Predictors of mortality in hospitalized African American COVID-19 patients with cancer.

Background: Coronavirus disease 2019 (COVID-19) manifest differently depending on patients' background and pre-existing conditions. It remains unclear how African Americans with cancer have been affected in comparison to those without. In this study, we aim to identify demographic, clinical, and laboratory markers associated with mortality in COVID-19 patients with cancer. Methods: We reviewed all COVID-19 hospitalized patients' records from Dec. 2019 to Oct. 2021 at Howard University Hospital. Patients having a history of, or active, cancer were reviewed. Clinical, treatment, lab test values, and pathological data were extracted. Univariable and multivariable analyses were conducted on the entire cohort as well as on cases and controls separately, using SPSS software. Results: Out of 512 COVID-19 infected patients, 49 had cancer, either active or history of cancer (cases) and 463 COVID-19 were cancer-free (controls), allowing for comparison. African American race was predominant in both cases and controls, 83.7% and 66.7% respectively. Cancer patients were older than non-cancer patients (mean age: 70.6 vs. 56.3 years) and had an increased length of hospital stay (mean 13.9 vs. 9.4 days). Mortality is significantly higher among cancer patients (n=10, 20.4%, P=0.03) compared to non-cancer COVID-19 patients (n=41, 8.9%). Among cancer patients, breast cancer was more prevalent in females and prostate cancer in males (54% and 52%, respectively). A comparison of patients with active vs. previous cancer showed no significant difference in the clinical outcome, death vs. discharge (P=0.34). A higher reduction in albumin level in cancer cases, from the time of admission to day 5, was significantly associated with death during the hospital stay compared to those discharged (n=24, 49.0%, P<0.001). In controls, lymphopenia (n=436, 94.2%, P=0.05), aspartate aminotransferase (AST) (n=59, 12.7%, P=0.008) and albumin (n=40, 8.6%, P=0.02) have shown an association with increased mortality. Conclusions: Albumin level has an inverse relationship with clinical outcomes among all COVID-19 infected cancer patients. Reduction in albumin level during the hospital stay, particularly in COVID-19 cancer patients should be considered as a predictor of mortality. Further research with a large cohort size is needed to verify and identify other predictors of outcomes in COVID-19 patients with cancer.

Circulating Nucleic Acids in Colorectal Cancer: Diagnostic and Prognostic Value.

Colorectal cancer (CRC) is the third most prevalent cancer in the world and the fourth leading cause of cancer-related mortality. DNA (cfDNA/ctDNA) and RNA (cfRNA/ctRNA) in the blood are promising noninvasive biomarkers for molecular profiling, screening, diagnosis, treatment management, and prognosis of CRC. Technological advancements that enable precise detection of both genetic and epigenetic abnormalities, even in minute quantities in circulation, can overcome some of these challenges. This review focuses on testing for circulating nucleic acids in the circulation as a noninvasive method for CRC detection, monitoring, detection of minimal residual disease, and patient management. In addition, the benefits and drawbacks of various diagnostic techniques and associated bioinformatics tools have been detailed.

High-throughput sequencing and in-silico analysis confirm pathogenicity of novel MSH3 variants in African American colorectal cancer.

The maintenance of DNA sequence integrity is critical to avoid accumulation of cancer-causing mutations. Inactivation of DNA Mismatch Repair (MMR) genes (e.g., MLH1 and MSH2) is common among many cancers, including colorectal cancer (CRC) and is the driver of classic microsatellite instability (MSI) in tumors. Somatic MSH3 alterations have been linked to a specific form of MSI called elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) that is associated with patient poor prognosis and elevated among African American (AA) rectal cancer patients. Genetic variants of MSH3 and their pathogenicity vary among different populations, such as among AA, which are not well-represented in publicly available databases. Targeted exome sequencing of MSH3 among AA CRC samples followed by computational bioinformatic pipeline and molecular dynamic simulation analysis approach confirmed six identified MSH3 variants (c.G1237A, c.C2759T, c.G1397A, c.G2926A, c.C3028T, c.G3241A) that corresponded to MSH3 amino-acid changes (p.E413K; p.S466N; p.S920F; p.E976K; p.H1010Y; p.E1081K). All identified MSH3 variants were non-synonymous, novel, pathogenic, and show loss or gain of hydrogen bonding, ionic bonding, hydrophobic bonding, and disulfide bonding and have a deleterious effect on the structure of MSH3 protein. Some variants were located within the ATPase site of MSH3, affecting ATP hydrolysis that is critical for MSH3's function. Other variants were in the MSH3-MSH2 interacting domain, important for MSH3's binding to MSH2. Overall, our data suggest that these variants among AA CRC patients affect the function of MSH3 making them pathogenic and likely contributing to the development or advancement of CRC among AA. Further clarifying functional studies will be necessary to fully understand the impact of these variants on MSH3 function and CRC development in AA patients.

Ceramide promotes lytic reactivation of Epstein-Barr virus in gastric carcinoma.

Epstein-Barr virus (EBV) has a lifelong latency period after initial infection. Rarely, however, when the EBV immediate early gene BZLF1 is expressed by a specific stimulus, the virus switches to the lytic cycle to produce progeny viruses. We found that EBV infection reduced levels of various ceramide species in gastric cancer cells. As ceramide is a bioactive lipid implicated in the infection of various viruses, we assessed the effect of ceramide on the EBV lytic cycle. Treatment with C6-ceramide (C6-Cer) induced an increase in the endogenous ceramide pool and increased production of the viral product as well as BZLF1 expression. Treatment with the ceramidase inhibitor ceranib-2 induced EBV lytic replication with an increase in the endogenous ceramide pool. The glucosylceramide synthase inhibitor Genz-123346 inhibited C6-Cer-induced lytic replication. C6-Cer induced extracellular signal-regulated kinase 1/2 (ERK1/2) and CREB phosphorylation, c-JUN expression, and accumulation of the autophagosome marker LC3B. Treatment with MEK1/2 inhibitor U0126, siERK1&2, or siCREB suppressed C6-Cer-induced EBV lytic replication and autophagy initiation. In contrast, siJUN transfection had no impact on BZLF1 expression. The use of 3-methyladenine (3-MA), an inhibitor targeting class III phosphoinositide 3-kinases (PI3Ks) to inhibit autophagy initiation, resulted in reduced beclin-1 expression, along with suppressed C6-Cer-induced BZLF1 expression and LC3B accumulation. Chloroquine, an inhibitor of autophagosome-lysosome fusion, increased BZLF1 protein intensity and LC3B accumulation. However, siLC3B transfection had minimal effect on BZLF1 expression. The results suggest the significance of ceramide-related sphingolipid metabolism in controlling EBV latency, highlighting the potential use of drugs targeting sphingolipid metabolism for treating EBV-positive gastric cancer.IMPORTANCEEpstein-Barr virus remains dormant in the host cell but occasionally switches to the lytic cycle when stimulated. However, the exact molecular mechanism of this lytic induction is not well understood. In this study, we demonstrate that Epstein-Barr virus infection leads to a reduction in ceramide levels. Additionally, the restoration of ceramide levels triggers lytic replication of Epstein-Barr virus with increase in phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and CREB. Our study suggests that the Epstein-Barr virus can inhibit lytic replication and remain latent through reduction of host cell ceramide levels. This study reports the regulation of lytic replication by ceramide in Epstein-Barr virus-positive gastric cancer.

LOX-1 acts as an N6-methyladenosine-regulated receptor for Helicobacter pylori by binding to the bacterial catalase.

The role of N6-methyladenosine (m6A) modification of host mRNA during bacterial infection is unclear. Here, we show that Helicobacter pylori infection upregulates host m6A methylases and increases m6A levels in gastric epithelial cells. Reducing m6A methylase activity via hemizygotic deletion of methylase-encoding gene Mettl3 in mice, or via small interfering RNAs targeting m6A methylases, enhances H. pylori colonization. We identify LOX-1 mRNA as a key m6A-regulated target during H. pylori infection. m6A modification destabilizes LOX-1 mRNA and reduces LOX-1 protein levels. LOX-1 acts as a membrane receptor for H. pylori catalase and contributes to bacterial adhesion. Pharmacological inhibition of LOX-1, or genetic ablation of Lox-1, reduces H. pylori colonization. Moreover, deletion of the bacterial catalase gene decreases adhesion of H. pylori to human gastric sections. Our results indicate that m6A modification of host LOX-1 mRNA contributes to protection against H. pylori infection by downregulating LOX-1 and thus reducing H. pylori adhesion.

Kinesin Family Member B18 Is Related to Gastric Mucin Phenotype and Contributes to Gastric Cancer Progression by Regulating Epithelial-Mesenchymal Transition.

INTRODUCTION: Gastric cancer (GC) remains a common health concern worldwide and is the third leading cause of death in Japan. It can be broadly classified into gastric and intestinal mucin phenotypes using immunohistochemistry. We previously reported numerous associations of kinesin family member (KIF) genes and mucin phenotypes with GC. However, no previous studies have reported on the importance of KIF18B in GC using immunostaining. Thus, in this study, we investigated the expression and functions of KIF18B, which is highly expressed in gastric mucin phenotype GC. METHODS: We performed RNA-seq of gastric and intestinal mucin type GCs, and clinicopathological studies of the KIF18B we found were performed using 96 GC cases. We also performed functional analysis using GC-derived cell lines. RESULT: RNA-seq showed the upregulation of matrisome-associated genes in gastric mucin phenotype GC and a high expression of KIF18B. KIF18B was detected in 52 of the 96 GC cases (54%) through immunohistochemistry. Low KIF18B expression was significantly associated with poor overall survival (p < 0.01). Other molecules that were significantly associated with KIF18B were MUC5AC and claudin 18; these were also significantly associated with the gastric mucin phenotype. KIF18B small interfering RNA (siRNA)-transfected GC cells showed greater growth and spheroid colony formation than the negative control siRNA-transfected cells. Furthermore, expression of snail family transcriptional repressor 1 and cadherin 2 was significantly increased and that of cadherin 1 was significantly decreased in KIF18B siRNA-transfected GC cells. CONCLUSION: These findings not only suggest that KIF18B may be a useful prognostic marker, but also provide insight into the pathogenesis of the GC phenotype.

Exploring the Incidence and Associated Risk Factors of Barrett's Esophagus in African Americans: A Retrospective Study.

Background: The prevalence of Barrett's esophagus (BE) in African Americans (AA) is uncertain. However, several potential risk factors, includes family history, male sex, ethnicity, chronic heartburn and acid reflux, age over 60, current or past smoking, and obesity are associated with BE. The aim of this study is to determine the incidence of BE in AA patients who underwent Esophageal Gastro Endoscopy (EGD). Methods: Medical and demographic data of 1,253 AA patients with various symptoms, including BE, Esophageal adenocarcinoma (EAC), esophageal squamous adenocarcinoma (SCC), hiatal hernia, H. pylori infection, Gastro-Esophageal Reflux Disease (GERD), Gastritis, and esophagitis, were collected from January 2004 to December 2014 at Howard University Hospital. Results: Among the 1,253 patients, the median age was 61 and 49% were male out of the total. The frequencies of EAC (p= 0.05), and SCC (p= 0.002) were significantly high in males, along with SCC frequency significantly increased with older age (p<0.001). Furthermore, esophageal polyps with hiatal hernia (p=0.008) and H. pylori (p=<0.001) were found to be associated with esophagitis, and its presence may contribute to the development of BE. Conclusion: The findings highlighted the high prevalence of GERD symptoms and pathologic gastritis along with EAC was less common than SCC and both types of esophageal cancer were associated with male gender and older age whereas, H. pylori infection was identified as a risk factor for pathologic gastritis in AA. Overall data emphasize the need for extensive research, increased awareness, diagnosis, and management of GERD, gastritis, and related conditions to uncover the underlying mechanisms and factors contributing to these conditions in the AA population.

Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression.

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152 IMs) across 692 subjects from a prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell and spatial profiles highlight changes in tissue ecology and IM lineage heterogeneity, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes of IM associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to transform to GC. By highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression, our results raise opportunities for GC precision prevention and interception.

IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing.

Constant communication between mitochondria and nucleus ensures cellular homeostasis and adaptation to mitochondrial stress. Anterograde regulatory pathways involving a large number of nuclear-encoded proteins control mitochondrial biogenesis and functions. Such functions are deregulated in cancer cells, resulting in proliferative advantages, aggressive disease and therapeutic resistance. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein regulating AS of distinct gene subsets in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic and RNA-seq analyses of IQGAP1KO and parental cells show that IQGAP1KO alters an AS event of the mitochondrial respiratory chain complex I (CI) subunit NDUFS4 and downregulates a subset of CI subunits. In IQGAP1KO cells, CI intermediates accumulate, resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial CI activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 reverses mitochondrial defects of IQGAP1KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of CI activity through AS regulation in gastric cancer cells relying highly on mitochondrial respiration.

Microbiomic and Metabolomic Analyses Unveil the Protective Effect of Saffron in a Mouse Colitis Model.

Despite the existence of effective drugs used to treat inflammatory bowel disease (IBD), many patients fail to respond or lose response over time. Further, many drugs can carry serious adverse effects, including increased risk of infections and malignancies. Saffron (Crocus sativus) has been reported to have anti-inflammatory properties. Its protective role in IBD and how the microbiome and metabolome play a role has not been explored extensively. We aimed to establish whether saffron treatment modulates the host microbiome and metabolic profile in experimental colitis. Colitis was induced in C57BL/6 mice with 3% DSS and treated with either saffron in a dose of 20 mg/kg body weight or vehicle through daily gavage. On day 10, stool pellets from mice were collected and analyzed to assess saffron's effect on fecal microbiota and metabolites through 16S rRNA sequencing and untargeted primary metabolite analysis. Saffron treatment maintained gut microbiota homeostasis by counter-selecting pro-inflammatory bacteria and maintained Firmicutes/Bacteroides ratio, which was otherwise disturbed by DSS treatment. Several metabolites (uric acid, cholesterol, 2 hydroxyglutaric acid, allantoic acid, 2 hydroxyhexanoic acid) were altered significantly with saffron treatment in DSS-treated mice, and this might play a role in mediating saffron's colitis-mitigating effects. These data demonstrate saffron's therapeutic potential, and its protective role is modulated by gut microbiota, potentially acting through changes in metabolites.

Comprehensive molecular phenotyping of ARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities.

OBJECTIVE: Gastric cancer (GC) is a leading cause of cancer mortality, with ARID1A being the second most frequently mutated driver gene in GC. We sought to decipher ARID1A-specific GC regulatory networks and examine therapeutic vulnerabilities arising from ARID1A loss. DESIGN: Genomic profiling of GC patients including a Singapore cohort (>200 patients) was performed to derive mutational signatures of ARID1A inactivation across molecular subtypes. Single-cell transcriptomic profiles of ARID1A-mutated GCs were analysed to examine tumour microenvironmental changes arising from ARID1A loss. Genome-wide ARID1A binding and chromatin profiles (H3K27ac, H3K4me3, H3K4me1, ATAC-seq) were generated to identify gastric-specific epigenetic landscapes regulated by ARID1A. Distinct cancer hallmarks of ARID1A-mutated GCs were converged at the genomic, single-cell and epigenomic level, and targeted by pharmacological inhibition. RESULTS: We observed prevalent ARID1A inactivation across GC molecular subtypes, with distinct mutational signatures and linked to a NFKB-driven proinflammatory tumour microenvironment. ARID1A-depletion caused loss of H3K27ac activation signals at ARID1A-occupied distal enhancers, but unexpectedly gain of H3K27ac at ARID1A-occupied promoters in genes such as NFKB1 and NFKB2. Promoter activation in ARID1A-mutated GCs was associated with enhanced gene expression, increased BRD4 binding, and reduced HDAC1 and CTCF occupancy. Combined targeting of promoter activation and tumour inflammation via bromodomain and NFKB inhibitors confirmed therapeutic synergy specific to ARID1A-genomic status. CONCLUSION: Our results suggest a therapeutic strategy for ARID1A-mutated GCs targeting both tumour-intrinsic (BRD4-assocatiated promoter activation) and extrinsic (NFKB immunomodulation) cancer phenotypes.

Mechanism of Antitumor Effects of Saffron in Human Prostate Cancer Cells.

Prostate cancer is the most common cancer and the second leading cause of cancer deaths among men in the USA. Several studies have demonstrated the antitumor properties of saffron in different types of cancers, including prostate cancer. The oral administration of saffron extract has been reported to have antitumor effects on aggressive prostate-cancer-cell-line-derived xenografts in nude male mice. The objective of this study was to carry out in vitro studies of saffron-treated prostate cancer cells to ascertain the effects of saffron on key intermediates in prostate carcinogenesis. Our studies demonstrated the significant inhibition of cell proliferation for androgen-sensitive prostate cancer cell lines via apoptotic pathways. We also demonstrate the statistically significant down-regulation of DNA methyltransferases (COMT, MGMT, EHMT2, and SIRT1 deacetylase) in saffron-treated prostate cancer cells. In addition, saffron-treated prostate cancer cells displayed a statistically significant dysregulation of DNA repair intermediates (WRN, p53, RECQ5, MST1R, and WDR70) in a time-dependent manner. Furthermore, Western blot analysis demonstrated that saffron treatment induced changes in the expression of other key genes (DNMT1, DNMT3b, MBD2, CD44, HDAC3, c-Myc, NF-kB, TNFα, AR, N-RAS, and PTEN) in prostate cancer cells. Collectively, our findings demonstrate the important mechanisms by which saffron mediates anti-tumor properties in prostate cancer. These findings suggest that the use of saffron supplements alongside standard treatment protocols may yield beneficial effects for individuals with prostate cancer.

Circ_CEA promotes the interaction between the p53 and cyclin-dependent kinases 1 as a scaffold to inhibit the apoptosis of gastric cancer.

Circular RNAs (circRNAs) have been reported to play essential roles in tumorigenesis and progression. This study aimed to identify dysregulated circRNAs in gastric cancer (GC) and investigate the functions and underlying mechanism of these circRNAs in GC development. Here, we identify circ_CEA, a circRNA derived from the back-splicing of CEA cell adhesion molecule 5 (CEA) gene, as a novel oncogenic driver of GC. Circ_CEA is significantly upregulated in GC tissues and cell lines. Circ_CEA knockdown suppresses GC progression, and enhances stress-induced apoptosis in vitro and in vivo. Mechanistically, circ_CEA interacts with p53 and cyclin-dependent kinases 1 (CDK1) proteins. It serves as a scaffold to enhance the association between p53 and CDK1. As a result, circ_CEA promotes CDK1-mediated p53 phosphorylation at Ser315, then decreases p53 nuclear retention and suppresses its activity, leading to the downregulation of p53 target genes associated with apoptosis. These findings suggest that circ_CEA protects GC cells from stress-induced apoptosis, via acting as a protein scaffold and interacting with p53 and CDK1 proteins. Combinational therapy of targeting circ_CEA and chemo-drug caused more cell apoptosis, decreased tumor volume and alleviated side effect induced by chemo-drug. Therefore, targeting circ_CEA might present a novel treatment strategy for GC.

The scaffolding protein flot2 promotes cytoneme-based transport of wnt3 in gastric cancer.

The Wnt/ß-catenin signalling pathway regulates multiple cellular processes during development and many diseases, including cell proliferation, migration, and differentiation. Despite their hydrophobic nature, Wnt proteins exert their function over long distances to induce paracrine signalling. Recent studies have identified several factors involved in Wnt secretion; however, our understanding of how Wnt ligands are transported between cells to interact with their cognate receptors is still debated. Here, we demonstrate that gastric cancer cells utilise cytonemes to transport Wnt3 intercellularly to promote proliferation and cell survival. Furthermore, we identify the membrane-bound scaffolding protein Flotillin-2 (Flot2), frequently overexpressed in gastric cancer, as a modulator of these cytonemes. Together with the Wnt co-receptor and cytoneme initiator Ror2, Flot2 determines the number and length of Wnt3 cytonemes in gastric cancer. Finally, we show that Flotillins are also necessary for Wnt8a cytonemes during zebrafish embryogenesis, suggesting a conserved mechanism for Flotillin-mediated Wnt transport on cytonemes in development and disease.

Saffron, Its Active Components, and Their Association with DNA and Histone Modification: A Narrative Review of Current Knowledge.

Intensive screening for better and safer medications to treat diseases such as cancer and inflammatory diseases continue, and some phytochemicals have been discovered to have anti-cancer and many therapeutical activities. Among the traditionally used spices, Crocus sativus (saffron) and its principal bioactive constituents have anti-inflammatory, antioxidant, and chemopreventive properties against multiple malignancies. Early reports have shown that the epigenetic profiles of healthy and tumor cells vary significantly in the context of different epigenetic factors. Multiple components, such as carotenoids as bioactive dietary phytochemicals, can directly or indirectly regulate epigenetic factors and alter gene expression profiles. Previous reports have shown the interaction between active saffron compounds with linker histone H1. Other reports have shown that high concentrations of saffron bind to the minor groove of calf thymus DNA, resulting in specific structural changes from B- to C-form of DNA. Moreover, the interaction of crocin G-quadruplex was reported. A recent in silico study has shown that residues of SIRT1 interact with saffron bio-active compounds and might enhance SIRT1 activation. Other reports have shown that the treatment of Saffron bio-active compounds increases γH2AX, decreases HDAC1 and phosphorylated histone H3 (p-H3). However, the question that still remains to be addressed how saffron triggers various epigenetic changes? Therefore, this review discusses the literature published till 2022 regarding saffron as dietary components and its impact on epigenetic mechanisms. Novel bioactive compounds such as saffron components that lead to epigenetic alterations might be a valuable strategy as an adjuvant therapeutic drug.

Inflammation, microbiome and colorectal cancer disparity in African-Americans: Are there bugs in the genetics?

Dysregulated interactions between host inflammation and gut microbiota over the course of life increase the risk of colorectal cancer (CRC). While environmental factors and socio-economic realities of race remain predominant contributors to CRC disparities in African-Americans (AAs), this review focuses on the biological mediators of CRC disparity, namely the under-appreciated influence of inherited ancestral genetic regulation on mucosal innate immunity and its interaction with the microbiome. There remains a poor understanding of mechanisms linking immune-related genetic polymorphisms and microbiome diversity that could influence chronic inflammation and exacerbate CRC disparities in AAs. A better understanding of the relationship between host genetics, bacteria, and CRC pathogenesis will improve the prediction of cancer risk across race/ethnicity groups overall.

Vimentin binds to a novel tumor suppressor protein, GSPT1-238aa, encoded by circGSPT1 with a selective encoding priority to halt autophagy in gastric carcinoma.

Circular RNAs (circRNAs) are covalently closed, endogenous molecules that are widespread in eukaryotes. Recent evidence indicates that circRNAs play important roles in carcinogenesis. Several circRNAs have been reported to comprise translatable RNA; however, whether circRNAs encode functional proteins remains unknown. In our study, circRNA sequencing was carried out using five pathologically diagnosed gastric carcinoma (GC) samples and their paired adjacent normal tissues, we characterized the circRNA GSPT1 (circGSPT1), which is expressed at low levels in GC. Antibody detections, and mass spectrometry were used to validate active circRNA translation. The spanning junction open reading frame in circGSPT1, driven by an internal ribosome entry site (IRES), encodes a functional peptide, termed GSPT1-238aa. Interestingly, GSPT1-238aa tends to select the start codon used to initiate translation. This is the first finding of selective translation driven by IRES. CircGSPT1 and GSPT1-238aa halted the proliferation, migration, and invasion in GC cells in vitro. We also confirmed that the vimentin/Beclin1/14-3-3 complex interacts with GSPT1-238aa and modulates autophagy via the PI3K/AKT/mTOR signaling pathway in GC cells. Our study reveals that GSPT1-238aa, a novel protein encoded by circGSPT1, halts GC tumorigenesis. We also provide insights into the function and underlying molecular mechanisms of GSPT1-238aa in GC and suggest that this protein represents a novel target for GC treatment.

Symptomatic, clinical and biomarker associations for mortality in hospitalized COVID-19 patients enriched for African Americans.

BACKGROUND AND AIMS: Initial reports on US COVID-19 showed different outcomes in different races. In this study we use a diverse large cohort of hospitalized COVID-19 patients to determine predictors of mortality. METHODS: We analyzed data from hospitalized COVID-19 patients (n = 5852) between March 2020- August 2020 from 8 hospitals across the US. Demographics, comorbidities, symptoms and laboratory data were collected. RESULTS: The cohort contained 3,662 (61.7%) African Americans (AA), 286 (5%) American Latinx (LAT), 1,407 (23.9%), European Americans (EA), and 93 (1.5%) American Asians (AS). Survivors and non-survivors mean ages in years were 58 and 68 for AA, 58 and 77 for EA, 44 and 61 for LAT, and 51 and 63 for AS. Mortality rates for AA, LAT, EA and AS were 14.8, 7.3, 16.3 and 2.2%. Mortality increased among patients with the following characteristics: age, male gender, New York region, cardiac disease, COPD, diabetes mellitus, hypertension, history of cancer, immunosuppression, elevated lymphocytes, CRP, ferritin, D-Dimer, creatinine, troponin, and procalcitonin. Use of mechanical ventilation (p = 0.001), shortness of breath (SOB) (p < 0.01), fatigue (p = 0.04), diarrhea (p = 0.02), and increased AST (p < 0.01), significantly correlated with death in multivariate analysis. Male sex and EA and AA race/ethnicity had higher frequency of death. Diarrhea was among the most common GI symptom amongst AAs (6.8%). When adjusting for comorbidities, significant variables among the demographics of study population were age (over 45 years old), male sex, EA, and patients hospitalized in New York. When adjusting for disease severity, significant variables were age over 65 years old, male sex, EA as well as having SOB, elevated CRP and D-dimer. Glucocorticoid usage was associated with an increased risk of COVID-19 death in our cohort. CONCLUSION: Among this large cohort of hospitalized COVID-19 patients enriched for African Americans, our study findings may reflect the extent of systemic organ involvement by SARS-CoV-2 and subsequent progression to multi-system organ failure. High mortality in AA in comparison with LAT is likely related to high frequency of comorbidities and older age among AA. Glucocorticoids should be used carefully considering the poor outcomes associated with it. Special focus in treating patients with elevated liver enzymes and other inflammatory biomarkers such as CRP, troponin, ferritin, procalcitonin, and D-dimer are required to prevent poor outcomes.