TAVR and cancer: machine learning-augmented propensity score mortality and cost analysis in over 30 million patients.

INTRODUCTION: Cardiovascular disease (CVD) and cancer are the top mortality causes globally, yet little is known about how the diagnosis of cancer affects treatment options in patients with hemodynamically compromising aortic stenosis (AS). Patients with cancer often are excluded from aortic valve replacement (AVR) trials including trials with transcatheter AVR (TAVR) and surgical AVR (SAVR). This study looks at how cancer may influence treatment options and assesses the outcome of patients with cancer who undergo SAVR or TAVR intervention. Additionally, we sought to quantitate and compare both clinical and cost outcomes for patients with and without cancer. METHODS: This population-based case-control study uses the most recent year available National Inpatient Sample (NIS (2016) from the United States Department of Health and Human Services' Agency for Healthcare Research and Quality (AHRQ). Machine learning augmented propensity score adjusted multivariable regression was conducted based on the likelihood of undergoing TAVR versus medical management (MM) and TAVR versus SAVR with model optimization supported by backward propagation neural network machine learning. RESULTS: Of the 30,195,722 total hospital admissions, 39,254 (0.13%) TAVRs were performed, with significantly fewer performed in patients with versus without cancer even in those of comparable age and mortality risk (23.82% versus 76.18%, p < 0.001) despite having similar hospital and procedural mortality. Multivariable regression in patients with cancer demonstrated that mortality was similar for TAVR, MM, and SAVR, though LOS and cost was significantly lower for TAVR versus MM and comparable for TAVR versus SAVR. Patients with prostate cancer constituted the largest primary cancer among TAVR patients including those with metastatic disease. There were no significant race or geographic disparities for TAVR mortality. DISCUSSION: Comparison of aortic valve intervention in patients with and without cancer suggests that interventions are underutilized in the cancer population. This study suggests that patients with cancer including those with metastasis have similar inpatient outcomes to patients without cancer. Further, patients who have symptomatic AS and those with higher risk aortic valve disease should be offered the benefit of intervention. Modern techniques have reduced intervention-related adverse events, provided improved quality of life, and appear to be cost effective; these advantages should not necessarily be denied to patients with co-existing cancer.

Glycogen synthase kinase-3 (Gsk-3) plays a fundamental role in maintaining DNA methylation at imprinted loci in mouse embryonic stem cells.

Glycogen synthase kinase-3 (Gsk-3) is a key regulator of multiple signal transduction pathways. Recently we described a novel role for Gsk-3 in the regulation of DNA methylation at imprinted loci in mouse embryonic stem cells (ESCs), suggesting that epigenetic changes regulated by Gsk-3 are likely an unrecognized facet of Gsk-3 signaling. Here we extend our initial observation to the entire mouse genome by enriching for methylated DNA with the MethylMiner kit and performing next-generation sequencing (MBD-Seq) in wild-type and Gsk-3α(-/-);Gsk-3ß(-/-) ESCs. Consistent with our previous data, we found that 77% of known imprinted loci have reduced DNA methylation in Gsk-3-deficient ESCs. More specifically, we unambiguously identified changes in DNA methylation within regions that have been confirmed to function as imprinting control regions. In many cases, the reduced DNA methylation at imprinted loci in Gsk-3α(-/-);Gsk-3ß(-/-) ESCs was accompanied by changes in gene expression as well. Furthermore, many of the Gsk-3-dependent, differentially methylated regions (DMRs) are identical to the DMRs recently identified in uniparental ESCs. Our data demonstrate the importance of Gsk-3 activity in the maintenance of DNA methylation at a majority of the imprinted loci in ESCs and emphasize the importance of Gsk-3-mediated signal transduction in the epigenome.

Heterotrimeric G-protein, Gα16, is a critical downstream effector of non-canonical Wnt signaling and a potent inhibitor of transformed cell growth in non small cell lung cancer.

G-protein-coupled receptors (GPCR) are the largest family of cell surface molecules that play important role/s in a number of biological and pathological processes including cancers. Earlier studies have highlighted the importance of Wnt7a signaling via its cognate receptor Frizzled9, a GPCR, in inhibition of cell proliferation, anchorage-independent growth, and reversal of transformed phenotype in non small cell lung cancer primarily through activation of the tumor suppressor, PPARγ. However, the G-protein effectors that couple to this important tumor suppressor pathway have not been identified, and are of potential therapeutic interest. In this study, by using two independent Wnt7a/Frizzled9-specific read-outs, we identify Gα16 as a novel downstream effector of Wnt7a/Frizzled9 signaling. Interestingly, Gα16 expression is severely down-regulated, both at the messenger RNA levels and protein levels, in many non small cell lung cancer cell lines. Additionally, through gene-specific knock-downs and expression of GTPase-deficient forms (Q212L) of Gα16, we also establish Gα16 as a novel regulator of non small cell lung cancer cell proliferation and anchorage-independent cell growth. Taken together, our data not only establish the importance of Gα16 as a critical downstream effector of the non-canonical Wnt signaling pathway but also as a potential therapeutic target for the treatment of non small cell lung cancer.