General practitioners (GPs), community pharmacists and allergic rhinitis (AR) patients in Italy were surveyed in order to gain insight from all three perspectives into the diagnosis, management and burden of AR in Italy.General practitioners and pharmacists (n = 100 for each) were surveyed by telephone; questions related to overall practice and to last AR patient seen. Patients (n = 552) completed a questionnaire after visiting specialist allergy centres. Questions related to diagnosis and treatment, degree of everyday limitation from AR, and satisfaction with treatment. The data were analysed descriptively.Allergic rhinitis was managed mainly by GPs, who reported making the diagnosis themselves in 68 % of cases; rhinorrhea (64 %), sneezing (57 %) and congestion (49 %) were the symptoms most frequently taken into account. Limitation from AR on everyday life was rated 6.2 out of 10 by GPs. Pharmacists most often considered eye tearing (54 %) in their diagnosis. Almost half of GPs (49 %) and 87 % of pharmacists were unaware of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines. The most commonly reported prescribed treatments by GPs were branded mometasone furoate, desloratadine, ebastine and generic mometasone; 21 % prescribed homeopathic products occasionally. On average, GPs remembered that their last patient case had moderate/severe disease, was prescribed anti-histamine monotherapy (37 % of cases), and did not change prescription (78 %). Pharmacists recommended an antihistamine for 56 % of clients who asked for advice, and a nasal decongestant for 21 %. Patients rated limitation from AR on everyday life as 5.7/10. 55 % reported using multiple therapies, and 43 % were not satisfied or weakly satisfied with their current treatment. Patients’ main expectation for the future was to succeed in managing their AR symptoms (45 %), while 22 % hoped for a definitive cure. Many patients (61 %) were concerned their health would deteriorate.Allergic rhinitis is largely managed by GPs in Italy, with pharmacists also playing a role, yet awareness of the ARIA guidelines among these groups is low. Patient satisfaction with treatment is moderate or low. New more effective treatments are needed to improve AR management in Italy. Allergy education programs need to be better targeted to GPs and pharmacists, and communication with patients regarding symptom control must be improved.The online version of this article (doi:10.1186/s12948-015-0029-5) contains supplementary material, which is available to authorized users. Allergic rhinitis (AR) is the ‘poor relation’ of the allergy world, firmly placed behind asthma and atopic dermatitis in order of importance. The burden of AR is often ignored, but it is associated with a significant negative impact on productivity (comparable with that of heart disease and diabetes)  and highThere are several reasons why AR remains poorly controlled for many patients, including the complexity of its underlying pathology, lack of a universally accepted ‘control-concept’ and control language , a shiftIn Italy the prevalence of AR is high, estimated at 18.9 % of the population and rising , 3. As iThe burden of AR in Italy has been assessed in the past, but these surveys have focused on a particular patient population (e.g. children)  or else The aim of the current survey was to fill gaps in our knowledge on the burden and management of AR in Italy. We sought to collect a global perspective on AR management in Italy for the first time, by surveying GPs, pharmacists and patients from diagnosis to treatment and beyond. Specifically, the survey aimed to compose a picture of how AR is diagnosed and treated by GPs and pharmacists and to assess concerns and expectations for the future from the patient perspective.Separate surveys were conducted of GPs, community pharmacists and AR patients. Survey questions are listed in Additional file Information was collected on participant demographics, length of practice, number of patients with AR seen each month, practice in relation to diagnosis and referral of AR, symptoms considered when diagnosing AR, pathologies and comorbidities associated with AR, practice relating to the treatment of AR patients , and awareness of the ARIA guidelines. GPs were also asked how much AR limited their patients’ everyday life .The information collected from pharmacists was similar to that described above for GPs, except that beliefs about underlying inflammation and relationship to asthma were surveyed instead of more open questions on pathology and comorbidity, and questions on treatment patterns were broken down into doctors’ prescriptions, cases where the patient asked for a recommendation, and cases where the patient chose their own treatment. Pharmacists were not questioned on the degree of limitation suffered by patients.The GP and pharmacist surveys referred to participants’ practice in general, except for a section that questioned them specifically on the last AR patient seen. This ‘last patient case’ approach enabled more specific questions to be asked about the case severity and treatment approach, and was also expected to provide a greater degree and accuracy of memory recall.Patients were recruited from multiple specialist allergy centres throughout Italy. Eligible patients were those with AR attending participating centres for the first time. Patients were surveyed via a self-completed written questionnaire, which was completed by a total of 552 individuals. Questions covered duration of symptoms, time since diagnosis, role of different categories of HCP in patient’s diagnosis and treatment, sources of information about AR, treatments used, satisfaction with treatment, degree of limitation from AR in everyday life , beliefs on links with other pathologies, chief concerns relating to AR, and expectations of future treatment.Statistical analysis of responses was descriptive only, and presented as mean, standard deviation, median and range.Tables showing detailed summary statistics for the responses from each group  are available in Additional file Participant characteristics are summarised in Table The average rating for limitation from AR on daily life given by GPs was 6.2 out of a maximum of 10, but 50 % gave a rating of 7 or 8 and 4 % a rating of 9 or 10. The average rating of limitation among patients themselves was slightly lower, at 5.7, but 30 % gave a rating of 7 or 8 and 15 % a rating of 9 or 10. When GPs were asked to rate the severity of AR in their last patient seen , the average rating was 6.03 and 38 % gave a rating of 7–8, indicating that on average the last patient seen had moderate-to-severe AR.When asked to choose which of three options was their main concern for the future with respect to AR, 61 % of patients chose ‘my health getting worse’, 28 % chose ‘limitations on my everyday life’, and 7 % chose ‘cost of treatment’ (5 % did not record a choice). This indicates that AR is a source of anxiety or concern for many patients. Fifty-nine per cent thought that AR could lead to the onset of other diseases, most notably asthma, which was mentioned by 81 % of patients who thought other diseases could develop.In Italy, AR appears to be diagnosed and managed mainly by GPs . On average GPs estimated that they made the diagnosis personally in 68 % of cases, referred 17 % to another doctor , and referred 15 % to a specialist allergy centre. Most GPs said that some patients prefer not to go a specialist centre, mainly for reasons of convenience, trust in the GP or the desire for immediate diagnosis and treatment. Of the patients surveyed, 79 % said a specialist had made the diagnosis, which was not unexpected given that participating patients were all under the care of specialist centres. Only 30 % had independently sought information on AR before diagnosis. General practitioners and internet sites were the most frequent sources of such information.When making the diagnosis of AR, 18 % of GPs said they did not use diagnostic tests. Those who did use tests were most likely to use total serum IgE , specific serum IgE measurement  or skin prick tests; usage of other tests was negligible.The symptoms most frequently taken into account by GPs when diagnosing AR were nasal secretion, fits of sneezing and nasal obstruction. Ocular symptoms were given substantially less significance in the diagnosis Table . In contAsthma was by far the most likely comorbidity to be taken into account by GPs when diagnosing AR. Of pharmacists, 8 out of 10 believed that AR is associated with underlying inflammation, and three-quarters believed that AR can cause asthma if not treated in a timely manner.The GPs estimated that for 69 % of their patients they decided on the treatment themselves, while a specialist decided the treatment for 20 % and an allergy centre for 11 %. The average duration of a consultation in which a treatment was formulated for the first time was 16 min, while consultation times for patients whose treatment was already formulated were reduced to 9 min on average. In consultations involving new treatments, an average of 38 % of the time was spent framing the pathology, 23 % was spent detailing the administration method, 21 % giving reasons for proper treatment compliance, and 18 % educating the patient about any risk linked to comorbidity.Of the patients, just over half had their current treatment prescribed by a specialist  and a third were using treatment prescribed by a GP. Only 4 % had their treatment recommended by a pharmacist and 4 % had chosen their own. However, pharmacists appear to play an important role in treatment decisions in the wider patient population: pharmacist respondents estimated that a third of patients they saw asked the pharmacist for a treatment recommendation. A quarter asked for a specific treatment without a prescription, and 40 % presented a doctor’s prescription.Almost half of GPs (49 %) and the great majority of pharmacists (87 %) were unaware of the ARIA guidelines Fig. . Of all For the ‘last patient’ case, which had moderate-to-severe AR on average, 37 % of GPs reported prescribing antihistamine alone and 27 % prescribed two products, most commonly an antihistamine and an INS  who asked for a recommendation, followed by a vasoconstrictor (21 %), homeopathic therapy (12 %) or an intranasal/oral corticosteroid (12 %). They estimated that 55 % of doctors’ prescriptions they dealt with were for antihistamines, 37 % for intranasal or oral corticosteroids, and 15 % for vasoconstrictors. Half of independent requests by patients were estimated to be for antihistamines, and a quarter each for INS and vasoconstrictors. These trends were broadly reflected in the ‘last patient’ case responses (data not shown).When patients were asked what products they currently used to control their AR, 69 % said they used an antihistamine and 25 % an INS, which was in agreement with the GP and pharmacist surveys. However, only 4 % used vasoconstrictors and 3 % homeopathy. Nine per cent used other remedies and 17 % were not using any treatment. A quarter said they would consider using homeopathy. On average, patients were using 1.7 products, and 55 % reported using multiple therapies , with an average rating of 6.47 Fig. . SatisfaThis survey details for the first time the practices of GPs and pharmacists in relation to diagnosis and treatment of AR in Italy. It also gives significant insight into patients’ behaviours and attitudes to this prevalent condition and its treatment.Allergic rhinitis is on the increase  and becoAllergic Rhinitis and its Impact on Asthma recommends that patients who present with two or more symptoms of AR  for >1 h a day, and who have a positive allergen test, should be referred to a specialist for diagnosis and disease classification  , 23. HowWith regard to treatment, the ARIA algorithm recommends a step-up, step-down approach depending on whether the symptoms are intermittent or persistent. Antihistamines and leukotriene-receptor antagonists (LTRA) are recommended as first-line for patients with mild symptoms, while INSs are considered first-line for patients with moderate-to-severe AR , 23. ThiDespite reporting satisfaction with the management of their AR by doctors and pharmacists, patients in Italy are less happy with AR treatments. The average satisfaction rating was reported as 6.4 out of 10, with 43 % of patients reporting a rating of 6 or below. One reason for the low satisfaction may be the knowledge base from which GPs and pharmacists are working, and therefore prescribing. However, AR is known to be a difficult condition to treat. It is likely that patients’ dissatisfaction also stems from the therapeutic deficits of commonly prescribed therapies; participating patients were using an average of 1.7 therapies and 55 % of patients were on more than one treatment. Adding an oral antihistamine or LTRA to an INS is neither officially recommended by the guidelines , 25.Patients have a significant impact on their own AR management. Many AR medications are over the counter and patients frequently self-diagnose. Pharmacists reported that 1 in 4 patients asked for a specific treatment, and that it was most often an antihistamine. Patients also decide whether or not to adhere to prescribed medication. Perhaps surprisingly, GPs and pharmacists on average perceived a slightly greater degree of limitation to daily life from AR symptoms than was reported by patients themselves, even though the patients recruited were under the care of specialist centres. This suggests that failure by HCPs to take AR seriously is not a major issue in Italy. However, 15 % of patients gave a limitation rating of 9 or 10, showing that for a minority of sufferers AR imposes a very severe limitation on everyday activities.What can be done to improve the management of AR in Italy and elsewhere? It is clear that a greater awareness of formal guidelines for treatment would be beneficial for all parties. It would enable GPs to assess disease severity with greater accuracy and to prescribe the most effective treatment options for individual patients. For pharmacists, it is important to be able to accurately recognise AR and assess its severity, and make a guideline-informed treatment recommendation, whether it is medication or referral to a physician.®, Meda, Solna, Sweden) is now available in Italy which is twice as effective as an INS and provides rapid symptom control in real-life [To close the gap between current practices and the most up-to-date evidence-based treatment strategies, allergy societies and guidelines need to adapt to the reality that AR is diagnosed and managed by generalist physicians in the majority of cases. Assessment of AR needs to be standardised and simplified, for example by using a visual analogue scale (VAS). This would likely lead to improved prescribing for moderate-to-severe disease. Patients on multiple therapies and those whose symptoms are insufficiently controlled on INS or intranasal antihistamine monotherapy could benefit from increased awareness of new and more effective AR treatments, which could potentially increase treatment satisfaction through improved convenience and more efficient drug delivery . For exaeal-life –31. Impreal-life . CompaniAllergic rhinitis is largely managed by GPs in Italy. Pharmacists are also important, acting as gatekeepers to treatment. Awareness of the ARIA guidelines among GPs and pharmacists is low, and treatment is not always in accordance with evidence-based best practice. Patient satisfaction with treatment is moderate or low. Allergy education programs need to be targeted at GPs and pharmacists, and communication with patients regarding symptom control needs to be improved.


Background. The deregulated tumorigenic long non-coding RNA (lncRNA) has been reported in several malignancies. However, there is still no comprehensive study on tongue squamous cell carcinoma (SCC). Methods. Functional reannotation for the human lncRNA was carried out by ncFANs. Real-time quantitative PCR was used to validate the identified lncRNAs. Results. Using the functional annotation algorithm from ncFANs, 8 differentially expressed lncRNAs were identified. Lnc-PPP2R4-5, lnc-SPRR2D-1, lnc-MAN1A2-1, lnc-FAM46A-1, lnc-MBL2-4:1, and lnc-MBL2-4:3 were upregulated in the microdissected tongue SCC tissues. In comparison, lnc-AL355149.1-1 and lnc-STXBP5-1 showed significant downregulation. High level of lnc-MBL2-4:3 was significantly associated with the node positive tongue SCC patients. Further, patients with advanced T-stage demonstrated a further reduction of lnc-AL355149.1-1 in the tumor tissues. Treatment of tongue SCC cells with 5-fluorouracil and paclitaxel can reserve the expression patterns observed in the tongue SCC tissues. Further, changes of lnc-MBL2-4:3 and lnc-AL355149.1-1 expression levels were noticed in the cisplatin-resistant tongue SCC cells. Conclusions. Our results demonstrated that functional reannotation allows us to identify novel lncRNAs using the existing gene expression array dataset. The association of lncRNA with the T-stage and nodal status of tongue SCC patients suggested that lncRNA deregulation was involved in the pathogenesis of tongue SCC. Tongue squamous cell carcinoma (SCC) is a common epithelial cancer identified in the oral cavity. In USA, tongue is the most common site of oropharyngeal cancer  and the major histological form is squamous cell carcinoma . Major cDifferent from the mRNA transcript, the codon on the long non-coding RNA (lncRNA) do not code for any peptides or proteins. lncRNA refers to RNA molecules with size over 200 b.p. long and without protein coding functions. To date, the precise control mechanisms of lncRNA are not completely understood. LncRNA could be transcribed by RNA polymerases I, II, and III . LncRNA To the best of our knowledge, comprehensive lncRNA study aiming at identifying novel lncRNA signature has not yet been carried out in the tongue squamous cell carcinoma. Hence, in the present study, we aimed at identifying the candidate lncRNA associated with tongue SCC using the microarray dataset available in the public microarray data repository. Real-time quantitative PCR was then used to confirm the expression and validate the results in the primary tongue SCC tissues and the paired normal epithelia. We also correlated the expression patterns with the clinical characteristics of tongue SCC patients in order to reveal any potential clinical use of the lncRNA.http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE9844/) was obtained from Gene Expression Omnibus (GEO). The dataset contains 26 microdissected tongue squamous cell carcinoma tissues and 12 control tissues examined with Human Genome U133 (HG-U133) Plus 2.0 array (Affymetrix).Microarray data set GSE9844 containing 38 microarray data  as described . Differen = 32) were collected. Histological confirmation of the tissues was performed by hospital's pathologists.Tongue SCC patients were recruited at Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong. Written consent of tissue donation for research purposes was obtained from patients before tissue collection. The protocol was approved by the IRB of the hospital (IRB reference number UW 12-123). Paired tumor and normal tissues (http://www.roche-applied-science.com/). The LNA-labeled probe was obtained from the Universal Probe Library (Roche Applied Science). The lncRNA transcript levels were measured by LightCycler 480 (Roche Applied Science) and normalized with the GAPDH levels using 2−ΔCt algorithm. Primer and probe sequences were listed in Total RNA was extracted and purified from the frozen tissues using TRIzol reagent (Invitrogen). The quality and quantity of the isolated RNA were examined with Nanodrop. Reverse transcription was carried out using cDNA conversion kit (Invitrogen). Primers for lncRNA detection and quantification were designed at Universal ProbeLibrary Assay Design Center (μg/mL streptomycin Sulfate (Gibco), and 0.5 μg/mL amphotericin B (Gibco). The cell line was incubated in humidified incubator with 5% CO2 at 37°C. 5-Fluorouracil (5-Fu) and paclitaxel were obtained from sigma. Stock solutions were prepared by dissolving the drugs in dimethyl sulfoxide (DMSO) at the concentration of 100 mM and 1.2 mM respectively. Cisplatin (Sigma) was dissolved in distilled water at a concentration of 3.3 mM. The stock solutions were freshly diluted to appropriate concentrations in RPMI 1640 medium before treatment. HN21B cells were treated by 0–10 μM 5-Fu, 0–8 nM paclitaxel, or 0–64 μM cisplatin for 72 hours followed by in vitro toxicity test. The toxicity test was performed using the Toxicology Assay Kit Sulforhodamine B (SRB) assay (Sigma-Aldrich) according to manufacturer's manual. The inhibitory concentration (IC) was calculated from the dose-response curve of HN21B upon drug treatment.Tongue SCC cell line HN21B was cultured in RPMI 1640 medium supplied with 10% fetal bovine serum (Gibco), 200 Unit/mL penicillin G sodium (Gibco), 200 The cisplatin-resistant HN21B cell line was developed by chronic cisplatin treatment. HN21B cells were exposed to cisplatin for 3 days, followed by growth recovery in drug-free medium. The concentration of cisplatin was increased in the subsequent cycle and the procedure was repeated until resistance was achieved in HN21B cells.HN21B cells were seeded on glass slides and fixed with 4% paraformaldehyde. The nucleus was stained by blue-fluorescent 4′,6-diamidino-2-phenylindole (DAPI) (Invitrogen); F-actin was labeled in red with Alexa Fluor 635 phalloidin (Invitrogen).P value <0.05 was considered as statistically significant.Statistical analysis was performed using SPSS V16.0 . The statistical difference between tongue SCC and paired normal epithelia was examined using Wilcoxon signed-rank test. All the tests were two-sided. Using the functional annotation algorithm from ncFANs, 8 differentially expressed lncRNAs were identified . Of the Of the 8 lncRNAs, lnc-MAN1A2-1 (OTTHUMG00000012147) was not detectable in all tissue samples. Lnc-MBL2-4:1 (OTTHUMT00000048111) was detectable in 3% (1/32) tumor tissue samples and was not detectable in all the normal tissue samples. Lnc-FAM46A-1 (OTTHUMG00000015099) was detectable in 22% (7/32) of tumor tissue samples and 13% of (4/32) normal tissue samples.P = 0.004 & 0.035 resp., Wilcoxon signed-rank test). Overexpression of the lnc-MBL2-4:3 (OTTHUMT00000048112) in the tongue SCC was highly significant in comparison with the paired normal epithelia . Lnc-AL355149.1-1 (OTTHUMG00000002490) was the only lncRNA found to be downregulated in the tongue SCC tissues . The fold-change patterns (upregulated/downregulated) in the tongue tissues matched the fold-change patterns in the microarray dataset  and lnc-PPP2R4-5 (OTTHUMG00000020778) was found in the tongue SCC tissue . Further, lnc-AL355149.1-1 (OTTHUMG00000002490), the downregulated lncRNA in tongue SCC tissues, displayed substantial downregulation when the cancer progressed from early (T1-2) to advanced stages (T3-4). The expression levels of the 4 differentially expressed lncRNAs were correlated with the clinical parameters of the patients . High le10, IC30, and IC50 were 0.6 μM, 2.2 μM, and 4.3 μM, respectively  and lnc-AL355149.1-1 (OTTHUMG00000002490) in response to the drug treatment. We use toxicity test to determine the inhibitory concentrations of 5-Fu and paclitaxel on tongue SCC cell line HN21B. For 5-Fu, the ICectively . 5-Fu trectively ; for pacectively . Similarectively . In addiectively .50 of cisplatin-resistant HN21B was 22.7 μM, which was obviously higher than that of the parental HN21B cells (7.0 μM). Cisplatin-resistant HN21B cells displayed spindle-like changes in cell morphology, implicating a more aggressive phenotype  in the recent years, considerable attention has been dedicated to identify the active players during the progression and development of human malignancies. Although the deregulated lncRNA patterns have been identified in several cancers, such as prostate and liver cancers, little is known in oral tongue carcinoma. Using serial analysis of gene expression (SAGE), lncRNA expression has been demonstrated in the oral cavity and premalignant oral lesions located on tongue, gingiva, and buccal mucosa . RecentlIn this study, we used the existing microarray data to explore the differentially expressed lncRNA patterns in the tongue SCC tissues. The probesets on the microarray chips were originally designed to detect the protein-coding genes. Usually, multiple probes are assigned to individual genes to cover the entire length of the transcript in order to ensure the accuracy of measurement. With the advance in our understanding of lncRNA and their sequence, it was recognized that particular probesets on the microarray chips match with the lncRNA sequence. By reannotation of the microarray for lncRNA, the expression information of the microarray dataset could be revealed for subsequent inspection . To asceLncRNA could contribute to the cancer progression by controlling the process of proliferation and migration , 17. In In conclusion, our results indicated that oncogenic/tumor-suppressing lncRNA could potentially be identified through computational exploration of the existing microarray data. The associations of lncRNA with the clinical features of tongue SCC patients substantiate the claim that lncRNA deregulation is linked to the biology activity of tongue SCC. Whether the deregulated lnRNA could possibly be used as diagnostic/prognostic indicators has yet to be elucidated. Further studies are warranted to decipher the functional roles of lncRNA in the pathogenesis of tongue SCC.


It is now understood that persistent activation of the androgen receptor (AR) signaling pathway often underlies the development of castration-resistant prostate cancer (CRPC). This realization led to renewed interest in targeting the AR and ultimately to the development of the potent next-generation AR-directed agents abiraterone and enzalutamide. While these drugs prolong survival in men with CRPC, they are unfortunately not curative. Perhaps not surprisingly, evidence points to persistent AR signaling as one of the key drivers by which resistances to these agents develops. In this context, activation of the AR signaling program can occur through a number of molecular adaptations, including alterations leading to persistent canonical AR signaling , activation of the AR program via feedback pathways , and activation of the AR program via mutation or substitution . This review will provide an overview of the more clinical relevant  pathways that have been implicated in the emergence of drug resistance in men with CRPC and highlight some of the ongoing efforts towards developing therapeutics to impair these mechanisms. Androgen deprivation therapy (ADT) has remained the backbone of treatment for advanced prostate cancer since the remarkable palliative effects of surgical castration were first described by Huggins and Hodges back in the 1940s ) also documented no PSA50 responses (the primary endpoint). Finally, in a phase II trial enrolling men with CRPC (both metastatic [N = 14] and non-metastatic [N = 7]), lapatinib was also shown to have minimal single agent activity, with only 1/21 patients achieving a PSA50 response (the primary endpoint) [50 response.Based on the aforementioned observations, a handful of trials exploring the utility of targeting HER2 and/or EGFR signaling have been completed . A phaseSA slope . Anotherndpoint) . Similarndpoint) , 130. InSimilar to EGFs, the insulin-like growth factors (IGFs) have far-reaching biologic effects, promoting the growth, development, and survival of cells . IGF sigBased on these observations, a randomized phase II study in men with hormone-sensitive metastatic prostate cancer comparing androgen deprivation therapy with or without cixutumumab, a monoclonal antibody targeting IGF-IR, was launched . UltimatCytokines, particularly IL-6, have also been implicated in the maintenance of AR signaling—likely through enhanced JAK/STAT signaling. IL-6 has also been shown to associate with advanced stage prostate cancer and survival –144. STA2 IV every 21 days [Agents targeting this pathway include siltuximab, a monoclonal antibody targeting IL-6. In a phase I pre-surgical neoadjuvant study testing siltuximab as a monotherapy, it was shown to be well tolerated, associates with increased Ki-67 expression (a marker of apoptosis), and results in downregulation of genes downstream of IL-6 . This ag 21 days –150. The 21 days .Wnt signaling plays an important role in early embryonic development as well as in promoting the growth and progression of several malignancies , 152. Ca. placebo has been reported [Small molecule inhibitors of Wnt/β-catenin have been developed and shown to inhibit proliferation in prostate cancer cells . Clinicareported , 159. ThAR mutations, AR alternative splicing events, AR overexpression/copy number gains, AR substitutions, ligand persistence, and feedback pathways) in response to the evolutionary pressure exerted through chronic AR signaling inhibition, we will hopefully begin to see the emergence of therapeutic regimens that are able to impair key resistance mechanisms. Ideally, this will allow us to offer our patients a personalized regimen based on their cancer’s molecular profile and the specific resistance mechanisms operative within them.Even in its late stages, AR signaling remains an important driver of prostate cancer progression, with most of the adaptive changes that occur within a prostate cancer cell stemming from a persistent addiction to the AR. As our understanding of the alterations that occur  is growing exponentially. Armed with this improved understanding, the next challenge will be to take this knowledge and translate it into the next generation of targeted therapies—allowing us to extend the health and well-being of men suffering with the most advanced forms of CRPC.


The present study attempted to test McCullough and Willoughby’s hypothesis that self-control mediates the relationships between religiosity and psychosocial outcomes. Specifically, this study examined whether trait self-control (TSC) mediates the relationship of identified-introjected religiosity with positive and negative health-related-feelings (HRF) in healthy Muslims.ageM = 28.15, ageSD = 6.90) answered questionnaires. One hundred ninety participants were retained for the analyses because they reported to be healthy . To examine the relationships between religiosity, TSC and HRF, two competing mediation models were tested using structural equation model analysis: While a starting model used TSC as mediator of the religiosity-HRF relationship, an alternative model used religiosity as mediator of the TSC-HRF relationship.Two hundred eleven French-speaking participants , whereas the alternative model explained 6.877% of the variance (goodness of fit = 0.987).These results show that the starting model is the most effective model to account for the relationships between religiosity, TSC, and HRF. Therefore, this study provides initial insights into how religiosity influences psychological health through TSC. Important practical implications for the religious education are suggested. Self-regulation is defined as “…the process by which a system uses information about its present state to change that state.” ..self-conGlobally, research revealed that global religiousness, defined as the adherence to a religion that involves predefined behaviors and rituals , was poidentified religiosity , selBecause no study, to date, examined whether self-control may mediate the link between religiosity and health-related-feelings (HRF), the present study attempted to examine whether trait self-control (TSC) mediates the relationships between identified-introjected religiosity and HRF  in healthy Muslims. Identified religiosity was assessed through global religiousness, intrinsic religious motivation, and positive religious coping, while introjected religiosity was assessed through extrinsic religious motivation and negative religious coping. Concerning the hypotheses, consistent with previous findings, it was expected that identified and introjected religiosity would be linked to HRF through TSC. Specifically, within the mediations, it was expected that the identified religiosity and TSC would be positively related to positive HRF and negatively related to negative HRF. It was also expected that introjected religiosity would be positively related to negative HRF and negatively related to positive HRF. Moreover, to test the effectiveness of these hypotheses, we compared two competing models, where the starting model used TSC as mediator of the relationship between religiosity and HRF, whereas the alternative model used religiosity as mediator of the relationship between TSC and HRF. To compare both models, we used a structural equation model (SEM) analysis.Mage = 28.15, SDage = 6.90) were recruited through Islamic schools, cultural associations, mosques, Islamic conferences, and universities, in May/June 2013 (thus outside the Ramadan period); they volunteered to participate in the study. They came from non-Muslim countries  and Muslim countries . They were all Sunni Muslims.Two hundred eleven French-speaking participants , coming from non-Muslim countries  and Muslim countries , were retained for analyses because they reported that they had no current psychiatric and/or somatic illness. Removing participants who reported having current psychiatric , somatic illness , or both kinds of illness  enabled us to focus only on healthy people. As a result, the present study was interested in examining the psychological functioning of healthy Sunni Muslims. This sample included participants who were heterogeneous on their professional status  and their relationship status .One hundred ninety participants . Its setup included a form that was accessible to participants via a specific web address. This form included general information about the study, a consent form, and questions. Before answering questions, participants were ensured that their responses would remain confidential. Then, they were asked to enter a pseudonym on the website (to preserve their anonymity) and were invited to pursue the study in answering questions.strongly disagree”; 9 = “strongly agree”). The 2-item global religiousness subscale of PMIR  (α = .53) was also measured . The Religious Orientation Scale-Revised questionnaire  to 9 (“strongly agree”). TSC was measured using the 13-item scale provided by Tangney, Baumeister, and Boone [not at all”, 9 = “very much so”) (α = .74).The 7-item positive religious coping subscale  (α = .83) and the 3-item negative religious coping subscale  (α = .84) of the Psychological Measure Islamic Religiousness  were mee  was adand Boone   to 9 (“very much so”). Wellbeing was measured by the “optional” item of the Personal Wellbeing Index—Adult [completely dissatisfied”; 9 = “completely satisfied”).The 5-item positive affect scale  (α = .78) and the 5-item negative affect scale  (α = .76) of the International Positive and Negative Affect Schedule Short Form , the 5-iex—Adult   to indicate the strength of the causal links of the competing structural models. The quality of each model was assessed with a non-parametric measurement, called goodness of fit (Gof) . The datA direct pathway corresponds to the link connecting the input variable and the output variable, while the indirect pathways corresponds to the links between the input variable and the mediator, and between the mediator and the output variable. In the starting  model, the input variable was religiosity (TSC), while the mediator was TSC (religiosity). In both models, the output variable was HRF. There was a mediating effect when the indirect pathways were significant. When the direct pathway connecting the input variable and HRF was not significant, so that the input variable had no direct effect on HRF, full mediation was found. Conversely, when the direct pathway was significant, a partial mediation was found.r’s = .64 to .74). However, the variables related to the notion of introjected religiosity displayed inconsistent findings: While extrinsic personal motivation was positively related to extrinsic social motivation (r = .21) and to negative religious coping (r = .33), extrinsic social motivation appeared to be unrelated to negative religious coping (r = .10). Second, TSC and identified religiosity were both positively related to wellbeing (r’s = .25 to .34), while they were unrelated to negative HFR. Among the variables related to the notion of introjected religiosity, only negative religious coping was positively related to negative HRF, such as anxiety (r = .26) and depression (r = .22). Third, positive HRF (r’s = .34 to .66), as well as negative HRF (r’s = .58 to .72), were all positively related to each other. Positive HRF were negatively related to negative HRF (r’s = -.17 to-.45).Zero-order correlations revealed several findings see . First, The factor analysis yielded three factors with eigenvalues greater than 1: identified religiosity 3 MVs), positive HRF (4 MVs), and negative HRF (3 MVs) . This suggests that the hypothesis that TSC mediates the relationship between religiosity and HRF is stronger than the competing hypothesis.To test the effectiveness of the starting model , which uWe would hasten to point out that the present study is not without its limitations. Firstly, we used a sample including only Muslims. As a result, caution should be taken when generalizing the present results to the whole religious people, and further studies should examine whether and how psychosocial benefits of religion explained by TSC can be found with other religions . Secondly, this study was based on correlations, and stronger causal tests would be required to examine the hypothesis that religiosity predicts HRF through self-control. In so doing, experimental studies should examine the effects of the activation of concepts and themes related to identified or introjected religiosity on self-control and affects, thereby allowing examining the mediating role of self-control in the relationship between religiosity and affects. Moreover, by considering religiousness as a developmental process, longitudinal studies should examine how religiosity, self-control, and affects fluctuate over the life. This research direction should not only explore how these variables are interconnected within long-term changes, but also shed the light on the mediating mechanisms underlying affects changes in religious people.From an applied perspective, given that personality can be shaped by religious education , teacherThe present study represents the first temptation consisting in testing the hypothesis that TSC mediates the relationships between identified-introjected religiosity and HRF, and evidenced this hypothesis by reporting that TSC mediated the link between identified religiosity and HRF. This study also evidenced that identified religiosity mediated the relationship between TSC and negative HRF. Thus, this study also evidenced that the relationship between religiosity, self-control and HRF is by nature complex.


An improved teaching-learning-based optimization with combining of the social character of PSO (TLBO-PSO), which is considering the teacher's behavior influence on the students and the mean grade of the class, is proposed in the paper to find the global solutions of function optimization problems. In this method, the teacher phase of TLBO is modified; the new position of the individual is determined by the old position, the mean position, and the best position of current generation. The method overcomes disadvantage that the evolution of the original TLBO might stop when the mean position of students equals the position of the teacher. To decrease the computation cost of the algorithm, the process of removing the duplicate individual in original TLBO is not adopted in the improved algorithm. Moreover, the probability of local convergence of the improved method is decreased by the mutation operator. The effectiveness of the proposed method is tested on some benchmark functions, and the results are competitive with respect to some other methods. Global optimization is a concerned research area in science and engineering. Many real-world optimization applications can be formulated as global optimization problems. To efficiently solve the global optimization problems, the efficient and robust optimization algorithms are needed. The traditional methods often fail to solve complex global optimization problems. A detailed overview of the research progress in deterministic global optimization can be found in . To overw, c1, and c2) that should be determined in updating equations of PSO. Moreover, the optimal parameters of the algorithms are often difficult to be determined. To decrease the effects of parameters for the algorithms, teaching-learning-based (TLBO) algorithm . At any iteration g, assume that the population size of the class is m, the mean result of students in current iteration is Xgmean = (1/m). The student with the best fitness is chosen as the teacher of current iteration; it is represented as Xteacher. All the students will update their position as follows:Xi,new and Xi,old are the new and the old position of the ith student and r1 is the random number in the range . If the new solution is better than the old one, the old position of individual will be replaced by the new position. The value of TF is randomly decided by the algorithm according toIn the teacher phase of TLBO algorithm, the task of the teacher is to increase the mean grades of the class. Suppose that an objective function is ith individual Xi in the jth generation, randomly select the kth individual Xk which is different from Xi, and the updated formula of Xi is defined in ..ith indiXi is better than Xk according to their fitness, then If ri is the random number in the range .ElseXi,new is better than the old one Xi,old, the old position Xi,old is replaced by the new Xi,new; otherwise, the position of the ith individual is not changed. The detail algorithm is shown in If the new position r1, r2 are the random number in the range . With this modification, the performance of TLBO algorithm might be improved.As previously reviewed, the main idea of TLBO is to imitate the teaching-learning process in a class. The teacher tries to disseminate knowledge among the learners to increase the knowledge level of the whole class, and the learners also study knowledge from the others to improve its grade. Algorithm displays that all individuals update their positions based on the distance between one or two times of the mean solution and the teacher in teacher phase. An individual also renewed its position based on the distance between it and a randomly selected individual from the class. Equation  indicatei and k have the same genes in t generation, and the new position of these two individuals might be different when TF is a random number (1 or 2). At the beginning of evolution, all individuals generate better positions easily. Random operator for TF may benefit for maintaining diversity of class, but, in the anaphase of evolution, the positions of individuals might be close to each other. When the mean solution equals the best solution, the individual does not change (TF = 1) or the large change of genes might destroy the individual in large degree (TF = 2) so that the better individual is difficult to be generated. To decrease the computational effort of comparing all the individuals, the removing of the duplicate individual process in the original TLBO is deleted in the improved TLBO algorithm and a mutation operator according to the best fitness of successive generations is introduced in the paper. If the best fitness of continuous n generations is not changed or changed slightly, an individual will be randomly selected according to mutation possibility pc to be mutated. To maintain the global performance of the algorithm, the best individual is not mutated. The subroutine for the mutation is described as shown in In original TLBO algorithm, all genes of each individual should be compared with those of all other individuals for removing the duplicate individual. This operator is a heavy computation cost process, and the function evaluations required are not clearly known. In our opinion, duplication testing is not needed in every generation especially in the beginning of evolution. Assume that individuals n is the setting generation, pc is the mutation possibility, and ε is a small number which is given by the designer. α is a mutation parameter between 0.01 and 0.1.In Xmax and minimum Xmin of position, the maximal evolution generation genmax, mutation possibility pc and mutation parameter α, the population size popsize, and the dimension size of the task. Initialize the initial population pop as follows:r is the random number in the range .Set the maximum Xteacher as the teacher, and calculate the mean solution Xgmean of the population.Evaluate the individual, select the best individual Xi,new is better than Xi,old, then Xi,old = Xi,new.For each individual, update its position according to . If Xi,Xi,old and Xi,new as the new position of the individual.For each individual, randomly select another individual, update its position according to  and 7),,7), and Execute mutation operator for the population according to If the ended condition of TLBO-PSO is not satisfied, the algorithm will go back to To test the performance of the improved TLBO-PSO algorithm, nine benchmark functions are simulated in this section. These nine benchmark functions are listed in fmin” is the theory global minimum solution. “Acceptance” is the acceptable solutions of different functions. For CLPSO, TLBO, and ETLBO algorithms, the training parameters are the same as those used in the corresponding references except that the maximal FEs are 50000 and the size of population is 30. The size of elitism is 2 in ETLBO algorithm. When the best fitness is changed to be smaller than ε, the large value of mutation will possibly be chosen. In our experiments, the mutation possibility pc is 0.6, ε is 0.01, and α is 0.05.To reduce statistical errors, each function in the paper is independently simulated 30 runs, and their mean results are used in the comparison. The value of function is defined as the fitness function. All the experiments are carried out on the same machine with a Celeron 2.26 GHz CPU, 512-MB memory, and Windows XP operating system with Matlab 7.0. All functions are simulated in 10 and 30 dimensions. The nine functions are summarized in The performance of different algorithms for 10- and 30-dimensional functions in terms of the best solution, the mean (Mean), and standard deviation (STD) of the solutions obtained in the 30 independent runs is listed in Tables f1, f2, f3, and f4. For function f5, ETLBO has the best performance. For function f6, the mean best solution of TLBO-PSO is the best, and the STD of TLBO is the smallest. For functions f7 and f9, CLPSO has the best performance. For function f8, three TLBOs have the same solutions in terms of the mean best solutions and standard deviations (STD).The results for 10-dimensional functions in f1, f2, f3, and f4 with 30 dimensions. TLBO has the best performance for function f5. For function f6, TLBO and ETLBO have the same performance in terms of the mean best solutions and standard deviations (STD). For function f7, the mean best solution of TLBO is the smallest, and the standard deviation of TLBO-PSO is the smallest. Three TLBOs have the same solutions for functions f8 and f9.The results for 30-dimensional functions in The mean number of function evolutions (FEs) is often used to measure the convergence speed of algorithms. In this paper, the mean value of FEs is used to measure the speed of all algorithms. The average FEs  of all algorithms for nine functions with 10 and 30 dimensions are shown in Tables f5. The merit in terms of mean FEs for 10-dimensional function f5 with ETLBO is the best and the four algorithms cannot converge to the acceptable solution for 30-dimensional function. For function f6, all algorithms can converge to the global optima with 100% successful ratios on 30 dimensions except CLPSO. For function f7, CLPSO can converge to optima with 100% successful ratios for 10-dimensional function. They all cannot converge to 30-dimensional function except that the successful ratio of TLBO-PSO is 10%. The convergence speed of average best fitness of four algorithms is shown in Tables An improved TLBO-PSO algorithm which is considering the difference between the solutions of the best individual and the individual that want to be renewed is designed in the paper. The mutation operator is introduced to improve the global convergence performance the algorithm. The performance of TLBO-PSO is improved for larger part of functions especially for 30-dimension functions in terms of convergence accuracy and mFEs. The local convergence of TLBO-PSO is major caused by the lost diversity in the later stage of the evolution.Further works include researches into adaptive selection of parameters to make the algorithm more efficient. Moreover, it needs to seek a better method to improve the TLBO algorithm for functions with optimal parameters displaced from all zeroes. Furthermore, the algorithm may be applied to constrained, dynamic optimization domain. It is expected that TLBO-PSO will be used in real-world optimization problems.


In recent years the development of human-machine interfaces for medical applications and rehabilitation medicine has rapidly increased and still continues to grow . The maiBefore any computation or control of human activity is possible, information on movement of body segments is required. When information from natural sensors is not accessible, external devices such as accelerometers and gyroscopes can provide sufficient information on gait, standing up, balance, or specific motion of lower or upper extremities. However, these sensors are prone to bias, integration, and temperature drift and cannot provide sufficient accuracy for closed-loop control. The use of various mathematical tools, especially extended Kalman filter, can help to partly overcome the specified problem and can assure measurement of selected parameters up to the acceptable level of accuracy . Besidesἅπτικóς) and is related to the sense of touch. This is nowadays particularly important in rehabilitation of patients suffering from stroke. In combination with virtual reality technologies, an upper extremity, and balance, grasping of hand rehabilitation devices can be designed [The accurate and reliable sensory information is a prerequisite for the design of a closed-loop control system, especially when a human is in interaction with the machine in terms of “feeling the environment” or haptics . The wordesigned . The hapdesigned  or smartdesigned . On the designed .We hope the readers of the Journal of Computational and Mathematical Methods in Medicine will find in this special issue solid theoretical and technological solutions as well as their possible applications in the rehabilitation medicine. However, we would like to encourage the readers to raise new research questions and issues which will significantly contribute to the development and rapid uptake of technologies in rehabilitation medicine.Imre CikajloImre CikajloTakashi WatanabeTakashi WatanabeStrahinja DosenStrahinja Dosen


To assess the effectiveness and safety of Chinese herbal medicine (CHM) for the treatment of aspirin resistance (AR).A comprehensive research of seven electronic databases was performed for comparative studies evaluating CHM for AR. Two authors independently extracted data and assessed the methodological quality of the included trials using the Cochrane risk of bias tool. Data wasere synthesized by using RevMan 5.3 software. (PROSPERO Registration #CRD42015020182)2 (TXB2) in patients with CHM plus aspirin versus aspirin were significantly reduced (Random Effect model (RE), Standard Deviation (SD) = -95.93, 95% Confidential Interval (CI), P<0.00001). Subgroup analysis showed that TXB2 (Fixed Effect model (FE), SD = -89.23, 95%CI, P<0.00001) had significant difference in Tongxinluo capsule plus aspirin versus aspirin. 2 RCTs reported the clinical effective rate, and the meta-analysis result showed a significant difference in intervention and control group  = 1.67, 95%CI, P = 0.007<0.05). In 4 trials, CHM plus aspirin had better effects of reducing the reoccurrence of cerebral infarction than aspirin . And one trial showed that CHM plus aspirin could decrease the National Institutes of Health Stroke Scale (NHISS) score (P<0.05) and increase the Barthel Index (BI) score (P<0.05). 4 trials stated that there were no adverse effects occurred in intervention group, and analysis showed significant difference of CHM or CHM plus aspirin in reducing the occurrence of adverse events . 5 trials claimed that the CHM monotherapy and CHM adjunctive therapy for AR did not add the risk of bleeding .18 randomized controlled trials (RCTs) involving 1,460 patients were included. 15 RCTs reported significant difference in the reduction of platelet aggregation rate (PAR) induced by adenosine diphosphate (ADP) (P<0.05), and 11 reported significant effect of CHM plus aspirin to reduce PAR induced by arachidonic acid (AA) (P<0.05) compared with aspirin 100mg/d treatment. The pooling data of 3 RCTs showed the thromboxane BCHM may be effective and safe as an alternative and collaborative therapy for AR. However, the current evidence and potential promising findings should be interpreted with caution due to poor and varying methodological quality of included studies and the heterogeneity of interventions. Thus, further exploration of this strategy with adequately powered RCTs is warranted. And oneSong SJ 2008 reported significant effect of Tongxinluo capsule plus aspirin for reducing C reactive protein (CRP) compared with aspirin (P<0.05). Liu YJ 2013 reported significant difference in the reduction of interleukin-6 (IL-6) by compared Sanqi Tongshu capsule plus aspirin with aspirin (P<0.05). Zhang X 2013 also showed significant effect in reducing the high-sensitivity C-reactive protein (hs-CRP).The RCT (Yin CH 2010) using the electrical impedance to test the PAR induced by ADP and collagen (COL) showed significant differences in Tongxinluo capsule plus aspirin versus aspirin (P<0.05).2 = 1.20, I2 = 0%, P<0.00001, shown as 7 of the included 18 trials reported adverse events. Adverse events included stomach discomfort, dizziness, nausea, changes of blood pressure, an increase in clotting time and so on. Among 7 trials, 4 trials stated that there were no adverse events occurred in intervention group. There was significant difference of CHM or CHM plus aspirin in reducing the occurrence of adverse events   .2 and could also reduce the cerebral infarction reoccurrence rate. (2) CHM monotherapy and CHM adjunctive therapy for AR would not add the risk of bleeding. (3) CHM plus aspirin could decrease the NHISS score (P<0.05) and increase the BI score (P<0.05). (4) There was significant difference in the reduction of C reactive protein (CRP) and interleukin-6 (IL-6) by comparing CHM plus aspirin with aspirin.In this systematic review and meta-analysis of 1,460 patients from 18 studies of CHM for AR, we observed the results as following:(1) CHM could reduce the PAR induced by ADP and AA, TXBThe phenomenon of AR also exits in China. More and more published researches in the past few years showed that the enthusiasm of applying CHM for AR is growing. Majority of CHM (88.9%) in our study was Chinese patent drug, which has a stringent quality control, and its quality is more stable than the water decoction of Chinese medicine.2 = 0%). This result has certain guiding significance for clinical application of Chinese patent drug for AR.2 RCTs applying Chinese patent drugs reported the clinical effective rate, and the meta-analysis result showed a significant difference in intervention and control group . There may be several reasons: The course of treatment was not consistent (from 2 weeks to 1month). Patients with different kinds of diseases were included in these studies . Induction dose was also very different .Compound danshen dripping pill is the patent drug which first successfully completed the United States Food and Drug Administration (FDA) phase II clinical trial. The phase II clinical trial results confirmed Compound danshen dripping pill’s effectiveness and safety. But the results of subgroup analysis in our study of the Compound danshen dripping pill showed a high clinical heterogeneity and CHM adjunctive therapy for AR would not add the risk of bleeding events, meanwhile CHM plus aspirin had better effect of reducing the recurrence of cerebral infarction than aspirin. Although the sample size of some results were too small to draw very positive conclusions, the trends were very consentaneous.The biochemical definition of AR is still controversial at present, the diagnostic criteria of AR are not unified. As we all know, platelet function plays an important role in the diagnostic criteria of AR. There are many kinds of methods to detect the function of platelet nowadays. Although studies have shown that the detection of platelet function in vitro is related to clinical events, there is not enough evidence to evaluate the clinical prognosis of aspirin-treated patients according to the results of platelet function test in vitro.Platelet function is determined by COX-1 related pathway  and other pathways (such as ADP or collagen induced platelet aggregation). While the specific detection method of AR should be the PAR induced by AA, such as light or optical transmission and the detection of Verify Now. Currently the FDA has approved the use of Verify Now detection method in clinical trials to observe the efficacy of aspirin for AR.2, as the stable metabolite of TXA2, is an ideal indicator of adverse thrombotic events. The pooling data of meta-analysis showed the TXB2 in patients with CHM plus aspirin was significantly reduced. The CHM might reduce the PAR via keeping the balance of TXB2 and 6-keto-prostaglandin F1α(6-Keto-PGF1α).TXB2 and prostacyclin (PGI2) are metabolites of AA. Under normal physiological conditions, TXA2 and PGI2 are in relative balance state to maintain the normal vascular tension and patency, and their balance disorders can cause vascular spasm and occlusion. TXB2 and 6-Keto-PGF1α are stable metabolites of TXA2 and PGI2. The contents of TXB2 and 6-Keto-PGF1α are determined by TXA2 and PGI2. The plasma TXB2and 6-Keto-PGF1α assay can reflect the overall activity of platelets, but have not been recommended for the diagnosis of AR at present. Whether TXB2 and 6-Keto-PGF1α can become new diagnostic indicators also depends on validation of more basic and clinical research.TXA2 (11-dTXB2) is an independent risk factor for cardiovascular events, having a high clinical value [A study, followed up 976 patients with high risk of cardiovascular events for 5 years, found that 11-dehydro thromboxane Bal value .The results of subgroup analysis show significant difference in the reduction of CRP and IL-6by comparing CHM plus aspirin with aspirin (P<0.05). The latest study found that some inflammatory markers, such as CRP and IL-6 are associated with AR .Aspirin only blocks COX-1 pathway of platelet activation and cannot block other platelet activation pathways, which may occur in patients with AR .The decline in the level of inflammation markers has some inspiration for the further research. Ongoing trials of CHM therapy in patients with AR may provide more definitive conclusions. Results from upcoming large sample size trials would help clarify the effects of CHM with greater precision, including whether the benefits differ between male and female.The main patterns of syndrome distribution of patients with AR are Qi deficiency, phlegm dampness and blood stasis. Blood stasis syndrome accounts for a larger proportion. Qi deficiency and phlegm dampness syndrome are the pathological basis of AR. The etiology of blood stasis is not only the pathological basis of AR but also the pathological products of AR. Blood stasis is the cause of AR in the theory of Chinese medicine and plays a role in the accumulation of blood stasis and transformation for turbidity toxin. Blood stasis will finally develop into AR.In TCM theory, constitution is closely related to the occurrence of diseases. And constitution determines the susceptibility to the disease and the tendency of the pathological changes. But the reported studies ignored the effect of constitution and syndrome differentiation. We only include the studies based on disease differentiation in order to affirm the clinical curative effect, and to reduce clinical heterogeneity.In our opinion, TCM diagnosis and treatment system for AR should follow the model of differentiation of constitution, disease and syndrome. It is a clinical diagnostic and treatment model which reflects the nature, regulation, characteristics of the disease from different angles and different levels, and makeups for their limitations with each other.The study has several limitations that should be addressed:Although the intervention and control groups were included in the study strictly, varied diagnostic criteria (such as different revulsants and induction dosages) may become an important factor for the clinical heterogeneity. The methodological quality of most included trials with small sample size was poor. Most trials had not been registered, and most of which did not mention random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessments.Great clinical heterogeneity existed in this systematic review and meta-analysis because different kinds of PAR testing measures, diagnosis criteria, and different CHM interventions are used in included trials involving various diseases.Most of included trials conducted short term interventions  which may not be long enough to reflect the long-term effect of CHM for AR.We performed a funnel plot of 18 trials involved PAR induced by ADP to analyze the public bias. The funnel plot implied that the public bias existed in these trials .Although this study shows that CHM may be effective and safe for AR treatment as a kind of complementary and alternative medical therapy, whether CHM is used alone or in combination with aspirin still need to be tackled:The current evidence and potential findings should be interpreted carefully because of poor methodological quality of these studies, insufficient evidence of effectivity and safety and the clinical heterogeneity. Further rigorous RCTs are called to overcome the limitations.Contemporary, we should pay attention to the problems that why particular patients do not benefit from aspirin therapy and how to identify them? Since the mechanisms of AR still require further research and specific therapy remains absent, new studies need to be designed to sift out the most appropriate test measures to diagnosis AR and to find out economical alternative therapies that are effective for AR patients. The diagnosis criteria of AR should be unified.Large scale clinical research should be carried out to compare the reliability and sensitivity of different detection in AR diagnosis, and to observe the incidence of cardiovascular events in varied treatment carefully.So far, western medicine has not yet formed a comprehensive prevention and treatment strategy of AR, the treatment of TCM syndrome differentiation and treatment has a promising application prospect in the therapy of AR.The treatment integrating Chinese and Western medicine for AR should be based on the dual diagnosis. Combining western medicine with the treatment by differentiation of constitution, disease and syndrome in TCM theory is better for AR therapy. But no unified diagnostic criteria for AR in TCM theory at present brings some difficulties for the dual diagnosis.Our study is a new systematic review and meta-analysis of CHM for AR, which is also the first meta-analysis on clinical outcomes, clinical effective rate and adverse events of CHM for AR. It suggests that CHM may be effective and safe for the treatment of AR, and can be used as an alternative medicine of aspirin for enhancing pharmacy efficiency, decreasing the risk of hemorrhage and reoccurrence of cerebral infarction. However, owing to poor methodological quality of included studies, different diagnosis criteria and determination methods, and the varied CHM interventions, the current evidence and potential promising findings should be interpreted with caution. In the future, rigorous multicenter, large sample size clinical RCTs are proposed to surmount the limitations of current trials to improve the strength of evidence. And the diagnosis criteria of AR should be unified.S1 Checklist(PDF)Click here for additional data file.S1 Text(PDF)Click here for additional data file.


The formation of the cardiovasculature, consisting of both the heart and blood vessels, is a critical step in embryonic development and relies on three processes termed vasculogenesis, angiogenesis, and vascular remodeling. The transmembrane protein NRP1 is an essential modulator of embryonic angiogenesis with additional roles in vessel remodeling and arteriogenesis. NRP1 also enhances arteriogenesis in adults to alleviate pathological tissue ischemia. However, in certain circumstances, vascular NRP1 signaling can be detrimental, as it may promote cancer by enhancing tumor angiogenesis or contribute to tissue edema by increasing vascular permeability. Understanding the mechanisms of NRP1 signaling is, therefore, of profound importance for the design of therapies aiming to control vascular functions. Previous work has shown that vascular NRP1 can variably serve as a receptor for two secreted glycoproteins, the VEGF-A and SEMA3A, but it also has a poorly understood role as an adhesion receptor. Here, we review current knowledge of NRP1 function during blood vessel growth and homeostasis, with special emphasis on the vascular roles of its multiple ligands and signaling partners. The cardiovascular system forms during embryonic development to supply growing organs with oxygen and nutrients via a hierarchical blood vessel network, with blood flow generated by the pumping heart. Developmental blood vessel growth occurs through the complementary processes of vasculogenesis to form new vessels from single cell precursors and angiogenesis to expand existing vessels by sprouting growth or intussusception . After birth, angiogenesis continues to support growing tissues, but most blood vessels become quiescent during adulthood. The reactivation of quiescent vessels occurs only under specific circumstances in adults, for example in the cycling uterus and ovary, in the placenta during pregnancy, and in skeletal muscle to support exercise-induced muscle growth . In this review, we will describe current knowledge of vascular signaling pathways mediated by the transmembrane protein NRP1, a bifunctional receptor for the secreted glycoproteins VEGF-A and SEMA3A that can additionally promote cell-matrix interactions and adhesion . We NRP1 is a single-pass transmembrane glycoprotein of 130 kDa  that was165-binding pocket, such as tyrosine (Y) 297 and aspartic acid (D) 320 [The class 3 semaphorins bind the a1 and a2 domains of NRP1, and the disruption of this interaction leads to axonal patterning defects without affecting vascular development ,87. The  (D) 320 ,86,88. I (D) 320 ,28,51,69The neuropilin family also includes NRP2, which has roughly 44% amino acid homology with NRP1 and an identical domain structure . NRP2 alDuring development, NRP1 expression is prominent in growing blood vessels, for example on the endothelial cells of capillaries, arteries, and veins in the postnatal mouse retina and in capillaries in the mouse embryo hindbrain on embryonic day (E) 11.5 –23. The nrp1a, whose sequence is phylogenetically more similar to the mammalian gene, and nrp1b, which originates from an early duplication of the NRP1 gene during the evolution of teleost fish [nrp1 genes are required for vascular development in fish [In zebrafish, two NRP1 homologs have been identified: ost fish ,57,96. K in fish ,57,90.Cre-LoxP technology to create cell type-specific NRP1 mutants in the hindbrain angiogenesis model, we recently examined the dependence of vascular development on endothelial versus nonendothelial NRP1. Surprisingly, we found that, NRP1 was required only on the vascular endothelium for normal angiogenesis, despite its abundant expression by nonendothelial cells [Several studies had raised the possibility that non-endothelial NRP1 regulates angiogenesis. For example, NRP1 is expressed on multiple cell types in an angiogenic setting. Thus, NRP1 is expressed by the tumor cells as well as the tumor vasculature  display vascular defects that are different to those of full NRP1 knockout mice; for example, the perisomitic vessels branch normally in E10.5 Nrp1-null mutants, whereas their branching is reduced in Vegfa120/120 mutants [Nrp1-null brains show a severe reduction in vessel branching specifically in the subventricular zone, with vessels terminating in bulbous vascular tufts [Vegfa120/120 brains show a milder reduction in vessel branching that is accompanied by increased vascular diameter and impaired sprouting both into and within the brain [Vegfa120/120 mutants are better explained by the differential affinity of VEGF-A isoforms for the extracellular matrix than their distinct receptor binding properties. Thus, VEGF121 is highly and VEGF165 partly diffusible, whereas VEGF189 is retained in the matrix, unless released by proteases [Based on prior biochemical and tissue culture studies, vascular NRP1 functions are widely thought to be mediated by its binding to VEGF165, as this is the VEGF-A isoform with the strongest affinity for NRP1. However, our genetic mouse studies had raised the possibility that NRP1 can also function in angiogenic endothelial cells in a VEGF-independent manner. Most notably, mice expressing only VEGF120 at the expense of NRP1-binding VEGF , the anin vivo evidence for this suggestion is still lacking). In contrast to mice, zebrafish show defective vascular development in the absence of the SEA motif in the NRP1 cytoplasmic domain [in vivo.Several tissue culture studies raised the possibility that NRP1 can promote endothelial migration and extracellular matrix remodeling independently of VEGFR2. First, fusion of the extracellular domain of the EGF receptor to the transmembrane and cytoplasmic domains of NRP1 creates a chimeric receptor that promotes endothelial cell migration in response to EGF, independently of VEGFR2 . Second,c domain  or its ic domain . These sNrp2-null mice develop to term without obvious arteriovenous or other type of blood vascular defects [Nrp1 knockouts [Vegfa120/120 mice lacking NRP1-binding VEGF165 have similar defects [NRP2 is enriched in the venous and NRP1 in the arterial parts of vascular networks in chick, mouse and zebrafish ,39,44,57 defects , specifinockouts . The artnockouts . In agrenockouts ,80. Endonockouts . This obnockouts , agreein defects . However defects . AccordiNrp1cytoΔ/Δ mutants at an abnormally high frequency [Despite its essential role in arterial morphogenesis, the NRP1 cytoplasmic domain is dispensable for NRP1-mediated arterial differentiation in the retina; instead, the NRP1 cytoplasmic domain promotes the spatial segregation of arteries and veins to regulate arteriovenous patterning in this tissue. Specifically, retinal arteries and veins cross over each other in the requency . In humarequency ,92. Arterequency , suggestrequency ,94.Although VEGF-A is best known as an angiogenic growth factor, it was first described as a vascular permeability factor, because it disrupts endothelial barrier function in tumors and increases the leakage of serum proteins and therefore interstitial pressure . In an iIt is not yet clear how NRP1 and VEGFR2 cooperate to regulate vascular permeability. On the one hand, NRP1 and VEGFR2 need to be coexpressed in porcine aortic endothelial cells to restore the VEGF165-induced decrease in transendothelial electrical resistance, an inverse indicator of permeability .in vivo.In addition to binding VEGF165, NRP1 can also bind SEMA3A to induce permeability in the Miles assay that measures vascular permeability in the skin . SEMA3A Due to its pleiotropic roles in angiogenesis, arteriogenesis, and vascular permeability, NRP1 provides a promising molecular target for diseases involving aberrant vascular growth or excessive vascular leak. In particular, a better understanding of NRP1 signaling may enable the design of therapies that can revascularize ischemic tissues via VEGF-A-stimulated angiogenesis and arteriogenesis, but avoid induction of excess vascular leak.


The prevalence of allergic rhinitis (AR) in China has increased with an apparent geographic variation. The current study aims to investigate the AR prevalence/classification, diagnosis/treatment conditions, trigger factors, and risk factors in the general population of Guangzhou, the third biggest city in China. A cross-sectional survey was performed in the citizens in Guangzhou from December 2009 to March 2010 by using a stratified multistage cluster sampling method. All subjects were asked to complete a comprehensive questionnaire via a face to face interview. A total of 9,899 questionnaires were valid. The prevalence rate of AR in the general population of Guangzhou was 6.24%, with a significant higher prevalence in urban area (8.32%) versus rural area (3.43%). Among the AR subjects, most (87%) were diagnosed with intermittent AR and 87% suffered from moderate-severe symptoms. High percentages of the AR patients did not have previously physician-based diagnosis (34%) or specific medical treatment (55%). Morning time, winter season, and cold air were the most common trigger factors of AR. Family history of AR, current living place, living place during babyhood, smoking, home renovation, and pet ownership were the significant risk factors associated with AR prevalence in the population. The study demonstrated comprehensive epidemiological and clinical information about the AR in Guangzhou population. Change of living environment and lifestyles had strong impacts on the prevalence of AR. Public health policies should help the patients benefit from a proper diagnosis/treatment and specifically target the local risk factors, in order to control the AR incidence. Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa. An increase of release of inflammatory mediators and cytokines is significant in AR which is triggered by allergens and is mediated by antibody immunoglobulin E (IgE). The prevalence of AR has increased substantially in recent decades in China and it imposes a heavy healthy and socioeconomic burden on the patients. Although several cross-sectional population-based studies have been performed to analyze the prevalence of AR in multiple major cities To gain the prevalence, the distribution and the health economic information in Chinese general population about the allergic diseases , and to formulate the prevention interventions of them which can adapt the different income levels in China, a national wide project called “National Epidemiology Study of Asthma and Allergy in China (NESAAC)” was established in 2007 by the Chinese Ministry of Health. The project is an epidemiological survey, leading by Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, and participated by a number of medical units . Guangzhou is the third biggest city in China, with a population of around 8.3 million citizens and highest gross domestic product in the southern part of China. This study investigated the prevalence/classification of AR, diagnosis/treatment conditions, triggers factors, and associated risk factors of AR in the general population of Guangzhou city. The analysis of comprehensive parameters will estimate a more accurate prevalence rate of AR, describe the clinically epidemiological information of AR, and determine the risk factors of AR in the local population, in order to provide useful information for clinicians and health policymakers making specific strategies to control the AR prevalence.The study was approved by the ethics committee of the First Affiliated Medical Hospital of Sun Yat-Sen University in Guangzhou, China. Before doing the questionnaire, the adult participants had signed the informed consent, while the consent document for the children aged less than 18 years had been signed by their parents or guardians. The questionnaire forms for those younger people aged less than 18 years old were completed by a parent or a guardian of the child.A cross-sectional survey was conducted among the general population in Guangzhou city during Dec. 2009 to Mar. 2010, using a stratified multistage sampling method . The popThe standardized questionnaire was derived from the well-documented questionnaires used by the International Study of Asthma and Allergies in Childhood (ISAAC) The study was conducted by the department of otolaryngology & department of allergy, The First Affiliated Hospital of Sun Yat-Sen University in Guangzhou, China. The survey was administered by the ENT doctors and well-trained graduate students from medical school via a face-to-face interview. Under the coordination of the local government, all the residents who were sampled were recruited to the community centers by staff from the neighborhood or village committees. For those residents who could not come to the center, the interviewers would visit their home to complete the survey. Before doing the questionnaire, the adult participants had signed the informed consent, while the consent document for the children aged less than 18 years had been signed by their parents or guardians. The questionnaire forms for those younger people aged less than 18 years old were completed by a parent or a guardian of the child. All the respondents need to fill out the screening questionnaire and the risk factor questionnaire; while the professional questionnaire of AR was completed only by patients. According to the diagnostic criteria of AR in the ARIA 2001 Guideline p-value less than 0.05 was considered as statistically significant.All questionnaires were verified and invalid questionnaires were removed. Database was established with EpiData3.1 by the staffs. All statistical analyses were performed by a professional statistician using SPSS 18.0 software . The chi-square test was used to analyze the AR prevalence in the categories of gender, age group, and living areas; and to analyze the relationship between AR classification and diagnosis/treatment conditions. The Generalized Estimating Equations (GEE) which allows for dealing with correlated observations were used to analyze the risk factors. In the GEE procedure, family was considered subject variable and the people was within-subject variable; binary logistic regression was selected as the analytic model. A A total number of 10,153 questionnaires were assigned, and the response rate was 99.8%. There were 9,899 valid screening questionnaires (effective rate 97.7%) for the study. Of all subjects, 5,266 (53%) were male and 4,632 (47%) female. 5,696 subjects (58%) lived in urban area while 4,203 (42%) lived in rural area.Based on the screening questionnaire of AR, the information of AR-related symptoms within pass 12 months was noted and the prevalence rate of AR in the population was 6.2% . Among the 618 subjects with AR, 352 (57%) were male and 266 (43%) female Fig. 2A.The AR subjects (n = 618) were asked to filled in the professional questionnaires and 34 forms were not responded, leaving 584 questionnaires were validated. The data provided information about the classification of AR, previous diagnosis/medication and the relevant trigger factors of AR. Based on the symptom severity, 87% of the patients were grouped into moderate-severe AR, and 13% into mild AR Fig. 3A.p = 0.08) (p = 0.08)  had a significant higher chance to have a previous physician-based diagnosis of AR than those with mild symptoms  Fig. 3E;Trigger factors which contribute to exacerbation of the symptoms were analyzed. The patients were asked whether the symptoms vary by time of day or season, and exposure to environmental and lifestyle factors. The majority (69%) of the patients indicated that the most severe symptom episodes occurred in the early morning, and the symptom severity gradually reduced over time until midnight Fig. 4A.To evaluate the AR risk factors, 9,853 out of 9,899 questionnaires were successfully completed. Fifteen relevant risk factors were analyzed, including biological condition ; environment/lifestyle ; socioeconomic status (monthly income and car ownership). Three factors had too many missing values , which were considered leading to large errors, and they were excluded in the analysis.p<0.05), including family history of AR, living place during babyhood, smoking, home renovation, computer usage, and pet ownership  and medication (45%) rates were low in AR patients. Although the subjects with persistent AR experienced more severe discomfort, only 72% of these patients had a physician-based diagnosis and 37% received treatment before. In addition, among the patients who had been diagnosed by clinicians, just 54% of them received specific treatment. The lower diagnosis rate may be attributed to the strained medical resources and the busy lifestyle in the big city in China, making patients reluctant or no time to visit clinics. The imbalance in the allocation of medical resources in some province , where the patients from small to medium sized cities would prefer seeking medical specialists in the capital city , leads to a shortage of medical resources in those big cities. With regard to the lower treatment rate, we consider the patients may concern the cost of the treatment, since both pharmacological therapy and specific immunotherapy are not cheap in China and it usually requires a long course of treatment, leading to a decline in the rate of treatment. Therefore, disseminating information about the disease treatment, optimization of the medical resources and introduction of the therapies in medical insurance scheme supported by government may improve the diagnosis and treatment rates.Based on the analysis of AR trigger factors, cold air or cold weather appears the top 1 inducing factor. In winter, the level of the dust and contaminants is elevated, and the indoor ventilation is poor , leading to the increase of opportunity to contact allergens. On the other hand, the big variation of temperature in cold weather or cold environment would affect the stability of the parasympathetic nervous system and the dry air would also increase the vascular permeability, resulting in the hypersensitivity of the topical nasal mucosa. Other trigger factors like spring pollen, wet environment and dust environment are related to a high chance of allergen (pollen and house dust mite) exposure; while sports, irritant odor and outdoor air pollution are associated with the stimulation of local mucosa response.The highest risk factor for AR in general population in Guangzhou is the family history, i.e. genetic factor. It is in line with many epidemiological investigations performed in both Chinese and Caucasians which found that AR has a significant familial aggregation Accumulating evidence has confirmed that both genetic and environmental factors play important roles in the development of AR. A sharp rise of AR prevalence in recent years could be not only explained by genetic background, but also environmental factors, especially the rapid urbanization and the widespread of “westernization” lifestyles in China can be considered an essential reason. Our study found a cluster of “modern” lifestyle factors  were significant risk factors of AR in Guangzhou general population, indicating these may be unhealthy habits with regard to the incidence of AR. Among these non-genetic aspects, living place during birth to 2 years old is the most significant factor for AR. Compared to living in village, the risk of developing AR progressively increases in the people who staying in town and in urban city. Similar results were reported that the farming environment in childhood provided a protective effect in adult against the development of allergic diseases An increased risk of allergic diseases among individuals who are exposed to tobacco smoke has been reported One interesting finding is that the use of computer may pose a risk to AR incidence. Since the computer is not cleaned frequently, dust, dirt, hair, and other debris can build up on the surface of the hardware and also accumulate on the surface of the monitor, where this is a favorite environment for dust mites. Use of computer will increase the chance to contact the allergens and may be an important risk for sensitizations in patients with AR. Although the trend of larger AR proportion in the group of higher frequency of computer use (>5 hs per day) existed , we failHome renovation is also a risk factor associated with AR. Formaldehyde is the major air pollutant when making interior decoration and can irritate nasal mucosa, resulting in airway inflammation. Pet ownership has been increased in the urban city in China and our results showed that exposure to pets increase slightly the risk of AR. Pet fur and dander are the sourced materials of pet allergens.In conclusion, the present study showed that in Guangzhou city, the AR prevalence was significantly higher in the urban area than the rural areas, intermittent AR was the predominant type, and a high proportion of AR patients was clinically undiagnosed or without specific medical therapy. Public health policies should optimized the medical resources and help the patients benefit from a proper diagnosis and treatment. The results also demonstrated a spectrum of AR trigger factors and risk factors and indicated that other than genetic aspect, change of living environment and lifestyles would pose potential risks for AR incidence and exacerbation of symptoms. Strategies are required to monitor and reduce the exposure to risk factors. The epidemiological information will benefit the public health policy maker to design some guideline or medical scheme on the prevention and treatment of AR in Guangzhou, and even in other metropolitan cities in China.S1 FigureProportion of the AR prevalence in the groups of computer usage. The trend of the AR prevalence was analyzed by Chi-Square test. A p-value below 0.05 was considered statistically significant.(TIFF)Click here for additional data file.


Background: Triple-negative breast cancers (TNBC) are characterized by aggressive tumour biology resulting in a poor prognosis. Androgen receptor (AR) is one of newly emerging biomarker in TNBC. In recent years, ARs have been demonstrated to play an important role in the genesis and in the development of breast cancer, although their prognostic role is still debated. In the present study, we explored the correlation of AR expression with clinical, pathological and molecular features and its impact on prognosis in early TNBC. Patients and Methods: ARs were considered positive in case of tumors with >10% nuclear-stained. Survival distribution was estimated by the Kaplan Meier method. The univariate and multivariate analyses were performed. The difference among variables were calculated by chi-square test. Results: 81 TNBC patients diagnosed between January 2006 and December 2011 were included in the analysis. Slides were stained immunohistochemically for estrogen and progesterone receptors, HER-2, Ki-67, ALDH1, e-cadherin and AR. Of the 81 TNBC samples, 18.8% showed positive immunostaining for AR, 23.5% and 44.4% of patients were negative for e-cadherin and ALDH1, respectively. Positive AR immunostaining was inversely correlated with a higher Ki-67 (p < 0.0001) and a lympho-vascular invasion (p = 0.01), but no other variables. Univariate survival analysis revealed that AR expression was not associated with disease-free survival (p = 0.72) or overall survival (p = 0.93). Conclusions: The expression of AR is associated with some biological features of TNBC, such as Ki-67 and lympho-vascular invasion; nevertheless the prognostic significance of AR was not documented in our analysis. However, since ARs are expressed in a significant number of TNBC, prospective studies in order to determine the biological mechanisms and their potential role as novel treatment target.  Triple negative breast cancer (TBNC) is a subtype of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) negativity. Therefore it cannot benefit from endocrine therapy and HER-2-target therapy. Owing to the aggressive tumor biology and lack of targeted therapy, TNBC is characterized by a dismal although heterogeneous outcome. Recently, considerable efforts have been made to sub-classify TNBC into different prognostic groups to select patients who are candidates for more or less aggressive therapy regimens. Many studies have assessed new biomarkers able to identify patients with different prognosis. One of the most extensively investigated but also controversial biomarker is the androgen receptor (AR). Androgens are involved in the functions of different female organs, including the reproductive tract, bone, kidneys and muscle, acting indirectly as pro-hormones of estradiol or directly by binding to the androgen receptor (AR) . The AR Breast cancer patients diagnosed with stage I–III TNBC, undergoing adjuvant chemotherapy at our Institution from January 2006 and December 2011, were eligible for this analysis. Patients who received preoperative chemotherapy or with stage IV of disease were excluded. We analyzed several parameters: clinical , pathological  and molecular (ALDH1 and e-cadherin). Tissue samples were fixed in 10% buffered formalin and embedded in paraffin wax for routine histological examinations. The slides were stained with hematoxylin and eosin (H & E) with additional immunostaining for ER , PR , Her2/neu , Ki-67 , AR , ALDH1  and e-cadherin . ER, PR and AR were considered positive if there were at least 10% positive invasive tumor nuclei in the sample. HER-2 status was evaluated by immunohistochemistry (IHC) using a semiquantitative score (0–3+). Tumor staining was compared to the staining of normal breast epithelium from the same patient as a negative control. For clinical purposes, no staining or weak (1+) and incomplete membrans’staining was considered a negative result. Patients with 2+ IHC staining for HER2 underwent fluorescence in-situ hybridization to confirm HER2 negativty. Triple-negative status  was finally diagnosed and re-reviewed by the single study pathologist of our Institution. Carcinoma cells with cytoplasmic staining were considered to be ALDH1-positive cells. Any proportion of ALDH1-positive carcinoma cells was considered to represent epithelial ALDH1 expression. E-cadherin expression was semi-quantitative analysed according to the percentage of cells showing membrane positivity: 0, 0% to 10%; 1+, 10% to 30%; 2+ 30% to 70%; 3+ > 70%. E-cadherin expression was considered positive when scores were ≥2 and negative when scores were ≤1. Disease-free survival (DFS) was defined as the interval between the date of diagnosis of TNBC to the date of relapse or progression of disease, or the date of death from any cause. Overall survival (OS) was defined as the interval between the date of diagnosis of TNBC to death or last follow-up visit. Patients who were not reported to be dead at the time of the analysis were censored at the date they were last known to be alive. Survival distribution was estimated by the Kaplan Meier method. The association between categorical variables was estimated by Chisquare test. The Cox multivariate proportional hazard regression model was used to evaluate the effects of the prognostic factors on survival. Significant differences in probability of surviving between the strata were evaluated by log-rank test. Hazard ratios and 95% confidence intervals (CIs) were estimated from regression coefficients. A significance level of 0.05 was chosen to assess the statistical significance. Statistical analysis was performed with MedCalc package .p < 0.0001) and lympho-vascular invasion (p = 0.01). No significant difference between the groups with and without positive AR immunostaining in age at diagnosis, menopausal status, size of tumor, histological features, ALDH1 and e-cadherin immunostaining was identified (Eighty one (81) patients were included in the analysis. All patients were female, with a median age of 54 years (range 28–79 years). The majority of them (59.4%) had a menopausal status. Sixty-eight (83.8%) were treated with quadrantectomy and radiotherapy, 13 (16.2%) with radical mastectomy. Almost all patients (97.6%) received systemic adjuvant chemotherapy. Regimens are summarized in entified . p = 0.72) and OS (p = 0.93) (p = 0.002). Multivariate analysis confirmed that the presence of necrosis was the significant independent prognostic variable influencing OS . Univariate survival analysis revealed that positive immunostaining for AR was not associated with DFS ( = 0.93) . No clinTNBC represents a group of breast cancer with poor prognosis, owing to aggressive tumor biology and lack of targeted therapy-like HER2 blocking agents or hormonal therapy . Howeverin situ and invasive disease including early and metastatic setting) [et al. [There is a growing body of evidence that androgen signaling pathway plays a critical role in normal and malignant breast tissue . The AR setting) ,3,4 and setting) ,6. The osetting) ,15,16. A [et al.  proposed [et al. ,19,20. W [et al. ,22, theiet al.’s [in vitro analyses indicated a growth inhibition effect of AR pathway in cell lines expressing ER and PR, while proliferative effects were found in ER and PR negative cell lines. The authors suggested that androgen action may be mediated, beyond by binding of androgen to the androgen receptors, by metabolites of dihydrotestosterone (DHT), also due to its estrogenic activity. Garay et al. [in vitro investigations suggested that AR may displace ER and PR as a driver of tumor proliferation and growth in TNBC cell lines [et al. [Birell et al.’s  in vitroy et al.  reportedll lines ,26,27,28ll lines ,30,31. O [et al.  reportedp < 0.0001) and lympho-vascular invasion (p = 0.01), while we did not find any relationship with age, menopausal status, size of tumor, histological features, ALDH1 and e-cadherin immunostaining , suggesting that androgens might have an antiproliferative effect. AR immunostaining was also inversely correlated with higher clinical stage  and higher histological grade (p = 0.038), but no significant difference between two groups in vascular invasion and other parameters. Sutton et al. [AR positivity was inversely correlated with higher Ki-67  and lympho-vascular invasion (p = 0.01), although in multivariate analysis this effect was not significant. These findings were in line with some of previously published studies. No significant correlation between AR status and survival was found. This data is of importance to a growing body of evidence documenting the association between AR expression and biological factors in TNBC. However, the role of AR pathway in TNBC is still uncertain; conflicting results are reported in preclinical studies and their impact on clinical outcome is still debated. Further prospective studies are needed to determine the pathogenetic mechanism underlying androgen and their receptors in TNBC to adequately assess the potential role of AR pathway as druggable target. In conclusion, our study examined the relationship between AR expression and clinical and prognostic outcomes in an italian cohort of 81 patients with early TNBC. Univariate analysis revealed that AR positivity was inversely correlated with higher Ki-67 (