Combined inhibition of FGFR4 and VEGFR signaling enhances efficacy in FGF19 driven hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive liver malignancy that is difficult to treat with no approved biomarker based targeted therapies. FGF19-FGFR4 signaling blockade has been recently identified as a promising avenue for treatment of a subset of HCC patients. Using HCC relevant xenograft and PDX models, we show that Lenvatinib, an approved multi-kinase inhibitor, strongly enhanced the efficacy of FGFR4 inhibitor H3B-6527.

Sensitivity to splicing modulation of BCL2 family genes defines cancer therapeutic strategies for splicing modulators.

Dysregulation of RNA splicing by spliceosome mutations or in cancer genes is increasingly recognized as a hallmark of cancer. Small molecule splicing modulators have been introduced into clinical trials to treat solid tumors or leukemia bearing recurrent spliceosome mutations. Nevertheless, further investigation of the molecular mechanisms that may enlighten therapeutic strategies for splicing modulators is highly desired.

Splicing modulators act at the branch point adenosine binding pocket defined by the PHF5A-SF3b complex.

Pladienolide, herboxidiene and spliceostatin have been identified as splicing modulators that target SF3B1 in the SF3b subcomplex. Here we report that PHF5A, another component of this subcomplex, is also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074 and SF3B1-V1078 confer resistance to these modulators, suggesting a common interaction site.

Problem-Based Learning Discussion on Neuraxial Anesthesia in Parturients With Repaired Tetralogy of Fallot.

Introduction: Approximately 1% of all children born in the United States suffer from congenital heart disease, and 25% of those affected are born with critical congenital heart disease requiring surgical intervention. Advances in cardiac surgery have allowed an increasing number of patients with complex congenital heart disease to live into adulthood. It is important that anesthesiologists understand the particularities of providing safe clinical care for these patients in different situations.