Fragment-based development of small molecule inhibitors targeting cholesterol metabolism.

( ) is the world's most deadly infectious pathogen and new drugs are urgently required to combat the emergence of multi-(MDR) and extensively-(XDR) drug resistant strains. The bacterium specifically upregulates sterol uptake pathways in infected macrophages and the metabolism of host-derived cholesterol is essential for long-term survival Here, we report the development of antitubercular small molecules that inhibit the cholesterol oxidases CYP125 and CYP142, which catalyze the initial step of cholesterol metabolism. An efficient biophysical fragment screen was used to characterize the structure-activity relationships of CYP125 and CYP142, and identify a non-azole small molecule that can bind to the heme cofactor of both enzymes.

The impact of deep response to ursodeoxycholic acid in primary biliary cholangitis - should it be the new clinical standard?

Purpose Of Review: This review explores the emerging concept of "deep response" in primary biliary cholangitis (PBC), defined by the normalization of biochemical markers, particularly alkaline phosphatase and bilirubin. It examines its potential as a new standard for disease management and its implications for long-term patient outcomes, health policies, and clinical decision-making.

Recent Findings: Recent studies suggest that achieving a deep response significantly improves long-term outcomes in some patients with PBC.

The cGAS-STING, p38 MAPK, and p53 pathways link genome instability to accelerated cellular senescence in ATM-deficient murine lung fibroblasts.

Ataxia-telangiectasia (A-T) is a pleiotropic genome instability syndrome resulting from the loss of the homeostatic protein kinase ATM. The complex phenotype of A-T includes progressive cerebellar degeneration, immunodeficiency, gonadal atrophy, interstitial lung disease, cancer predisposition, endocrine abnormalities, chromosomal instability, radiosensitivity, and segmental premature aging. Cultured skin fibroblasts from A-T patients exhibit premature senescence, highlighting the association between genome instability, cellular senescence, and aging.

The Impact of Tumor Stage and Histopathology on Survival Outcomes in Esophageal Cancer Patients over the Past Decade.

Background: Esophageal cancer (EC) is the sixth leading cause of cancer-related mortality worldwide, continuing to be a significant public health concern. The purpose of this study is to assess the impact of staging and histopathology of EC on associated mortality. The study also aims to further investigate clinical characteristics, prognostic factors, and survival outcomes in patients diagnosed with EC between 2010 and 2017.