Association of Genetic Variants Related to Combined Exposure to Higher Body Mass Index and Waist-to-Hip Ratio on Lifelong Cardiovascular Risk in UK Biobank

OBJECTIVE: This study examines the individual and combined association of body mass index (BMI) and 7 waist-to-hip ratio (WHR) with cardiovascular diseases (CVD) risk using genetic scores of the 8 obesity measurements as proxies. DESIGN: A 2×2 factorial analysis approach was applied, with participants divided into four groups of lifetime exposure to low BMI and WHR, high BMI, high WHR, and high BMI and WHR based on weighted genetic risk scores. The difference in CVD risk across groups was evaluated using multivariable logistic regression. SETTING: Cohort study. PARTICIPANTS: A total of 408,003 participants were included from the prospective observational UK Biobank study. RESULTS: A total of 58,429 of CVD events were recorded. Compared to the low BMI and WHR genetic scores group, higher BMI or higher WHR genetic scores were associated with an increase in CVD risk (high BMI: odds ratio (OR), 1.07; 95%CI, 1.04-1.10; high WHR: OR, 1.12; 95%CI, 1.09-1.16). A weak additive effect on CVD risk was found between BMI and WHR (high BMI and WHR: OR, 1.16; 95%CI, 1.12-1.19). Subgroup analysis showed similar patterns between different sex, age (<65, ≥65 years old), smoking status, Townsend deprivation index, fasting glucose level and medication uses, but lower systolic blood pressure was associated with higher CVD risk in obese participants. CONCLUSIONS: High BMI or WHR were associated with increased CVD risk, and their effects are weakly additive. Even though there were overlapping of effect, both BMI and WHR are important in assessing the CVD risk in the general population

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Whole-genome sequencing reveals potent therapeutic strategy for monomorphic epitheliotropic intestinal T-cell lymphoma

10.1182/bloodadvances.2020001782BLOOD ADVANCES4194769-477

Oncogenic activation of the stat3 pathway drives pd-l1 expression in natural killer/t-cell lymphoma

Mature T-cell lymphomas, including peripheral T-cell lymphoma (PTCL) and extranodal NK/T-cell lymphoma (NKTL), represent a heterogeneous group of non-Hodgkin lymphomas with dismal outcomes and limited treatment options. To determine the extent of involvement of the JAK/STAT pathway in this malignancy, we performed targeted capture sequencing of 188 genes in this pathway in 171 PTCL and NKTL cases. A total of 272 nonsynonymous somatic mutations in 101 genes were identified in 73% of the samples, including 258 single-nucleotide variants and 14 insertions or deletions. Recurrent mutations were most frequently located in STAT3 and TP53 (15%), followed by JAK3 and JAK1 (6%) and SOCS1 (4%). A high prevalence of STAT3 mutation (21%) was observed specifically in NKTL. Novel STAT3 mutations (p.D427H, E616G, p.E616K, and p.E696K) were shown to increase STAT3 phosphorylation and transcriptional activity of STAT3 in the absence of cytokine, in which p.E616K induced programmed cell death-ligand 1 (PD-L1) expression by robust binding of activated STAT3 to the PD-L1 gene promoter. Consistent with these findings, PD-L1 was overexpressed in NKTL cell lines harboring hotspot STAT3 mutations, and similar findings were observed by the overexpression of p.E616K and p.E616G in the STAT3 wild-type NKTL cell line. Conversely, STAT3 silencing and inhibition decreased PD-L1 expression in STAT3 mutant NKTL cell lines. In NKTL tumors, STAT3 activation correlated significantly with PD-L1 expression. We demonstrated that STAT3 activation confers high PD-L1 expression, which may promote tumor immune evasion. The combination of PD-1/PD-L1 antibodies and STAT3 inhibitors might be a promising therapeutic approach for NKTL, and possibly PTCL.ASTAR (Agency for Sci., Tech. and Research, S’pore)NMRC (Natl Medical Research Council, S’pore)MOH (Min. of Health, S’pore

Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma

10.1182/blood-2018-01-829424BLOOD132111146-115

A composite single-nucleotide polymorphism prediction signature for extranodal natural killer/T-cell lymphoma

10.1182/blood.2020010637BLOOD1386452-463Complete

A genomic-augmented multivariate prognostic model for the survival of Natural-killer/T-cell lymphoma patients from an international cohort.

10.1002/ajh.26636Am J Hemato

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field