Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent Activities in Mouse Models of Hematological and Solid Tumors.

Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound , that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments.

A Precarious Path to Partnership? The Moderating Effects of Labour Market Regulations on the Relationship Between Unstable Employment and Union Formation in Europe.

Rising employment uncertainty featured by higher risks of being temporarily employed or unemployed is often seen as the driving force behind delayed and declined partnering in Western countries. However, such an employment-partnering relationship is contextualized by labour market institutions and thus could diverge across countries over time. This paper aims to investigate how country-level variations in labour market regulations moderate individual-level effects of unstable employment on union formation, including the transitions into marriage or cohabitation unions.

Discovery of a Novel Potent EGFR Inhibitor Against EGFR Activating Mutations and On-Target Resistance in NSCLC.

Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) serve as the standard first-line therapy for EGFR-mutated non-small cell lung cancer (NSCLC). Despite the sustained clinical benefits achieved through optimal EGFR-TKI treatments, including the third-generation EGFR-TKI osimertinib, resistance inevitably develops. Currently, there are no targeted therapeutic options available postprogression on osimertinib.

Education and age trajectories of chronic conditions: Are tests of the cumulative advantage and disadvantage hypothesis biased by underreporting?

Objective: This study examined the impact of underreporting on tests of the cumulative advantage and disadvantage hypothesis (CAD), which predicts age-related increases in health disparities between individuals with higher and lower education.

Methods: Using the English Longitudinal Study of Ageing (ELSA), we identified underreporting by comparing self-reported hypertension and diabetes with biomedically measured hypertension (systolic blood pressure≥140 mm Hg and/or diastolic blood pressure≥90 mm Hg) and diabetes (fasting glucose level≥7 mmol/l and/or HbA1c≥6.5%).

Cross-sectoral impacts of the 2018-2019 Central European drought and climate resilience in the German part of the Elbe River basin.

Unlabelled: The 2018-2019 Central European drought was probably the most extreme in Germany since the early sixteenth century. We assess the multiple consequences of the drought for natural systems, the economy and human health in the German part of the Elbe River basin, an area of 97,175 km including the cities of Berlin and Hamburg and contributing about 18% to the German GDP. We employ meteorological, hydrological and socio-economic data to build a comprehensive picture of the drought severity, its multiple effects and cross-sectoral consequences in the basin.