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Medical and Health Sciences, Clinical Medicine, Medicin och hälsovetenskap, and Klinisk medicin

INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor alpha (ERalpha) are among the most effective systemic treatments for ERalpha-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERalpha transcriptional regulatory plasticity. Here, we identify VAV3 as a critical component in this process.METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERalpha was evaluated by molecular docking analyses, an agonist fluoligand assay, and short-hairpin (sh) RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot of signaling and proliferation markers and shRNA-mediated protein depletion in viability and clonogenic assays were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine the association with therapy response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase) but instead a result of binding to ERalpha. VAV3 was selectively reduced upon exposure to YC-1 or ERalpha depletion and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.CONCLUSIONS: This study proposes VAV3 as a biomarker and rationale signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

NEISSERIA gonorrhoeae, SEXUALLY transmitted diseases, ANTIBIOTICS, CHLAMYDIA trachomatis, GYNECOLOGISTS, DIAGNOSIS, CHLAMYDIA infection diagnosis, GENITOURINARY disease diagnosis, GONORRHEA diagnosis, CLINICS, GENITOURINARY diseases, GONORRHEA, DISEASES in men, NEISSERIA, PHARYNGEAL diseases, PHYSICIANS, GENERAL practitioners, CROSS-sectional method, and RECTAL diseases

Background: Gonorrhoea, caused by Neisseria gonorrhoeae (NG), can cause reproductive morbidity, is increasingly becoming resistant to antibiotics and is frequently asymptomatic, which shows the essential role of NG test practice. In this study we wanted to compare NG diagnostic testing procedures between different STI care providers serving a defined geographic Dutch region (280,000 inhabitants).Methods: Data on laboratory testing and diagnosis of urogenital and extragenital (i.e. anorectal and oropharyngeal) NG were retrieved from general practitioners (GPs), an STI clinic, and gynaecologists (2006-2010). Per provider, we assessed their contribution regarding the total number of tests performed and type of populations tested, the proportion of NG positives re-tested (3-12 months after treatment) and test-of-cure (TOC, within 3 months post treatment).Results: Overall, 17,702 NG tests (48.7% STI clinic, 38.2% GPs, 13.1% gynaecologists) were performed during 15,458 patient visits. From this total number of tests, 2257 (12.7%) were extragenital, of which 99.4% were performed by the STI clinic. Men were mostly tested at the STI clinic (71%) and women by their GP (43%). NG positivity per visit was 1.6%; GP 1.9% (n = 111), STI clinic 1.7% (n = 131) and gynaecology 0.2% (n = 5). NG positivity was associated with Chlamydia trachomatis positivity (OR: 2.06, 95% confidence interval: 1.46-2.92). Per anatomical location, the proportion of NG positives re-tested were: urogenital 20.3% (n = 36), anorectal 43.6% (n = 17) and oropharyngeal 57.1% (n = 20). NG positivity among re-tests was 16.9%. Proportions of NG positives with TOC by anatomical location were: urogenital 10.2% (n = 18), anorectal 17.9% (n = 7) and oropharyngeal 17.1% (n = 6).Conclusions: To achieve best practice in relation to NG testing, we recommend that: 1) GPs test at extragenital sites, especially men who have sex with men (MSM), 2) all care providers consider re-testing 3 to 12 months after NG diagnosis and 3) TOC is performed following oropharyngeal NG diagnosis in settings which provide services to higher-risk men and women (such as STI clinics). [ABSTRACT FROM AUTHOR]