NF-κB-mediated effects on behavior and cartilage pathology in a non-invasive loading model of post-traumatic osteoarthritis.

OBJECTIVE: This study aimed to examine the temporal activation of NF-κB and its relationship to the development of pain-related sensitivity and behavioral changes in a non-invasive murine knee loading model of PTOA. METHOD: Following knee injury NF-κB activity was assessed longitudinally via in vivo imaging in FVB. Cg-Tg (HIV-EGFP,luc)8Tsb/J mice. Measures of pain-related sensitivity and behavior were also assessed longitudinally for 16 weeks. Additionally, we antagonized NF-κB signaling via intra-articular delivery of an IκB kinase two antagonist to understand how local NF-κB inhibition might alter disease progression. RESULTS: Following joint injury NF-κB signaling within the knee joint was transiently increased and peaked on day 3 with an estimated 1.35 p/s/cm2/sr (95% CI 0.913.1.792 p/s/cm2/sr) fold increase in signaling when compared to control joints. Furthermore, injury resulted in the long-term development of hindpaw allodynia. Hyperalgesia withdrawal thresholds were reduced at injured knee joints, with the largest reduction occurring 2 days following injury (estimate of between group difference 129.1 g with 95% CI 60.9,197.4 g), static weight bearing on injured limbs was also reduced. Local delivery of an NF-κB inhibitor following joint injury reduced chondrocyte death and influenced the development of pain-related sensitivity but did not reduce long-term cartilage degeneration. CONCLUSION: These findings underscore the development of behavioral changes in this non-invasive loading model of PTOA and their relationships to NF-κB activation and pathology. They also highlight the potential chondroprotective effects of NF-κB inhibition shortly following joint injury despite limitations in preventing the long-term development of joint degeneration in this model of PTOA.

Prevalence and mutational determinants of high tumor mutation burden in breast cancer.

BACKGROUND: High tumor mutation burden (TMB) can benefit immunotherapy for multiple tumor types, but the prevalence of hypermutated breast cancer is not well described. The aim of this study was to evaluate the frequency, mutational patterns, and genomic profile of hypermutated breast cancer. PATIENTS AND METHODS: We used de-identified data from individuals with primary or metastatic breast cancer from six different publicly available genomic studies. The prevalence of hypermutated breast cancer was determined among 3969 patients' samples that underwent whole exome sequencing or gene panel sequencing. The samples were classified as having high TMB if they had ≥10 mutations per megabase (mut/Mb). An additional eight patients were identified from a Dana-Farber Cancer Institute cohort for inclusion in the hypermutated cohort. Among the patients with high TMB, the mutational patterns and genomic profiles were determined. A subset of patients was treated with regimens containing PD-1 inhibitors. RESULTS: The median TMB was 2.63 mut/Mb. The median TMB significantly varied according to the tumor subtype (HR-/HER2- >HER2+ >HR+/HER2-, P < 0.05) and sample type (metastatic > primary, P = 2.2 × 10-16). Hypermutated tumors were found in 198 patients (5%), with enrichment in metastatic versus primary tumors (8.4% versus 2.9%, P = 6.5 × 10-14). APOBEC activity (59.2%), followed by mismatch repair deficiency (MMRd; 36.4%), were the most common mutational processes among hypermutated tumors. Three patients with hypermutated breast cancer-including two with a dominant APOBEC activity signature and one with a dominant MMRd signature-treated with pembrolizumab-based therapies derived an objective and durable response to therapy. CONCLUSION: Hypermutation occurs in 5% of all breast cancers with enrichment in metastatic tumors. Different mutational signatures are present in this population with APOBEC activity being the most common dominant process. Preliminary data suggest that hypermutated breast cancers are more likely to benefit from PD-1 inhibitors.

Nipple candidiasis among breastfeeding mothers. Case-control study of predisposing factors.

OBJECTIVE: To investigate factors that predispose breastfeeding mothers to nipple candidiasis. DESIGN: A retrospective case-control study of women attending the Calgary Breastfeeding Clinic. SETTING: Ambulatory breastfeeding referral centre. PARTICIPANTS: All women (105) who attended the clinic during a 3.5-month study period. All were referred for problems with breastfeeding; 27 (the case group) had positive diagnostic criteria for nipple candidiasis. The other 78 formed a control group. MAIN OUTCOME MEASURE: A patient information sheet, completed while taking a medical history, recorded the presence or absence of four possible predisposing factors. Two infant variables were also noted on physical examination. Patients were diagnosed as having or not having nipple candidiasis on the basis of specific clinical criteria, and statistics on other variables were compared for those with positive and with negative diagnoses. RESULTS: A statistically significant correlation (P < 0.05) was found between nipple candidiasis and three factors: vaginal candidiasis (P = 0.001), previous antibiotic use (P = 0.036), and nipple trauma (P = 0.001). CONCLUSIONS: Further research is required to establish clear causality. However, we recommend that physicians be suspicious of nipple candidiasis; avoid antibiotics or use the shortest effective course; treat yeast vaginitis during the third trimester and after delivery aggressively; and treat mothers for nipple yeast if babies have oral or diaper candidiasis. Breastfeeding mothers can also be counseled in preventive measures.