Discovery of INCB159020, an Orally Bioavailable KRAS G12D Inhibitor.

The inhibition of mutant KRAS proteins has emerged as a promising approach for treating KRAS-driven cancers, as evidenced by the clinical success of KRAS G12C inhibitors. KRAS G12D, the most common mutant, promises significant expansion of the addressable patient population; however, the reduced nucleophilicity of aspartate compared to cysteine poses significant challenges in balancing sufficient potency with ADME properties to support oral exposure. Herein, we describe the discovery of KRAS G12D inhibitor (), which achieves oral exposure in nonhuman primate (NHP).

Diverse microbiome functions, limited temporal variation and substantial genomic conservation within sedimentary and granite rock deep underground research laboratories.

Background: Underground research laboratories (URLs) provide a window on the deep biosphere and enable investigation of potential microbial impacts on nuclear waste, CO and H stored in the subsurface. We carried out the first multi-year study of groundwater microbiomes sampled from defined intervals between 140 and 400 m below the surface of the Horonobe and Mizunami URLs, Japan.

Results: We reconstructed draft genomes for > 90% of all organisms detected over a four year period.

A multicontinental dataset of butterfly thermal physiological traits.

Butterflies serve as key indicators of climate change impacts such as shifts in emergence timing and shifts in geographic range and distribution. However, the development of commonly used ecological forecasts based on butterfly physiological tolerance of temperature change has lagged behind that of other taxonomic groups. Here, we provide a series of related datasets comprising butterfly thermal physiological traits to enable such forecasts.

Effects of Salt Concentration on a Magnetic Nanoparticle-Based Aggregation Assay with a Tunable Dynamic Range.

Magnetic nanoparticles (MNPs) can be functionalized with antibodies to give them an affinity for a biomarker of interest. Functionalized MNPs (fMNPs) cluster in the presence of a multivalent target, causing a change in their magnetization. Target concentration can be proportional to the 3rd harmonic phase of the fMNP magnetization signal.

Hypophosphatemia Correction Reduces ICANS Incidence and Duration in CAR T-cell Therapy: A Pooled Clinical Trial Analysis.

Unlabelled: A common complication of chimeric antigen receptor (CAR) T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS), which presents with encephalopathy, aphasia, inattention, somnolence, seizures, weakness, or cerebral edema. Despite its significant morbidity, there are currently no effective targeted treatments. Given the clinical similarities between ICANS and the neurological manifestations of acute hypophosphatemia, we retrospectively reviewed 499 patients treated with CD19-targeted CAR T-cell therapy across multiple clinical trials between 2015 and 2020.