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.

Thiophene and diaminobenzo- (1,2,5-thiadiazol)- based DAD-type near-infrared fluorescent probe for nitric oxide: A theoretical research.

A near-infrared fluorescent probe (LS-NO) for the real-time detection of nitric oxide (NO) in inflammatory bowel disease (IBD) was developed recently. The probe used oligoglycol morpholine-functionalized thiophene as strong electron donors and diaminobenzene (1,2,5-thiadiazole) as a weak electron acceptor and NO trapping group. It could detect exogenous and endogenous NO in the lysosomes of living cells with high sensitivity and specificity. To further understand the fluorescent mechanism and character of the probes LS-NO and LS-TZ (after the reaction of the probe LS-NO with NO), the electron transfer in the excitation and emitting process within the model molecules DAD-NO and DAD-TZ was analyzed in detail under the density functional theory. The calculation results indicated the transformation from diaminobenzene (1,2,5-thiadiazole) as a weak electron acceptor to triazolo-benzo-(1,2,5-thiadiazole) as a strong electron acceptor made LS-NO an effective "off-on" near-infrared NO fluorescent probe.

Heme oxygenase-1 directly binds STAT3 to control the generation of pathogenic Th17 cells during neutrophilic airway inflammation.

BACKGROUND: Specific JAK/STAT pathways play a critical role in the functional differentiation of distinct Th subsets. Previously, we showed that HO-1, a stress-inducible protein, inhibits Th17 cell differentiation and alleviates neutrophilic airway inflammation, but the responsible molecular basis remains unclear. METHODS: We employed Th17-skewing differentiation and NEA mouse models to study the role of HO-1 in regulating IL-6-STAT3-RORγt/SOCS3 signaling pathway to control Th17 cell-mediated neutrophilic airway inflammation. The levels of cytokines and expressions of relative signaling molecules were measured by ELISA, western blot, and qPCR, respectively. Frequency of CD4+ IL-17A+ , CD4+ IL-6R+ , and CD4+ IL-23R+ cells was analyzed by FCM. The interaction between HO-1 and signaling pathway-related proteins was determined by co-immunoprecipitation and western blot. RESULTS: Here, we show that hemin-induced HO-1 overexpression is required to mediate this process. Specifically, HO-1 decreased STAT3 phosphorylation but not IL-6R/IL-23R expression or JAK1/JAK2 activation in CD4+ T cells. The effect was accompanied by co-inhibition of SOCS3, a negative feedback factor of STAT3 activation. HO-1 bound to three domains on STAT3 (DNA-binding, linker, and transactivation domains) to directly regulate STAT3 activation. Conversely, either forced expression of a constitutively active STAT3 mutant or application of small-interfering RNA (siRNA) for HO-1 reversed these effects. CONCLUSIONS: Our data suggest that HO-1 exerts its inhibitory effect on Th17 cell differentiation by directly associating and blocking STAT3 phosphorylation. We speculate that hemin may be a potential therapeutic candidate for the treatment of other types of immune and pulmonary inflammatory-related diseases.

Clinical significance of changes of expression of the Wnt/ß-catenin signaling pathway in renal clear cell carcinoma.

OBJECTIVE: To explore the changes and clinical significance of expression of ß-catenin in renal carcinoma. PATIENTS AND METHODS: We selected 46 patients with renal clear cell carcinoma who were hospitalized from May 2013 to March 2016 and healthy adults (controls) matched for age and body weight, who were hospitalized in the physical examination center of our hospital during the same period. Peripheral blood of patients and controls was drawn for ELISA. After surgery, renal carcinoma and normal peritumoral tissue samples were harvested for immunohistochemical staining, Western blot analysis and qRT-PCR was used to observe changes of ß-catenin expression in renal carcinoma tissues. RESULTS: Compared with controls, ELISA showed that there were significant differences in ß-catenin levels in peripheral blood of patients with renal carcinoma (p<0.05). Western blot and qRT-PCR showed that the expression levels of ß-catenin in renal carcinoma tissues were higher than in normal peritumoral tissues and the differences were statistically significant (p<0.05). Immunohistochemical staining showed that ß-catenin was increased significantly in renal carcinoma tissue compared with normal peritumoral tissues (p<0.05). CONCLUSIONS: ß-catenin expression was significantly increased in the tumor tissues of patients with renal carcinoma. The measurement of ß-catenin expression levels in peripheral blood from patients could be used for early diagnosis of renal carcinoma, which is of great clinical significance.

Berbamine inhibited the growth of prostate cancer cells in vivo and in vitro via triggering intrinsic pathway of apoptosis.

BACKGROUND: Berbamine (BBM) has been reported with antitumor activities. BBM inhibited the growth of prostate cancer (PCa) cells and caused vacuolization of mitochondria in preliminary study. We hypothesized BBM could enhance apoptosis of PCa cells through mitochondrial pathway. METHODS: Growth of PC-3 and LNCaP cells treated by BBM was determined by cell viability assay. The morphology of mitochondria was observed by electron microscopy. Apoptosis was quantified by flow cytometry. Expressions of bax/bcl-2, active caspase-9 and active caspase-3 were examined by western blot and real-time PCR. Methazolamide, an inhibitor of cytochrome c, was added to examine its blockade effect on BBM. PC-3 cells were injected subcutaneously into athymic mice, and BBM or saline was administrated intravenously. Diameters of induced tumors were compared, and ratios of apoptotic cells in tumor tissues were calculated. RESULTS: BBM inhibited viability of cultured PC-3 and LNCaP cells in dose- and time-dependent manners. Flow cytometry showed BBM induced apoptosis in cultured cells. Mitochondria showed swelling, vacuolization and fused mitochondrial cristae. Western blot and real-time PCR analysis both showed increases of bax/bcl-2, active caspase-9 and active caspase-3. Methazolamide impeded effect of BBM on inducing apoptosis of cultured cells, and activations of caspase-9 and caspase-3 were also inhibited. Growth of tumors by grafted PC-3 cells was significantly slower in BBM group. Ratios of apoptotic cells in tumors were significantly higher in BBM group. Expressions of active caspase-9 and active caspase-3 in tumors were significantly upregulated by BBM. CONCLUSIONS: BBM exhibited strong anti-PCa activities in vitro and in vivo relying on activating caspase-3 via intrinsic pathway of apoptosis, holding a great promise to develop new strategies for PCa.

A novel aptasensor for thrombin detection based on alkaline phosphatase decorated ZnO/Pt nanoflowers as signal amplifiers.

To remedy the problems caused by the introduction of an additional electron mediator and realize signal amplification, a new strategy has been presented to construct an electrochemical aptasensor for thrombin detection based on the cascade electrocatalysis of alkaline phosphatase (ALP) and Pt nanoparticle (PtNP)-functionalized ZnO nanoflowers.

Comparison between the EQ-5D-5L and the EQ-5D-3L in patients with hepatitis B.

OBJECTIVES: The purpose of the study was to compare psychometric properties of the EQ-5D-5L (5L) and the EQ-5D-3L (3L) health outcomes assessment instruments in patients with hepatitis B in China. METHODS: Patients, including hepatitis B virus carriers and those with active or inactive chronic hepatitis B, compensated cirrhosis, decompensated cirrhosis or hepatocellular carcinoma, answered a questionnaire composed of 5L, socio-demographic information, 3L, and the visual analog scale (VAS), respectively. After 1 week, a retest was conducted for inpatients. We compared acceptability, face validity, redistribution properties, convergent validity, known-group validity, discriminatory power, ceiling effect, test-retest reliability, and responsiveness of 5L and 3L. RESULTS: A total of 369 outpatients and 276 inpatients were recruited for the first interview. Of the inpatients, 183 were used in the retest. Most patients preferred 5L-3L. The 3L-5L response pairs had an inconsistency rate of 2.4%. Correlation with the VAS was greater with 5L than with 3L. Age, education, and comorbidity were associated with health-related quality of life (HRQoL). 5L discriminated more infectious conditions than 3L. In all dimensions, the Shannon's index from 5L was larger while in three dimensions the Shannon's evenness index from 5L was slightly larger. The ceiling effect was reduced in 5L. In patients with stable health states, no significant difference was detected in the weighted kappa between 5L and 3L, but intraclass correlation coefficient of 5L was higher than that of 3L. In patients with improved health states, HRQoL was seen as increased in both 5L and 3L, without significant difference. CONCLUSIONS: The EQ-5D-5L was more suitable than the EQ-5D-3L in the patients with hepatitis B in China.