IGLV3-21∗01 is an inherited risk factor for CLL through the acquisition of a single-point mutation enabling autonomous BCR signaling

© 2020 National Academy of Sciences. All rights reserved. The prognosis of chronic lymphocytic leukemia (CLL) depends on different markers, including cytogenetic aberrations, oncogenic mutations, and mutational status of the immunoglobulin (Ig) heavy-chain variable (IGHV) gene. The number of IGHV mutations distinguishes mutated (M) CLL with a markedly superior prognosis from unmutated (UM) CLL cases. In addition, B cell antigen receptor (BCR) stereotypes as defined by IGHV usage and complementaritydetermining regions (CDRs) classify ∼30% of CLL cases into prognostically important subsets. Subset 2 expresses a BCR with the combination of IGHV3-21-derived heavy chains (HCs) with IGLV3- 21-derived light chains (LCs), and is associated with an unfavorable prognosis. Importantly, the subset 2 LC carries a single-point mutation, termed R110, at the junction between the variable and constant LC regions. By analyzing 4 independent clinical cohorts through BCR sequencing and by immunophenotyping with antibodies specifically recognizing wild-type IGLV3-21 and R110-mutated IGLV3-21 (IGLV3-21R110), we show that IGLV3-21R110-expressing CLL represents a distinct subset with poor prognosis independent of IGHV mutations. Compared with other alleles, only IGLV3-21∗01 facilitates effective homotypic BCR-BCR interaction that results in autonomous, oncogenic BCR signaling after acquiring R110 as a single-point mutation. Presumably, this mutation acts as a standalone driver that transforms IGLV3-21∗01-expressing B cells to develop CLL. Thus, we propose to expand the conventional definition of CLL subset 2 to subset 2L by including all IGLV3-21R110-expressing CLL cases regardless of IGHV mutational status. Moreover, the generation ofmonoclonal antibodies recognizing IGLV3-21 or mutated IGLV3-21R110 facilitates the recognition of B cells carrying this mutation in CLL patients or healthy donors

Human cell dedifferentiation in mesenchymal condensates through controlled autophagy

Tissue and whole organ regeneration is a dramatic biological response to injury that occurs across different plant and animal phyla. It frequently requires the dedifferentiation of mature cells to a condensed mesenchymal blastema, from which replacement tissues develop. Human somatic cells cannot regenerate in this way and differentiation is considered irreversible under normal developmental conditions. Here, we sought to establish in vitro conditions to mimic blastema formation by generating different three-dimensional (3D) condensates of human mesenchymal stromal cells (MSCs). We identified specific 3D growth environments that were sufficient to dedifferentiate aged human MSCs to an early mesendoderm-like state with reversal of age-associated cell hypertrophy and restoration of organized tissue regenerating capacity in vivo. An optimal auophagic response was required to promote cytoplasmic remodeling, mitochondrial regression, and a bioenergetic shift from oxidative phosphorylation to anaerobic metabolism. Our evidence suggests that human cell dedifferentiation can be achieved through autonomously controlled autophagic flux

Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion.

Mycobacterium tuberculosis (MTB) remains a major challenge to global health made worse by the spread of multidrug resistance. We therefore examined whether stimulating intracellular killing of mycobacteria through pharmacological enhancement of macroautophagy might provide a novel therapeutic strategy. Despite the resistance of MTB to killing by basal autophagy, cell-based screening of FDA-approved drugs revealed two anticonvulsants, carbamazepine and valproic acid, that were able to stimulate autophagic killing of intracellular M. tuberculosis within primary human macrophages at concentrations achievable in humans. Using a zebrafish model, we show that carbamazepine can stimulate autophagy in vivo and enhance clearance of M. marinum, while in mice infected with a highly virulent multidrug-resistant MTB strain, carbamazepine treatment reduced bacterial burden, improved lung pathology and stimulated adaptive immunity. We show that carbamazepine induces antimicrobial autophagy through a novel, evolutionarily conserved, mTOR-independent pathway controlled by cellular depletion of myo-inositol. While strain-specific differences in susceptibility to in vivo carbamazepine treatment may exist, autophagy enhancement by repurposed drugs provides an easily implementable potential therapy for the treatment of multidrug-resistant mycobacterial infection

Are adolescents with high socioeconomic status more likely to engage in alcohol and illicit drug use in early adulthood?

<p>Abstract</p> <p>Background</p> <p>Previous literature has shown a divergence by age in the relationship between socioeconomic status (SES) and substance use: adolescents with low SES are more likely to engage in substance use, as are adults with high SES. However, there is growing evidence that adolescents with high SES are also at high risk for substance abuse. The objective of this study is to examine this relationship longitudinally, that is, whether wealthier adolescents are more likely than those with lower SES to engage in substance use in early adulthood.</p> <p>Methods</p> <p>The study analyzed data from the National Longitudinal Survey of Adolescent Health (AddHealth), a longitudinal, nationally-representative survey of secondary school students in the United States. Logistic regression models were analyzed examining the relationship between adolescent SES (measured by parental education and income) and substance use in adulthood, controlling for substance use in adolescence and other covariates.</p> <p>Results</p> <p>Higher parental education is associated with higher rates of binge drinking, marijuana and cocaine use in early adulthood. Higher parental income is associated with higher rates of binge drinking and marijuana use. No statistically significant results are found for crystal methamphetamine or other drug use. Results are not sensitive to the inclusion of college attendance by young adulthood as a sensitivity analysis. However, when stratifying by race, results are consistent for white non-Hispanics, but no statistically significant results are found for non-whites. This may be a reflection of the smaller sample size of non-whites, but may also reflect that these trends are driven primarily by white non-Hispanics.</p> <p>Conclusions</p> <p>Previous research shows numerous problems associated with substance use in young adults, including problems in school, decreased employment, increases in convictions of driving under the influence (DUI) and accidental deaths. Much of the previous literature is focused on lower SES populations. Therefore, it is possible that teachers, parents and school administrators in wealthier schools may not perceive as great to address substance abuse treatment in their schools. This study can inform teachers, parents, school administrators and program officials of the need for addressing drug abuse prevention activities to this population of students.</p

MASked-unconTrolled hypERtension management based on office BP or on ambulatory blood pressure measurement (MASTER) Study: a randomised controlled trial protocol.

Masked uncontrolled hypertension (MUCH) carries an increased risk of cardiovascular (CV) complications and can be identified through combined use of office (O) and ambulatory (A) blood pressure (BP) monitoring (M) in treated patients. However, it is still debated whether the information carried by ABPM should be considered for MUCH management. Aim of the MASked-unconTrolled hypERtension management based on OBP or on ambulatory blood pressure measurement (MASTER) Study is to assess the impact on outcome of MUCH management based on OBPM or ABPM