Selective BH3-mimetics targeting BCL-2, BCL-X-L or MCL-1 induce severe mitochondrial perturbations

Abstract Induction of apoptosis by selective BH3-mimetics is currently investigated as a novel strategy for cancer treatment. Here, we report that selective BH3-mimetics induce apoptosis in a variety of hematological malignancies. Apoptosis is accompanied by severe mitochondrial toxicities upstream of caspase activation. Specifically, the selective BH3-mimetics ABT-199, A-1331852 and S63845, which target BCL-2, BCL-XL and MCL-1, respectively, induce comparable ultrastructural changes including mitochondrial swelling, a decrease of mitochondrial matrix density and severe loss of cristae structure. These shared effects on mitochondrial morphology indicate a similar function of these anti-apoptotic BCL-2 proteins in maintaining mitochondrial integrity and function.</jats:p

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma.

The BCL-2 specific inhibitor, venetoclax/ABT-199 has exhibited remarkable clinical activity in nearly all cases of chronic lymphocytic leukemia. In contrast, responses are usually much less in diffuse large B-cell lymphoma, despite high level expression of BCL-2 in over 40% of cases, indicating that co-expression of related anti-apoptotic BCL-2 family proteins may limit activity. We have investigated the roles of the BCL-2 proteins in diffuse large B-cell lymphoma cells using a panel of specific BCL-2 Homology 3 mimetics and identified subgroups of diffuse large B-cell lymphoma cells that exhibited marked and specific dependency on either BCL-2, BCL-XL or MCL-1 for survival. Dependency was associated with a sequestration of the pro-apoptotic proteins BIM, BAX and BAK selectively by the specific anti-apoptotic BCL-2 protein that was important for cellular survival. Sensitivity to BCL-2 Homology 3 mimetics was independent of genetic alterations involving the BCL-2 family and only partially correlated with protein expression levels. Treatment with ABT-199 displaced BAX and BIM from BCL-2, leading subsequently to BAK activation and apoptosis. In contrast, apoptosis induced by inhibiting BCL-XL with A1331852 was associated with a displacement of both BAX and BAK from BCL-XL and occurred independently of BIM. Finally, the MCL-1 inhibitor S63845 induced mainly BAX-dependent apoptosis mediated by a displacement of BAK, BIM and NOXA from MCL-1. In conclusion, our study indicates that in diffuse large B-cell lymphoma, the heterogeneous response to BCL-2 Homology 3 mimetics is mediated by selective interactions between BAX, BAK and anti-apoptotic BCL-2 proteins

The lowland stream monitoring dataset (KgM, Kleingewässer-Monitoring) 2018, 2019

Plant protection products in the environment are partly responsible for the progressive loss of biodiversity. The mostly insufficient ecological status of surface waters is often explained by habitat degradation and excessive nutrient input. But what role do plant protection products play in this context? The Kleingewässermonitoring (KgM) project provides a worldwide unique quantitative assessment of the impact of pesticides from diffuse agricultural sources on small and medium-sized streams. The dataset comprises 124 monitoring stream sections all over Germany covering a wide pollution gradient where consistent measurements were carried out in 2018 and 2019 during the major pesticide application period from April to July. These measurements include event-driven sampling to record surface rainfall-induced short-term peak concentrations in addition to regular grab sampling of pesticides and a wide range of other pollutants resulting in more than 1,000 water samples. All further relevant anthropogenic and environmental parameters reigning ecological stream quality were recorded comprehensively (morphological and stream bed structure, temperature, flow velocity, dissolved oxygen, pH, catchment land use, stream profile). The dataset also contains effect monitoring data featuring sampled invertebrate communities and bioassay analyses of water samples. The data enables an assessment of pesticide exposure and related effects as well as the analysis of complex causal relationships in streams