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Most ovarian cancers are infiltrated by prognostically relevant activated T cells 1 – 3 , yet exhibit low response rates to immune checkpoint inhibitors 4 . Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer 5 , 6 , but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors. In patients with high-grade serous ovarian cancer, robust and protective humoral responses are dominated by B-cell-derived polyclonal IgA that binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells.

Elevated plasma levels of branched chain amino acids detected prior to pancreatic cancer diagnosis may result from whole body tissue breakdown occurring during the early stages of this disease. Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months 1 . PDAC has been linked with obesity and glucose intolerance 2 , 3 , 4 , but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras -driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.

Rigorous studies are necessary to demonstrate suitability of metabolomics platforms to profile metabolites in archived plasma within epidemiologic studies of human disease, for which attenuation of effect estimates due to measurement error is a key concern. Using a liquid chromatography-tandem mass spectrometry platform, we quantified 257 metabolites from archived plasma to evaluate metabolite interassay reproducibility, reproducibility with delayed processing, and within-person reproducibility over time. Interassay reproducibility was assessed with CVs from 60 duplicate plasma samples donated by participants in the Nurses' Health Study and Health Professionals Follow-up Study, and 20 QC pool plasma replicates. Metabolite reproducibility over a 24- to 48-h processing delay (n = 48 samples) and within-person reproducibility over 1-2 years (n = 80 samples) were assessed using Spearman and intraclass correlation coefficients (ICCs). CVs were <20% for 92% of metabolites and generally were similar by plasma anticoagulant type (heparin or EDTA) and fasting time. Approximately 75% of metabolites were reproducible over delays in processing of blood samples (Spearman correlation or ICC ≥ 0.75, comparing immediate and 24-h delayed processing). Carbohydrates and purine/pyrimidine derivatives were most adversely affected by the processing delay. Ninety percent of metabolites were reproducible over 1-2 years within individuals (Spearman correlation or ICC ≥ 0.4). For potential use in epidemiologic studies, the majority of plasma metabolites had low CVs and were reproducible over a 24-h processing delay and within individuals over 1-2 years. Certain metabolites, such as carbohydrates and purine/pyrimidine derivatives, may be challenging to evaluate if samples have delayed processing.

The objectives of this study were to estimate the prevalence of fecal incontinence (FI) in older women and examine associations between potential risk factors and prevalent FI. We conducted a cross-sectional study of prevalent FI in 64,559 women, aged 62-87 years, in the Nurses' Health Study. Since 1976, participants provided information on health and lifestyle on mailed biennial questionnaires. Data on FI were collected in 2008. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for FI were calculated using logistic regression models. The reported prevalence of liquid or solid stool incontinence at least monthly increased from 9% in women aged 62 to 64 years to 17% in women aged 85 to 87 years. Prevalent FI was 50% less common in black women compared with white women (6% vs. 12%, respectively). Other variables associated with increased odds of FI at least monthly were pregnancy, higher body mass index (BMI), lower physical activity, functional limitations, current cigarette smoking, type 2 diabetes, high blood pressure, and neurologic disease. Urinary incontinence (UI) was a strong correlate of FI, with 63% of women with FI reporting UI at least monthly compared with 45% of women in the whole study population. FI is a common condition among older women, and often co-occurs with UI. Potentially modifiable risk factors include BMI, physical activity, and cigarette smoking.

Background Associations of bisphenol A and phthalates with chronic disease health outcomes are increasingly being investigated in epidemiologic studies. The majority of previous studies of within-person variability in urinary bisphenol A and phthalate metabolite concentrations have focused on reproducibility over short time periods. Long-term reproducibility data are needed to assess the potential usefulness of these biomarkers for prospective studies, particularly those examining risk of diseases with long latency periods. Low within-person reproducibility may attenuate relative risk estimates and reduce statistical power to detect associations with disease. Therefore, we assessed within-person reproducibility of bisphenol A, eight phthalate metabolites, and phthalic acid in spot urine samples over 1 to 3 years among women enrolled in two large cohort studies. Methods Women in the Nurses’ Health Study and Nurses’ Health Study II provided two spot urine samples, 1 to 3 years apart (n = 80 women for analyses of bisphenol A; n = 40 women for analyses of phthalate metabolites; n = 34 women for analyses of phthalic acid). To measure within-person reproducibility, we calculated Spearman rank correlation coefficients and intraclass correlation coefficients for creatinine-adjusted concentrations of bisphenol A, phthalate metabolites, and phthalic acid. Results Over 1 to 3 years, within-person variability of bisphenol A was high relative to total variability (intraclass correlation coefficient = 0.14) and rankings of bisphenol A levels between time-points were weakly correlated (Spearman correlation = 0.19). Seven of the eight phthalate metabolites and phthalic acid demonstrated moderate within-person stability over time (Spearman correlation or intraclass correlation coefficient = 0.39-0.55). Restricting analyses to first-morning urine samples did not alter results. Conclusions Single measurements of bisphenol A in spot urine samples were highly variable within women over 1 to 3 years, indicating that investigation of associations between a single urinary bisphenol A measurement and disease risk may be challenging in epidemiologic studies. The majority of urinary phthalate metabolites and phthalic acid appeared moderately reproducible within women over time, suggesting single measurements may be useful in epidemiologic studies, although observed relative risks can be substantially attenuated.

Observational studies have documented inverse associations between moderate alcohol consumption and risk of premature death. It is largely unknown whether moderate alcohol intake is also associated with overall health and well-being among populations who have survived to older age. In this study, we prospectively examined alcohol use assessed at midlife in relation to successful ageing in a cohort of US women. Alcohol consumption at midlife was assessed using a validated food frequency questionnaire. Subsequently, successful ageing was defined in 13,894 Nurses' Health Study participants who survived to age 70 or older, and whose health status was continuously updated. \"Successful ageing\" was considered as being free of 11 major chronic diseases and having no major cognitive impairment, physical impairment, or mental health limitations. Analyses were restricted to the 98.1% of participants who were not heavier drinkers (>45 g/d) at midlife. Of all eligible study participants, 1,491 (10.7%) achieved successful ageing. After multivariable adjustment of potential confounders, light-to-moderate alcohol consumption at midlife was associated with modestly increased odds of successful ageing. The odds ratios (95% confidence interval) were 1.0 (referent) for nondrinkers, 1.11 (0.96-1.29) for ≤ 5.0 g/d, 1.19 (1.01-1.40) for 5.1-15.0 g/d, 1.28 (1.03-1.58) for 15.1-30.0 g/d, and 1.24 (0.87-1.76) for 30.1-45.0 g/d. Meanwhile, independent of total alcohol intake, participants who drank alcohol at regular patterns throughout the week, rather than on a single occasion, had somewhat better odds of successful ageing; for example, the odds ratios (95% confidence interval) were 1.29 (1.01-1.64) and 1.47 (1.14-1.90) for those drinking 3-4 days and 5-7 days per week in comparison with nondrinkers, respectively, whereas the odds ratio was 1.10 (0.94-1.30) for those drinking only 1-2 days per week. These data suggest that regular, moderate consumption of alcohol at midlife may be related to a modest increase in overall health status among women who survive to older ages.

Background Increasing evidence, including multiple putative inflammatory risk factors (e.g., c‐reactive protein, and adiposity), supports that inflammation plays an important role in ovarian carcinogenesis. Resistance training (RT) is associated with lower levels of circulating inflammatory markers, independent of physical activity. Methods We evaluated the relationship between RT and risk of ovarian cancer accounting for other physical activity (e.g., walking) in two large prospective cohorts, the Nurses’ Health Study (NHS) and NHSII. Key Results In total, analyses included 42,005 NHS participants (2000–2016) and 67,289 NHSII participants (2001–2017) with RT assessed every 4 years. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of RT with ovarian cancer risk overall and by tumor subtype, adjusting for known and putative ovarian cancer risk factors. We identified a total of 609 cases over 1,748,884 person‐years. No association was observed with overall ovarian cancer risk (RT ≥60 vs 0 min/wk, HR = 0.95, 95%CI: 0.74–1.22) or by histotype (comparable HR = 0.86 and 0.98 for type I and II tumors, respectively). Results did not differ by body mass index (Pinteraction = 0.97), or other physical activity (Pinteraction = 0.31). Conclusions & Inferences We observed no evidence that moderate levels of RT were associated with risk of ovarian cancer. Further investigations are required to confirm these findings. Inflammation is thought to play a role in ovarian carcinogenesis. Physical activity and resistance training may reduce risk via lowering inflammation, although prior studies have had mixed results. In one of the largest prospective cohort studies evaluating resistance training and ovarian cancer risk, we observed no associations. Future work should explore the combination of modifiable anti‐inflammatory factors that decreases ovarian cancer risk.

Little is known regarding associations between inflammatory biomarkers and objectively measured physical activity and sleep during and after chemotherapy for gynecologic cancer; thus, we conducted a longitudinal study to address this gap. Women with gynecologic cancer (patients) and non-cancer controls (controls) completed assessments before chemotherapy cycles 1, 3, and 6 (controls assessed contemporaneously), as well as at 6- and 12-month follow-ups. Physical activity and sleep were measured using wrist-worn actigraphs and sleep diaries, and blood was drawn to quantify circulating levels of inflammatory markers. Linear and quadratic random-effects mixed models and random-effects fluctuation mixed models were used to examine physical activity and sleep over time, as well as the associations with inflammatory biomarkers. On average, patients (n = 97) and controls (n = 104) were 62 and 58 years old, respectively. Compared to controls, patients were less active, more sedentary, had more time awake after sleep onset, and had lower sleep efficiency (p-values < 0.05). Across groups, higher levels of TNF-α were associated with more sedentary time and less efficient sleep (p-values ≤ 0.05). Higher levels of IL-1β, TNF-α, and IL-6 were associated with lower levels of light physical activity (p-values < 0.05). Associations between inflammatory biomarkers, physical activity, and sleep did not differ between patients and controls. Given these results, we speculate that inflammation may contribute to less physical activity and more sleep problems that persist even 12 months after completing chemotherapy.

Prospective evidence regarding associations for exposures to bisphenol A (BPA) and phthalates with type 2 diabetes (T2D) is lacking. We prospectively examined urinary concentrations of BPA and phthalate metabolites with T2D risk. We measured BPA and eight major phthalate metabolites among 971 incident T2D case-control pairs from the Nurses' Health Study (NHS) (mean age, 65.6 years) and NHSII (mean age, 45.6 years). In the NHSII, BPA levels were not associated with incident T2D in multivariate-adjusted analysis until body mass index was adjusted: odds ratio (OR) comparing extreme BPA quartiles increased from 1.40 (95% CI: 0.91, 2.15) to 2.08 (95% CI: 1.17, 3.69; p(trend) = 0.02) with such an adjustment. In contrast, BPA concentrations were not associated with T2D in the NHS (OR = 0.81; 95% CI: 0.48, 1.38; p(trend) = 0.45). Likewise, urinary concentrations of total phthalate metabolites were associated with T2D in the NHSII (OR comparing extreme quartiles = 2.14; 95% CI: 1.19, 3.85; p(trend) = 0.02), but not in the NHS (OR = 0.87; 95% CI: 0.49, 1.53; p(trend) = 0.29). Summed metabolites of butyl phthalates or di-(2-ethylhexyl) phthalates were significantly associated with T2D only in the NHSII; ORs comparing extreme quartiles were 3.16 (95% CI: 1.68, 5.95; p(trend) = 0.0002) and 1.91 (95% CI: 1.04, 3.49; p(trend) = 0.20), respectively. These results suggest that BPA and phthalate exposures may be associated with the risk of T2D among middle-aged, but not older, women. The divergent findings between the two cohorts might be explained by menopausal status or simply by chance. Clearly, these results need to be interpreted with caution and should be replicated in future studies, ideally with multiple urine samples collected prospectively to improve the measurement of these exposures with short half-lives.

BackgroundEvidence is limited on inflammation-related dietary patterns and mortality in ovarian cancer survivors.MethodsWe examined the associations between pre- and post-diagnosis dietary patterns, including change in diet from before to after diagnosis, and mortality among 1003 ovarian cancer survivors in two prospective cohort studies. Dietary pattern scores for empirical dietary inflammatory pattern (EDIP) and Alternative Healthy Eating Index (AHEI) were calculated based on food frequency questionnaires. We used Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for ovarian cancer-specific and all-cause mortality.ResultsPre-diagnosis EDIP score and AHEI were not associated with mortality. Among non-high grade serous cases, a higher post-diagnosis EDIP score was associated with increased risk of all-cause mortality (HR5th vs 1st quintile = 1.95, 95% CI = 1.04–3.67, p-trend = 0.06). Compared to survivors consuming a low EDIP score diet before and after diagnosis, high post-diagnosis EDIP was associated with increased risk of ovarian cancer specific mortality (pre-to-post diagnosis low/high, HR = 1.38, 95% CI = 0.99–1.92; high/high HR = 1.58, 95% CI = 1.09–2.30) and all-cause mortality (low/high HR = 1.44, 95% CI = 1.06–1.95; high/high HR = 1.55, 95% CI = 1.10–2.19).ConclusionConsuming a more inflammatory dietary pattern post-diagnosis was associated with increased mortality in ovarian cancer survivors, suggesting limiting the inflammatory potential of diet post-diagnosis could lead to enhanced survivorship.