Mu opioid receptor agonists with a preference for the non-GTP-bound state of the G protein promote GTP release, thereby potentiating antinociceptive effects of drugs such as morphine and fentanyl with...

In a trial involving 45 clinics and 15,596 visits, the use of an AI-based screening tool applied to ECG for opportunistic detection of advanced chronic liver disease led to a significant increase in n...

Beneficial effects of fasting combined with endocrine therapy for oestrogen receptor-α-expressing breast cancers can be recapitulated using exogenous glucocorticoid receptor ligands instead of fasting...

“We can no longer lend our credibility to an organization that has lost its integrity,” write four scientists and administrators who recently resigned from the NIH.

Abstract. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor type with poor patient outcomes. Most patients present with metastatic disease, which generally has reduced immune infiltration...

This review discusses current evidence about the therapeutic use of cannabis and cannabinoids in adults, potential harms, and evidence-based clinical guidance, including pretreatment screening and add...

In this Consensus Statement, an international panel of experts present an overview of the latest developments in the field of cholangiocarcinoma. A set of consensus recommendations and research priori...

Protein kinases catalyze the transfer of phosphate groups from ATP to specific substrates, initiating, modulating, or terminating signaling cascades. …

Interactions between cancer cells and surrounding stromal cells are critical for tumor biology and treatment response. We compare drug screening resul…

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...