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Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors.
J Med Chem
October 2023
D. E. Shaw Research, 120 W. 45th St., 39th Fl., New York, New York 10036, United States.
Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest in oncology, both for treating with a single agent and in combination with a KRAS inhibitor. We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation.
View Article and Find Full Text PDFContribution of LRP1 in Human Congenital Heart Disease Correlates with Its Roles in the Outflow Tract and Atrioventricular Cushion Development.
Genes (Basel)
April 2023
Department of Developmental Biology, School of Medicine, University of Pittsburgh, 530 45th St, Pittsburgh, PA 15201, USA.
Due to the prevalence of congenital heart disease in the human population, determining the role of variants in congenital heart disease (CHD) can give a better understanding of the cause of the disorder. A homozygous missense mutation in the LDL receptor-related protein 1 () in mice was shown to cause congenital heart defects, including atrioventricular septal defect (AVSD) and double outlet right ventricle (DORV). Integrative analysis of publicly available single-cell RNA sequencing (scRNA-seq) datasets and spatial transcriptomics of human and mouse hearts indicated that is predominantly expressed in mesenchymal cells and mainly located in the developing outflow tract and atrioventricular cushion.
View Article and Find Full Text PDFLearning from five bad arguments against mandatory vaccination.
Vaccine
May 2023
Perelman School of Medicine and The Wharton School, University of Pennsylvania, 423, Guardian Drive, Blockley Hall, Philadelphia, PA 19104-4884, USA.
Rare and Common Variants Uncover the Role of the Atria in Coarctation of the Aorta.
Genes (Basel)
April 2022
Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th St, Pittsburgh, PA 15201, USA.
Coarctation of the aorta (CoA) and bicuspid aortic valve (BAV) often cooccur and are genetically linked congenital heart defects (CHD). While CoA is thought to have a hemodynamic origin from ventricular dysfunction, we provide evidence pointing to atrial hemodynamics based on investigating the genetic etiology of CoA. Previous studies have shown a rare variant in an Icelandic cohort, and two common deletions in the protocadherin α cluster ( delCNVs) are significantly associated with CoA and BAV.
View Article and Find Full Text PDFThe energy of the lowest-lying triplet state (T1) relative to the ground and first-excited singlet states (S0, S1) plays a critical role in optical multiexcitonic processes of organic chromophores. Focusing on triplet-triplet annihilation (TTA) upconversion, the S0 to T1 energy gap, known as the triplet energy, is difficult to measure experimentally for most molecules of interest. predictions can provide a useful alternative, however low-scaling electronic structure methods such as the Kohn-Sham and time-dependent variants of Density Functional Theory (DFT) rely heavily on the fraction of exact exchange chosen for a given functional, and tend to be unreliable when strong electronic correlation is present.
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