Effects of lipopolysaccharide-induced inflammation on hypoxia and inflammatory gene expression pathways of the rat testis

Résumé Contexte L’infection et l’inflammation bactériennes du testicule altèrent la fertilité; cependant la compréhension des réponses inflammatoires du testicule est. encore incomplète. Nous nous sommes intéressés à l’identification des voies des gènes impliqués dans la détection et l’élimination des microbes infectieux dans l’appareil reproductif masculin. Dans de précédentes études menées dans notre laboratoire, et centrées sur des gènes sensibles à l’hypoxie, les expérimentations préliminaires suggéraient que les gènes classiquement catégorisés comme gènes de l’hypoxie étaient aussi activés au cours des réponses antimicrobiennes. Le but de la présente étude était d’identifier les voies des gènes qui contribuaient à la protection antimicrobienne du testicule et d’examiner de potentiels intermodulations et interactions entre ces voies. L’inflammation a été induite chez des rats Sprague-Dawley en utilisant des lypopolysaccharides (LPS) de P. aeruginosaet d’E. coli. Les taux de protéine du facteur-1 inductible par l’hypoxie (HIF1- α) et du facteur nucléaire kappa B (NF- kB) ont été mesurés; les profils d’expression des gènes de l’hypoxie et de l’inflammation dans le testicule ont été analysés par profilage de l’expression génique par PCR quantitative en temps réel. Résultats Chez les rats traités par LPS, la protéine HIF-1 α a augmenté sans modification de Hif-1αmRNA. L’analyse par Western Blot a aussi montré l’absence de modifications des taux de NF-kB et de la protéine inhibitrice NFKB alpha (IkB α) après traitement. Cinq gènes de la voie hypoxie (Angptl4, Egr1, Ier3, Pai1,et Glut1), et 11 gènes de la voie inflammatoire (Ccl12, Cc13, Cd14, Cxcl10, Icam1, Il10, Il1b, Il6, Egr1, Nfkbia, Tlr2, et Tnf) ont été régulés à la hausse après 3 heures d’inflammation. Angptl4, Ccl12, Cc13, Cd14, Egr1, Nfkbia, Tlr2, et Tnfsont restés élevés à 6 heures. Six gènes n’ont ont été régulés à la hausse qu’à 6 heures (Bhlhe40, C3, Jak2, Nlrp3, Slc11a1, Tlr1). Un gène (Tlr5) a été régulé à la baisse après 3 heures et aucun gène à 6 heures. Les résultats du test de décalage de la mobilité électrophorétique suggèrent une baisse de l’activité de liaison de NF- kB après traitement par LPS. Conclusions HIF-1α testiculaire est. régulé à la hausse après inflammation induite par LPS. Contrairement à d’autres tissus, dans lesquels HIF-1α est. régulé à la hausse par activation transcriptionnelle via NF- kB, nous concluons que HIF-1α dans le testicule n’est. pas régulé à la hausse par une augmentation de Hif-1 αmRNA ou par des mécanismes NF-kB-dépendants. Les gènes de la voie hypoxie et les gènes impliqués dans le récepteur Toll-like (TLR) et dans la signalisation médiée par les cytokines comprennent des catégories fonctionnelles majeures de gènes régulés à la hausse, ce qui démontre qu’à la fois les voies de l’hypoxie et les voies classiques de l’inflammation sont impliquées dans les réponses inflammatoires du testicule

Survival Outcomes in Women with Unilateral, Triple-Negative, Breast Cancer Correlated with Contralateral Prophylactic Mastectomy

BACKGROUND: Despite increased utilization of contralateral prophylactic mastectomy (CPM), there is insufficient evidence that it improves survival in average-risk women with unilateral breast cancer. CPM may be of heightened interest to patients with triple negative breast cancer (TNBC) because these patients are more likely to have BRCA1 mutation-associated disease and are not candidates for the chemoprevention benefits of adjuvant endocrine therapy. METHODS: Survival and recurrence outcomes were evaluated for all TNBC patients from a multi-institutional database (1999-2018) at two academic cancer programs in two metropolitan cities of the Northeast and Midwest. Median follow-up time was 3.7 years. RESULTS: Seven hundred and nighty six TNBC patients were evaluated and 15.45% underwent CPM. Women undergoing CPM were more likely to be white (p \u3c 0.001), younger (p \u3c 0.001), and underwent genetic testing (p \u3c 0.001). A borderline survival benefit was observed for TNBC patients undergoing CPM (5-year overall survival 95.1% vs. 85.0%; p = 0.05). There was no difference in survival when BRCA mutation carriers were excluded (5-year overall survival 94.1% vs. 85.2%; p = 0.12). For BRCA mutation carriers, a numeric trend was observed for improved survival for patients undergoing CPM (5-year overall survival 97.2% vs. 84.1%; p = 0.35). Among patients not undergoing CPM, the rate of developing a new primary breast cancer was 2.2% (15/673). Among these 15 patients, 20% (3/15) were known BRCA mutation carriers. CONCLUSIONS: Our data demonstrate no survival benefit for TNBC patients without BRCA1/2 mutations undergoing CPM

Effect of small bowel bacterial overgrowth on the immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR

Several live oral vaccines (polio, bovine rotavirus, CVD 103-HgR cholera) are less immunogenic in developing than in industrialized countries. It was hypothesized that proximal small bowel bacterial overgrowth (common in children in less developed countries but rare in industrialized settings) diminishes the vibriocidal antibody response to CVD 103-HgR. In total, 202 fasting Santiago schoolchildren aged 5-9 years had lactulose breath H2 tests to detect proximal small bowel bacteria 1 day before ingesting CVD 103-HgR. Florid small bowel overgrowth was observed in 10 (5.6%) of 178 analyzable children. In children with florid overgrowth, vibriocidal seroconversion differed little from other children (60% vs. 67%), but the geometric mean titer was lower (160 vs. 368; P = .25). By logistic regression, increased peak breath H2 at small bowel time points was associated with diminished seroconversion (P = .04), as was the interaction of H2 value and weight (children >25 kg had lower seroconve

Benefit of adjuvant chemotherapy in node-negative T1a versus T1b and T1c triple-negative breast cancer

PURPOSE: National comprehensive cancer network guidelines recommend delivery of adjuvant chemotherapy in node-negative triple-negative breast cancer (TNBC) if the tumor is \u3e 1 cm and consideration of adjuvant chemotherapy for T1b but not T1a disease. These recommendations are based upon sparse data on the role of adjuvant chemotherapy in T1a and T1b node-negative TNBC. Our objective was to clarify the benefits of chemotherapy for patients with T1N0 TNBC, stratified by tumor size. METHODS: We performed a retrospective analysis of survival outcomes of TNBC patients at two academic institutions in the United States from 1999 to 2018. Primary tumor size, histology, and nodal status were based upon surgical pathology. The Kaplan-Meier plot and 5-year unadjusted survival probability were evaluated. RESULTS: Among 282 T1N0 TNBC cases, the status of adjuvant chemotherapy was known for 258. Mean follow-up was 5.3 years. Adjuvant chemotherapy was delivered to 30.5% of T1a, 64.7% T1b, and 83.9% T1c (p \u3c 0.0001). On multivariable analysis, factors associated with delivery of adjuvant chemotherapy were tumor size and grade 3 disease. Improved overall survival was associated with use of chemotherapy in patients with T1c disease (93.2% vs. 75.2% p = 0.008) but not T1a (100% vs. 100% p = 0.3778) or T1b (100% vs. 95.8% p = 0.2362) disease. CONCLUSION: Our data support current guidelines indicating benefit from adjuvant chemotherapy in node-negative TNBC associated with T1c tumors but excellent outcomes were observed in the cases of T1a and T1b disease, regardless of whether adjuvant chemotherapy was delivered

Impact of the COVID-19 breast cancer screening hiatus on clinical stage and racial disparities in New York City

BACKGROUND: The impact of the COVID-19 mammography screening hiatus as well as of post-hiatus efforts promoting restoration of elective healthcare on breast cancer detection patterns and stage distribution is unknown. METHODS: Newly diagnosed breast cancer patients (2019-2021) at the New York Presbyterian (NYP) Hospital Network were analyzed. Chi-square and student\u27s t-test compared characteristics of patients presenting before and after the screening hiatus. RESULTS: A total of 2137 patients were analyzed. Frequency of screen-detected and early-stage breast cancer declined post-hiatus (59.7%), but returned to baseline (69.3%). Frequency of screen-detected breast cancer was lowest for African American (AA) (57.5%) and Medicaid patients pre-hiatus (57.2%), and this disparity was reduced post-hiatus (65.3% for AA and 63.2% for Medicaid). CONCLUSIONS: The return to baseline levels of screen-detected cancer, particularly among AA and Medicaid patients suggest that large-scale breast health education campaigns may be effective in resuming screening practices and in mitigating disparities