Helicobacter pylori infection induces chronic inflammation that contributes to gastric tumorigenesis. Tumor necrosis factor (TNF-a) is a proinflammatory cytokine, and polymorphism in the TNF-a gene increases the risk of gastric cancer. We herein investigated the role of TNF-a in gastric tumorigenesis using Gan mouse model, which recapitulates human gastric cancer development. We crossed Gan mice with TNF-a (Tnf) or TNF-a receptor TNFR1 (Tnfrsf1a) knockout mice to generate Tnf À / À Gan and Tnfrsf1a À / À Gan mice, respectively, and examined their tumor phenotypes. Notably, both Tnf À / À Gan mice and Tnfrsf1a À / À Gan mice showed similar, significant suppression of gastric tumor growth compared with control Tnf þ / þ or Tnfrsf1a þ / þ Gan mice. These results indicate that TNF-a signaling through TNFR1 is important for gastric tumor development. Bone marrow (BM) transplantation experiments showed that TNF-a expressed by BM-derived cells (BMDCs) stimulates the TNFR1 on BMDCs by an autocrine or paracrine manner, which is important for gastric tumor promotion. Moreover, the microarray analysis and colony formation assay indicated that NADPH oxidase organizer 1 (Noxo1) and Gna14 are induced in tumor epithelial cells in a TNF-a-dependent manner, and have an important role in tumorigenicity and tumor-initiating cell property of gastric cancer cells. Accordingly, it is possible that the activation of TNF-a/TNFR1 signaling in the tumor microenvironment promotes gastric tumor development through induction of Noxo1 and Gna14, which contribute to maintaining the tumor cells in an undifferentiated state. The present results indicate that targeting the TNF-a/TNFR1 pathway may be an effective preventive or therapeutic strategy for gastric cancer.

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It has been confirmed that the systemic inflammation response index (SIRI) based on peripheral blood neutrophil, monocyte and lymphocyte counts can be used for the prognostication of patients with various malignant tumors. However, the prognostic value of SIRI in cervical cancer patients has not yet been reported. This study found that a higher SIRI was related to lymphovascular invasion and was also significantly associated with FIGO stage, radiotherapy, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR) but not related to other clinical and pathological parameters. According to the Kaplan-Meier survival analysis, a high SIRI was associated with the poor prognosis of cervical cancer patients in the primary and validation groups. SIRI, NLR, PLR, and MLR can all be used to determine the prognosis of patients with operable cervical cancer. Moreover, it was confirmed that only SIRI was an independent prognostic factor for patients with operable cervical cancer. The same result was obtained in the propensity score matching (PSM) analysis. In the ROC curve analysis, SIRI was more accurate in predicting the prognosis of cervical cancer patients. Then, a nomogram was established based on SIRI, FIGO stage and lymphovascular invasion, which could determine the prognosis of cervical cancer patients more accurately than FIGO stage. The validation cohort showed the same results. In addition, the changes in SIRI relative to the baseline value at 4-8 weeks after surgery were closely related to the survival of cervical cancer patients. Compared with those with unchanged SIRI (absolute value of variation <25%), cervical cancer patients with an increase in SIRI > 75% had worse OS (P < 0.001), while patients with a decrease in SIRI > 75% had a better prognosis (P < 0.001). SIRI can serve as a new independent prognostic index and a potential marker for therapeutic response monitoring in patients with curable cervical cancer. Compared with the traditional FIGO staging system, the nomogram integrating SIRI can predict the survival of cervical cancer patients more objectively and reliably after radical surgery.

Genetic alterations in the TGFb signaling pathway in combination with oncogenic alterations lead to cancer development in the intestines. However, the mechanisms of

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Methane hydrates, widely found in permafrost and deep marine sediments, have great potential as a future energy source. Conventional production schemes perform poorly for challenging hydrate reservoirs with low permeability. We propose an efficient production scheme by combining hydraulic fracturing from horizontal wells and hot water circulation through fractures. A fully coupled thermo-hydro-chemical (THC) model is developed to simulate the key physical processes during gas production from a hydrate reservoir representative of typical geological settings in Shenhu, South China Sea. We found that the gas production process has two distinct stages divided by thermal breakthrough: a relatively short prebreakthrough stage and a postbreakthrough stage yielding stable gas production. Heat advection along and near the hydraulic fracture dominates the prebreakthrough stage, whereas conduction-driven thermal recovery in the volume around fractures dominates the postbreakthrough stage. We identified that the steady-state injection temperature has a strong effect on the performance of the proposed scheme while the fluid mass circulation rate has a moderate impact beyond a threshold. The proposed scheme proves to be efficient and robust over a range of reservoir conditions with respect to initial hydrate saturation and intrinsic permeability, including their spatial heterogeneities, thereby offering a promising solution for challenging reservoir conditions.

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