Citations

The impact of coronavirus disease, 2019 (COVID-19), has been profound. Though COVID-19 primarily affects the respiratory system, it has also been associated with a wide range of cardiovascular (CV) manifestations portending extremely poor prognosis. The principal hypothesis for CV involvement is through direct myocardial infection and systemic inflammation. We conducted a systematic review of the current literature to provide a foundation for understanding the CV manifestations and outcomes of COVID-19. PubMed and EMBASE databases were electronically searched from the inception of the databases through 27 April 2020. A second literature review was conducted to include major trials and guidelines that were published after the initial search but before submission. The inclusion criteria for studies to be eligible were case reports, case series, and observation studies reporting CV outcomes among patients with COVID-19 infection. This review of the current COVID-19 disease and CV outcomes literature revealed a myriad of CV manifestations with potential avenues for treatment and prevention. Future studies are required to understand on a more mechanistic level the effect of COVID-19 on the myocardium and thus provide avenues to improve mortality and morbidity.

Abstract Background The availability of real-world data regarding the impact of the catheter ablation in patients with concomitant atrial flutter (AFL) and heart failure with preserved ejection fraction (HFpEF) is limited. Methods 2016 and 2017 National Readmission Database (NRD) was subjected to appropriate ICD-10 codes to identify and extract patients having coexistent atrial flutter and heart failure with preserved ejection fraction including who had undergone ablation. At 1 year, all-cause mortality was utilized as the primary outcome while readmissions due to AFL, heart failure (HF) and any other causes were designated as secondary outcomes. Kaplan Meier curves were used for a time to event analysis. Cox proportional hazard regression was used to generate hazard ratios. Results Out of a total 6099 patients with AFL and HFpEF, 906 (14.85%) underwent catheter ablation. At 1 year all cause mortality (3%, vs. 4.4%, HR: 0.661, 95% CI: 0.444–0.985, p=0.042) and readmissions due to AFL (2.3% vs. 5.3%, HR: 0.424, 95% CI: 0.272–0.661, p<0.001) were significantly less among ablation group. Readmission due to HF (9.3% vs. 9.7%, HR: 0.938, 95% CI: 0.745–1.182, p=0.587) and other causes (37% vs.40.3%, HR: 0.926, 95% CI: 0.825–1.040, p=0.193) did not show any significant difference in outcomes at the end of 1 year. Conclusion The utilization of catheter ablation amongst AFL patients with concomitant HFpEF showed a significant reduction in all-cause mortality and readmission due to AFL. However, it did not show any significant changes in readmissions due to HF or other causes at the end of one year. Outcomes of AFL and HFpEF Funding Acknowledgement Type of funding source: None

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium ( n Stage1 : 111,666; n Stage2 : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea ( PPM1J , EDEM3, ACP1, SPEG, EYA4, CYP1A1 , and ATXN2L ; P Stage1 <3.7×10 −7 ), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 ( P =5.4×10 −8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2 -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

Significance Cancer cells reprogram their metabolism for optimal growth and survival. AMPK-activated protein kinase (AMPK) is a key energy sensor that controls many metabolic pathways including metabolic reprogramming. However, its role in cancer is poorly understood. Some studies claim that it has a tumor suppressor role while others show its protumor role. Two AMPK-activating compounds (including metformin, now in many clinical trials) are widely used to suppress cancer cell proliferation. We found that AMPK is abundantly expressed in high-grade gliomas and, in contrast to popular belief, these two AMPK activators suppressed glioma cell proliferation through unique AMPK-independent mechanisms.

Abstract In order to identify novel targets and clinically exploitable vulnerabilities, we performed high-throughput RNA-interference (RNAi) synthetic lethality screening using myeloid cell lines TF-1 and ML-2 in combination with the hypomethylating agent 5-Azacytidine. A custom small interfering RNA (siRNA) library targeting nearly 1000 cancer-associated genes, including the human kinome, was utilized. Bcl-XL emerged as the strongest 5-Azacytidine sensitizing target in the erythroid cell line TF-1 but not in ML-2 cells. Additional siRNA sequences targeting Bcl-XL were transfected into a panel of myeloid cell lines and tested in drug dose response experiments using a ten-point serial dilution of 5-Azacytidine. The erythroid differentiated myeloid cell lines TF-1 and HEL both exhibited a 3 to 4-fold reduction in the IC50 of 5-Azacytidine upon knockdown of Bcl-XL, whereas IC50 values for non-erythroid, myeloid cell lines ML-2, THP-1 and MDS-L were unchanged. Furthermore, we tested lentiviral delivery of short-hairpin RNA (shRNA) targeting Bcl-XL in additional cell lines. Lentiviral knockdown of Bcl-XL confirmed 2 to 3-fold 5-Azacytidine sensitization in TF-1 and HEL cells while U937, HL-60, ML-2, THP-1 and MDS-L were not sensitized by Bcl-XL knockdown. Interestingly, while Bcl-XL knockdown with shRNA potentiated the effects of 5-Azacytidine in TF-1 and HEL, Bcl-XL knockdown alone resulted in considerable reductions in cell viability in TF-1 and HEL cells. These results demonstrate erythroid lineage-specific responses to Bcl-XL knockdown and suggest that Bcl-XL may represent an erythroid lineage-specific therapeutic vulnerability. To begin to explore this possibility we examined the putative BH3 mimetics Gossypol, Obatoclax and ABT-737 with 5-Azacytidine drug dose response experiments in myeloid cell lines. Neither Gossypol nor Obatoclax potentiated the effects of 5-Azacytdine. In striking contrast, ABT-737 resulted in a 2 to 4-fold reduction in the IC50 of 5-Azacytidine in all cell lines tested to date (TF-1, HEL, ML-2 and THP-1). ABT-737 sensitization to 5-Azacytidine was dose dependent. Furthermore, Combination Index (CI) values calculated with Calcusyn software demonstrate synergy between ABT-737 and 5-Azacytidine at clinically relevant concentrations. These results suggest that inhibition of anti-apoptotic Bcl-2 family members with a BH3 mimetic may represent an effective strategy for 5-Azacytidine combination therapy that can be directly translated into design of combination clinical trials in patients with myeloid leukemias. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-128.