Human organoids provide physiologically relevant, 3D models for studying disease mechanisms, drug efficacy and toxicity. This Review examines organoid generation methods, applications in preclinical d...

This randomized clinical trial examines whether sodium bicarbonate infusion decreases day 90 all-cause mortality for patients with severe metabolic acidosis and moderate to severe acute kidney injury.

Adjuvant chemotherapy in stage III colon cancer provides uncertain benefit at the individual level. Circulating tumor DNA (ctDNA) may help refine risk-adjusted treatment selection. In this multicenter, randomized, phase 2/3 trial, patients with stage III colon cancer underwent ctDNA testing 5-6 week …

Dual cyclin A/B RxL inhibitors selectively kill small cell lung cancer cells and other cancer cells with high E2F activity.

Phosphoinositide signaling is a major cellular mechanism controlling cancer cell viability, proliferation, and survival. Yet, inhibition of lipid kinases that produce oncogenic phosphoinositides has a...

Tissue fibrosis arises from a critical imbalance between the production and breakdown of extracellular matrix (ECM) components. Whereas current strategies predominantly focus on curbing ECM production...

imageimageIn mouse spermatocytes, the X and Y chromosomes undergo rapid non-homologous synapsis and desynapsis during early pachynema. This study reveals that X-Y desynapsis initiated by the atypical ...

This Review summarizes the pathophysiology of adrenal insufficiency and approaches to diagnosis, treatment, and prevention of adrenal crisis.

Guo et al. perform a systematic assessment of genetic dependencies and cell surface targets in pancreatic adenocarcinoma, identifying biomarkers, mapping interpatient and intratumoral heterogeneity, a...

Hepatic and renal pathways are traditionally considered the primary routes of drug clearance. However, emerging evidence highlights the significant role of direct intestinal excretion of unchanged drugs and metabolites. Intestinal excretion is often unrecognized due to complications arising from unabsorbed drugs and direct biliary excretion. Consequently, the extent and mechanisms of intestinal excretion remain systematically underexplored. Using bile duct cannulated rats, we investigated intestinal excretion for a library of drugs and proposed a predicative decision tree based on molecular descriptors. Mechanistically, passive permeability and efflux transporters emerged as key drivers of intestinal excretion in rats. We also demonstrated that modulating a single functional group can alter the clearance pathways between intestinal and biliary excretion. The insights into intestinal excretion as a major clearance pathway for metabolically stable small-molecule drugs provide a more comprehensive understanding for drug clearance and offer new considerations for drug design and pharmacokinetic assessment.

Nature Medicine - Perspectives of biomedical trainees during a time of policy disruption

KRAS remains a challenging therapeutic target with limited effective inhibitors currently available. Here, we report the discovery of MCB-294, a potent dual-state pan-KRAS inhibitor capable of binding...

Oncogenic KRAS is a hallmark of pancreatic cancer, one of the deadliest malignancies, and inhibition of oncogenic KRAS alone is, in most patients, not sufficient to eradicate the tumor. The two studie...

Journal of General Internal Medicine -

Intrinsically disordered proteins and peptides play key roles in biology, but a lack of defined structures and high variability in sequence and conformational preferences have made targeting such syst...

High-throughput screening (HTS) remains central to small molecule lead discovery, but increasing assay complexity challenges the screening of large compound libraries. While retrospective studies have assessed active-learning-guided screening, extensive prospective validations are rare. Here, we report the first prospective evaluation of machine learning (ML)-assisted iterative HTS in a large-scale drug discovery project. Using a mass spectrometry-based assay for salt-inducible kinase 2, we screened just 5.9% of a two million-compound library in three batches and recovered 43.3% of all primary actives identified in a parallel full HTS─including all but one compound series selected by medicinal chemists. This demonstrates that ML-guided iterative screening can significantly reduce the experimental cost while maintaining hit discovery quality. Retrospective benchmarks further showed that the ML approach outperforms similarity-based methods in hit recovery and chemical space coverage. In summary, this study highlights the potential of ML-driven iterative HTS to improve efficiency also in large-scale drug discovery projects.

An AI-generated small-molecule inhibitor treats fibrosis in vivo and in phase I clinical trials.

Cholangiocarcinoma (CCA) is a highly lethal malignancy originating from the biliary tract and characterized with exposure to high levels of bile acids…

This randomized clinical trial compares the effectiveness of mailed self-collection kits, with and without patient navigation, to telephone reminders to increase cervical cancer screening in a safety-...

Journal of General Internal Medicine -