Bell’s palsy is an acute idiopathic facial nerve paralysis of sudden onset. It is the most common cause of lower motor neuron facial nerve paralysis with an annual incidence of 15-30 per 100,000.The objective of this work is to study the prevalence and the management of Bell’s palsy in the Sudan. A descreptive retrospective cross-sectional study was carried at Khartoum Teaching Dental Hospital, Khartoum General Teaching Hospital.In the retrospective, the records and files of 698 patients with Bell’s palsy, were reviewed in relation to age, gender, site, risk factors, season, and type of treatment.In addition, 48 patients with Bell’s palsy were evaluated using the House–Brackman scale in relation to the above-mentioned variables.Therefore, a total number of 746 cases were studied. Fifty five percent of them were females and the remaining 45% were males, around 38% of them were in the age group 21-40 year. Fifty seven percent of the patients were affected on the right side of the face. Winter was the commonest season of onset where 53.5% of the cases occurred. Steroids are the commonly prescribed drugs in majority of the cases, accounting for 47.3%.The study is a retrospective cross sectional hospital based study. The study was carried out in Khartoum Teaching Dental Hospital and in the Physiotherapy Department of Khartoum Teaching General hospital.The files and records of the patients with Bell’s palsy in Khartoum Teaching Dental Hospital in the years 1/1/2004 -31/12/2008, and Khartoum Teaching General Hospital (physiotherapy department) in the years 2007- July 2009 .A total number of 746 cases were studied . Fifty five percent of them were females and the remaining 45% were male. Around 38% of them were in the group 21-40 year. Fifty seven percent of the patients were affected on the right side of the face. Winter was the commonest season of the onset where 53.5% of the cases occurred.The study showed predominance of females. A peak incidence was seen in the age group 21-40 years. A predilection was found for the right side of face. It is the most common cause of lower motor neuron facial nerve paralysis .Facial nerve paralysis has been known since ancient times by the Egyptians, Greeks, Romans, Incas and other native cultures .The oldeIn the Middle Ages and during the Renaissance, many artists portrayed figures with asymmetrical and distorted faces. The portrait of Mona Lisa is the most famous and her enigmatic smile has been discussed for many years all over the world and at several facial nerve symposiums.The first medical studies of the disease should be attributed to Avicenna . He was Although the name of Sir Charles Bell, who published his findings in 1821, is usually associated with this condition, there are two papers, one published by Niclaus A. Friedrich in 1798, and the other by Richard Powell in 1813, whose observation of onset, physical findings, natural history and recovery preceded those of Charles Bell .Acute idiopathic peripheral facial palsy is a common disease with an annual incidence of 15-30 per 100,000 population .There are many possible causes of Bell’s palsy, but still the aetiology remains obscure . The terVery little has been published on the incidence of Bell’s palsy for various reasons. Physicians from many specialties see and treat patients with Bell’s palsy; and some patients with the disorder do not seek treatment because it is painless and because the paralysis may be limited, or of short duration .The epidemiology of acute idiopathic peripheral facial palsy has been discussed in several articles, sometimes with contradictory findings .In Sudan, no study has been done on the epidemiology, the course, treatment and recovery of Bell’s palsy.The only published study was a case report of Bell’s palsy in seven Sudanese children, by Abbas and Prabhu in 1981 [The purpose of this study is to study the course and treatment of Bell’s palsy among Sudanese patients.1.1et al., concluded that seasonal trend in the incidence of Bell’s palsy does exist (Winter season), with few cases occurring in summer [Acute peripheral facial palsy is a common disease with an annual incidence of 15-30 per 100,000 population . Familian summer .1.2et al., demonstrated a calculated frequency of Bell’s palsy in the pregnant female 3.3 times that of non-pregnant females of the same age  [et al, suggested a significantly greater likelihood of an unsatisfactory recovery compared with the non-pregnant population [Hilsinger ctively) . For womctively) . Grant epulation . Generalpulation .et al., reported a greater frequency of arterial hypertension and lipid disorders in patients with Bell’s palsy than in controls [Paolino controls , 17. Preet al., proposed that sparing of taste fibres in cases of concurrent diabetes and Bell’s palsy may be related to diabetic small vessel disease, and that these cases of Bell’s palsy may in fact be regarded as a diabetic mononeuropathy [The risk of Bell’s palsy is increased in diabetes . A suggeuropathy .1.3To study the course and treatment of Bell’s palsy among Sudanese patients.22.1The study is a retrospective cross sectional hospital based study. The study was carried out in Khartoum Teaching Dental Hospital and in the Physiotherapy Department of Khartoum Teaching General hospital.The files and records of patients with Bell’s palsy in Khartoum Teaching Dental Hospital in the years 1/1/2004 -31/12/2008, and Khartoum Teaching General Hospital (physiotherapy department) in the years 2007-July 2009  were reviewed in relation to:AgeGenderSiteRisk factorSeasonType of treatment2.2Patients affected by acute onset facial paralysis without detectable cause.2.3Known traumatic, inflammatory and neoplastic, pathology of the facial nerve in its intra or extracranial course.Bilateral facial paralysis.Concurrent disease of central or peripheral nervous system.2.4SPSS) version 15.The data was analysed using Statistical Package of Social Sciences  patients. Fifty five percent of the patient were females showing clearly a predominance of females and that the difference is statistically significant (p = 0.007).The question of a gender predominance among patients having Bell’s palsy has been discussed in the majority of the published reports if not all of them Table 2, shows a peak incidence in the group 21-40 years accounting for 37.8% of the series, which is statistically significant (p=.001).Table p=.001) which was illustrated in Table 3.From the total number of patients the study 57.2% of patients were affected on the right side of the face. The study showed that the right side is predominantly affected, and that the predilection for this side is statistically significant (4), there is no influence of the gender on the side affected. On the other hand, as can be seen from Table 5 there is also noinfluence of the age group or the gender on the side affected by Bell’s palsy.On correlating the gender with the side  were seen in Summer.Table 7. and the relation between it and Bells’ palsy appears to be statistically significant.In the present study, around 8% of our patients were suffering from hypertension as shown in Table 8, out of 746 patients with Bell’s palsy 10.7% were found to be diabetics.As shown in Table 9 and 10, the total number of females in the study is (n=410) patients. Of these, 67.3% of the patients are in the age of pregnancy years of this group, 43.4% of the patients are married and in the pregnancy age. The percentage of pregnant females (n=58) from the total number of married women and in the pregnancy age is 32.5% which is a high percentage, suggesting a strong association between Bell’s palsy and pregnancy, as illustrated in Table 8.As shown in Tables 11 and 12.47.3% of the patients received steroid therapy alone, 31.1% received a combination of steroids and physiotherapy, 15.8 % received physiotherapy only, and the remaining patients (5.8%) received other treatments which include vit B12, antiviral drugs, and non-steroidal anti- inflammatory drugs, as shown in Tables 4Not much is published on the epidemiology of Bell’s palsy and in the dearth of literature published on it contradicting results can be seen. In this study, a total number of 746 of cases of Bell’s palsy were studied. Of these, 746 cases are records of patients seen in the period 2004 -2008 in Khartoum Teaching Dental Hospital, and at Khartoum General Teaching Hospital (Physiotherapy Department) in the period from Jan 2007 to July 2009.4.14.1.11 the question of a gender predominance among patients having Bell’s palsy has been discussed in the majority of the published reports if not all of them. In this study, the total number of patients was (n= 746) patients. Fifty five percent of the patient were females showing clearly a predominance of females and that the difference is statistically significant (p = 0.007). Similar figures were reported by Valenca et al., from Portugal [,where the female gender comprised 66.7% of the cases. Our finding in this respect are also in agreement with the figures shown by Goncalves et al., in Brazil [As shown in Table Portugal  ,where tn Brazil , who rep4.1.2This subject has also been debated, without reaching a definitive conclusion.2, shows a peak incidence in the group 21-40 years accounting for 37.8% of the series, which is statistically significant (p=.001) . The incidence of Bell’s palsy shows a decline below the age of 20 years 23.8% (n=175) patients, and above the age of 61years, (10.2%)) (n=76) patients.Table et al., from Brazil [This study demonstrated convincingly the influence of age on the incidence of Bell’s palsy. Pietersen from Denmark  reportedm Brazil  showed s4.1.3p=.001) which was illustrated in Table 3. Because the sample size is small we can’t assume this result representing the actual situation. Further investigation is needed to verify or negate this observation. Nevertheless, our findings are similar to those reported by Savettieri et al., from Italy [From the total number of patients the study 57.2% of patients were affected on the right side of the face. The study showed that the right side is predominantly affected, and that the predilection for this side is statistically significant , there is no influence of the gender on the side affected. On the other hand, as can be seen from Table 5 there is also no influence of the age group or the gender on the side affected by Bell’s palsy. These finding are in accordance with findings of Pietersen [et al., from the United states [et al., from Spain [On correlating the gender with the side  were seen in Summer.Table et al., from Brazil [et al., Spain [et al., from UK [The findings of our study showed a seasonal clustering of cases in Winter. This is in accordance with the findings of Goncalves m Brazil  which sh., Spain  who repo., Spain  from Den from UK  did not 4.24.2.1et al., [et al., [Holland, Devriese et al.,  in a sam[et al., , supportThe relation of Bell’s palsy and some systemic diseases that are prevalent in the community need to be addressed more scientifically. The studies that associate the incidence of Bell’s palsy with some of these systemic diseases, none has mentioned the issue of the prevalence of these diseases in the community concerned.7 and the relation between it and Bells’ palsy appears to be statistically significant. Nonetheless, it is difficult to assume that the patients with hypertension are more prone to have Bell’s palsy than their normal counterparts.In Sudan, hypertension as well as diabetes are now common diseases with a prevalence ranging from 18% and 20%, respectively. In the present study, around 8% of our patients were suffering from hypertension as shown in Table 4.2.2et al., from Iran [et al., from Israel [Many studies have reported an association between the incidence of Bell’s palsy and diabetes. Yazdi rom Iran  found inm Israel  demonstr8, out of 746 patients with Bell’s palsy 10.7% were found to be diabetics. The prevalence of diabetes mellitus in the Sudan is 20% percent. When we correlate this percentage to the percentage of the diabetics among our Bell’s palsy patients, it would not be logical to assume that diabetes mellitus is a risk factor for Bell’s palsy.As shown in Table 4.2.39 and 10, the total number of females in the study is (n=410) patients. Of these, 67.3% of the patients are in the age of pregnancy years of this group, 43.4% of the patients are married and in the pregnancy age. The percentage of pregnant females (n=58) from the total number of married women and in the pregnancy age is 32.5% which is a high percentage, suggesting a strong association between Bell’s palsy and pregnancy, as illustrated in Table 8.As shown in Tables et al., [et al., [These findings in our study are in accordance with the findings of many investigators. Hilsinger et al., , from th[et al., , from USThe increased prevalence of Bell’s palsy in pregnant females may be due to gestational immune suppression resulting from the rising cortisol levels in pregnant women. This might induce reactivation of dormant or inhabitant viruses in the body . General4.311 and 12.47.3% of the patients received steroid therapy alone, 31.1% received a combination of steroids and physiotherapy, 15.8% received physiotherapy only, and the remaining patients (5.8%) received other treatments which include vit B12, antiviral drugs, and non-steroidal anti- inflammatory drugs, as shown in Tables et al., [Generally, Bell’s palsy should be considered an emergency that should be treated using all available measures against possible multiple factors . The earet al.,  corticosFemales are more susceptible to Bell’s palsy than the males in the Sudan.The age group 21- 40 was the commonest age group involved in Bell’s palsy.There is a predilection of Bell’s palsy for the right side of the face, with no influence of gender or ages observed.There is an association between Bell’s palsy and pregnancy and Winter is the commonest season of the onset. It is difficult to draw an association between Bell’s palsy with hypertension and diabetes mellitus, as both diseases are prevalent with high frequencies in the Sudan.The treatment of choice of Bell’s palsy is a combination therapy that includes steroids.A large population-based epidemiological study of Bell’s palsy is needed in Sudan to determine the prevalence of the disease.


ZBTB46, SPDEF, and ETV6) that were demonstrated to play critical roles in CRPC progression, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) drug resistance, and the epithelial-to-mesenchymal transition (EMT) for patients treated with ADT or AR inhibition. In addition, we summarize how these potential biomarkers can be used in the clinic for diagnosis and as therapeutic targets of PCa.Prostate cancer (PCa) is the second most common killer among men in Western countries. Targeting androgen receptor (AR) signaling by androgen deprivation therapy (ADT) is the current therapeutic regime for patients newly diagnosed with metastatic PCa. However, most patients relapse and become resistant to ADT, leading to metastatic castration-resistant PCa (CRPC) and eventually death. Several proposed mechanisms have been proposed for CRPC; however, the exact mechanism through which CRPC develops is still unclear. One possible pathway is that the AR remains active in CRPC cases. Therefore, understanding AR signaling networks as primary PCa changes into metastatic CRPC is key to developing future biomarkers and therapeutic strategies for PCa and CRPC. In the current review, we focused on three novel biomarkers ( Prostate cancer (PCa) is the most common cancer expected to occur in men with an estimated 164,690 new cases annually in the US, and it is the second most common cause of cancer deaths in men after lung cancer . The fivPSA, which was first described in 1979, is produced by the prostatic epithelium and periurethral gland, and it can be detected in blood samples. Annual PSA screening was recommended for men over 50 years of age in the past two decades ,7,8. A rPCA3), HOXC6/DLX1, or imaging [Recently, several guidelines were developed to enhance PCa screening in place of the PSA test, decrease unnecessary biopsies, and increase the specificity for cancer detection. For example, according to the National Comprehensive Cancer Network (NCCN), in 2016, several biomarkers were recommended for screening before taking biopsies from men with PSA of >3 ng/ml such as the percent of free PSA, 4K score, and a prostate health index (PHI) . Additio imaging .Treatment options for PCa include a prostatectomy, radiotherapy, chemotherapy, hormonal therapy, and even active surveillance (AS). In AS treatment, patients require no radiation, surgery, or chemotherapy. Patients undergo a conservative management approach such as routine screening to monitor the progression of cancer for those with a low risk or men with a Gleason score of ≤6 and a PSA level of <10 ng/mL ,16. HoweNormally, the androgen hormones, testosterone and dihydrotestosterone (DHT), are important for prostate function and growth in males. The androgen receptor (AR) is expressed by luminal prostate cells . HoweverDespite the heterogeneity of the etiology and progression of PCa, the influence of androgen signaling on PCa seems to include all aspects of the disease. Therefore, androgen deprivation therapy (ADT) is the key regimen for patients with advanced PCa ,26. NeveSeveral mechanisms have been proposed to explain the development of CRPC ,31,32,33Nowadays, screening and diagnosis of PCa involve a physical examination. A digital rectal examination (DRE) is considered the primary assessment test for the prostate , while mThe only biomarkers for PCa that have been approved in clinics by the US Food and Drug Administration are the total and free PSA . PSA hasRecently, several proposed biomarkers for PCa were identified in either tissues or body fluids. For example, α methylacyl coenzyme A racemose (AMACR) was detected in PCa tissues ; an immuBone turnover biomarkers (BTMs) are a group of proteins and their derivatives that are expressed during bone remodeling activities. PCa was reported to metastasize to bone, and this will lead to the involvement of several bone biomarkers during bone metabolism in PCa. Therefore, measuring BTMs in either the serum or tumor tissues can provide a new platform for PCa screening and prognosis . For exaHepsin is a member of type II transmembrane serine proteases (TTSPs), which are thought to play key roles in cell growth and tumor invasion by breaking down membranes. Overexpression of hepsin was reported in several solid tumors, including PCa, and was thus suggested as a biomarker for PCa ,57,58. TNR3C4), is considered to be a nuclear receptor transcriptional factor (TF) [The AR gene is located on X-chromosome q11-12 and consists of eight exons that code about a 111-kDa protein. The protein contains three major functional domains: an N-terminal domain (NTD) encoded by the first exon (residues 1–555), a DNA-binding domain (DBD) encoded by exons 2 and 3 (residues 556–623), and a ligand-binding domain (LBD) encoded by exons 4–8 at the C-terminal end (residues 665–919) ,60,61. Ttor (TF) . By trantor (TF) .CK8), CK18, and NkX3.1. On the other hand, basal cells make up a layer that supports luminal cells and is characterized by CK5 and CK14 with a low or undetectable level of the AR [The human prostate is mainly organized into an epithelial bilayer of cells: basal and luminal epithelial cells. There are also some neuroendocrine (NE) cells, which are less understood . Luminalf the AR . It was f the AR ,68,69. Mf the AR . Recent f the AR ,72, fibrf the AR , and vasf the AR . A decref the AR .It is believed that human PCa originates from luminal cells because it mostly has luminal epithelial phenotypes, which are characterized by high levels of AR and an absence of basal epithelial cells ,77. SeveNE cells are scattered and arise from epithelial stem cell units . The numAZGP1)—in induction of PCa proliferation and metastasis. The authors revealed that AR signaling was responsible for upregulation of AZGP1 and enhancement of cell proliferation in vitro and in vivo through the androgen/AR axis [In the absence of testosterone or DHT, the AR is stabilized by heat shock protein (HSP)-90, HSP-70, and HSP-56 as well as cytoskeletal proteins ,89 in th/AR axis .Therefore, any interruption or mutation of the AR gene or androgen-regulated pathways may affect the growth and development of the prostate and lead to PCa progression. Like normal prostate cells, PCa cells also require the AR to grow and survive. Androgen and the AR regulate the ratio between cell proliferation and cell death, which is higher in PCa and results in continuous cell proliferation and growth .Both ADT and androgen-suppression therapy are hormonal manipulation therapies aimed at preventing PCa progression by reducing testosterone or DHT levels or by blocking AR signaling pathways ,95. FurtDuring the progression of PCa from primary to CRPC, several changes occur to the AR and AR signaling pathway that could provide an explanation for the CRPC mechanism. The most common genetic change in CRPC patients is AR gene amplification , which aSeveral AR point mutations have been identified, which enhance the AR’s activity even at low levels of androgen. Most AR mutations occur in the NTD and/or LBD regions ,102. ForA biomarker is defined as a “characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention" . HoweverZBTB46, also known as BTBD4, zDC, and BZEL, is a TF that belongs to the POZ and Krüppel (POK)/zing finger and BTB (ZBTB) protein family [ZBTB46 was specifically and selectively expressed by classical dendritic cells , but not by other immune cells such as macrophages, monocytes, or cells of a lymphoid or myeloid lineage, and it maintains cDCs in a quiescence state [ZBTB46 makes it a useful biomarker for clinical diagnoses of DC malignancies [ZBTB46 by IHC staining in patients with histiocytic disorders, which are human malignancies of DCs and related myeloid cell types [ZBTB46 showed a clear DC lineage identity.n family . It was ce state ,109. Thignancies . Satpathgnancies  examinedll types . ZBTB46 ZBTB46 is also expressed in quiescent endothelial cells (ECs). Using in vitro and in vivo systems, ZBTB46 was found to inhibit EC proliferation, and overexpression of ZBTB46 in an EC line led to decreased cell proliferation by increasing the G0-G1 cell population, which was characterized by low Ki67 expression. Furthermore, overexpression of ZBTB46 caused decreased expressions of several cell cycle genes, viz., cyclins and cyclin-dependent kinases (CDKs), and increased p21 but not p27 [ZBTB46 regulates expressions of several genes by binding to the gene zinc finger-binding domain and mediates chromatin remodeling and transcriptional regulation [Outside of the immune system,  not p27 . Normallgulation .ZBTB46 as a novel tumor promoter in PCa, which was negatively regulated by AR signaling via microRNA-1 (miR-1)-mediated downregulation [ZBTB46. In PCa cells, in response to ZBTB46 knockdown, only Snail was reduced, while E-cadherin expression was enhanced. However, overexpression of ZBTB46 enhanced expression of Snail and decreased E-cadherin levels. Since Snail was shown to have a role in the EMT and metastasis in PCa [ZBTB46 promotes AR-independent proliferation [Recently, Chen et al. identified gulation . Androges in PCa ,115,116,feration .ZBTB46 in promoting NEPC progression and its association with inflammatory responses were elucidated [ZBTB46 levels were enhanced by loss of the expression of the SAM pointed domain-containing ETS transcriptional factor (SPDEF), which is believed to act as a tumor suppressor gene and to be regulated by AR signaling [SPDEF leads to an increase in the expression of ZBTB46, thus facilitating an abundance of prostaglandin endoperoxide synthase 1 (PTGS1), which was reported to participate in inflammation, arthritis, and cancer pathophysiology [ZBTB46 acts as a transcriptional coactivator and induces PTGS1 expression. Increasing the PTGS1 level contributes to NE differentiation of PCa cells following ADT. ZBTB46 activation of the AR inhibits PCa, resulting in NEPC differentiation and an abundance of PTGS1 in PCa patients. Overall, ZBTB46 can be used as a new novel biomarker and therapeutic target for PCa and NEPC.In parallel, the role of ucidated . Chen etignaling . A low lysiology ,121,122.ZBTB46 was shown to be involved in induction of the leukemia inhibitory factor (LIF)-signal transducer and activator of transcription 3 (STAT3) signaling pathway in ADT PCa cells [ZBTB46 and an association with cytoplasmic LIF, which was observed in high-grade patients. ZBTB46 regulates LIF expression by directly binding to the LIF-regulatory sequence, which then activates the LIF/STAT3 signaling pathway in ADT patients and facilitates NE differentiation [More recently, Ca cells . LIF is Ca cells . In addiCa cells . LIF oveCa cells ,126,127.ntiation   TF [SPDEF in normal human tissues indicated that the highest levels were detected in prostate tissues and the salivary gland [SPDEF should be considered a tumor-suppressor gene in PCa [SPDEF in PCa is associated with worse clinical outcomes and poor differentiation [SPDEF led to enhanced prostatic cell migration, invasion, and metastasis [SPDEF efficiently suppressed the in vitro and in vivo metastasis of PCa [SPDEF was regulated by the AR pathway in PCa, and downregulation of SPDEF may be involved in the EMT of PCa in response to ADT. Recently, Tsai et al. reported a mechanistic link between ADT and the EMT in a subset of ADT-resistant PCa cells, where the chemokine C-C motif ligand 2 (CCL2) was stimulated through inactivation of AR-mediated SPDEF [SPDEF–CCL2 in PCa and metastatic CRPC. An inverse correlation was observed between SPFDEF and CCL2 after ADT compared to the intensity of both proteins before ADT. Low SPDEF and high CCL2 levels after ADT were detected using IHC and tissue samples from PCa patients. Once the AR is activated, the SPDEF expression level is enhanced, and it is translocated to nuclei to suppress CCL2 expression after binding to the CCL2 promoter region, consequently inhibiting the EMT in PCa. However, in CRPC, AR inhibition by ADT leads to suppression of SPDEF expression and enhancement of CCL2 and the EMT. This novel model could help in predicting therapeutic outcomes after ADT or standard PCa regimens [(ETS) TF  and has (ETS) TF . An analry gland . A numbee in PCa . Loss ofntiation ,133. Knotastasis . On the s of PCa . It was ed SPDEF . In thatregimens .SPDEF [SPDEF–TGF-β signaling pathway in regulation of the EMT and development of metastatic CRPC under ADT or AR-inhibitor conditions [TGFBI), was shown to be associated with PCa EMT and activation in androgen-deprived PCa cells with a variety of metastatic properties. Gain of TGFBI function in vitro or in vivo revealed a significant correlation with EMT markers measured by p-Smad2 and vimentin. Knockdown of the AR in AR-positive cells enhanced TGFBI expression, and ectopic expression of the AR in AR-negative cells reduced TGFBI levels. Based on a gene set enrichment analysis (GSEA), Chen et al. identified the SPDEF gene as the upstream mediator between AR signaling and TGFBI expression. A clinical study using IHC reveled an inverse correlation between SPDEF and TGFBI in PCa before or after ADT. With loss of SPDEF function, TGF-β expression was retained, while ectopic expression of SPDEF decreased TGFBI in PCa cells. That study was the first to elucidate a role of the TF in the AR–TGF-β axis, which could provide another explanation for the common clinical problem of metastatic CRPC developing after a standard ADT regimen in PCa patients. Targeting the AR–SPDEF–TGFBI pathway could prevent further progression to metastatic CRPC (A previous report demonstrated that transforming growth factor (TGF)-β signaling acts as a driver for activation of the AR in ADT treatment of CRPC . MoreoveSPDEF . Recentlnditions . In thattic CRPC .ETV6, also known as TEL, is a transcription repressor that belongs to the ETS TF gene family, located on chromosome 12p13 with eight exons and encoding a 452-amino acid protein. There are two domains present in ETV6: the ETS domain, which mediates DNA binding to the GGAA-rich region and is encoded by 6th and 7th exons, and the pointed (PNT) domain for protein–protein interactions, which is encoded by the 3rd and 4th exons [ETV6 translocation was reported in several types of cancers: in mesoblastic nephromas, congenital fibrosarcomas, human secretory breast carcinoma, and secretory carcinoma of the salivary gland [ETV6 plays a vital role in hematopoiesis and embryonic development.th exons ,140. ETVry gland ,144,145.ETV6 and more than 25 partner genes, which have been molecularly characterized [ETV6-mediated leukemogenesis that have been identified: (1) constitutive activation of the kinase activity of the partner protein, (2) change in the original functions of a TF, (3) loss of function of a fusion gene, (4) activation of a proto-oncogene in the vicinity of a chromosomal translocation, and (5) a dominant negative effect of a fusion protein resulting from transcriptional repression mediated by wild-type ETV6 [ETV6–RUNX1 fusion protein is present in 25% of pediatric patients with B-cell precursor acute lymphoblastic leukemia [LPXN was reported to be a fusion partner gene at exon 2 with exon 6 in ETV6 in relapsed acute myeloid leukemia (AML), and it played a crucial role in the enhanced proliferation response of the 32D myeloid cell line to granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine 12 (CXCL12) [In hematological malignancies, translocation at chromosome 12p13 is most commonly observed and involves cterized . There aype ETV6 . The ETVleukemia , and thileukemia ,150 and leukemia . LPXN wa(CXCL12) .TMPRSS2) and ETS occurred in more than 50% of patients [TMPRSS2 region (21q22.2) with ETS members, ERG at 21q22.2 and ETV1 at 7q21.2 [ETV4 [ETV6 and TMPRSS2 in PCa has not been reported. Frequent deletions and mutations of ETV6 in advanced and metastatic PCa were observed [In PCa, a number of reports demonstrated that gene fusion between transmembrane protease serine 2  signaling-mediated increase in miR-96 expression contributed to PCa development based on in vitro and in vivo analyses [ETV6 expression was negatively associated with TWIST1. Furthermore, the researchers identified one ETV6 response element that was sequence-specific for the TWIST1 promoter, suggesting the inhibition of EMT activation by repression of TWIST1’s transcriptional activity. In addition, disruption of ETV6 promotes EGFR-tyrosine kinase inhibitor (TKI) resistance through perturbation of the ETV6–TWIST1 axis by derepression of both TWIST1 and EGFR–RAS signaling in an animal model [In PCa, mutational analysis of sor gene . Tsai etanalyses . A more al model .miR-96 induction and ETV6 inactivation, resulting in activation of TWIST1-stimulated metastatic phenotypes. Those studies proposed a novel function for ETV6, in which it acted as a central regulatory axis that connected EGFR signaling activation, and it may act as a potential marker for predicting single-agent therapy using EGFR-based anticancer therapy (These data support the hypothesis that prostatic metastasis involves EGFR signaling-mediated  therapy .Although new biomarkers for PCa screening and diagnosis continue to be identified, current efforts should be focused on tracing the line between the early stage of primary PCa through metastatic CRPC, which occurs in 50% of PCa patients and remains incurable and lethal. Recently, several proposed mechanisms at the molecular level were revealed that suggested targeting both AR signaling by known ADT and suppressing downstream targets, which were shown to be responsible for activation of the EMT or metastatic CRPC after ADT. Previously, AR overexpression and AR mutations were identified as the main mechanisms for resistance to AR therapies. Most PCa cells express the wild-type AR gene, and AR mutations frequently occur in the late stage of PCa. One of the mechanisms for the failure of ADT is the presence of mutations in the AR that enhance AR’s activity in response to antiandrogen drugs. Also, these mutations can enhance AR’s transactivation and exert resistance to drugs such as the F876L point mutation to enzalutamide. Furthermore, an AR coactivator may activate the wild-type or mutant AR in response to adrenal androgen, which can progress to CRPC.ETV6 mutations and chromosomal abnormalities [ETV6 gene at the mRNA or protein level are recommended using blood samples or by taking tissue biopsies for IHC staining. However, analyzing translocations of the ETV6 gene in PCa by karyotyping has not been reported. In earlier stages of PCa, patients may still have a wild-type form of ETV6 and drug sensitivity to TKIs. Therefore, earlier screening for ETV6 is highly recommended.In hematological malignancies, molecular cytogenetics or DNA sequencing of blood or bone marrow samples are often used in the clinic to investigate malities ,163. HowSPDEF or ZBTB46 genes in blood samples or their protein expressions using biopsies from PCa patients by IHC staining could help in tracking the progression of PCa from primary to CRPC or monitoring the efficiency of treatment with ADT.Furthermore, measuring the mRNA levels of the Nowadays, several potential targets for patients with CRPC—like the AR-NTD inhibitor, EPI-002; the oral PARP inhibitor, olaparib; and the PI3K/mTOR inhibitor, BEZ235—have provided improvements in clinical outcomes. However, most patients still progress to an incurable stage. Understanding the AR oncogenic networks may provide a new strategy for diagnosis or therapeutic targets of primary and CRPC, which could improve PCa management and reduce high levels of morbidity and mortality. Inhibition of the AR by manipulating the ligand could provide additive therapeutic benefits. Modulation of intracellular pathways, such as kinases or nonkinases, with the ablation of androgen may improve clinical outcomes and delay PCa development.While the mechanism of CRPC is still under investigation, one of the main drivers is the AR signaling pathway. There is a big challenge to identify suitable therapies for those patients with multiple aberrant AR signaling. In addition to patients with several point mutations or AR variants, coactivators that also play important roles in AR activity could be targeted. Accumulating evidence suggests that combinatorial therapies are recommended to overcome this disease.


Using technology in stroke rehabilitation is attractive. Devices such as robots or smartphones can help deliver evidence-based levels of practice intensity and automated feedback without additional labor costs. Currently, however, few technologies have been adopted into everyday rehabilitation.This project aimed to identify stakeholder  priorities for stroke rehabilitation technologies and to generate user-centered solutions for enhancing everyday adoption.We invited stakeholders (n=60), comprising stroke survivors , therapists , caregivers, and technology developers , to attend 2 facilitated workshops. Workshop 1 was preceded by a national survey of stroke survivors and therapists (n=177) to generate an initial list of priorities. The subsequent workshop focused on identifying practical solutions to enhance adoption.A total of 25 priorities were generated from the survey; these were reduced to 10 nonranked priorities through discussion, consensus activities, and voting at Workshop 1: access to technologies, ease of use, awareness of available technologies, technologies focused on function, supports self-management, user training, evidence of effectiveness, value for money, knowledgeable staff, and performance feedback. The second workshop provided recommendations for improving the adoption of technologies in stroke rehabilitation: an annual exhibition of commercially available and developing technologies, an online consumer-rating website of available technologies, and a user network to inspire and test new technologies.The key outcomes from this series of stakeholder workshops provides a starting point for an integrated approach to promoting greater adoption of technologies in stroke rehabilitation. Bringing technology developers and users together to shape future and evaluate current technologies is critical to achieving evidence-based stroke rehabilitation. Stroke has been a priority for the National Health Service (NHS) in Scotland for the last 15 years. In that time, there has been a 21% decrease in incidence and a 41% improvement in survival rates .There is good evidence that rehabilitation can improve recovery from stroke . The recIn response to this need, technology has been used to increase rehabilitation practice intensity ,7, enhanA perceived mismatch between research and patient priorities for life after stroke motivated a Priority Setting Partnership (PSP) that produced a list of agreed priorities for future research  that hasOur aim was to identify stakeholder priorities for stroke rehabilitation technologies using an adapted version of the James Lind Alliance approach to priority setting  and thenThe objectives were (1) to gather stakeholder priorities for the development of technologies in stroke rehabilitation, (2) to produce a top 10 list of priorities through a process of consensus across stakeholders, and (3) to generate new ideas from stakeholders on ways to improve the adoption of technology in stroke rehabilitation.To achieve our aim, we planned a consensus-building process that emulated the James Lind PSP . This coSurveys were sent to stroke survivors, caregivers, and rehabilitation professionals working in stroke to generate a long list of priorities from the broad community. These surveys were distributed electronically and manually through professional  and patient support networks (CHSS) to reach as broad a population as possible. As the survey was designed with the single purpose of generating a long list of priorities, only 6 questions were posed. These included background information on the use of rehabilitation technologies and a request to state their perceived priorities for stroke rehabilitation technologies. A copy of the survey can be found in Workshop 1 was located at a neutral , city center venue with good public transport links and disabled access. The workshop lasted 7 hours with breaks for lunch and refreshments. Sixty delegates representing the three stakeholder groups  attended the workshop. Delegates were recruited through general invitations sent out to members of the Scottish Allied Health Professions Forum (therapists), CHSS patient networks (patients and caregivers), and individuals known to the committee as being active and experienced in this area . The final delegate list was agreed upon by the organizing committee to ensure an even proportion from each group. Delegates were placed at 7 tables so that each table had at least 2 individuals from each of the stakeholder groups and a facilitator. Facilitators experienced in working with stroke survivors and therapists were supplied by CHSS.The workshop included presentations of different models of rehabilitation provision including community therapy delivered according to the current NHS model, private rehabilitation delivered in the patient’s home, and a third sector (charitable organization) service based around a gym and activity center, which made use of technologies such as virtual reality. There were also short demonstrations of rehabilitation technologies designed for mobility and communication impairments. These presentations and demonstrations were intended to help participants engage with the subject matter and were arranged by the organizing committee. After these presentations, the long list of priorities (n=25) generated by the survey were graphically presented to the group and placed as individual pieces of paper, in no particular order, on each table. The short-listing process consisted of each table reducing their list from 25 to 15 priorities through consensus discussions, which they subsequently presented and justified to the whole group for broader discussion.A final selection of 10 priorities was then agreed through discussion by the whole group with a consensus on the inclusion of each priority reached by voting (raising a colored card for yes and no).The following priorities were agreed at the end of the workshop. A short description is appended to each priority because the group felt that these clarifications were important to avoid ambiguity. They were initially ranked (based on the group vote) in the order set below. However, the workshop delegates requested the list should not be ranked, as the level of priority may differ according to the context and role of the individual, but they were happy that these were the 10 most important priorities. To encapsulate this lack of hierarchy, the final list was expressed as a circle .The priorities for rehabilitation technology were as follows:Access to equipment: This referred to users being able to access specific pieces of equipment without too much trouble and being able to use them within NHS facilities. The latter was particularly relevant to healthcare professionals using software apps that were blocked by NHS IT systems.Ease of use: Although considered largely self-explanatory, there was a specific desire for devices to be operable with one hand and for all devices to be easy to use by all end users .Awareness: This referred to the awareness of what technologies were actually available to the users in their local area as well as how they could access them.Functional: Workshop delegates felt that any technology should be clearly focused on improving functional outcomes .Supported self-management: This was a priority identified as overlapping with other priorities , but the consensus was that it should have its own position on the list. Technologies should, therefore, be designed with the ambition that they can be used to assist the user to manage their own condition by enabling them to practice rehabilitation activities.Training: For all end users, training should available in accessible formats.Evidence of effectiveness: This was widely debated as it was felt that definitive proof is unlikely to be achieved for technologies in the near future. The group felt that while a lack of research evidence on efficacy should not pose a barrier to a technology being adopted, the stakeholder community  should work together to provide this evidence. Initially, this may be collated experiential evidence but should progress toward definitive evidence suitable for inclusion in practice guidelines.Value for money: This term was originally described as “cost” but was altered so that the benefit of the technology, at both individual and societal levels, was considered relative to its monetary cost.Knowledgeable staff: Stroke survivor end users felt that a technology was more likely to be used and be effective if their healthcare professional was knowledgeable  in its use.Feedback: Where possible, technologies should provide information on general rehabilitation progress to users (therapists and patients) as well as detailed information on the performance of the specific activity. It was recognized that this was not always possible, for example, when using resistance bands. This information should be presented in an accessible format that takes into consideration the potential visual, cognitive, and communication impairments that people with stroke may be dealing with and should be available to healthcare professionals, provided this was agreed.The second workshop took place in a neighboring city to broaden the stakeholder representation. Delegates (n=60) were recruited in the same manner as Workshop 1, with the organizing committee again deciding on the final delegate list to ensure an even distribution across the three stakeholder groups . It is worth noting that 40 of the delegates attended Workshop 1. This was a deliberate decision to maintain some consistency. The aim of this workshop was to develop practical ideas for improving technology adoption considering the outcomes from the first workshop. To facilitate discussion, innovative rehabilitation practices (both models and use of technologies) were presented by local (Scotland and United Kingdom) and international  speakers. The structure of the workshop, including presentation topics and speakers, was agreed by the organizing committee.Following these presentations, delegates were organized into 7 tables of approximately 8 individuals with a mix of backgrounds (as per Workshop 1) to discuss the following question: “What practical steps could be taken to progress the aim of improving adoption of stroke rehabilitation technologies?”The discussions from each table were summarized by a facilitator and presented to the whole group for further discussion. This process continued until clear outcomes, with consensus from the whole group, emerged. An agreement was finally reached on three practical steps to promote greater adoption of technologies in stroke rehabilitation: (1) an annual exhibition of rehabilitation technologies for all stakeholders, (2) formation of a network consisting of users, technology developers, and policymakers with the ambition of creating a road map for rehabilitation technologies, and (3) development of a consumer rater website inspired by websites such as TripAdvisor with the objectives of enhancing awareness of rehabilitation technologies, providing clear access to available research findings on the efficacy of these technologies, and allowing consumers to rate technologies on key attributes such as ease of use, value for money, and provision of feedback.By providing the means to increase engagement with rehabilitation, technology has been shown to improve outcomes after stroke . DespiteThe 10 priorities identified by users through our survey and consensus workshops were similar to those reported by Hughes et al  and the The use of facilitated workshops to develop a consensus among stakeholders was the strength of our approach since it provided the opportunity for broad face-to-face discussions among individuals with real and often contrasting experiences of using rehabilitation technologies. This open discourse was deemed necessary to reveal the range of factors involved and has been used successfully in similar priority setting exercises . FurtherThe limitations of our study are similar to other approaches that depend on engagement with users, namely that the users responding to the survey and attending the workshops may not be typical of the entire user group in that they are likely to have a pre-existing interest in the area. Furthermore, there may be some social desirability bias, particularly from arranging therapists and patients around the same table .A series of workshops and surveys focusing on the adoption of technologies in stroke rehabilitation identified 10 key priorities by users . To improve adoption, practical steps including organization of an annual rehabilitation technology exhibition, formation of a network consisting of users, technology developers, and policymakers, and development of a consumer rater website were recommended.


The pharmaceutical management of allergic rhinitis rests on symptomatic treatment with antihistamines that perhaps are more effectively administered intranasally than orally and intranasal corticosteroids. Allergen immunotherapy is very effective, even for local allergic rhinitis, and the shortcomings of subcutaneous immunotherapy of inconvenience and safety are reduced by the introduction of sublingual immunotherapy (SLIT). Use of the latter is currently somewhat limited by the lack of appropriate dosing information for SLIT liquids and the limited number of allergens for which SLIT tablets are available.Allergic rhinitis affects 20 to 30% of adults in both the United States and Europe and perhaps a somewhat higher percentage of children. In addition to nasal and ocular symptoms directly related to the allergic process, interference of these symptoms with sleep leads to daytime sleepiness and impaired quality of life. Patients miss work because of symptoms but an even greater problem is interference with work productivity, or presenteeism, which has been reported to be the biggest contributor to the total economic cost of allergic rhinitis. There has been increasing awareness that many patients with either seasonal or perennial symptoms but negative skin and Symptoms can have significant negative impact on the patients’ quality of life, often interfere with sleep, and contribute to poor performance at work and school. In approaching the patient with rhinitis symptoms, clinicians must distinguish AR from non-AR (NAR) and nasal symptoms due to mechanical factors but not miss the presence of local nasal allergy. Treatment for more severe disease should employ anti-inflammatory as well as symptomatic medication, and allergy immunotherapy (AIT) should be strongly considered for not only its effectiveness but also its disease-modifying effects. The main challenges in AR relate to its treatment. Symptomatic and topical anti-inflammatory medication is often not fully effective, and AIT can be inconvenient and expensive, and there is much room for improvement in both forms of treatment.Allergic rhinitis (AR) is a common condition. Estimates of its prevalence vary widely but good epidemiologic studies suggest that 20 to 30% of adults and up to 40% of children are affected2. Of 19,678 adult responders, 44.3% reported nasal symptoms on at least seven days per year, 30.2% attributed these symptoms to allergies, and 20.7% reported a physician diagnosis of nasal allergies. In 2001, a two-step survey was conducted in Belgium, France, Germany, Italy, Spain, and the UK3. A questionnaire was administered by telephone to 9646 adults to determine the presence of a diagnosis of or symptoms suggestive of AR. Self-awareness of AR was reported by 19%, and 13% reported a physician diagnosis of AR. All of those with positive responses were invited to a clinical center for definitive diagnosis and 725 were examined. On clinical examination, 411 out of 725 were diagnosed as having AR; 45% of these 411 had not received a previous physician diagnosis. This led to estimates of clinically confirmable AR varying from 17% in Italy to 29% in Belgium and overall 23% for the European population studied. The incidence and prevalence of AR in the children were studied in an Isle of Wight birth cohort (n = 1456) recruited in 19894. Prevalence of AR increased from 3.4% at 4 years of age to 27.3% at 18 years and was more common in boys than girls at that age.In 2004, a mail survey in the US elicited responses from two thirds contacted5. At the peak of their or their child’s allergy season, 39% rated nasal congestion and 34% red itchy eyes as “extremely bothersome” whereas 29% said daily life was “impaired a lot”5.In a telephone survey of 2765 adults and children (at least five years old) with a diagnosis of nasal or ocular allergies or both, 78% reported seasonal symptoms, and the peak was during the tree season (March to May) and a lesser peak occurred in the fall weed season (September)6. In a survey of 100 patients who had moderate/severe AR, sleep disturbances were reported by 66% of adults and 43% of children7. Patients with moderate/severe AR, compared with those with mild disease, had significantly more anxiety, depression, fatigue, trouble with social interactions, and perceived signs of cognitive dysfunction7. The disturbances of sleep extend to parents of children with AR, 75% of whom reported poor-quality sleep8.The symptoms of AR interfere with the ability to sleep, leading to daytime sleepiness and impaired quality of life9. Pooled analysis of studies in which the validated Work Productivity and Activity Impairment (WPAI) questionnaire had been used to collect data found an estimated 3.6% of missed work time (absenteeism) and 35.9% of work performance impairment (presenteeism) due to AR. The cost of absenteeism and presenteeism was estimated to be 3.2- to 13.5-fold higher than direct medical costs and to represent 76 to 93% of the total costs of AR9. School performance is also affected by AR. In a case control study in the UK, students who were 15 to 17 years of age and currently symptomatic with AR were significantly more apt to have lower examination scores in the summer compared with the winter10. The cost of AR was assessed in a representative sample of the Swedish population (18 to 65 years of age) in a report published in 201611. The mean annual direct and indirect costs because of AR were 210 Euros and 750.8 Euros, respectively. Of the total cost, 8.1% was due to absenteeism and 70.0% was due to presenteeism. The remainder was equally divided between pharmaceutical and health-care costs11. The cost for the European Union countries for absenteeism and presenteeism caused by AR in untreated or inadequately treated individuals has been estimated at 55 to 151 million Euros per year12.A Medline search retrieved original studies from 2005 to 2015 on the impact of AR on work productivity15. Increasing temperature and carbon dioxide exposure have been shown to increase the production of pollen from individual plants13. At the same time, the increase in the number of frost-free days and the later occurrence of the first frost have been shown to correlate with longer ragweed pollen seasons and are predicted to allow ragweed to propagate further north14. This is of special concern in Europe, where ragweed is established in the Rhone Valley/Burgundy in France, northern Italy, Hungary, and surrounding countries15. Thus, with favorable climatic conditions, it is poised to extend into Poland, Germany, and northern France15.The potential effect of climate change on the severity and extent of AR has been examined, most intensively in the case of ragweed pollen16.The first step in rhinitis management is determining the type(s) of rhinitis that an individual has and this can be complicated given the various phenotypes and endotypes of rhinitis. A phenotype is defined by clinical presentation, whereas an endotype is defined by underlying pathophysiologic mechanism. AR is generally differentiated from NAR by the presence of positive allergy skin testing or serum-specific IgE testing. As discussed below, there has been an increasing interest recently in local AR (LAR), which is generally diagnosed in individuals with negative serum and skin allergy tests but histories suggestive of AR, through a positive nasal allergen challenge or the identification of specific IgE (sIgE) in nasal secretions or both17. Nasal symptoms can also occur as a result of structural or mechanical issues, such as choanal atresia, adenoidal hypertrophy, septal deviation, nasal tumors, or cerebrospinal fluid leaks, as well as systemic conditions, such as cystic fibrosis, primary ciliary dyskinesia, eosinophilic granulomatosis and polyangiitis, sarcoidosis, and amyloidosis. Occupational rhinitis, which can be either allergic or non-allergic, has many causative agents and can present either shortly after starting an occupation with a new antigenic exposure or following a latency period, when an individual is developing sensitization to the new antigen. Oftentimes, patients have more than one type of rhinitis, leading to a mixed phenotype or endotype or both18.NAR has many subtypes, including infectious, drug-induced, gustatory, hormone-induced, atrophic, senile, and idiopathic rhinitis (IR)19. Young children with NAR are more likely to go into remission than their AR counterparts. In a birth cohort of over 2000 children, 73% of NAR subjects and only 12% of AR subjects went into remission between ages 4 and 8. The proportion of children with NAR decreased slightly from age 4 (8%) to age 8 (6%), whereas AR rates increased between these ages from 5% to 14%. Sensitization often precedes AR as over half of those who were sensitized but asymptomatic at age 4 developed AR by age 819. In a questionnaire-based study of adults who were 20 to 59 years old, about 23% of cases demonstrated remission of their AR symptoms within an eight-year period from 1992 to 2000, and the highest rate of remission was in the oldest age group (50 to 59 years) and the lowest rate of remission was in those with concomitant asthma. The highest incidence of new-onset AR was seen in the youngest age group (20 to 29 years)20.The natural history of AR seems to be different from that of NAR21. They defined intermittent AR as affecting patients less than four days a week or less than four consecutive weeks, whereas symptoms in persistent AR lasted more than four days a week or more than four consecutive weeks21. Since their initial publication, these guidelines have been updated and refined multiple times24.ARIA (Allergic Rhinitis and its Impact on Asthma), the World Health Organization initiative on AR, published guidelines in 2001 that shifted the paradigm from classifying AR as either seasonal AR (SAR) or perennial AR (PAR) to a classification based on frequency  and severity 3. Another study, by Ciprandiet al., demonstrated that 80% of patients with AR have a mixed form of SAR and PAR, suggesting to the authors that the terms PAR and SAR are poorly reflective of real life and that intermittent and persistent may be more applicable25.Based on a study from Western Europe in which telephone interviews were performed on 9646 individuals, 726 of whom came to the clinical center for an evaluation, the investigators found a poor correlation between the seasonal/perennial terms and the intermittent/persistent classifications, respectively, and about half of the persistent subjects had SAR and half of the intermittent subjects had PARIn the last decade and a half, there has been increasing interest  in LAR, a term applied to patients whose allergy skin and blood testing is negative but who have a history suggestive of allergic sensitization and local evidence of atopy diagnosed by sIgE in nasal secretions or by positive nasal allergen challenge or both.et al. found a similar nasal leukocyte-lymphocyte phenotype in the nasal lavage of PAR and PNAR patients, both of which differed from normal controls, who tended to have fewer eosinophils, total lymphocytes, and CD3+CD4+ lymphocytes26. A positive nasal challenge withDermatophagoides pteronyssinus (D. pt.) was present in 54% of the patients with PNAR, and sIgE was identified in 22% of these individuals26. In another study, in which 40 patients with LAR due to D. pt. underwent nasal challenge with D. pt., 60% had isolated and 40% had dual positive responses27. Tryptase was present in the nasal secretions of 45%, elevated eosinophil chemotactic factor in 65%, and D. pt.–specific IgE in 25%. LAR to pollens has also been demonstrated by this group in a similar study comparing individuals with seasonal IR with those with pollen-induced AR. This study found similar nasal leukocyte-lymphocyte profiles in both sets of rhinitis patients, which were different from that of controls. Of the subjects with IR, 62.5% had a positive nasal allergen provocation test (NAPT) and 35% demonstrated nasal sIgE28. Rondón,et al. also have investigated multiple NAPT (NAPT-M), in which four different allergen extracts are administered at 15-minute intervals, and have demonstrated 100% concordance with single-aeroallergen NAPTs, suggesting that this may be an efficient and cost-effective way to detect polysensitization in patients with LAR29.In a study of 50 patients with perennial NAR (PNAR), 30 with PAR, and 30 healthy controls, Rondón30. A study evaluating LAR to house dust mites (HDMs), specifically evaluating a pediatric population with NAR (mean age of 11 years and median disease duration of 6.3 years), used nasal tryptase, symptoms, physiologic measures , and local production of HDM-sIgE and demonstrated that LAR to HDM is rare in children. Only two (3.7%) of the 54 children showed significant change in symptoms and physiologic measures following HDM-NAPT31. In contrast, a study by Bozeket al. looking at an elderly population  with undiagnosed persistent rhinitis demonstrated a rate of LAR of 21%, and D. pt. was the main sensitizing aeroallergen in those with LAR (63%)32. In this study, symptom changes during NAPT were accompanied by an increase in nasal sIgE. The large, questionnaire-based studies conducted to determine the prevalence of AR in the general population could not assess the prevalence of LAR since nasal allergen challenges were not part of the protocol3.A study to determine the prevalence of LAR in a Spanish population evaluated 452 unselected adult patients with rhinitis by means of skin-prick tests, sIgE, and NAPT; they diagnosed LAR in 25.7%, AR in 63.1%, and NAR in 11.2%33. At 10 years, the rate of development of systemic atopy was similar in the LAR patients and controls . This indicates that LAR is usually a persistent condition and not a precursor to AR. The patients with LAR in this study demonstrated a significant worsening of their rhinitis over time and this was clinically relevant and associated with development of asthma34. Treatment of LAR with immunotherapy is discussed in the section on immunotherapy, below.A five-year follow-up study in 194 patients with LAR demonstrated worsening in 26.3% of the patients, and the development of atopy at five years was detected by skin-prick test or sIgE (or both) in 6.81% of LAR and 4.5% of normal control patientsManagement of AR continues to revolve around allergen avoidance, medications that provide symptomatic relief, anti-inflammatory therapies, and AIT. Recent advances in therapy include intranasal antihistamines and novel methods of delivery for intranasal steroids, which continue to be the mainstay of therapy for AR and now can be found over-the-counter in the US for some formulations.36, have broadened the landscape of intranasal medications for the treatment of AR. They have been shown to improve the total nasal symptom score (TNSS) as well as each individual nasal symptom score (INSS) for sneezing, rhinorrhea, nasal congestion, and nasal itching with faster onset and similar efficacy when compared with intranasal steroids37. Intranasal antihistamines also have a faster onset than oral antihistamines and can improve all INSSs to a similar degree, except for nasal congestion, which is better controlled by nasal compared with oral antihistamines38.Intranasal antihistamines, introduced in the US in 200039; a mist formulation of fluticasone furoate, approved by the US Food and Drug Administration (FDA) in 200740; and aerosol devices using hydrofluoroalkane (HFA) propellant to deliver beclomethasone41 and ciclesonide42, both approved by the FDA in 2012. The newest delivery mechanism for intranasal therapy is an exhalation-activated device, which currently (2017) is approved only for the delivery of fluticasone propionate to treat nasal polyps43 but which eventually might be approved for the treatment of AR.Novel delivery methods of intranasal steroids include a nasal preparation of ciclesonide, a steroid pro-drug that is converted to its active form only upon tissue delivery, introduced in aqueous form in the US in 200644. Aggregate data from 3398 subjects in three multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group trials demonstrated a faster onset and superior efficacy as compared with each of the individual components. The onset of action was 30 minutes, and clinical improvement was observed during the first day of assessment and there was sustained benefit for the entire two-week study period45. An updated consensus treatment algorithm proposes an approach to treatment that is in keeping with the ARIA guidelines and highlights a more prominent role for nasal antihistamines46.In 2012, a combination spray containing both fluticasone propionate and azelastine hydrochloride was approved by the FDA50. Several review articles have been published on the topic of CAM and its role in treating allergic disease, including AR53. The consensus among these articles is that although CAM is considered to be low-risk and to have potential benefit, additional studies are needed to fully evaluate the efficacy and potential long-term benefit of these therapies53.Although there has been a recent increase in interest among the general population regarding complementary and alternative medicine (CAM) approaches, including acupuncture, traditional Chinese medicine, and homeopathy, there is a paucity of randomized controlled studies evaluating these approaches. Acupuncture has the greatest amount of data and shows promise in smaller randomized studies54. They identified 17 SRs published through the end of October 2015. These SRs suggested that, in carefully selected patients, SCIT and SLIT resulted in significant reductions in symptom scores and medication requirements for ARC with reassuring safety data. The data could not support conclusions on the relative clinical effectiveness or the cost-effectiveness of the two approaches to AIT.A number of systematic reviews (SRs) of subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT) (or both) for AR have been conducted. A committee of the European Academy of Allergy and Clinical Immunology critically assessed these SRs for evidence of the effectiveness, safety, and cost-effectiveness of AIT for allergic rhinoconjunctivitis (ARC)Dermatophagoides farinae) extracts. The doses of the five tablets chosen for commercial development, expressed as the content of major allergen, are listed in59. In the case of ragweed and HDMs, there were also studies that suggested that doses higher than those eventually approved carried safety concerns61.The major recent development in AIT in the US for ARC has been the introduction of SLIT tablets containing Timothy grass, a five-grass mixture, short ragweed, or HDM (D. pt. and64. The use of epinephrine to treat SLIT tablet-related adverse events (TRAEs) was reported for 29 studies conducted for the registration of the ALK Timothy, short ragweed, and HDM SLIT tablets65. Epinephrine was administered to treat 16 TRAEs: six systemic and 10 local application site reactions. Of the six systemic reactions, none were considered serious, five occurred with the first administration under physician observation, and one occurred on the sixth day of treatment. The occurrence of adverse reactions to short ragweed SLIT tablet was tabulated for the first 28 days of four safety or efficacy studies (or both) conducted for registration of the product66. Local application site reactions were common but usually mild-moderate, of brief duration, and occurring mostly in the first week or two of treatment.The safety data in these phase III studies of SLIT tablets have been reassuring, and no fatal or life-threatening adverse reactions have been reported67 and the five-grass68 SLIT tablets, in which treatment administered either continuously67 or pre- and co-seasonally68 was continued for three years, and the subjects were followed for two years after cessation of treatment to determine whether there was persisting benefit. With the Timothy tablet, there was 36% improvement compared to placebo in the symptom/medication score during the third year of treatment and persisting improvement of 34% and 27% the two follow-up years67. With the five-grass SLIT tablet, the improvement in the symptom/medication score during the third year of treatment was 39%, and that the two follow-up years was 30% and 28%68. Both results suggest that there has been modification of the underlying immunologic process by the immunotherapy. On the other hand, a study with the same dose of Timothy SLIT tablet, administered daily but for only two years, produced a clinical response that was lost one year after treatment discontinuation, suggesting that treatment of at least three years was required to produce persisting improvement69.Five-year studies were conducted with both the Timothy70. In the 812 children, three years of treatment produced persisting improvement in clinical AR during two years of follow-up. More importantly, the development of both summertime and wintertime asthma was significantly reduced in the group that had received the Timothy SLIT tablets when compared with those who had received placebo treatment  and NAPT after one year showed markedly increased tolerance for D. pt. allergen77. The same group also conducted a two-year trial of SCIT with a Timothy grass allergoid extract in 56 LAR subjects with positive NAPT to Timothy78. In the first grass pollen season, after about six months of SCIT, combined symptom medication scores were reduced 54%. The efficacy of SCIT in pollen-induced LAR was also demonstrated in a two-year study in 28 subjects with birch sensitivity79. The efficacy of SLIT in patients with LAR has not been reported.AIT has also been used in patients with LAR (see section on LAR above). Thirty-six subjects with perennial symptoms and positive NAPTs to D. pt. received SCIT with D. pt. extract. At the end of 24 months, daily combined symptom/medication scores were reduced 42% compared with placebo (80. There also is a need for new approaches to AIT that overcome the factors of safety and inconvenience with SCIT but also the limited number of allergens with established dosing with SLIT. Both of these forms of AIT involve several years of treatment to produce lasting results and in many patients this leads to poor adherence with the treatment program81. Forms of AIT that require far fewer treatments over shorter periods of time are sorely needed.There is no question that AR is a very common and often very burdensome disease. It can be classified as seasonal or perennial, which has the attraction of directing attention to the relevant aeroallergen, or as intermittent and persistent and mild or moderate/severe that reflects more the burden of the disease on the patient. It is important not to confuse NAR with AR but also not to miss LAR if indeed it is as common as reports indicate. There is a need for more effective forms of symptomatic therapyDermatophagoides pteronyssinus; FDA, US Food and Drug Administration; HDM, house dust mite; INSS, individual nasal symptom score; IR, idiopathic rhinitis; LAR, local allergic rhinitis; NAPT, nasal allergen provocation test; NAR, non-allergic rhinitis; PAR, perennial allergic rhinitis; PNAR, perennial non-allergic rhinitis; SAR, seasonal allergic rhinitis; SCIT, subcutaneous immunotherapy; sIgE, specific IgE; SLIT, sublingual immunotherapy; SR, systematic review; TRAE, treatment-related adverse eventAIT, allergy immunotherapy; AR, allergic rhinitis; ARC, allergic rhinoconjunctivitis; ARIA, Allergic Rhinitis and its Impact on Asthma; CAM, complementary and alternative medicine; D. pt.,


Walking aids are widely used by older adults, however, alarmingly, their use has been linked to increased falls-risk, yet clinicians have no objective way of assessing user stability. This work aims to demonstrate the application of a novel methodology to investigate how the type of walking task, the amount of body weight supported by the device , and task performance strategy affect stability of rollator users. In this context, ten users performed six walking tasks with an instrumented rollator. The combined stability margin “SM” was calculated, which considers user and rollator as a combined system. A Friedman Test was used to investigate the effects of task on SM and a least-squares regression model was applied to investigate the relationship between device loading and SM. In addition, the effects of task performance strategy on SM were explored. As a result, it was found that: the minimum SM for straight line walking was higher than for more complex tasks (p<0.05); an increase in device loading was associated with an increase in SM (p<0.05); stepping up a kerb with at least 1 rollator wheel in ground contact at all times resulted in higher SM than lifting all four wheels simultaneously. Hence, we conclude that training should not be limited to straight line walking but should include various everyday tasks. Within person, SM informs on which tasks need practicing, and which strategy facilitates stability, thereby enabling person-specific guidance/training. The relevance of this work lies in an increase in walking aid users, and the costs arising from fall-related injuries. Falls and fall-related injuries among older people are a major health problem; around 40% of the over 65s living at home are estimated to fall at least once a year, with around one in forty of the falls leading to hospitalisation . The incRegarding the circumstances of falls, ‘walking’ has been reported as the activity during which 48% of community-dwelling residents came to fall . WalkingNevertheless, a vast number of clinical and manufacturer leaflets exist that aim to provide straight-forward instructions to users of walking aids. Guidance is generally brief, with varying levels of detail between clinical trusts and/or manufacturers. Basic instructions appear sensible, however, they fail to address everyday tasks such as turning in confined spaces, opening doors, and negotiating obstacles and changes in flooring level, some of which have previously been reported to be problematic . MoreoveSystem), is calculated using force measurements taken from each of the walking aid legs and the user’s shoes, together with the position of the anatomical feet relative to the walking aid. The smaller the SM, the closer the system is to the point of tipping over, and the more susceptible it is to perturbations. To measure the required forces for calculation of SM, we initially instrumented a walking frame without wheels  with load cells, which together with pressure sensing insoles and optical motion tracking allow for calculation of SM. Our approach is novel in that it considers the person and their walking aid to be a single system. We proved that combining information of walking aid and person is vital to accurately evaluate overall stability [In this context, we recently developed a novel, objective measure of the stability of walking aid users . The meatability , and ourtability . Interestability , with astability .Our approach, which provides an objective measure of stability, has the potential to support current clinical practice through evidence-based training. In the work reported here, we adapted our approach for use with a 4-wheeled rollator frame and, in a cohort of 10 in-patients in a geriatric ward, assessed stability across a range of everyday tasks. The objectives were:Hypothesis: Stability is greatest for straight line walking as compared to more complex tasks such as turning or obstacle crossing.Investigate the effects of the task being undertaken on stability. Hypothesis: Increased leaning onto the rollator causes the centre of pressure of the system to move forward into the base of support, thereby increasing stability.Investigate the relationship between device loading (i.e. the amount of body weight supported by the rollator) and stability. Hypothesis: the strategy employed for performance of a single task may either facilitate or impede stability.Investigate the effects of rollator use strategy on stability: System) of user and device from wheel-force, insole-pressure, and position data using bespoke Matlab algorithms. SMSystem is defined as the shortest distance between the Centre of Pressure of the combined system (CoPSystem) and the nearest edge of the combined Base of Support (BoSSystem) . It seems reasonable to think that when BoSSystem is smaller, SMSystem is also likely to be smaller; but this should not be confused with an unsafe gait as BoSSystem may well be being sensibly utilised. For this reason, SMSystem has been normalised by a parameter representative of the size of BoSSystem   and indioSSystem .System (referred to simply as SM in this work) is dimensionless as it is the ratio of two lengths.The normalised SMFinally, to further characterise rollator use, we also present the movement pattern (foot placements in relation to rollator movements), and device loading (DL), defined as the percentage of body weight transferred to the device through the user’s upper limbs.For the purpose of this study, the technology of our original instrumented pick-up walker  was adapSystem as derived from the load cell and insole data was tested by placing the device onto a force plate (600 × 900 mm AMTI BP600900) and asking a user to step onto the same force plate while holding the rollator. Subsequently, CoPSystem was calculated from “gold standard” force plate data and compared to CoPSystem as calculated from instrumented rollator data. Results of this accuracy evaluation are shown in The accuracy of CoPTen rollator users aged 84.2 ± 5 years were recruited from the Geriatric Rehabilitation Clinic of the Robert-Bosch-Hospital Stuttgart, Germany. Inclusion criteria were: 1) age 65 years or older, 2) able to walk household distances with a rollator, but not able to walk such distances unaided. Exclusion criteria were: 1) history of head injury or concussion, 2) visual disorders not correctable by glasses, 3) diagnosed peripheral or central nerve dysfunction, 4) terminal disease, 5) inability to follow verbal instructions. Of the 10 participants, 8 were women, and 5 had a previous fall-related history of lower limb fracture. Moreover, 4 participants were new users, 2 participants had had their rollator for less than 6 months, and the remaining 4 participants were experienced users (had used the rollator for more than 6 months). Additional descriptive parameters are presented in The experiments took place in the gait laboratory of the Robert-Bosch-Hospital in Stuttgart, Germany. All participants performed 6 tasks with the instrumented rollator representative of activities of daily living: straight line walk (5 m); 90° turn; 180° turn; obstacle crossing ; backwards walk (2.5 m) as if to open a door; and negotiating a 50mm step up. Participants performed each task twice at their self-selected speed. As it was expected that some participants might experience fatigue during the assessment, the order in which tasks 2–6 were performed was rotated.To test whether the task has an effect on stability and, if so, which tasks are more or less challenging to the user’s stability, the minimum SM for each task (which corresponds to the instant during the whole task in which the user was the least stable) was compared to the minimum SM of all other tasks including straight line walking. For this, a Friedman test, which is robust to non-normality, followed by post-hoc one-sided Wilcoxon Signed-Rank Tests was run in R  to analyThe relationship between SM and DL was investigated with a least-squares regression for each participant and for each task using a purpose-written FORTRAN program:th participant, j = 1,2,…, 6 the jth task, and α and β are, respectively, the intercept and slope of the model.Where i = 1,2,…,10 indicates the iij and ΔDLij, and then, since ΔSMij and ΔDLij showed very low autocorrelation (<0.1), the least-squares regression without intercept was calculated (ΔijSM = ijβΔijDL). Finally, the overall regression coefficient, β, was obtained by calculating the weighted mean of all the βij with weights given by the computed inverse variance of βij.However, since SM and DL are both time series, the assumption that observations are independent could not be made; therefore, the time series have been first differenced obtaining ΔSMTo explore whether regression coefficients vary statistically between participants and tasks, a general linear model computed in SPSS was used, with tasks and patients as fixed effects.To explore the effects of different strategies on stability, the strategy used spontaneously by each participant to get up the 50mm step was recorded, together with the corresponding minimum SM. How the adopted strategy influenced the corresponding minimum SM was then examined.All tasks were completed by all patients within a maximum of 20 minutes and without any obvious signs of fatigue (not tested).To illustrate the measures derived from our instrumented rollator system, 2 = 20.2, degrees of freedom = 5, p = 0.001), and the post-hoc Wilcoxon tests used to further investigate the effect of the individual tasks confirmed that that the minimum SM for each task is significantly lower than that during straight line walking  and, hence, that SM increases with DL. Moreover, the general linear model showed that β varies significantly between participants (p<0.001) but not between tasks (p = 0.69). The mean (weighted) values of β for the 6 tasks and the 10 participants are shown in Three different strategies to step onto a 50 mm-high platform were observed in the rollator users tested. Seven out of ten users adopted a lateral approach which consisted of:User lifts either the right or left side of the rollator first;User places the front wheel of the lifted side onto the platform;User lifts the rest of the rollator and places it onto the platform.Two users adopted an “all together” approach (referred to as “All together V1”), using the handles to lift the rollator up completely in a single manoeuvre and placing all 4 wheels simultaneously on top of the platform. Finally, 1 user adopted an alternative “all together” approach (referred to as “All together V2”) as follows:User leans forward and grabs the rollator horizontal bar with one hand while holding one handle with the other hand;User lifts the rollator up completely in a single manoeuvre.Of the 3 different approaches adopted by the rollator users, the lateral approach was the one with the highest minimum SM (0.13 ± 0.03), followed by the “All together V1” approach (0.12 ± 0.01) and, lowest of all, the “All together V2” approach .System is now normalized to take into account the size of the BoS, because a smaller SMSystem may simply be the consequence of a smaller BoS. However, despite this normalization, the sample data of two participants (one fit and one comparatively frail) indicate that, whilst SM is a direct measure of stability (nearness to tipping), a larger SM (as observed for the more frail user) does not necessarily mean a safer gait and lower risk of falling. For instance, those users who need a rollator only as a balance aid, and which do not transfer substantial amounts of body weight onto the device, will likely have a lower SM than those who need it for weight-bearing support. In future, a measure representative of overall stability that does not depend on absolute values of SM would be more informative, especially when it is the aim to characterize relative stability of participants.This is the first study that, in a cohort of 10 in-patients in a geriatric ward, assessed stability with an instrumented rollator for six everyday walking tasks. Stability was investigated with an objective assessment methodology previously developed by the authors [Investigating effects of task on SM, the data provide evidence that stability decreases substantially from straight line walking to all other tasks. Yet, no significant differences between the other tasks  could be found, indicating that the level of challenge for each task may be similar or subjective. These findings provide initial evidence as to how safe use of a rollator may be facilitated: training should target daily activities other than straight line walking, and it should be customised to focus on those activities for which a user exhibits particularly low stability.System moves forward towards the centre and away from the edges of BoSSystem. Hence, advice to those who show generally low SM, and especially to those whose SM is often directed towards the rear of BoSSystem, could include instruction to lean more onto the rollator. However, we acknowledge that this may not always be possible if users have weak upper limbs, and it may also lead to new pathologies such as tendonitis or osteoarthritis [Investigating stability in relation to device loading, findings showed that SM generally increases significantly when DL increases, thereby supporting our hypothesis that as more weight is transferred onto the rollator, CoPrthritis , 17. FurIt must also be noted that, considering the different strategies used to stepping up a kerb, it may be that the relationship between SM and DL is influenced by the specific strategy used and may need to be treated separately from other tasks. Future work needs to investigate this further, however, at this time the authors did verify in a post-hoc analysis that the exclusion of the stepping-up task from the regression and general linear models did not change the significance of the models and neither the results for the remaining tasks.Finally, for the first time, we have shown how stability data can inform rollator use strategies. Specifically, when going up a step the “lateral approach” appears to be the most stable strategy, because the rollator never leaves the ground completely and hence provides the user with continued support; the “All together” approaches, instead, require greater strength as the user has to lift the rollator in one manoeuvre and leave him/her with no support during the lifting-up phase. The authors note that none of the participants went up the step as stated in some guidance documents, i.e. lifting the front wheels first, then the rear, then squeezing the brakes before stepping up.within user , but that, in order to compare users and inform on who’s at greater risk of falling, further work is needed. Therefore, future analysis should investigate additional factors such as DL and their effects on SM, and/or focus on analysis techniques that do not depend on absolute values of SM, for example, the regularity of the SM time series (e.g. as measured by autocorrelation) [One limitation that emerges from the above discussion is that SM, despite its normalization by (elation) . Indeed,For these reasons, future work should investigate techniques such as autocorrelation functions applied to the stability margin to identify whether this approach may complement the methods presented here.Finally, we acknowledge that the number of users tested in this work (10) is small, and that we have not validated SM against existing stability measures. Regarding the latter, however, to date, no gold standard measure adequate for assessment of stability of walking aid users exists: methods previously designed for unassisted walking such as investigations of linear variability of basic gait parameters  ignore tIn summary, our approach provides objective data on walking stability of the combined system (user and rollator) for a range of everyday tasks, and provides first insights into how to objectively assess alternative rollator use strategies to inform evidence-based training. The relevance of our approach lies in an increase in users of walking aids within our ageing population, and the associated costs arising from fall-related injuries. One key insight gained is that training should not be limited to straight line walking alone, but should include more complex tasks representative of daily walking activities. Within person, the stability margin SM can be used to identify which tasks needs to be practiced, and which strategy facilitates stable performance of a given task. Indeed, in principle, the use of instrumented rollators as assessment tools in clinics could enable person specific guidance and training. Longer-term, evidence-based training should increase the benefits of using rollators as a means of fall prevention.S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.


In ER-positive tumors, AR high tumors enriched UV response down , and AR low tumors enriched DNA repair . AR high tumors were significantly associated with procancer regulatory T-cells, and AR low tumors were associated with anticancer immune cells, such as CD4, CD8, and Gamma-Delta T-cells and memory B-cells in ER-positive BC (p < 0.01). Further, cytolytic activity was significantly lower in AR high BC in both cohorts. Finally, AR high tumors had a significantly lower rate of attaining pathological complete response to NAC (GSE22358), but better survival. In conclusion, our results demonstrated that high AR has fewer tumor infiltrating lymphocytes as well as cytolytic activity and an inferior response to NAC, but better survival in ER-positive BC.Estrogen receptor (ER) positive breast cancer (BC), the most abundant BC subtype, is notorious for poor response to neoadjuvant chemotherapy (NAC). The androgen receptor (AR) was reported to support estradiol-mediated ER activity in an in vitro system. Recently, ER-positive BC with fewer tumor infiltrating lymphocytes (TILs) was shown to have a better prognosis, opposite to the trend seen with ER-negative BC. We hypothesized that ER-positive BC with high expression of AR will have fewer TILs and an inferior response to NAC, but with a better prognosis. In both TCGA and METABRIC cohorts, AR expression was significantly higher in ER-positive BCs compared to ER-negatives ( Breast cancer (BC) is the most common cancer among women in the United States excluding skin cancers. About one in eight U.S. women about 12%) will develop invasive BC in their lifetime 2% will d,4, it isThe androgen receptor (AR) is one of the members of the steroid nuclear receptor family, which includes ER and progesterone receptor (PR). AR is expressed in 50–90% of breast cancers ,12 and sAR would rather be famous as the potential target in the therapy for triple negative breast cancer (TNBC), which does not express ER, PR, and HER2/neu and tends to be more aggressive than other subtypes of breast cancers. TNBC is considered not to be a single disease, and is classified into several molecular subtypes, among which there are luminal AR subtypes (LAR) . In vitrOn the other hand, several studies have reported the role of AR in ER-positive BC. A study had identified a crosstalk between AR and epidermal growth factor receptor (EGFR), which is involved in cancer cell growth, in ER-positive BC cells . AnotherWe hypothesized that ER-positive BC with high levels of AR expression attracts TILs and has a worse response to NAC, but better patient survival. In this study, we investigated the associations of AR mRNA expression with ER expression, the number of TILs, the response to NAC, and survival using gene expression data from the publicly available large cohorts.p < 0.001, AR expression has been reported to be higher in ER-positive compared with ER-negative BC; however, previous studies used immunohistochemistry (IHC) for AR measurement, which is semiquantitative and the antibodies used were not standardized ,24,25. Wr = 0.630, p < 0.001), but also in METABRIC  as well.Since several papers have shown the interaction of AR and ER, it was of interest whether high expression of AR mRNA correlates with that of ER mRNA . We founp < 0.001) hallmark gene sets in GSEA (p < 0.001) hallmark gene sets in GSEA  consistently in both TCGA and METABRIC cohorts  scores that assess tumor heterogeneity in TCGA whole cohort, but not in any other subtypes, including ER-positive BC  top row.In order to explore the relationship between AR expression and response to NAC and subsequent survival, ten NAC cohorts from the GEO database that reported gene expression data and pCR or distant relapse-free survival were analyzed . AlthougIn the present study, we found that AR mRNA expression was higher in ER-positive tumors and the level of AR expression correlated with that of ER expression. AR high tumors enriched UV response down gene sets, whereas AR low tumors enriched DNA repair gene sets. AR high tumors consistently had less infiltration of CD4 and Gamma Delta T cells, but there was a discrepancy with infiltration of CD8 and regulatory T cells between the cohorts. AR high tumors had low tumor heterogeneity only in the whole cohort, whereas CYT was consistently low in the whole cohort and the ER-positive BC cohort in both TCGA and METABRIC. Finally, while AR high tumors demonstrated low pCR rates, they were associated with better survival after NAC. Several studies have reported that AR is expressed higher in ER-positive primary BC than ER-negative BC ,28. D’AmAR was demonstrated to protect prostate cancer cells from DNA damage in vitro ,30. AR wAlthough there are not many articles investigating the relation between TIL and AR, it has been proposed that there is negative correlation between AR expression and immune cell infiltration in patients with HER2 and ER-positive tumors . In the High infiltration of TILs is a known indicator of a good response to NAC and a better prognosis in the vast majority of cancers, including ER-negative BC ,6. This Our study has some limitations. The first and biggest limitation is that our research has demonstrated only the association between AR expression, TIL, and NAC, but there is no data that indicates causality. The second limitation is that TCGA, METABRIC, and GEO databases have limited numbers of patients and have substantial missing values. In the future, further prospective studies with larger sample volume are needed in order to overcome these issues.https://www.ncbi.nlm.nih.gov/geo/). Patients were classified as either AR expression high or low group using the median of AR mRNA expression of the individual group. Distant relapse-free survival was determined from time of diagnosis to clinical confirmation of tumor recurrence.The gene expression level quantification data (mRNA Z-score of RNA-sequence) of 1093 breast cancer patients, and level three Z-score normalized gene expression data of 1904 patients from METABRIC data were downloaded through cBioPortal as described previously ,36,37,38http://software.broadinstitute.org/gsea/index.jsp), as previously described [GSEA was calculated by the Broad Institute software  [We utilized CIBERSORT, a bioinformatic algorithm, in order to calculate immune cell composition from gene expression profiles, in order to estimate tumor infiltrating immune cells in tumors . Immune at/home) . The immat/home) . The mutat/home) ,44. t-test was used to analyze the differences between continuous values. In all analyses, a two-sided p < 0.05 was considered statistically significant. All statistical analyses were performed using Microsoft Excel 2010, R software (http:///www.rproject.org/), and Bioconductor (http://bioconductor.org/).The Kaplan–Meier method with log-rank test was used to determine distant relapse-free survival as previously described ,36,37,45Our results demonstrated that high AR has fewer tumor infiltrating lymphocytes and a worse response to NAC, but better survival in ER-positive BC. The fact that AR expression plays some cancer-immunological role in ER-positive breast cancer is enhanced by this report, which can add a novel aspect to future research and treatment of ER-positive breast cancer.