Search

Type 2 diabetes has emerged as an important risk factor for poor prognosis in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hyperglycemia can independently predispose the patients with SARS-CoV-2 to adverse outcomes, irrespective of the diagnosis of diabetes.1 Despite the accentuated risk, there is limited evidence about the complex interplay of undiagnosed diabetes and SARS-CoV-2 pneumonia on the clinical outcomes. We propose to investigate the cardiovascular events and clinical outcomes in patients with undiagnosed and type 2 diabetes hospitalized with SARS-CoV-2 pneumonia. Methods This retrospective study included patients hospitalized with SARS-CoV-2 pneumonia between March 7, 2020, through March 30, 2021. The diagnosis of SARS-CoV-2 pneumonia required a positive reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2, presence of new or worsening pulmonary infiltrates on computed tomography scan or chest X-ray, and at least one of the following: new or increased cough, a temperature of >37.8 °C or dyspnea. The diagnosis of undiagnosed diabetes was determined in patients with no previous history of diabetes and glycated hemoglobin (HbA1c) ≥ 6.5% (48 mmol/mol) or an admission serum glucose ≥ 200 mg/dL (≥ 11.1 mmol/mol). The outcomes included in-hospital cardiovascular events, intensive care unit (ICU) admissions and in-hospital mortality. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for association of undiagnosed diabetes and type 2 diabetes for individual outcomes. Results Among the 1,645 adults hospitalized with SARS-CoV-2 pneumonia, 107 (10.8%) patients were identified with undiagnosed diabetes and 634 (39%) had established diagnosis of type 2 diabetes. Patients with undiagnosed diabetes had increased odds of developing cardiovascular events (OR: 1.73, 95% CI 1. 07, 2.80), ICU admissions (OR: 1.61, 95% CI 1.10, 2.34), and mortality (OR: 1.77, 95% CI 1. 02, 3. 07), compared to patients type 2 diabetes and no diabetes. A prior history of type 2 diabetes was not significantly associated with primary study outcomes. Conclusions Patients with undiagnosed diabetes hospitalized with SARS-CoV-2 pneumonia have an increased risk of developing cardiovascular complications and overall poor clinical outcomes compared to patients with type 2 diabetes and no diabetes. Implementation of healthcare-wide strategies for screening and early intervention of prediabetes and diabetes are needed to improve the disease outcomes in the current pandemic and future public health threats. References Khunti, K., et al., COVID-19, Hyperglycemia, and New-Onset Diabetes. Diabetes Care, 2021. 44(12): p. 2645-2655. Presentation: Saturday, June 11, 2022 1:00 p.m. - 2:00 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Background Sedentary lifestyles and changes in diet are fueling the worldwide epidemic of obesity and the prevalence of NAFLD and insulin resistance (IR). It has been predicted that NAFLD and its more advanced form, nonalcoholic steatohepatitis (NASH) will be the next epidemic in chronic liver diseases, and NAFLD/NASH will soon replace viral hepatitis as the primary cause of end-stage liver failure and transplantation. NAFLD is a significant risk factor for IR and cardiovascular diseases, and it highlights the importance of finding a way to control the epidemic. CARF is a multifunctional stress-responsive gene and was found to be reduced in response to metabolic stress in the fatty liver of diet-induced obesity mice (DIO). We also showed that CARF expression was down-regulated in palmitate (PA)-treated HepG2 cells. In this study, we aim to understand the consequences of the reduced expression of CARF on the development of NAFLD. Methods We performed RNA seq, RT-PCR and western blotting (WB) to evaluate the effect of CARF knockdown on lipid metabolism in HepG2 cells. Differentially expressed genes were analyzed by gene sort enrichment analysis (GSEA) and Ingenuity Pathway Analysis (IPA) to identify the metabolic pathways affected by CARF depletion. Apoptosis was assessed by TUNEL assay. To induce ER stress, HepG2 cells were treated with thapsigargin and evaluated its effect on CARF. Results By performing Sh-RNA mediated CARF knockdown, RNA-seq analysis, RT-PCR, western blotting (WB), we were able to show that ER-stress and de-novo lipogenesis pathways were significantly affected in HepG2 cells. We showed that GRP78, CHOP, PERK, ERN1a, genes associated with ER-stress were upregulated in CARF-depleted HepG2 cells. Additionally, thapsigargin-induced ER stress was found to reduce the expression of CARF along with the increased expression of ER stress marker genes. We also showed that overexpression of CARF mitigated the thapsigargin-induced ER stress suggesting that CARF protects against ER stress in HepG2 cells. In addition, the genes associated with triglyceride biosynthesis GPAT3, GPAM were significantly upregulated, indicating that lipogenesis was triggered by silencing of CARF in HepG2 cells. BODIPY staining and TG assay confirmed that silencing of CARF enhanced triglyceride biosynthesis in HepG2 cells. Furthermore, we showed that the expression of antioxidant genes GPX2, GPX3, and TXRND3 decreased, resulting in enhanced oxidative stress and higher apoptosis in CARF depleted cells. Conclusion We identified novel roles of CARF regulating cellular ER-Stress, lipid metabolism, and oxidative stress, and its impairment in response to metabolic stress could lead to the development of NAFLD in obese patients with metabolic abnormalities. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:42 p.m. - 12:47 p.m.

Background Prostate cancer (PCa) is a leading cause of cancer-associated death among men worldwide. Although localized prostate cancer can be cured by surgery and radiation therapy, metastatic PCa remains a challenge. Androgen therapy (ADT) and androgen signaling inhibitors are the first line of therapy against PCa. However, resistance against these treatments develops, leading to the emergence of castration resistance prostate cancer (CRPC). Studies are required to identify the pathways that contribute to the emergence of CRPC and identify pharmaceutical targets. CARF is a putative transcription regulator reported to play a pivotal role in different cancers, including breast cancer and hepatocarcinoma. We observed that CARF is highly expressed in prostate tumors, but the biological function of CARF in PCa is unknown yet. Methods We performed RNA seq, RT-PCR, and western blot (WB) analyses to show how knockdown of CARF affects the global gene expression in PC3 cells. Gene sort enrichment analysis (GSEA) and Ingenuity Pathway Analysis (IPA) of differentially expressed genes were done to identify the cellular pathways affected upon silencing of CARF. Scratch assay and trans-well migration assay were conducted to show how CARF overexpression influences the motility of the cells. The effect of CARF on PC3 cells growth and proliferation was evaluated by colony-forming and MTT assays. In addition, we analyzed patient datasets to show the relevance of CARF expression, androgen signaling, and epithelial-mesenchymal transformation (EMT) pathways in PCa. Results The silencing of CARF inhibited the growth and proliferation of PC3 cells, suggesting the necessity of CARF for PC3 growth and survival. In agreement, overexpression of CARF enhanced the PC3 cells proliferation. We found that silencing of CARF reduced PC3 cells motility in trans-well assay. Mechanistically, RNA seq analysis after CARF knockdown uncovered that gene of AR signaling and EMT pathways were significantly altered in PC3 cells. RT-PCR and WB data confirmed that silencing of CARF enhanced E-cadherin expression and reduced the expression of N-cadherin in PC3 cells, suggesting that CARF regulates EMT in PCa. Silencing of CARF altered the AR-regulated metastatic genes expression in PC3 cells. Our data revealed that the expression of PMEPA1, a negative regulator of metastasis, was increased, but the expression of SGK1, an inducer of EMT, was decreased in CARF cells. Furthermore, CARF could regulate the prostaglandins metabolism by suppressing the expression of HGPD1 and triggering inflammation and angiogenesis in prostate cancer. Conclusion We conclude that by controlling the AR and EMT signaling pathways, CARF may play a crucial role in the development of metastatic CRPC. Future studies by integrating the RNA seq and Chip-Seq will uncover how CARF regulates the AR and EMT signaling pathways contributing to the development and progression of CRPC and paving a way to find a target for intervention. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:18 p.m. - 1:23 p.m.