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Prostate ; 81(15): 1107-1124, 2021 11.
Article in English | MEDLINE | ID: covidwho-1380409


BACKGROUND: The 27th Annual Prostate Cancer Foundation (PCF) Scientific Retreat was held virtually from October 20 to 23, 2020. METHODS: The Annual PCF Scientific Retreat is a global scientific research conference that highlights the most promising and cutting edge advances in prostate cancer basic, translational and clinical research, as well as research from other fields with a strong potential for advancing prostate cancer research. RESULTS: Primary areas of research discussed at the 2020 PCF Retreat included: (i) the intersection between prostate cancer and COVID-19 research; (ii) lessons from the COVID-19 pandemic that may address prostate cancer disparities; (iv) the role of the microbiome in cancer; (v) current challenges in treatment of patients with metastatic prostate cancer; (viii) prostate cancer germline genetics and evolutionary genomics; (ix) advances in circulating DNA methylation biomarkers for diagnosis, prognosis, and treatment selection; (x) advances in the development of MYC-targeting therapeutics; (xi) advances in antibody-drug conjugates for the treatment of cancer; (xii) advances for immunotherapy in prostate cancer; and (xiii) updates from other recent prostate cancer clinical trials. CONCLUSIONS: This article summarizes the research presented at the 2020 PCF Scientific Retreat. We hope that dissemination of this knowledge will help to accelerate and direct the next major advances in prostate cancer research and care.

COVID-19 , Prostatic Neoplasms , SARS-CoV-2 , Androgens , Animals , Biomarkers, Tumor , Biomedical Research , DNA Methylation , Genetic Predisposition to Disease/ethnology , Genomics , Healthcare Disparities , Humans , Immunotherapy , Male , Mice , Microbiota , Mutation , Pandemics , Prognosis , Prostatic Neoplasms/genetics , Prostatic Neoplasms/microbiology , Prostatic Neoplasms/therapy
J Racial Ethn Health Disparities ; 8(4): 973-980, 2021 08.
Article in English | MEDLINE | ID: covidwho-754115


RATIONALE: Hypertension, obesity and diabetes are major risk factors associated with morbidities underlying COVID-19 infections. Regression analysis correlated presence of ACE insertion/deletion (I/D) polymorphism to COVID-19 incidence and mortality. Furthermore, COVID-19 prevalence correlated to allele frequency of angiotensin-converting enzyme (ACE) deletion (D) polymorphism within the European population. OBJECTIVE: Homozygous ACE deletion polymorphism is associated with increase in ACE and angiotensin II (Ang-II), sustained levels can result in inflammation, fibrosis and organ damage. The ACE DD polymorphism is also associated with hypertension, acute respiratory distress and diabetic nephropathy, all considered high risk for COVID-19 infection and outcomes. The study objective was to describe a biological framework associating ethnic prevalence of ACE deletion polymorphism to COVID-19 comorbidities providing rationale for therapeutic utility of ACE-I/ARBs to improve outcomes. METHOD AND RESULTS: The Allele Frequency Database (ALFRED) was queried for frequency of rs4646994 representing ACE I/D polymorphism. In a total of 349 worldwide population samples, frequency of ACE D allele was higher in European, Asian, and Africans cohorts. In the USA, the frequency of ACE D allele was higher in non-Hispanic Black compared with non-Hispanic White and Mexican Americans. CONCLUSION: COVID-19 binding mediated reduction/inactivation of ACE-II can increase ACE/Ang-II signalling pathway and related pathologies. The presence of ACE DD polymorphism with COVID-19 infection likely augments ACE/Ang-II activities, increasing severity of COVID-19 morbidities and impacts outcomes. Thus, ethnic prevalence of ACE DD polymorphism can explain in part the severity of COVID-19 morbidity providing rationale for the use of ACE-I/ARBs to improve outcomes.

COVID-19 Drug Treatment , COVID-19/ethnology , Ethnicity/genetics , Genetic Predisposition to Disease/ethnology , Peptidyl-Dipeptidase A/genetics , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Humans , Polymorphism, Genetic , Prevalence , Risk Factors
J Transl Med ; 18(1): 321, 2020 08 24.
Article in English | MEDLINE | ID: covidwho-727282


BACKGROUND: The outbreak of coronavirus disease (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), through its surface spike glycoprotein (S-protein) recognition on the receptor Angiotensin-converting enzyme 2 (ACE2) in humans. However, it remains unclear how genetic variations in ACE2 may affect its function and structure, and consequently alter the recognition by SARS-CoV-2. METHODS: We have systemically characterized missense variants in the gene ACE2 using data from the Genome Aggregation Database (gnomAD; N = 141,456). To investigate the putative deleterious role of missense variants, six existing functional prediction tools were applied to evaluate their impact. We further analyzed the structural flexibility of ACE2 and its protein-protein interface with the S-protein of SARS-CoV-2 using our developed Legion Interfaces Analysis (LiAn) program. RESULTS: Here, we characterized a total of 12 ACE2 putative deleterious missense variants. Of those 12 variants, we further showed that p.His378Arg could directly weaken the binding of catalytic metal atom to decrease ACE2 activity and p.Ser19Pro could distort the most important helix to the S-protein. Another seven missense variants may affect secondary structures (i.e. p.Gly211Arg; p.Asp206Gly; p.Arg219Cys; p.Arg219His, p.Lys341Arg, p.Ile468Val, and p.Ser547Cys), whereas p.Ile468Val with AF = 0.01 is only present in Asian. CONCLUSIONS: We provide strong evidence of putative deleterious missense variants in ACE2 that are present in specific populations, which could disrupt the function and structure of ACE2. These findings provide novel insight into the genetic variation in ACE2 which may affect the SARS-CoV-2 recognition and infection, and COVID-19 susceptibility and treatment.

Betacoronavirus/physiology , Mutation, Missense , Peptidyl-Dipeptidase A/genetics , Protein Interaction Domains and Motifs/genetics , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Substitution , Angiotensin-Converting Enzyme 2 , Betacoronavirus/metabolism , Binding Sites/genetics , COVID-19 , Coronavirus Infections/ethnology , Coronavirus Infections/genetics , Coronavirus Infections/virology , DNA Mutational Analysis/methods , Databases, Genetic , Genetic Predisposition to Disease/ethnology , Genetic Variation , Geography , Humans , Models, Molecular , Molecular Docking Simulation , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/ethnology , Pneumonia, Viral/genetics , Pneumonia, Viral/virology , Polymorphism, Single Nucleotide , Protein Binding , Protein Structure, Secondary/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Virus Internalization