Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma.

Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific deletion of KMT2D. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways, including glycolysis. KMT2D deficiency aberrantly upregulates glycolysis enzymes, intermediate metabolites, and glucose consumption rates. Mechanistically, KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states. Enhancer loss and subsequent repression of IGFBP5 activates IGF1R-AKT to increase glycolysis in KMT2D-deficient cells. Pharmacological inhibition of glycolysis and insulin growth factor (IGF) signaling reduce proliferation and tumorigenesis preferentially in KMT2D-deficient cells. We conclude that KMT2D loss promotes tumorigenesis by facilitating an increased use of the glycolysis pathway for enhanced biomass needs via enhancer reprogramming, thus presenting an opportunity for therapeutic intervention through glycolysis or IGF pathway inhibitors.

Fractional flow reserve to guide surgical coronary revascularization.

Coronary angiography has traditionally been used as the final diagnostic tool in the evaluation of coronary artery disease (CAD). However, conventional angiography identifies anatomically obstructive coronary disease, but it is limited in its ability to identify hemodynamically significant lesions. The emergence of fractional flow reserve (FFR) technology, in conjunction with angiography, offers a functional, as well as anatomic, assessment of epicardial coronary obstructions. Several pivotal studies have demonstrated that FFR-guided coronary revascularization is a safe and effective in patients with single and multivessel CAD. There are emerging data to suggest that FFR may also play an integral role in planning surgical revascularization and in the evaluation of post-coronary artery bypass patients and their graft patency. This review will explore the physiologic underpinnings of FFR methodology, its clinical value and limitations, and its applications in coronary artery bypass grafting (CABG) surgery.

Gender Differences in In-Hospital Outcomes After Coronary Artery Bypass Grafting.

Women historically have a greater risk of operative mortality than men after coronary artery bypass grafting (CABG). There is paucity of contemporary data in gender outcomes of surgical revascularization and understanding modifiable factors that contribute to gender differences are critical for quality improvement and practice change. We, therefore, sought to examine whether the gender gap in CABG outcomes is closing in the contemporary era by conducting a retrospective analysis from the Nationwide Inpatient Sample database from 2003 to 2012. We included all patients who underwent isolated CABG surgery (n = 2,272,998; female n = 623,423 [27.4%]; male n = 1,649,575 [72.6%]). The annual rate of CABG surgeries decreased by 53.7% in men and 57.8% in women over the 10-year study period. Although internal mammary artery use in women was less frequent than in men in 2003 (77.4% vs 81.9%, p <0.001), a significant uptrend closed this gap by 2012 (86.2% vs 87.0%, ptrend 0.003). Overall, unadjusted in-hospital mortality was greater in women (3.2% vs 1.8%, p <0.001). Female gender remained an independent predictor of mortality after multivariate adjustment (odds ratio 1.40, 95% CI 1.36 to 1.43, p <0.001) across all age groups. However, in-hospital mortality decreased at a faster rate in women (3.8% to 2.7%, RR -29.1%, ptrend 0.002) than in men (2.2% to 1.6%, RR -25.7%, ptrend <0.001) from 2003 to 2012. In conclusion, CABG rates in the United States are decreasing over time, yet in-hospital mortality continues to improve. Women have worse in-hospital outcomes than men; however, the gender gap is slowly closing.

Iron deficiency thrombocytopenia: a case report.

OBJECTIVE: To describe a rare case of thrombocytopenia secondary to iron deficiency. CLINICAL PRESENTATION AND INTERVENTION: A 34-year-old woman presented with severe microcytic hypochromic anemia and thrombocytopenia. Her ferritin was 1 ng/dl. A diagnosis of iron deficiency anemia and thrombocytopenia was made and the patient was treated with packed red blood cell transfusion and intravenous iron. Thrombocytopenia rapidly improved to normal. CONCLUSION: This case showed that iron deficiency should be considered as a cause of thrombocytopenia in the appropriate setting after ruling out common causes.