Pan-KRAS inhibitors BI-2493 and BI-2865 display potent anti-tumor activity in tumors with KRAS wild-type allele amplification.

KRASG12C selective inhibitors, such as sotorasib and adagrasib, have raised hopes of targeting other KRAS mutant alleles in cancer patients. We report that KRAS wild-type amplified tumor models are sensitive to treatment with the small molecule KRAS inhibitors BI-2493 and BI-2865. These pan-KRAS inhibitors directly target the "OFF" state of KRAS and result in potent anti-tumor activity in pre-clinical models of cancers driven by KRAS mutant proteins.

Cytosolic S100A8/A9 promotes Ca supply at LFA-1 adhesion clusters during neutrophil recruitment.

S100A8/A9 is an endogenous alarmin secreted by myeloid cells during many acute and chronic inflammatory disorders. Despite increasing evidence of the proinflammatory effects of extracellular S100A8/A9, little is known about its intracellular function. Here, we show that cytosolic S100A8/A9 is indispensable for neutrophil post-arrest modifications during outside-in signaling under flow conditions in vitro and neutrophil recruitment in vivo, independent of its extracellular functions.

Utilizing artificial intelligence for the detection of hemarthrosis in hemophilia using point-of-care ultrasonography.

Background: Recurrent hemarthrosis and resultant hemophilic arthropathy are significant causes of morbidity in persons with hemophilia, despite the marked evolution of hemophilia care. Prevention, timely diagnosis, and treatment of bleeding episodes are key. However, a physical examination or a patient's assessment of musculoskeletal pain may not accurately identify a joint bleed.

Pediatric metameric cervical spinal cord arteriovenous malformation managed with staged endovascular and spinal stabilization approach: a case report.

Introduction: Spinal cord arteriovenous malformations (SCAVM) are rare congenital vascular malformations, characterized by two or more AVMs affecting any of the spinal segments. SCAVM has complex pathophysiology and may be associated with acute, or progressively neurological deficits.

Case Presentation: A 12-year old girl, presented with progressive neurologic deficits secondary to compressive cervical myelopathy due to a cervical metameric SCAVM.

Synergistic Multi-Pronged Interactions Mediate the Effective Inhibition of Alpha-Synuclein Aggregation by the Chaperone HtrA1.

Unlabelled: The misfolding, aggregation, and the seeded spread of alpha synuclein (α-Syn) aggregates are linked to the pathogenesis of various neurodegenerative diseases, including Parkinson's disease (PD). Understanding the mechanisms by which chaperone proteins prevent the production and seeding of α-Syn aggregates is crucial for developing effective therapeutic leads for tackling neurodegenerative diseases. We show that a catalytically inactive variant of the chaperone HtrA1 (HtrA1*) effectively inhibits both α-Syn monomer aggregation and templated fibril seeding, and demonstrate that this inhibition is mediated by synergistic interactions between its PDZ and Protease domains and α-Syn.