The role of glutamine metabolism in castration-resistant prostate cancer / 亚洲男科学杂志(英文版)

Reprogramming of metabolism is a hallmark of tumors, which has been explored for therapeutic purposes. Prostate cancer (PCa), particularly advanced and therapy-resistant PCa, displays unique metabolic properties. Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes. Among the many nutrients, glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa. In addition to amino acid metabolism, glutamine is also widely involved in the synthesis of other macromolecules and biomasses. Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients. This review summarizes the metabolic landscape of PCa, with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa, and suggests novel therapeutic strategies.

Lung-selective Cas13d-based nanotherapy inhibits lethal SARS-CoV-2 infection by targeting host protease Ctsl

The COVID-19 pandemic persists as a global health crisis for which curative treatment has been elusive. Development of effective and safe anti-SARS-CoV-2 therapies remains an urgent need. SARS-CoV-2 entry into cells requires specific host proteases including TMPRSS2 and Cathepsin L (Ctsl)1-3, but there has been no reported success in inhibiting host proteases for treatment of SARS-CoV-2 pathogenesis in vivo. Here we have developed a lung Ctsl mRNA-targeted, CRISPR/Cas13d-based nanoparticle therapy to curb fatal SARS-CoV-2 infection in a mouse model. We show that this nanotherapy can decrease lung Ctsl expression in normal mice efficiently, specifically, and safely. Importantly, this lung-selective Ctsl-targeted nanotherapy significantly extended the survival of lethally SARS-CoV-2 infected mice by decreasing lung virus burden, reducing expression of pro-inflammatory cytokines/chemokines, and diminishing the severity of pulmonary interstitial inflammation. Additional in vitro analyses demonstrated that Cas13d-mediated Ctsl knockdown inhibited infection mediated by the spike protein of SARS-CoV-1, SARS-CoV-2, and more importantly, the authentic SARS-CoV-2 B.1.617.2 Delta variant, regardless of TMPRSS2 expression status. Our results demonstrate the efficacy and safety of a lung-selective, Ctsl-targeted nanotherapy against infection by SARS-CoV-2 and likely other emerging coronaviruses, forming a basis for investigation of this approach in clinical trials.

Clinicopathological features of metastatic castration-resistant prostate cancer / 中华老年医学杂志

Objective To investigate the histopathological characteristics of metastatic castration-resistant prostate cancer.Methods Clinical findings,morphologic features,immunophenotypes of androgen receptor (AR),prostatic specific antigen (PSA),chromogranin A (CgA),and phosphatase and tensin homolog deleted on chromosome ten(PTEN)(by EnVision method) of 178 core biopsies from patients with metastatic castration resistant prostate cancer encountered from January 2010 to January 2015 from West Coast Dream Team were analyzed.Results In the 178 cases,51(28.7％)were diagnosed with typical adenocarcinoma,41 cases(23.0％)with intermediate atypical carcinoma and 24 cases(13.5 ％)with small cell carcinoma.The expression of PSA was significantly lower in patients with intermediate atypical carcinoma or with small cell carcinoma(31/39,79.5 ％) than in those with adenocarcinoma(20/20,100 ％).The expression of PTEN was significantly higher in patient with intermediate atypical carcinoma or with small cell carcinoma (31/46,67.4％) than in those with adenocarcinoma (19/41,46.3％).Conclusions Three histopathological subtypes exists in metastatic castration-resistant prostate cancer,including adenocarcinoma,intermediate type atypical carcinoma and small cell carcinoma.They are entities with unique pathological features.The expression of PTEN is significantly lower in the patients with intermediate atypical carcinoma or with small cell carcinoma than in those with adenocarcinoma,indicating that intermediate atypical carcinoma and small cell carcinoma are different from typical adenocarcinoma in tumor occurrence and progression.