EMX2 inhibits clear cell renal cell carcinoma progress via modulating Akt/FOXO3a pathway.

Empty spiracles homeobox 2 (EMX2) is initially identified as a key transcription factor that plays an essential role in the regulation of neuronal development and some brain disorders. Recently, several studies emphasized that EMX2 could as a tumor suppressor, but its role in human clear cell renal cell carcinoma (ccRCC) remains unclear. In the present study, we investigated the role and underlying mechanism of EMX2 in the regulation of ccRCC progress. Our results demonstrated that EMX2 expression was markedly decreased in ccRCC tissues and cell lines, and low EMX2 expression predicted the poor prognosis of ccRCC patients. In addition, forced expression of EMX2 significantly inhibited the cell growth, migration, and invasion in vitro, as well as ccRCC tumor growth in nude mice, via, at least in part, regulating Akt/FOXO3a pathway. In detail, EMX2 could attenuate the phosphorylation levels of Akt and FOXO3a, and increase FOXO3a expression without affecting total Akt expression in vivo and in vitro. Meanwhile, shRNA-mediated knockdown of FOXO3a expression could obviously attenuate the effects of EMX2 on cell growth, migration, invasion, and tumor growth. Furthermore, EMX2 could significantly attenuate the interaction between Akt and FOXO3a. Taken together, our results demonstrated that EMX2 could inhibit ccRCC progress through, at least in part, modulating Akt/FOXO3a signaling pathway, thus representing a novel role and underlying mechanism of EMX2 in the regulation of ccRCC progress.

ß-Arrestin2 promotes docetaxel resistance of castration-resistant prostate cancer via promoting hnRNP A1-mediated PKM2 alternative splicing.

PURPOSE: To investigate the influence of ß-arrestin2 on the docetaxel resistance in castration-resistant prostate cancer (CRPC) and elucidate the underlying molecular mechanisms. METHODS: PC3 and DU145 cells with stable ß-arrestin2 overexpression and C4-2 cells with stable ß-arrestin2 knockdown, were constructed via using lentivirus and puromycin selection. MTT and colony formation assays were carried out to investigate the effect of ß-arrestin2 expression on the docetaxel resistance of CRPC cells. Glycolysis analysis was used to assess the glycolytic capacity modulated by ß-arrestin2. GO enrichment analysis, gene set enrichment analysis and Spearman correlation test were carried out to explore the potential biological function and mechanism via using public data from GEO and TCGA. The expressions of PKM2, Phospho-PKM2, Phospho-ERK1/2 and hnRNP A1 were detected by western blot. Functional blocking experiments were carried out to confirm the roles of PKM2 and hnRNP A1 in the regulation of ß-arrestin2's biological functions via silencing PKM2 or hnRNP A1 expression in cells with stable ß-arrestin2 overexpression. Finally, nude mice xenograft models were established to confirm the experimental results of cell experiments. RESULTS: ß-Arrestin2 significantly decreased the sensitivity of CRPC cells to docetaxel stimulation, through enhancing the phosphorylation and expression of PKM2. Additionally, ß-arrestin2 increased PKM2 phosphorylation via the ERK1/2 signaling pathway and induced PKM2 expression in a post-transcriptional manner through an hnRNP A1-dependent PKM alternative splicing mechanism, rather than by inhibiting its ubiquitination degradation. CONCLUSION: Our findings indicate that the ß-arrestin2/hnRNP A1/PKM2 pathway could be a promising target for treating docetaxel-resistant CRPC.

A critical appraisal of urolithiasis clinical practice guidelines using the AGREE II instrument.

Background: The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument was developed to improve the methodological quality of clinical practice guidelines (CPGs). High-quality guidelines can provide reliable recommendations for different clinical issues. Currently, there is no quality appraisal of CPGs for urolithiasis. This study evaluated the quality of evidence-based CPGs for urolithiasis and provided new insights into improving guideline quality on urolithiasis. Methods: Systematic reviews were conducted to identify urolithiasis CPGs in PubMed, electronic databases, and websites of medical associations from January 2009 to July 2022. The quality of included CPGs was evaluated by four reviewers using the AGREE II instrument. Subsequently, the scores of all domains in the AGREE II instrument were calculated. Results: A total of 19 urolithiasis CPGs were identified for review: seven from Europe, six from USA, three from international union, two from Canada, and one from Asia. The agreement among reviewers was rated good [intraclass correlation coefficient (ICC), 0.806; 95% CI: 0.779-0.831]. The domains with the highest scores were scope and purpose (69.7%, 54.2-86.1%) and clarity of presentation (76.8%, 59.7-90.3%). The domains of stakeholder involvement (44.9%, 19.4-84.7%) and applicability (48.5%, 30.2-72.9%) gained the lowest score. Only five guidelines (26.3%) were considered "strongly recommended". Conclusions: The overall quality of the eligible CPGs was relatively high; however, future work is still needed in the domains of rigor of development, editorial independence, applicability, and stakeholder involvement.

COVID-19 inhibits spermatogenesis in the testes by inducing cellular senescence.

Introduction: COVID-19 (SARS-CoV-2) has been linked to organ damage in humans since its worldwide outbreak. It can also induce severe sperm damage, according to research conducted at numerous clinical institutions. However, the exact mechanism of damage is still unknown. Methods: In this study, testicular bulk-RNA-seq Data were downloaded from three COVID-19 patients and three uninfected controls from GEO to evaluate the effect of COVID-19 infection on spermatogenesis. Relative expression of each pathway and the correlation between genes or pathways were analyzed by bioinformatic methods. Results: By detecting the relative expression of each pathway and the correlation between genes or pathways, we found that COVID-19 could induce testicular cell senescence through MAPK signaling pathway. Cellular senescence was synergistic with MAPK pathway, which further affected the normal synthesis of cholesterol and androgen, inhibited the normal synthesis of lactate and pyruvate, and ultimately affected spermatogenesis. The medications targeting MAPK signaling pathway, especially MAPK1 and MAPK14, are expected to be effective therapeutic medications for reducing COVID-19 damage to spermatogenesis. Conclusion: These results give us a new understanding of how COVID-19 inhibits spermatogenesis and provide a possible solution to alleviate this damage.

Quality changes of clinical practice guidelines for respiratory diseases in China: A systematic review.

BACKGROUND: After the low quality of Chinese clinical practice guidelines (CPGs) for respiratory diseases published from 1979 to 2013 was reported, some handbooks were published to standardize guidelines' development recently. There was a great increase in the production and dissemination of CPGs annually in China, whose quality and potential impact were unknown. METHODS: A systematic search of four literature databases was performed for the period January 2013 to December 2018 to identify Chinese CPGs for respiratory diseases. Eligible CPGs were evaluated using the appraisal of guidelines for research and evaluation II (AGREE II) instrument. RESULTS: A total of 197 CPGs were identified for review. Compared with the result of previous study, the increased scores of the six AGREE II domains were screened: Scope and purpose (57.3% vs. 57.8%), Stakeholder involvement (17.6% vs. 25.0%), Rigor of development (10.2% vs. 13.2%), Clarity and presentation (55.2% vs. 58.4%), Applicability (9.3% vs. 25.9%), and Editorial independence (1.1% vs. 6.3%). The improved overall assessment for included CPGs were: Recommended (4, 2.0% vs. 0, 0%) and Recommended with modifications (26, 13.2% vs. 3, 2.8%). The improved level of evidence used to make recommendations were 59, 11.9% versus 168, 22.4% and 88, 17.7% versus 195, 26.0%, A and B, respectively. CONCLUSIONS: The overall quality of CPGs for respiratory diseases published from 2013 to 2018 in China was slightly improved, but had a big gap with the optimum level, especially in Rigor of development and Editorial independence. Increased efforts are required to enable the development of high-quality evidence-based CPGs for respiratory diseases.

A quality assessment of evidence-based guidelines for the prevention and management of ventilator-associated pneumonia: a systematic review.

BACKGROUND: Numerous evidence-based guidelines (EBGs) pertaining to ventilator-associated pneumonia (VAP) have been published by domestic and international organizations, but their qualities have not been reported. METHODS: A systematic search of the literature was performed up to July 2018 for relevant guidelines. Guidelines were eligible for inclusion if they incorporated recommendation statements for prevention and/or management in adults or children with VAP and were developed on a systematic evidence-based method. Four reviewers evaluated each guideline using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument, which comprises 23 items organized into six domains in addition to two overall items. RESULTS: Thirteen EBGs were identified for review. An overall high degree of agreement among reviewers was reached [intra-class correlation coefficient (ICC), 0.885; 95% CI, 0.862-0.905] during their review. The scores (mean, range) for the six AGREE domains were: scope and purpose (61%, 51-74%), stakeholder involvement (36%, 18-68%), rigor of development (41%, 22-59%), clarity and presentation (56%, 47-71%), applicability (38%, 21-59%) and editorial independence (50%, 0-77%). Only two EBGs (15.4%) were rated "recommended" for clinical practice. Approximately 86% of recommendations were based on moderate or low levels of evidence (levels B-D were 46.2%, 19.0%, and 21.2%, respectively). The recommendations for prevention and management of VAP were similar among the different EBGs. CONCLUSIONS: The overall quality of the identified EBGs pertaining to VAP was classified as moderate. The management of VAP varied by guideline. More high-quality evidence is needed to improve guideline recommendations.