BackgroundHigh tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1.Patients and methodsWe reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360 mg d1, Q3W) with oxaliplatin 130 mg/m2 qd, d1, capecitabine 1000 mg/m2 b.i.d., d1–d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy.ResultsIn cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group [14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24–0.96), P = 0.038], while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs.ConclusionsToripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent.Trial registrationClinicalTrials.gov NCT02915432.

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A series of nanograined dense SrTiO 3 ceramics were examined for thermal conductivity, , as a function of average grain size d. The decreased gradually with decreasing d , primarily due to a significantly increased number of interfaces as heat transport barriers. Lowest at 300 and 1000 K, obtained in a 55-nm-grained sample, were about 50 and 24% smaller than those of a bulk single crystal. The Kapitza-type interfacial thermal resistance was estimated, and the dependence of on grain size was formalized, which shows the theoretical minimum could be achieved at d of about 10 nm.

Peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1 alpha (PGC-1α) coactivates multiple transcription factors and regulates several metabolic processes. The current study investigated the role of PGC-1α in the induction of apoptosis in human epithelial ovarian cancer cells. The PGC-1α mRNA level between human ovaries and human ovarian epithelial tumors was examined by quantitative RT-PCR. Less PGC-1α expression was found in the surface epithelium of malignant tumors compared with normal ovaries. Overexpression of PGC-1α in human epithelial ovarian cancer cell line Ho-8910 induced cell apoptosis through the coordinated regulation of Bcl-2 and Bax expression. Microarray analyses confirmed that PGC-1α dramatically affected the apoptosis-related genes in Ho-8910 cells. Mitochondrial functional assay showed that the induction of apoptosis was through the terminal stage by the release of cytochrome c. Furthermore, PGC-1α-induced apoptosis was partially, but not completely, blocked by PPARγ antagonist (GW9662), and suppression of PPARγ expression by siRNA also inhibited PGC-1α-induced apoptosis in Ho-8910 cells. These data suggested that PGC-1α exerted its effect through a PPARγ-dependent pathway. Our findings indicated that PGC-1α was involved in the apoptotic signal transduction pathways and downregulation of PGC-1α may be a key point in promoting epithelial ovarian cancer growth and progression.

The efficacy and safety of bevacizumab with modified irinotecan, leucovorin bolus, and 5-fluorouracil intravenous infusion (mIFL) in the first-line treatment of metastatic colorectal cancer (mCRC) has not been well evaluated in randomized clinical trials in Chinese patients. We conducted a phrase III trial in which patients with previously untreated mCRC were randomized 2:1 to the mIFL [irinotecan (125 mg/m2), leucovorin (20 mg/m2) bolus, and 5-fluorouracil intravenous infusion (500 mg/m2) weekly for four weeks every six weeks] plus bevacizumab (5 mg/kg every two weeks) group and the mIFL group, respectively. Co-primary objectives were progression-free survival (PFS) and 6-month PFS rate. In total, 214 patients were enrolled. Our results showed that addition of bevacizumab to mIFL significantly improved median PFS (4.2 months in the mIFL group vs. 8.3 months in the bevacizumab plus mIFL group, P < 0.001), 6-month PFS rate (25.0% vs. 62.6%, P < 0.001), median overall survival (13.4 months vs. 18.7 months, P = 0.014), and response rate (17% vs. 35%, P = 0.013). Grades 3 and 4 adverse events included diarrhea (21% in the mIFL group and 26% in the bevacizumab plus mIFL group) and neutropenia (19% in the mIFL group and 33% in the bevacizumab plus mIFL group). No wound-healing complications or congestive heart failure occurred. Our results suggested that bevacizumab plus mIFL is effective and well tolerated as first-line treatment for Chinese patients with mCRC. Clinical benefit and safety profiles were consistent with those observed in pivotal phase III trials with mainly Caucasian patients.