The mutational profiles and corresponding therapeutic implications of PI3K mutations in cancer.

Genetic alterations of the PIK3CA gene, encoding the p110α catalytic subunit of PI3Kα enzyme, are found in a broad spectrum of human cancers. Many cancer-associated PIK3CA mutations occur at 3 hotspot locations and are termed canonical mutations. Canonical mutations result in hyperactivation of PI3K and promote oncogenesis via the PI3K/AKT/mTOR and PI3K/COX-2/PGE2 signaling pathways. These mutations also may serve as predictive biomarkers of response to PI3K inhibitors, as well as NSAID therapy. A large number of non-canonical PIK3CA mutations have also been identified in human tumors, but their functional properties are poorly understood. Here we review the landscape of PIK3CA mutations in different cancers and efforts underway to define the functional properties of non-canonical PIK3CA mutations. In addition, we summarize what has been learned from clinical trials of PI3K inhibitors as well as current trials incorporating these molecular targeting agents.

Significant increase in mortality and risk of acute ischemic stroke in infective endocarditis patients with subarachnoid hemorrhage secondary to mycotic aneurysms.

Infective Endocarditis (IE) patients are known to have a variety of complications with one of the rarest, but serious being cerebral mycotic aneurysm, which can result in subarachnoid hemorrhage (SAH). Using the National In-Patient Sample database, we sought to determine the rate of acute ischemic stroke (AIS) and outcomes in IE- patients with and without SAH. In total, we identified 82,844 IE-patients from 2010 to 2016, of which 641 had a concurrent diagnosis of SAH. IE patients with SAH had a more complicated course, higher mortality rate (OR 4.65 CI 95% 3.9-5.5, P < 0.001), and worse outcomes. This patient population also had a significantly higher rate of AIS (OR 6.3 CI 95% 5.4-7.4, P < 0.001). Overall, 41.5% of IE-patients with SAH had AIS during their hospitalization as compared to 10.1% of IE only patients. IE-patients with SAH were more likely to undergo endovascular treatment (3.6%) with 0.8% of the IE patients with AIS undergoing mechanical thrombectomy. While IE-patients are at risk for various complications, our study suggests a significant increase in the mortality and risk of AIS in those with SAH.

Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes.

Enzymes catalyze organic transformations with exquisite levels of selectivity, including chemoselectivity, stereoselectivity, and substrate selectivity, but the types of reactions catalyzed by enzymes are more limited than those of chemical catalysts. Thus, the convergence of chemical catalysis and biocatalysis can enable enzymatic systems to catalyze abiological reactions with high selectivity. Recently, we disclosed artificial enzymes constructed from the apo form of heme proteins and iridium porphyrins that catalyze the insertion of carbenes into a C-H bond. We postulated that the same type of Ir(Me)-PIX enzymes could catalyze the cyclopropanation of a broad range of alkenes with control of multiple modes of selectivity. Here, we report the evolution of artificial enzymes that are highly active and highly stereoselective for the addition of carbenes to a wide range of alkenes. These enzymes catalyze the cyclopropanation of terminal and internal, activated and unactivated, electron-rich and electron-deficient, conjugated and nonconjugated alkenes. In particular, Ir(Me)-PIX enzymes derived from CYP119 catalyze highly enantio- and diastereoselective cyclopropanations of styrene with ±98% ee, >70:1 dr, >75% yield, and ∼10,000 turnovers (TON), as well as 1,2-disubstituted styrenes with up to 99% ee, 35:1 dr, and 54% yield. Moreover, Ir(Me)-PIX enzymes catalyze cyclopropanation of internal, unactivated alkenes with up to 99% stereoselectivity, 76% yield, and 1300 TON. They also catalyze cyclopropanation of natural products with diastereoselectivities that are complementary to those attained with standard transition metal catalysts. Finally, Ir(Me)-PIX P450 variants react with substrate selectivity that is reminiscent of natural enzymes; they react preferentially with less reactive internal alkenes in the presence of more reactive terminal alkenes. Together, the studies reveal the suitability of Ir-containing P450s to combine the broad reactivity and substrate scope of transition metal catalysts with the exquisite selectivity of enzymes, generating catalysts that enable reactions to occur with levels and modes of activity and selectivity previously unattainable with natural enzymes or transition metal complexes alone.