Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

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C ardiovascular disease (CVD) is a leading cause of mortality, accounting for >30% of deaths worldwide.1 There are several modifiable (ie, obesity, smoking, alcohol, physical activity, and diet) and also unmodifiable risk factors (ie, sex and age) associated with CVD; however, the pathophysiological mechanisms of the association between risk factors and disease are not yet fully understood. Clinical Perspective on p 494Metabolomics aims to quantify small molecules present in a biological system at a specific time point. This snapshot provides an indication of the current metabolic state of the whole organism at a given stage of life. Differences in metabolic profiles can be because of pathological stimuli, environmental impact, or normal physiological variations. Several studies have shown that metabolomics can identify distinct metabolic patterns in individuals affected by pathological conditions, that is, atherosclerosis, diabetes mellitus, or cardiovascular disorders. 2-5The effects of several classic modifiable CVD risk factors on metabolism have already been studied in different population-based cohorts. In particular, alcohol intake, obesity, diet patterns, and smoking were shown to be associated Background-The effects of lifestyle risk factors considered collectively on the human metabolism are to date unknown.We aim to investigate the association of these risk factors with metabolites and their changes during 4 years. Methods and Results-One hundred and sixty-three metabolites were measured in serum samples with the AbsoluteIDQ kit p150 (Biocrates) following a targeted metabolomics approach, in a population-based cohort of 1030 individuals, aged 45 to 83 years at baseline. We evaluated associations between metabolite concentrations (28 acylcarnitines, 14 amino acids, 9 lysophosphocholines, 72 phosphocholines, 10 sphingomyelins and sum of hexoses) and 5 lifestyle risk factors (body mass index [BMI], alcohol consumption, smoking, diet, and exercise). Multilevel or simple linear regression modeling adjusted for relevant covariates was used for the evaluation of cross-sectional or longitudinal associations, respectively; multiple testing correction was based on false discovery rate. BMI, alcohol consumption, and smoking were associated with lipid metabolism (reduced lyso-and acyl-alkyl-phosphatidylcholines and increased diacylphosphatidylcholines concentrations). Smoking showed positive associations with acylcarnitines, and BMI correlated inversely with nonessential amino acids. Fewer metabolites showed relative changes that were associated with baseline risk factors: increases in 5 different acyl-alkyl phosphatidylcholines were associated with lower alcohol consumption and BMI and with a healthier diet. Increased levels of tyrosine were associated with BMI. Sex-specific effects of smoking and BMI were found specifically related to acylcarnitine metabolism: in women higher BMI and in men more pack-years were associated with increases in acylcarnitines. with alterations in lipid metabolism. Additionally, obe...

In contrast to normal cells, tumor cells of multiple entities overexpress the Heat shock protein 70 (Hsp70) not only in the cytosol, but also present it on their plasma membrane in a tumor-specific manner. Furthermore, membrane Hsp70-positive tumor cells actively release Hsp70 in small extracellular vesicles with biophysical characteristics of exosomes. Due to conformational changes of Hsp70 in a lipid environment, most commercially available antibodies fail to detect membrane-bound and vesicular Hsp70. To fill this gap and to assess the role of vesicular Hsp70 in circulation as a potential tumor biomarker, we established the novel complete (comp)Hsp70 sandwich ELISA, using two monoclonal antibodies (mAbs), that is able to recognize both free and lipid-associated Hsp70 on the cell surface of viable tumor cells and on small extracellular vesicles. The epitopes of the mAbs cmHsp70.1 (aa 451–461) and cmHsp70.2 (aa 614–623) that are conserved among different species reside in the substrate-binding domain of Hsp70 with measured affinities of 0.42 nM and 0.44 nM, respectively. Validation of the compHsp70 ELISA revealed a high intra- and inter-assay precision, linearity in a concentration range of 1.56 to 25 ng/mL, high recovery rates of spiked liposomal Hsp70 (>84%), comparable values between human serum and plasma samples and no interference by food intake or age of the donors. Hsp70 concentrations in the circulation of patients with glioblastoma, squamous cell or adeno non-small cell lung carcinoma (NSCLC) at diagnosis were significantly higher than those of healthy donors. Hsp70 concentrations dropped concomitantly with a decrease in viable tumor mass upon irradiation of patients with approximately 20 Gy (range 18–22.5 Gy) and after completion of radiotherapy (60–70 Gy). In summary, the compHsp70 ELISA presented herein provides a sensitive and reliable tool for measuring free and vesicular Hsp70 in liquid biopsies of tumor patients, levels of which can be used as a tumor-specific biomarker, for risk assessment (i.e., differentiation of grade III vs. IV adeno NSCLC) and monitoring of therapeutic outcomes.

BACKGROUND: Although prostate cancer (PCa) is the most commonly diagnosed cancer in men of sub-Saharan Africa (SSA), little is known about its management and survival. The objective of the current study was to describe the presentation, patterns of diagnosis, treatment, and survival of patients with PCa in 10 countries of SSA. METHODS: In this observational registry study with data collection from 2010 to 2018, the authors drew a random sample of 738 patients with PCa who were registered in 11 population-based cancer registries. They described proportions of patients receiving recommended care and presented survival estimates. Multivariable Cox regression was used to calculate hazard ratios comparing the survival of patients with and without cancer-directed therapies (CDTs). RESULTS:The study included 693 patients, and tumor characteristics and treatment information were available for 365 patients, 37.3% of whom had metastatic disease. Only 11.2% had a complete diagnostic workup for risk stratification. Among the nonmetastatic patients, 17.5% received curative-intent therapy, and 27.5% received no CDT. Among the metastatic patients, 59.6% received androgen deprivation therapy. The 3-and 5-year age-standardized relative survival for 491 patients with survival time information was 58.8% (95% confidence interval [CI], 48.5%-67.7%) and 56.9% (95% CI, 39.8%-70.9%), respectively. In a multivariable analysis, survival was considerably poorer among patients without CDT versus those with therapy. CONCLUSIONS: This study shows that a large proportion of patients with PCa in SSA are not staged or are insufficiently staged and undertreated, and this results in unfavorable survival. These findings reemphasize the need for improving diagnostic workup and access to care in SSA in order to mitigate the heavy burden of the disease in the region.

Physical activity (PA) reduces the risk for mortality. Whether the beneficial effects of PA are domain specific is unclear. We associated leisure time (LTPA), sports (SPA) and work (WPA) related PA and cardiorespiratory fitness (CRF) with all-cause mortality in two German population-based cohorts. We used data of the Study of Health in Pomerania (SHIP, n = 2,935, median age 53; 48% male) and the Cardiovascular Disease, Living and Ageing in Halle study (CARLA, n = 1,776, median age 64 and 54% male). Mortality was determined after a median follow-up of 8.2 years in SHIP (n = 332) and 11.5 years in CARLA (n = 409). LTPA (SHIP: hazard ratio [HR] per standard deviation [SD] 0.82 95%-CI 0.73 to 0.91 and CARLA: HR per SD 0.70: 95%-CI 0.59 to 0.82) and SPA (SHIP: HR per SD 0.80 95%-CI 0.71 to 0.91 and CARLA: HR per SD 0.70 95%-CI 0.60 to 0.82) but not WPA were inversely associated with all-cause mortality. In a subsample CRF was inversely related to mortality and positively to LTPA and sports SPA. No association was found for WPA. Our results may suggest that the inverse association between PA and mortality are partly influenced by higher CRF.

The main findings were that the clinical impact of GTV changes during definitive radiotherapy is still unclear due to heterogeneous study designs with varying quality. Several potential confounding variables were found and need to be considered for future studies to evaluate GTV changes during definitive radiotherapy with respect to treatment outcome.

Objective: To study the association between socioeconomic status (SES) and annual relative change in anthropometric markers in the general German adult population. Methods: Longitudinal data of 56,556 participants aged 18-83 years from seven population-based German cohort studies (CARLA, SHIP, KORA, DEGS, EPIC-Heidelberg, EPIC-Potsdam, PopGen) were analyzed by meta-analysis using a random-effects model. The indicators of SES were education and household income. Results: On average, all participants gained weight and increased their waist circumference over the study's follow-up period. Men and women in the low education group had a 0.1 percentage points greater annual increase in weight (95% CI men: 0.06-0.20; and women: 0.06-0.12) and waist circumference (95% CI men: 0.01-0.45; and women: 0.05-0.22) than participants in the high education group. Women with low income had a 0.1 percentage points higher annual increase in weight (95% CI 0.00-0.15) and waist circumference (95% CI 0.00-0.14) than women with high income. No association was found for men between income and obesity markers. Conclusions: Participants with lower SES (education and for women also income) gained more weight and waist circumference than those with higher SES. These results underline the necessity to evaluate the risk of weight gain based on SES to develop more effective preventive measures.