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Neutrophil extracellular traps (NETs), a web-like structure of cytosolic and granule proteins assembled on decondensed chromatin, kill pathogens and cause tissue damage in diseases. Whether NETs can kill cancer cells is unexplored. Here, we report that a combination of glutaminase inhibitor CB-839 and 5-FU inhibited the growth of P/K3CA-mutant colorectal cancers (CRCs) in xenograft, syngeneic, and genetically engineered mouse models in part through NETs. Disruption of NETs by either DNase I treatment or depletion of neutrophils in CRCs attenuated the efficacy of the drug combination. Moreover, NETs were present in tumor biopsies from patients treated with the drug combination in a phase II clinical trial. Increased NET levels in tumors were associated with longer progression-free survival. Mechanistically, the drug combination induced the expression of IL-8 preferentially in P/OCA-mutant CRCs to attract neutrophils into the tumors. Further, the drug combination increased the levels of ROS in neutrophils, thereby inducing NETs. Cathepsin G (CTSG), a serine protease localized in NETs, entered CRC cells through the RAGE cell surface protein. The internalized CTSG cleaved 14-3-3 proteins, released BAX, and triggered apoptosis in CRC cells. Thus, our studies illuminate a previously unrecognized mechanism by which chemotherapy-induced NETs kill cancer cells., Introduction Neutrophils are the most abundant leukocytes in peripheral blood and play a vital role in host defenses against pathogens (1). Neutrophils kill pathogens, including bacteria and fungi, by phagocytosis [...]

We sought to develop and validate a national blood pressure (BP) reference based on age, sex, and height for Chinese children. Data were obtained on 197 430 children aged 7 to 17 who participated in the Chinese National Survey on Students' Constitution and Health in 2010. BP percentiles were estimated and fitted using the lambda, mu, and sigma method and then compared with a US reference and China existing reference. In an external independent validation sample of 59 653 children aged 7 to 18 from 7 Chinese provinces in 2013, the prevalence of elevated BP was compared applying the 3 references. BP values were similar for boys and girls at the younger ages (7-13 years) and lower height percentiles, whereas higher at the older ages (14-17 years) for boys than girls. At medial height in boys and girls aged 7 to 13, the 50th, 90th, 95th, and 99th percentiles of BP for the new national reference were consistent with US reference and lower than current Chinese reference. In the independent sample, elevated BP prevalence, based on the new national reference, ranged from 7.8% to 18.5% among children aged 7 to 17, which was higher than the US reference values (4.3%-14.5%) and lower than the current Chinese reference (12.9%-25.5%) in each age group. The new national BP reference for Chinese children based on age, sex, and height from large-scale and nationally representative data seems to improve the ability for identifying Chinese hypertensive children and for stratifying them with regard to cardiovascular risk.

Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal disease due, in large part, to a high rate of second primary tumor (SPT) formation. The 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis provides a robust system in which to study chemopreventive agents in the context of chemically induced HNSCC tumors. STAT3 is a potent oncogene that is hyperactivated by tyrosine phosphorylation early in HNSCC carcinogenesis and is a rational therapeutic target. We recently reported that loss-of-function of the STAT3 phosphatase PTPRT promotes STAT3 activation in HNSCC tumors and preclinical models and may serve as a predictive biomarker of response to STAT3 inhibitors, including the small-molecule Stattic. We therefore investigated the hypothesis that Ptprt-knockout (KO) mice would be more susceptible to 4-NQO-induced oral carcinogenesis and more sensitive to Stattic-mediated chemoprevention compared with wild-type (WT) mice. Herein, we demonstrate that Ptprt WT and KO mice develop similar spectra of HNSCC disease severity upon 12 weeks of 4-NQO administration, with no apparent effect of Ptprt genotype on carcinogenesis or treatment outcome. Targeting of STAT3 with Stattic resulted in a chemopreventive effect against 4-NQO-induced oral cancer (P = 0.0402). While these results do not support a central role for PTPRT in 4-NQO-induced HNSCC carcinogenesis, further investigation of STAT3 as a chemoprevention target in this cancer is warranted. Cancer Prev Res; 9(8); 657-63. ©2016 AACR.

The underpinnings of STAT3 hyperphosphorylation resulting in enhanced signaling and cancer progression are incompletely understood. Loss-of-function mutations of enzymes that dephosphorylate STAT3, such as receptor protein tyrosine phosphatases, which are encoded by the PTPR gene family, represent a plausible mechanism of STAT3 hyperactivation. We analyzed whole exome sequencing (n = 374) and reverse-phase protein array data (n = 212) from head and neck squamous cell carcinomas (HNSCCs). PTPR mutations are most common and are associated with significantly increased phospho-STAT3 expression in HNSCC tumors. Expression of receptor-like protein tyrosine phosphatase T (PTPRT) mutant proteins induces STAT3 phosphorylation and cell survival, consistent with a "driver" phenotype. Computational modeling reveals functional consequences of PTPRT mutations on phospho-tyrosine-substrate interactions. A high mutation rate (30%) of PTPRs was found in HNSCC and 14 other solid tumors, suggesting that PTPR alterations, in particular PTPRT mutations, may define a subset of patients where STAT3 pathway inhibitors hold particular promise as effective therapeutic agents.

Background: Numerous observational studies have documented an association between the circadian rhythm and the composition of the gut microbiota. However, the bidirectional causal effect of the morning chronotype on the gut microbiota is unknown. Methods: A two-sample Mendelian randomization study was performed, using the summary statistics of the morning chronotype from the European Consortium and those of the gut microbiota from the largest available genome-wide association study meta-analysis, conducted by the MiBioGen consortium. The inverse variance-weighted (IVW), weighted mode, weighted median, MR-Egger regression, and simple mode methods were used to examine the causal association between the morning chronotype and the gut microbiota. A reverse Mendelian randomization analysis was conducted on the gut microbiota, which was identified as causally linked to the morning chronotype in the initial Mendelian randomization analysis. Cochran's Q statistics were employed to assess the heterogeneity of the instrumental variables. Results: Inverse variance-weighted estimates suggested that the morning chronotype had a protective effect on Family Bacteroidaceae (β = −0.072; 95% CI: −0.143, −0.001; p = 0.047), Genus Parabacteroides (β = −0.112; 95% CI: −0.184, −0.039; p = 0.002), and Genus Bacteroides (β = −0.072; 95% CI: −0.143, −0.001; p = 0.047). In addition, the gut microbiota (Family Bacteroidaceae (OR = 0.925; 95% CI: 0.857, 0.999; p = 0.047), Genus Parabacteroides (OR = 0.915; 95% CI: 0.858, 0.975; p = 0.007), and Genus Bacteroides (OR = 0.925; 95% CI: 0.857, 0.999; p = 0.047)) demonstrated positive effects on the morning chronotype. No significant heterogeneity in the instrumental variables, or in horizontal pleiotropy, was found. Conclusion: This two-sample Mendelian randomization study found that Family Bacteroidaceae, Genus Parabacteroides, and Genus Bacteroides were causally associated with the morning chronotype. Further randomized controlled trials are needed to clarify the effects of the gut microbiota on the morning chronotype, as well as their specific protective mechanisms. [ABSTRACT FROM AUTHOR]