cal castration) is the cornerstone treatment of advanced prostate cancer. In 1941, Huggins and Hodges 1 first noted the beneficial effects of castration and injection of estrogens in patients with metastatic prostate cancer. The biological basis of the effect of ADT, the almost ubiquitous expression of the androgen receptor in prostate cancer, and growth dependence on the androgen receptor later became clear.Today, in addition to its wellestablished role in treating patients with metastatic disease, ADT is sometimes used to treat patients with increasing prostate-specific antigen (PSA) levels after local treatment, even without radiographic or other evidence of metastatic disease. Androgen deprivation therapy is also used as adjunct therapy for men undergoing radiation therapy for high-risk localized disease (TABLE 1). Despite frequently dramatic and sustained responses of many patients to ADT, treatment exposes patients to a host of important adverse effects (TABLE 2). We sought to systematically review existing evidence regarding the benefits and risks of ADT in contemporary management of local and metastatic prostate cancer. EVIDENCE ACQUISITIONWe performed MEDLINE searches of the English-language literature (1966 to March 2005) using the terms androgen deprivation therapy, hormone treatment, and prostate cancer. Relevant bibliographies of literature were manually reviewed for additional material. In evaluating the benefits of ADT, phase 3 randomized trial data were emphasized. On review of clinical trials, clinical end points of focus, in decreasing order of importance, were survival benefit, radiographic progression-free survival, and rising PSA level. Further information was obtained in oral and abstract form at the 2005 Prostate Cancer Symposium meeting, Orlando, Fla, and the 2005 American Society of Clini-cal Oncology meeting, Orlando, Fla. Published guidelines from the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology were also reviewed.

Background: Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has now been confirmed worldwide. Yet, COVID-19 is strangely and tragically selective. Morbidity and mortality due to COVID19 rise dramatically with age and co-existing health conditions, including cancer and cardiovascular diseases. Human genetic factors may contribute to the extremely high transmissibility of SARS-CoV-2 and to the relentlessly progressive disease observed in a small but significant proportion of infected individuals, but these factors are largely unknown. Main body: In this study, we investigated genetic susceptibility to COVID-19 by examining DNA polymorphisms in ACE2 and TMPRSS2 (two key host factors of SARS-CoV-2) from~81,000 human genomes. We found unique genetic susceptibility across different populations in ACE2 and TMPRSS2. Specifically, ACE2 polymorphisms were found to be associated with cardiovascular and pulmonary conditions by altering the angiotensinogen-ACE2 interactions, such as p.Arg514Gly in the African/African-American population. Unique but prevalent polymorphisms (including p.Val160Met (rs12329760), an expression quantitative trait locus (eQTL)) in TMPRSS2, offer potential explanations for differential genetic susceptibility to COVID-19 as well as for risk factors, including those with cancer and the highrisk group of male patients. We further discussed that polymorphisms in ACE2 or TMPRSS2 could guide effective treatments (i.e., hydroxychloroquine and camostat) for COVID-19. Conclusion: This study suggested that ACE2 or TMPRSS2 DNA polymorphisms were likely associated with genetic susceptibility of COVID-19, which calls for a human genetics initiative for fighting the COVID-19 pandemic.

Summary Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation leading to a gain-of-function in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in the conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3βHSD1 is a valid target for the treatment of CRPC.