a subset of patients volunteered for intense blood sampling on day 1 and week 2; all others had sparse sampling at week 2. Sparse sampling was also done at weeks 8, 12, 16, 20, 24, 32, 40, 48, and 56. The plasma concentration of CC-930 and its major circulating and pharmacologically inactive metabolite CC-17172 were measured using a validated liquid chromatography–tandem mass spectrometry method.Safety parameters were evaluated in all patients who received ≥1 dose of study drug using descriptive statistics. Treatment-emergent AEs were coded to the Medical Dictionary for Regulatory Activities (version 14.0). Pharmacokinetics and pharmacodynamics were evaluated in all patients from the safety population who had ≥1 pharmacokinetic and ≥1 biomarker assessment, respectively. In the phase I study in healthy volunteers, phospho-c-Jun IHC images were scored by three independent evaluators using a subjective scoring scale of 0–4 (increases in scores reflect higher immuno-staining). Individual phospho-c-Jun scores were subtracted by the corresponding placebo to reflect the individual response to CC-930. A repeated measure logistic regression was performed on the IHC scores of total c-Jun and phospho-c-Jun using the GENMOD procedure in SAS version 9.2 . The model included sequence, period, and treatment as fixed effects. In the analysis, scores of 0, 1, and 2 were grouped together (low score), and scores of 3 and 4 were grouped together (high score). All 14 subjects in the pharmacodynamic population were included in the analysis. In the phase II IPF clinical study, changes from baseline in biomarker values were summarized separately for the double-blind, ascending-dose phase and the entire study using descriptive statistics.® version 7.2 . Correlations between the model-predicted individual exposure to CC-930, as defined by the area under the plasma drug concentration-versus-time curve during the dosing interval, and the changes from baseline in MMP-7 were analyzed using a locally weighted polynomial regression method. Correlations between the changes from baseline in biomarker values versus changes from baseline in FVC percent of predicted were evaluated by Spearman’s correlation coefficient (r) and the associated P value based on the asymptotic test for H0.The CC-930 plasma concentration data from the phase II IPF clinical study were combined with data from a phase I study conducted in 13 healthy subjects to build a 2-compartment population pharmacokinetics model. Population modeling and simulation were performed using NONMEMThe JNK inhibitor CC-930 had previously been tested in the mouse bleomycin-induced pulmonary fibrosis model, having shown a dose-dependent reduction in lung fibrosis scores . HoweverWe next addressed the impact of CC-930 on HDM-induced mucus metaplasia, a prominent feature of allergic airways disease. Comparable periodic acid-Schiff (PAS) reactivity was observed in CC-930-treated and vehicle-treated mice exposed to HDM Fig. a. The aiThe effect of CC-930 on HDM-induced fibrotic airway remodeling was analyzed histopathologically using the Masson’s trichrome collagen stain. In response to HDM, collagen content was significantly enhanced around the bronchioles, consistent with earlier observations . RemarkaMajor features of HDM-induced disease are airway inflammation and hyperresponsiveness to methacholine. HDM-induced airway inflammation and hyperresponsiveness were not significantly affected by CC-930  completed each of the three 6-day study periods . The mean age of the study cohort was 31 years (range: 20–49 years); 100 % were white and 100 % were male. CC-930 administered for 6 days at doses of 75 mg QD and 200 mg QD was well tolerated in the healthy subjects. No subject discontinued because of an adverse event (AE), and no serious AEs were reported.P = 0.016) and 41.9 with CC-930 200 mg QD (P = 0.005).The mean CC-930 plasma concentration was 0.81 µM at the 75 mg QD dose and 1.89 µM at the 200 mg QD dose. The ability of CC-930 to inhibit JNK was determined by measuring phospho-c-Jun by IHC in skin punch biopsy specimens at 8 h after UVB exposure  compared with the placebo, CC-930 50 mg QD, and CC-930 100 mg QD dose groups .The study design is shown in Additional file Patients were exposed to CC-930 and placebo for a mean of 3.8 and 4.0 weeks, respectively, during the double-blind, ascending-dose phase. Total mean exposure to CC-930 during the entire treatment period, including that of patients who switched from placebo on entry into the open-label treatment-extension phase, was 25.9 weeks. Mean exposure decreased in a dose-dependent manner: 38.8 weeks with CC-930 50 mg QD, 22.5 weeks with CC-930 100 mg QD, and 7.8 weeks with CC-930 100 mg BID. Three patients receiving CC-930 100 mg BID were switched to CC-930 100 mg QD based on an ongoing blinded safety review and received the lower dose for a mean of 21.2 additional weeks.Clostridium difficile colitis), and 2 during the open-label treatment-extension phase (pneumonia and increased ALT/AST).The frequency of AEs during the double-blind, ascending-dose phase appeared to increase in a dose-related manner with CC-930  (Table n = 4), increased ALT (n = 3), and increased AST (n = 3), all of which occurred in patients receiving CC-930 100 mg BID. The six patients who discontinued because of increased ALT or AST were the only patients with ALT or AST values >3 times the upper limit of normal. None of these cases was accompanied by concurrent alkaline phosphatase or bilirubin values >2 times the upper limit of normal, and none met the criteria for Hy’s law. All hepatic transaminase elevations resolved within 2–4 weeks after discontinuation of CC-930. Three patients discontinued because of cardiac-related AEs; it is not known if these were related to the age and health of the patients or occurred as a consequence of CC-930. Because the benefit/risk profile of CC-930 did not support continuation, this study was terminated early during the extension phase.Overall, 13 patients discontinued CC-930 because of AEs, with the frequency increasing in a dose-related manner . The only AEs resulting in discontinuation of >1 patient were increased lactate dehydrogenase (0–8) was 3339 ng·h/mL. These values increased to 1040 ng/mL and 5912 ng·h/mL, respectively, when measured after daily dosing for 2 weeks. The accumulation ratio for CC-930 was approximately 1.8-fold, consistent with a terminal half-life of 25–31 h, as previously measured in healthy volunteers (data not shown). Because samples were taken only until 8 h postdose in this IPF study, the PK parameters of terminal phase half-life, apparent total clearance, and apparent volume of distribution cannot be accurately determined in this patient population and are therefore not reported.CC-930 was rapidly absorbed following oral administration, with mean peak plasma drug concentrations achieved by approximately 1 h , SP-D , and tenascin-C   patients receiving CC-930 50 mg QD, 6 of 10 (60.0 %) receiving CC-930 100 mg QD, and 3 of 7 (42.9 %) receiving CC-930 100 mg BID. HRCT data were missing for the other 2 patients. Improvements in reticular abnormality and honeycombing were not observed.During the double-blind treatment phase, the classes of concomitant medications used in at least 50 % of overall subjects were cardiovascular system (75.0 %), alimentary tract and metabolism (71.4 %), and respiratory system (57.1 %). The frequency of subjects with concomitant use of respiratory system therapies was lower for the 100 mg BID group (42.9 %) compared with the placebo, 50 mg QD, and 100 mg QD dose groups . During the open-label treatment phase, the classes of concomitant medications used in at least 50 % of subjects were cardiovascular system (84.6 %), alimentary tract and metabolism (73.1 %), respiratory system (73.1 %), nervous system (61.5 %), anti-infectives for systemic use (57.7 %), blood and blood-forming organs (53.8 %), and musculoskeletal system (53.8 %). As in the double-blind treatment phase, the frequency of subjects with concomitant use of respiratory system therapies was lower for cohort 3 (42.9 %) compared with the cohorts 1 and 2 .JNK1 recently has been shown to play an important role in the pathogenesis of bleomycin and TGF-β1-induced lung fibrosis  and in H50 values determined in cell-based studies. CC-930 inhibited UVB-induced phospho-c-Jun in cultured normal human epidermal keratinocytes with IC50 values between 0.1 and 3.0 μM, and it reduced growth factor-induced c-Jun phosphorylation and basal collagen protein expression in human fibroblasts from scleroderma patients at a concentration of 1 μM [Results from the healthy volunteer phase I study demonstrate that CC-930 inhibits JNK in human subjects in a dose-related manner. JNK inhibition was determined by IHC of phospho-c-Jun in UVB-exposed skin, a model that depends on JNK activation and subsequent phosphorylation of its substrate c-Jun . At the  of 1 μM . ResultsThe IPF phase II study enrolled a well-defined population of IPF patients with mild to moderate pulmonary function impairment. The primary objective was to evaluate the pharmacokinetics, pharmacodynamics, biologic activity, and safety of CC-930. Pharmacokinetic data indicated that CC-930 is rapidly absorbed following oral administration, with pharmacokinetic parameters similar to those observed previously in phase 1 participants. The change in FVC was an exploratory endpoint, and was included in the definition of disease progression used herein. Deterioration in FVC ≥10 % from baseline over 6 months has been shown to predict mortality in IPF patients . The meaCO [In the pharmacodynamic assessment, CC-930 reduced plasma MMP-7 and SP-D concentrations in a dose-dependent manner. Notably, the reduction in MMP-7 correlated with the population pharmacokinetic model-predicted exposure to CC-930, and the changes in plasma MMP-7 and SP-D significantly correlated with changes in pulmonary function (FVC percent of predicted) when data for all patients and from all visits were considered. As noted, elevated MMP-7 levels have been identified in IPF patients and are negatively correlated with FVC and DLCO . MoreoveCO . CC-930 CO . At the The JNK pathway plays an important role in the regulation of gene expression of MMP-7, SP-D, and tenascin-C. For example, mesothelin enhances the invasiveness of ovarian cancer cells by inducing MMP-7 through activation of mitogen-activated protein kinase/extracellular signal-regulated kinase and JNK pathways ; the humThe initial 4-week, double-blind, ascending-dose phase did not reveal any meaningful difference in safety and tolerability between CC-930 and placebo. Although the frequency of AEs was higher in patients receiving CC-930 100 mg QD or 100 mg BID than in patients receiving CC-930 50 mg QD, it was still largely similar to the patients receiving placebo. All but two patients completed the double-blind, ascending-dose phase and entered the open-label treatment extension. Elevated hepatic transaminases were observed in patients receiving the highest doses of CC-930, mostly occurring after 8–12 weeks of treatment. No proximate cause or risk factor was identified in any of these patients except for CC-930 treatment. Although these safety data indicate a dose-dependent, late-onset transaminitis that may be associated with liver injury, none of the cases met the criteria for Hy’s law, and each case resolved within 2–4 weeks of discontinuing CC-930. Because of these observations, the study protocol was amended to reduce the dose of CC-930 from 100 mg BID to 100 mg QD for the three patients who remained in the study on treatment. The effect of CC-930 was subsequently investigated in human and rat primary hepatocytes in vitro. No cytotoxicity was observed at clinically relevant concentrations of CC-930, and no specific toxicity related to the etiology of the transaminase elevations was identified (data not shown). In the literature, there are conflicting reports regarding the role of JNK in protection from liver damage. JNK1 knockout mice are resistant to high fat-diet induced excessive weight gain, insulin resistance, and steatohepatitis. While JNK2 knockout mice develop obesity and insulin resistance similarly to normal mice, they exhibit increased ALT enzyme levels and liver cell apoptosis compared to normal mice high fat diet-induced . In miceSeveral study limitations deserve mention. The study was blinded and placebo-controlled only for the first 4 weeks, and study cohorts showed some imbalances despite the randomization. Both of these factors may have contributed to an overestimation of the effect of CC-930 on disease progression and exploratory efficacy parameters. In addition, the study had a small sample size per dose level, which may have limited assessment of the potential benefit/risk profile of CC-930. Also, the study was stopped early, due to elevated hepatic transaminase levels, as described above.Several other agents have been evaluated in similar IPF populations, and two agents, pirfenidone and nintedanib, have recently been approved for use in the United States , 41. TheIn aggregate, we demonstrated that CC-930 attenuated phospho-c-Jun, MMP-7, and collagen deposition in a murine model of fibrotic airways remodeling. CC-930 attenuated phospho-c-Jun in human subjects, and was well tolerated during the initial 4-week, double-blind, ascending-dose phase, but elevated liver enzymes were observed in some patients without identifiable risk factors who were treated with higher doses for 8–12 weeks. In IPF patients treated with CC-930, a decline in FVC percent of predicted was observed after ≥6 months, although in the absence of a placebo control group beyond week 4 in this treatment period, no conclusions about the effect of CC-930 on pulmonary function can be made. Changes in FVC were significantly correlated with changes in plasma MMP-7, SP-D, and tenascin-C concentrations. Furthermore, the changes in plasma MMP-7 were associated with CC-930 dose and exposure. These findings demonstrate that it may be possible to use serum biomarkers to track disease progression in IPF patients as well as the potential clinical benefit of novel interventions.


The orientation of steel fibers in magnetically driven concrete and magnetically driven mortar was experimentally studied in this paper using a magnetic method. In the magnetically driven concrete, a steel slag was used to replace the coarse aggregate. In the magnetically driven mortar, steel slag and iron sand were used to replace the fine aggregate. A device was established to provide the magnetic force. The magnetic force was used to rotate the steel fibers. In addition, the magnetic force was also used to vibrate the concrete and mortar. The effect of magnetic force on the orientation of steel fibers was examined by comparing the direction of fibers before and after vibration. The effect of magnetically driven concrete and mortar on the orientation of steel fibers was also examined by comparing specimens to normal concrete and mortar. It is shown that the fibers could rotate about 90° in magnetically driven concrete. It is also shown that the number of fibers rotated in magnetically driven mortar was much more than in mortar vibrated using a shaking table. A splitting test was performed on concrete specimens to investigate the effect of fiber orientation. In addition, a flexural test was also performed on mortar test specimens. It is shown that the orientation of the steel fibers in magnetically driven concrete and mortar affects the strength of the concrete and mortar specimens. There has been many research studies about steel fiber reinforced concrete (SFRC) in the last four decades . StudiesAbrishambaf et al.  used an In total, four series of concrete specimens were tested, namely series MDC-M (steel slag with magnetic orientation), MDC-S (steel slag with shaking table vibration), NC-M , and NC-S . Each series had twelve specimens. Six specimens were tested at 7 days while another six specimens were tested at 28 days. The content of the concrete is presented in Steel fibers having a nominal length of 31.0 mm and nominal diameter of 0.689 mm were used. The elastic modulus and tensile strength obtained from the manufacturer were 210 GPa and 810 MPa, respectively. In total, two layers of 32 steel fibers were placed in each 100 × 100 mm cubic concrete specimen. Concrete was cast in the mold to a height of 60 mm and then the first layer of 4 × 4 = 16 steel fibers were placed into the concrete. The height of 60 mm was to leave enough spacing between the bottom plate of the mold and the bottom end of the steel fiber. Since there was no cover plate for the mold, the height of the second layer of concrete was 40 mm. The direction of the steel fibers was vertical to the direction of the magnetic force, as shown in The magnetic field was applied by a device developed by Chen et al.  as shownAll concrete cubic specimens were cured in the standard concrete curing room at a temperature of 20 °C and humidity of 90% for 7 and 28 days, respectively. Splitting tests were performed on cubic concrete specimens to obtain the tensile strengths, as shown in The direction of the steel fibers for specimens NC-S1, NC-M1, MDC-S1, and MDC-M1 are shown in fts is the tensile strength of the concrete obtained from the splitting test; F is the ultimate load obtained from the splitting test; A is the cross-section area of the concrete specimen, and 0.85 is the coefficient for 100-mm cubic specimens. Test results of F and fts obtained at 7 and 28 days are presented in The tensile strength obtained from the splitting test could be calculated using Equation (1):Test results obtained from the splitting tests are presented in The steel fibers used in the mortar specimens had a nominal length of 10 mm and nominal diameter of 0.02 mm. The elastic modulus and tensile strength obtained from the manufacturer were 205 GPa and 1245 MPa, respectively. A steel slag having a diameter less than 5 mm was used. However, the magnetic force applied to the steel slag was not large enough to vibrate the mortar. Therefore, iron sand was also used in the magnetically driven mortar. Six kinds of mortar were first tried in order to choose the most suitable magnetically driven mortar, as shown in Vf) of 0%, 0.5%, 1.0%, 1.5%, and 2.0% (volume), respectively. All test specimens in group A were vibrated by the magnetic method while all test specimens in group B were vibrated by a shaking table. Group B also contained five series of specimens with Vf of 0%, 0.5%, 1.0%, 1.5%, and 2.0%, respectively. All test specimens were cured for 7 days before the flexural loading test :The orientation coefficient ω of each series of test specimens could be calculated using Equation (2) based on the test results in Vf of 0.5% and 1.0% exhibited obvious differences between groups A and B. As fiber orientation becomes less favorable, the flexural strength characterizing the specimens decreased to 11.5% and 12.1% for the specimen series having a Vf of 0.5% and 1.0%, respectively. However, there was almost no difference in flexural strength between groups A and B for the specimen series having a Vf of 1.5% or 2.0%. It is probably related to an insignificant contribution from the fiber orientation since the number of fibers with favorable orientation was enough. It is also shown in The test results obtained from the flexural loading test are shown in The orientation of the steel fibers in MDC and MDM was investigated in this study. It was shown that the magnetic force was able to force the steel fibers to rotate in normal concrete and MDC. The effect of orientation in MDC was much better than in normal concrete. The fibers in MDC were almost aligned with the direction of the magnetic force after magnetic vibration. As fiber orientation became less favorable in the concrete, the splitting tensile strength decreased.The best mixture of MDM was obtained from a series of six test specimens. Iron sand was necessary to vibrate the mortar specimen. Magnetic force was able to effectively rotate the steel fibers in MDM. More steel fibers with favorable orientation were found in MDM vibrated using magnetic force than those vibrated using a shaking table. The orientation coefficient varied with the vibration method but had no obvious relationship to the fiber volume fraction. The orientation of steel fibers influenced the flexural strength of the specimen series with fiber volume fractions of 0.5% and 1.0%. The gain in strength is one of the material properties enhanced by fiber orientation. The benefits of fiber orientation on other material properties of concrete and mortar will be further investigated.