Rapid detection of BRCA1/2 recurrent mutations in Chinese breast and ovarian cancer patients with multiplex SNaPshot genotyping panels.

BRCA1/2 mutations are significant risk factors for hereditary breast and ovarian cancer (HBOC), its mutation frequency in HBOC of Chinese ethnicity is around 9%, in which nearly half are recurrent mutations. In Hong Kong and China, genetic testing and counseling are not as common as in the West. To reduce the barrier of testing, a multiplex SNaPshot genotyping panel that targeted 25 Chinese BRCA1/2 mutation hotspots was developed, and its feasibility was evaluated in a local cohort of 441 breast and 155 ovarian cancer patients. For those who tested negative, they were then subjected to full-gene testing with next-generation sequencing (NGS). BRCA mutation prevalence in this cohort was 8.05% and the yield of the recurrent panel was 3.52%, identifying over 40% of the mutation carriers. Moreover, from 79 Chinese breast cancer cases recruited overseas, 2 recurrent mutations and one novel BRCA2 mutation were detected by the panel and NGS respectively. The developed genotyping panel showed to be an easy-to-perform and more affordable testing tool that can provide important contributions to improve the healthcare of Chinese women with cancer as well as family members that harbor high risk mutations for HBOC

Connections of the human orbitofrontal cortex and inferior frontal gyrus

The direct connections of the orbitofrontal cortex (OFC) were traced with diffusion tractography imaging and statistical analysis in 50 humans, to help understand better its roles in emotion and its disorders. The medial OFC and ventromedial prefrontal cortex have direct connections with the pregenual and subgenual parts of the anterior cingulate cortex; all of which are reward-related areas. The lateral OFC (OFClat) and its closely connected right inferior frontal gyrus (rIFG) have direct connections with the supracallosal anterior cingulate cortex; all of which are punishment or nonreward-related areas. The OFClat and rIFG also have direct connections with the right supramarginal gyrus and inferior parietal cortex, and with some premotor cortical areas, which may provide outputs for the OFClat and rIFG. Another key finding is that the ventromedial prefrontal cortex shares with the medial OFC especially strong outputs to the nucleus accumbens and olfactory tubercle, which comprise the ventral striatum, whereas the other regions have more widespread outputs to the striatum. Direct connections of the OFC and IFG were with especially the temporal pole part of the temporal lobe. The left IFG, which includes Broca’s area, has direct connections with the left angular and supramarginal gyri

Hearing impairment is associated with cognitive decline, brain atrophy and tau pathology.

Hearing impairment was recently identified as the most prominent risk factor for dementia. However, the mechanisms underlying the link between hearing impairment and dementia are still unclear. We investigated the association of hearing performance with cognitive function, brain structure and cerebrospinal fluid (CSF) proteins in cross-sectional, longitudinal, mediation and genetic association analyses across the UK Biobank (N = 165,550), the Chinese Alzheimer's Biomarker and Lifestyle (CABLE, N = 863) study, and the Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 1770) database. Poor hearing performance was associated with worse cognitive function in the UK Biobank and in the CABLE study. Hearing impairment was significantly related to lower volume of temporal cortex, hippocampus, inferior parietal lobe, precuneus, etc., and to lower integrity of white matter (WM) tracts. Furthermore, a higher polygenic risk score (PRS) for hearing impairment was strongly associated with lower cognitive function, lower volume of gray matter, and lower integrity of WM tracts. Moreover, hearing impairment was correlated with a high level of CSF tau protein in the CABLE study and in the ADNI database. Finally, mediation analyses showed that brain atrophy and tau pathology partly mediated the association between hearing impairment and cognitive decline. Hearing impairment is associated with cognitive decline, brain atrophy and tau pathology, and hearing impairment may reflect the risk for cognitive decline and dementia as it is related to bran atrophy and tau accumulation in brain. However, it is necessary to assess the mechanism in future animal studies. A full list of funding bodies that supported this study can be found in the Acknowledgements section. [Abstract copyright: Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

Performance Measures Based on How Adults With Cancer Feel and Function: Stakeholder Recommendations and Feasibility Testing in Six Cancer Centers

PURPOSE Patient-reported outcome measures (PROMs) that assess how patients feel and function have potential for evaluating quality of care. Stakeholder recommendations for PRO-based performance measures (PMs) were elicited, and feasibility testing was conducted at six cancer centers. METHODS Interviews were conducted with 124 stakeholders to determine priority symptoms and risk adjustment variables for PRO-PMs and perceived acceptability. Stakeholders included patients and advocates, caregivers, clinicians, administrators, and thought leaders. Feasibility testing was conducted in six cancer centers. Patients completed PROMs at home 5-15 days into a chemotherapy cycle. Feasibility was operationalized as $75$ 75% patient acceptability. RESULTS Stakeholder priority PRO-PMs for systemic therapy were GI symptoms (diarrhea, constipation, nausea, vomiting), depression/anxiety, pain, insomnia, fatigue, dyspnea, physical function, and neuropathy. Recommended risk adjusters included demographics, insurance type, cancer type, comorbidities, emetic risk, and difficulty paying bills. In feasibility testing, 653 patients enrolled (approximately 110 per site), and 607 (93%) completed PROMs, which indicated high feasibility for home collection. The majority of patients (470 of 607; 77%) completed PROMs without a reminder call, and 137 (23%) of 607 completed them after a reminder call. Most patients (72%) completed PROMs through web, 17% paper, or 2% interactive voice response (automated call that verbally asked patient questions). For acceptability, . 95% of patients found PROM items to be easy to understand and complete. CONCLUSION Clinicians, patients, and other stakeholders agree that PMs that are based on how patients feel and function would be an important addition to quality measurement. This study also shows that PRO-PMs can be feasibly captured at home during systemic therapy and are acceptable to patients. PRO-PMs may add value to the portfolio of PMs as oncology transitions from fee-for-service payment models to performance-based care that emphasizes outcome measures

Upregulation of the Wnt Co-Receptor LRP6 Promotes Hepatocarcinogenesis and Enhances Cell Invasion

Background: Activation of the Wnt/b-catenin signaling pathway plays a crucial role in hepatocellular carcinoma (HCC). Lowdensity lipoprotein (LDL) receptor-related protein-6 (LRP6) is one of the co-receptors of the Wnt/b-catenin pathway and forms a signaling complex with Wnt ligand and Frizzled receptor to activate downstream signaling. However, the role of LRP6 in hepatocarcinogenesis is unclear. In this study, we examined its expression and roles in human HCC. Methodology/Principal Findings: Using real-time quantitative RT-PCR, we found that LRP6 was frequently (45%) overexpressed in human HCCs (P = 0.003). In vitro studies showed that ectopic expression of LRP6 increased the protein level of b-catenin. Moreover, overexpression of the full-length and constitutively active LRP6, respectively, activated the WNT/b-catenin signaling pathway, as shown by the TCF/b-catenin reporter assay. With regard to the effects of LRP6 overexpression in HCC cells, stable overexpression of the constitutively active LRP6 in BEL-7402 HCC cells enhanced cell proliferation, cell migration, and invasion in vitro as well as tumorigenicity in nude mice. Conclusions/Significance: Our findings indicate that overexpression of LRP6 contributes to the hyperactivation of the Wnt

Deleted in Liver Cancer 2 (DLC2) Was Dispensable for Development and Its Deficiency Did Not Aggravate Hepatocarcinogenesis

DLC2 (deleted in liver cancer 2), a Rho GTPase-activating protein, was previously shown to be underexpressed in human hepatocellular carcinoma and has tumor suppressor functions in cell culture models. We generated DLC2-deficient mice to investigate the tumor suppressor role of DLC2 in hepatocarcinogenesis and the function of DLC2 in vivo. In this study, we found that, unlike homologous DLC1, which is essential for embryonic development, DLC2 was dispensable for embryonic development and DLC2-deficient mice could survive to adulthood. We also did not observe a higher incidence of liver tumor formation or diethylnitrosamine (DEN)-induced hepatocarcinogenesis in DLC2-deficient mice. However, we observed that DLC2-deficient mice were smaller and had less adipose tissue than the wild type mice. These phenotypes were not due to reduction of cell size or defect in adipogenesis, as observed in the 190B RhoGAP-deficient mouse model. Together, these results suggest that deficiency in DLC2 alone does not enhance hepatocarcinogenesis

Waist circumference and waist-to-height ratio of Hong Kong Chinese children

<p>Abstract</p> <p>Background</p> <p>Central body fat is a better predictor than overall body fat for cardiovascular (CV) risk factors in both adults and children. Waist circumference (WC) has been used as a proxy measure of central body fat. Children at high CV risk may be identified by WC measurements. Waist-to-height ratio (WHTR) has been proposed as an alternative, conveniently age-independent measure of CV risk although WHTR percentiles have not been reported. We aim to provide age- and sex-specific reference values for WC and WHTR in Hong Kong Chinese children.</p> <p>Methods</p> <p>Cross sectional study in a large representative sample of 14,842 children aged 6 to 18 years in 2005/6. Sex-specific descriptive statistics for whole-year age groups and smoothed percentile curves of WC and WHTR were derived and presented.</p> <p>Results</p> <p>WC increased with age, although less after age 14 years in girls. WHTR decreased with age (particularly up to age 14). WHTR correlated less closely than WC with BMI (r = 0.65, 0.59 cf. 0.93, 0.91, for boys and girls respectively).</p> <p>Conclusion</p> <p>Reference values and percentile curves for WC and WHRT of Chinese children and adolescents are provided. Both WC and WHTR are age dependent. Since the use of WHRT does not obviate the need for age-related reference standards, simple WC measurement is a more convenient method for central fat estimation than WHRT.</p

Who wants a slimmer body? The relationship between body weight status, education level and body shape dissatisfaction among young adults in Hong Kong

Background: Body shape dissatisfaction has been thought to have an indispensable impact on weight control behaviors. We investigated the prevalence of body shape dissatisfaction (BSD) and explored its association with weight status, education level and other determinants among young adults in Hong Kong. Methods. Information on anthropometry, BSD, and socio-demographics was collected from a random sample of 1205 young adults (611 men and 594 women) aged 18-27 in a community-based household survey. BSD was defined as a discrepancy between current and ideal body shape based on a figure rating scale. Cross-tabulations, homogeneity tests and logistic regression models were applied. Results: The percentages of underweight men and women were 16.5% and 34.9% respectively, and the corresponding percentages of being overweight or obese were 26.7% and 13.2% for men and women respectively. Three-quarters of young adults had BSD. Among women, 30.9% of those underweight and 75.5% of those with normal weight desired a slimmer body shape. Overweight men and underweight women with lower education level were more likely to have a mismatch between weight status and BSD than those with higher education level. After controlling for other determinants, underweight women were found to have a higher likelihood to maintain their current body shapes than other women. Men were found to be less likely to have a mismatch between weight status and BSD than women. Conclusions: Overweight and obesity in men and underweight in women were prevalent among Hong Kong young adults. Inappropriate body shape desire might predispose individuals to unhealthy weight loss or gain behaviors. Careful consideration of actual weight status in body shape desire is needed in health promotion and education, especially for underweight and normal weight women and those with a low education level. © 2011 Cheung et al; licensee BioMed Central Ltd.published_or_final_versio

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes