Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study.

BACKGROUND: Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. PATIENTS AND METHODS: Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. CONCLUSION: In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.

[Evidence-based evaluation of recent clinical practice guidelines for the diagnosis and treatment of benign prostatic hyperplasia].

Objective: To systematically evaluate the quality of clinical practice guidelines for the diagnosis and treatment of benign prostatic hyperplasia (BPH), and to compare the context of recommendations in order to provide references for clinical application. Methods: We searched databases such as the National Guideline Clearinghouse (NGC), Guidelines International Network (GIN), National Institute for Health and Clinical Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN) and World Health Organization (WHO), PubMed, Embase, CNKI, VIP, WanFang Data, CBM, and Medlive from their establishment until August 13, 2016, to collect evidence-based guidelines and/or consensus on BPH. Method: Methodological quality of included guidelines was assessed according to the AGREE Ⅱ instrument, and differences and similarities among recommendations were compared. Results: A total of 15 guidelines were included. According to the AGREE Ⅱ instrument, the score of scope and purpose, stakeholder involvement, rigour of formulate, clarity of presentation, applicability, and editorial independence was 72%, 38%, 30%, 58%, 16%, and 40%, respectively. The recommendations of different guidelines were basically similar, only with conflicts in some areas. Conclusions: The quality of included guidelines remains to be unified, the context of them can provide valuable implications for development or improvement.

Promoter methylation negatively correlated with mRNA expression but not tissue differential expression after heat stress.

DNA methylation plays a central role in gene expression. In this study, we detected the promoter methylation pattern of the chicken heat shock protein 70 (HSP70) gene and its association with messenger RNA (mRNA) expression before and after heat shock. The results showed that mRNA expression increased in response to heat stress and peaked at 3 h before dropping. Hypomethylation of the HSP70 promoter occurred in all of the groups studied, but the difference between groups within tissue type was not significant. The DNA methylation level of the control and the 6-h treatment groups was slightly higher than that of the 3-h treatment group in brain tissue and leg muscle. Correlation analysis between mRNA expression and DNA methylation of HSP70 showed that DNA methylation was negatively associated with mRNA expression in leg muscle (P = 0.0124), indicating that DNA methylation may be negatively associated with the expression of HSP70, although the difference was not significant. We concluded that the expression of HSP70 is heat inducible and tissue dependent and that heat induction may correlate with DNA methylation pattern in the HSP70 promoter, whereas tissue dependence is unrelated to DNA methylation pattern.

Characterization of chicken natural resistance-associated macrophage protein encoding genes (Nramp1 and Nramp2) and association with salmonellosis resistance.

Natural resistance-associated macrophage protein 1 and 2 encoding genes (Nramp1 and Nramp2) are related to many diseases. We cloned the cDNA of chicken Nramp1 and Nramp2 genes, characterized their expression and polymorphisms, and investigated the association of some SNPs with resistance to salmonellosis. The Nramp1 cDNA was 1746 bp long and the Nramp2 cDNA was 1938 bp long. These cDNAs are similar to previously reported cDNAs, varying by two and one amino acids, respectively. The chicken Nramp1 gene expressed predominantly in liver, thymus and spleen in both females and males. The Nramp2 gene expressed in almost all tissues, but predominantly in breast muscle, leg muscle, cerebrum, cerebellum, lung, kidney, and heart in both females and males. We identified 45 SNPs and 2 indels in the chicken Nramp1 gene; three of 13 SNPs in the exons were missense mutations (Arg223Gln, Ala273Glu and Arg497Gln). Association analysis indicated that A24101991G is significantly associated with chicken salmonellosis resistance. These results will be useful for functional investigation of chicken Nramp1 and Nramp2 genes.

Profiling of differentially expressed microRNAs (miRNAs) during differentiation of rat hepatic oval cells (HOCs) into hepatocellular carcinoma (HCC) cells.

OBJECTIVE: To explore the expression profile of miRNAs during differentiation of rat hepatic oval cells (HOCs) into hepatocellular carcinoma cells (HCC). METHODS: Proliferation of rat HOCs was induced by chemical carcinogen, 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) in male rats. By using Percoll density gradient centrifugation method, HOCs were isolated, followed by continuous cultivation in vitro. The isolated HOCs were identified via Thy-1 and C-kit detection under laser scanning confocal microscope. Total miRNA was then extracted from HOCs during cell differentiation for microarray hybridization. Differentially expressed miRNAs among the indicated time points were identified. The target genes of identified miRNAs were predicted using PicTar, Target-Scan, and miRanda; then the functions and pathways of the genes were enriched. Y chromosome-specific polymerase chain reaction (PCR) technique was utilized to trace the differentiation of the male HOCs in carcinogen-induced HCC of female rats. RESULTS: It was shown that isolated HOCs expressed stem cells markers of Thy-1 and C-kit in cytoplasm and membrane. Among 1,210 miRNAs identified, 22 were differentially expressed (P < 0.05, fold change ≥2), including 19 up-regulated and 3 down-regulated ones. The predicted target genes of these miRNAs were enriched in several functions, including axon guidance, angiogenesis, post-transcriptional protein modification, and small molecular metabolism. For PCR-based SRY detection, HCC genomic DNA of female rats from the experimental group displayed the same PCR product as that from normal male rat. CONCLUSION: Differentially expressed miRNAs exerted important roles during the differentiation process of HOCs to HCC.