IMPORTANCE Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options.OBJECTIVE To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. DESIGN, SETTING, AND PARTICIPANTS FRESCO (Fruquintinib Efficacy and Safety in 3+ LineColorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017.INTERVENTIONS Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. MAIN OUTCOMES AND MEASURESThe primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded Ն8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. RESULTSOf the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% ( 27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization.CONCLUSIONS AND RELEVANCE Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China.

Deep eutectic solvents (DESs), as a green alternative technology, exhibit great potential to recycle valuable elements from spent lithium-ion batteries (LIBs).

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The Hsp20 genes are present in all plant species and play important roles in alleviating heat stress and enhancing plant thermotolerance by preventing the irreversible aggregation of denaturing proteins. However, very little is known about the CaHsp20 gene family in pepper (Capsicum annuum L.), an important vegetable crop with character of temperate but thermosensitive. In this study, a total of 35 putative pepper Hsp20 genes (CaHsp20s) were identified and renamed on the basis of their molecular weight, and then their gene structure, genome location, gene duplication, phylogenetic relationship, and interaction network were also analyzed. The expression patterns of CaHsp20 genes in four different tissues (root, stem, leaf, and flower) from the thermotolerant line R9 under heat stress condition were measured using semi-quantitative RT-PCR. The transcripts of most CaHsp20 genes maintained a low level in all of the four tissues under normal temperature condition, but were highly induced by heat stress, while the expression of CaHsp16.6b, 16.7, and 23.8 were only detected in specific tissues and were not so sensitive to heat stress like other CaHsp20 genes. In addition, compared to those in thermotolerant line R9, the expression peak of most CaHsp20 genes in thermosensitive line B6 under heat stress was hysteretic, and several CaHsp20 genes (CaHsp16.4, 18.2a, 18.7, 21.2, 22.0, 25.8, and 25.9) showed higher expression levels in both line B6 and R9. These data suggest that the CaHsp20 genes may be involved in heat stress and defense responses in pepper, which provides the basis for further functional analyses of CaHsp20s in the formation of pepper acquired thermotoleance.

Immunotherapy has revolutionized lung cancer treatment in the past decade. By reactivating the host's immune system, immunotherapy significantly prolongs survival in some advanced lung cancer patients. However, resistance to immunotherapy is frequent, which manifests as a lack of initial response or clinical benefit to therapy (primary resistance) or tumor progression after the initial period of response (acquired resistance). Overcoming immunotherapy resistance is challenging owing to the complex and dynamic interplay among malignant cells and the defense system. This review aims to discuss the mechanisms that drive immunotherapy resistance and the innovative strategies implemented to overcome it in lung cancer.

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BackgroundSTAT3 signaling plays the pivotal role in tumorigenesis through EZH2 epigenetic modification, which enhanced STAT3 activity by increased tyrosine phosphorylation of STAT3. Here, another possible feedback mechanism and clinical significance of EZH2 and STAT3 were investigated in gastric cancer (GC).MethodsSTAT3, p-STAT3 (Tyr 705) and EZH2 expression were examined in 63 GC specimens with matched normal tissues by IHC staining. EZH2 and STAT3 were also identified in five GC cell lines using RT-PCR and western blot analyses. p-STAT3 protein was detected by western blotting. In order to investigate whether EZH2 expression was directly regulated by STAT3, EZH2 expression was further detected using siRNA for STAT3 or IL-6 stimulation, with dual luciferase reporter analyses, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays. The clinical significance of STAT3, p-STAT3 and EZH2 expression was evaluated by multi-factor COX regression and Kaplan-Meier analyses.ResultsHyper-activation of STAT3, p-STAT3 and EZH2 expression were observed in GC cells and tissues. STAT3 signaling was correlated with EZH2 expression in GC (R = 0.373, P = 0.003), which was consistent with our data showing that STAT3 as the transcriptional factor enhanced EZH2 transcriptional activity by binding the relative promoter region (-214 ~ -206). STAT3 was an independent signature for poor survival (P = 0.002). Patients with STAT3+/EZH2+ or p-STAT3+/EZH2+ had a worse outcome than others (P < 0.001); Besides, high levels of STAT3 and EZH2 was associated with advanced TNM staging (P = 0.017). Moreover, treatment with a combination of siSTAT3 and EZH2-specific inhibitor, 3-deazaneplanocin A (DZNEP), increased the apoptotic ratio of cells. It is benefit for targeting STAT3-EZH2 interplay in GC treatment.ConclusionsOur results indicate that STAT3 status mediated EZH2 upregulation, associated with advanced TNM stage and poor prognosis, suggesting that combination with knockdown of STAT3 and EZH2 inhibitor might be a novel therapy in GC treatment. Collectively, STAT3, p-STAT3 and EZH2 expression were provided for the precision medicine in GC patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0561-z) contains supplementary material, which is available to authorized users.

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