Obesity increases the risk of cancers, including hepatocellular carcinomas (HCC). However, the precise molecular mechanisms through which obesity promotes HCC development are still unclear. Recent studies have shown that gut microbiota may influence liver diseases by transferring its metabolites and components. Here, we show that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes HCC development by creating a tumor-promoting microenvironment. LTA enhances the senescenceassociated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesityinduced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E 2 (PGE 2) production suppresses the antitumor immunity through a PTGER4 receptor, thereby contributing to HCC progression. Moreover, COX2 overexpression and excess PGE 2 production were detected in HSCs in human HCCs with noncirrhotic, nonalcoholic steatohepatitis (NASH), indicating that a similar mechanism could function in humans. SIGNIFICANCE: We showed the importance of the gut-liver axis in obesity-associated HCC. The gut microbiota-driven COX2 pathway produced the lipid mediator PGE 2 in senescent HSCs in the tumor microenvironment, which plays a pivotal role in suppressing antitumor immunity, suggesting that PGE 2 and its receptor may be novel therapeutic targets for noncirrhotic NASH-associated HCC.

The transformation, microstructural development, and densification of an a-alumina-seeded boehmite sol-gel was studied. a-Alumina particles are shown to act as nuclei for the transformation of 8-to a-alumina and to result in an increase in the transformation kinetics and lowering of the transformation temperature by as much as 170°C. By increasing the seed concentration (i.e., nucleation frequency), a submicrometer aggregate-free microstructure develops, rather than the vermicular microstructure that usually characterizes the a-alumina transformation. As a result, the transformed a-alumina sinters to full density with a submicrometer grain size at 1200°C. It is believed that seeding may represent a unique method for microstructure control in the many ceramic systems that transform by nucleation and growth.

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BackgroundThere are currently no promising therapies available to treat or prevent peripheral neuropathy (PN) induced by anticancer drugs in a cumulative dose-dependent manner. In this study, we investigated the efficacy of regional cooling of hands and feet in preventing paclitaxel (PTX)-induced PN.MethodsPatients with gynecologic cancer who received a tri-weekly cycle of chemotherapy including PTX at doses of 150–175 mg/m2 were included in this study. Regional cooling was performed by covering patient hands and feet with cold insulators during PTX administration (regional cooling group). The primary end-point was ≥grade 2 PN evaluated by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The secondary end-points were the frequency of PN therapeutic drug use, PTX dose reduction due to PN, and adverse events due to regional cooling. The efficacy of regional cooling was compared with data retrospectively extracted from the medical records of patients who did not receive regional cooling (control group). All end-points were evaluated for up to six cycles.ResultsThere were 40 and 142 patients in the regional cooling and control groups, respectively. As a primary end-point, incidences of ≥grade 2 PN in the fourth to sixth cycles were significantly lower than that in the cooling group (5.0–9.1 % vs. 19.8–31.6 %, p < 0.05 after the fourth cycle and p < 0.01 after the fifth cycle). Among secondary end-points, neither the use of PN therapeutic drugs nor the PTX dose reduction due to PN were significantly lower in the cooling group than in the control group (27.5 vs. 36.6 %, p = 0.378 and 5.0 vs. 3.5 %, p = 0.645, respectively). There were no serious regional cooling-associated adverse events such as frostbite.ConclusionsRegional cooling of hands and feet during PTX administration might have good effectiveness and tolerability, suggesting this approach as a potentially effective supportive care to prevent PTX-induced PN.Trial registrationThe trial approval number in the institution; H25-26. Registered 5 June 2014.