Peng Wang

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with dysregulation of liver metabolism and inflammation. G-protein coupled bile acid receptor 1 (TGR5) is a cell surface receptor that is involved in multiple metabolic pathways. However, the functions of TGR5 in regulating macrophage innate immune activation in NASH remain unclear. Here, we found that TGR5 expression was decreased in liver tissues from humans and mice with NASH. Compared to wild type (WT) mice, TGR5-knockout (TGR5 −/− ) mice exhibited exacerbated liver damage, increased levels of proinflammatory factors, and enhanced M1 macrophage polarization. Moreover, TGR5 deficiency facilitated M1 macrophage polarization by promoting NLRP3 inflammasome activation and caspase-1 cleavage. Taken together, our findings revealed that TGR5 signaling attenuated liver steatosis and inflammation and inhibited NLRP3-mediated M1 macrophage polarization in NASH.

As an important member of the interleukin (IL)-1 family, IL‑33 plays a significant role in tumor progression. To explore this, we previously analyzed the association between IL‑33 expression and the prognosis of patients with glioma. However, the function of the IL‑33/ST2 axis in glioma remained unclear. In the present study, immunofluorescent staining results revealed that the expression levels of IL‑33 and ST2 receptor in glioma tissues were higher than those in normal brain tissues. Invasion and migration assays demonstrated that IL‑33 significantly increased glioma cell invasion and migration in vitro. Furthermore, knockdown of ST2 by siRNA attenuated the IL‑33-induced increase in invasion and migration. In addition, ELISA results revealed that IL‑33 upregulated the expression of matrix metalloproteinase (MMP)2 and MMP9. Western blot analysis results indicated that IL‑33 stimulation increased the phosphorylation of nuclear factor-κB (NF-κB) in a time- and dose-dependent manner. Moreover, silencing of the NF-κB pathway by BAY 11‑7082 resulted in the inhibition of IL‑33-induced invasion and migration, as well as the downregulation of MMP2 and MMP9 production. These findings indicate that IL‑33 may be involved in the process of glioma cell invasion and migration by upregulating MMP2 and MMP9 via the ST2-NF-κB signaling pathway. Thus, IL‑33 may be a novel therapeutic target for glioma.

PURPOSE: To develop and investigate a method to identify, from dynamic contrast enhanced (DCE) MRI, significant subvolumes of tumors related to treatment outcomes. METHODS: A method, called global-initiated regularized local fuzzy clustering, was proposed to identify subvolumes of head-and-neck cancers (HNC) from heterogeneous distributions of tumor blood volume (BV) and blood flow (BF) for assessment of therapy response. BV and BF images, derived from DCE MRI, of 14 patients with advanced HNC were obtained before treatment and 2 weeks after the start of 7-week chemoradiation therapy (chemo-RT). The delineated subvolumes of tumors with low BV or BF before and during treatment were evaluated for their associations with local failure (LF). Receiver operating characteristic (ROC) analysis was used to assess performance of the method for prediction of local failure of HNC. RESULTS: The sizes of the subvolumes of primary tumors with low BV, delineated by our method before and week 2 during treatment, were significantly greater in the patients with LF than with local control (LC) (p = 0.02 for pre-RT and 0.01 for week 2). While the total primary tumor volumes were reduced from baseline to week 2 during therapy to a similar extent for both the patients with LF and LC, the percentage decreases in the subvolumes of the primary tumors with low BV in the same time interval were significantly smaller for the patients with LF than those with LC (p < 0.05). ROC analysis shows that for any given sensitivity, the subvolume of the tumor with low BV week 2 during treatment has greater specificity for prediction of local failure than the pretreatment total tumor volume, the percentage change in the tumor volume week 2 during treatment, or the change in the averaged BV values of the entire tumor week 2 during therapy. CONCLUSIONS: We developed a method to identify the significant subvolumes of primary tumors related to local failure. Large poorly perfused subvolumes of primary or nodal HNC before treatment and persisting during the early course of chemo-RT have the potential for prediction of local or regional failure, and could be candidates for local dose intensification.

OBJECTIVE: To explore the utility of multidisciplinary approaches in the treatment of patients with pancreatic cancer with liver metastases (PCLM). METHODS: From 2002 to 2007, a total of 164 consecutive patients with PCLM treated with chemotherapy, radiation therapy, and/or Chinese herbal medicine were included in this study. Clinical parameters, treatments received, and survival time from initial diagnosis were analyzed. RESULTS: Of the 164 patients, 113 (69%) were men and 51 (31%) were women, with median age of 58 years. One hundred thirty-two patients (80%) had synchronous liver metastases, and 57 patients (35%) had extrahepatic metastases. Overall median survival time of the 164 patients was 4.7 months; 23 (14%) were alive at least 12 months after initial diagnosis of liver metastases. Karnofsky performance status of less than 80, weight loss (>10% within 6 months), ascites, and carbohydrate antigen 19-9 of 1000 U/mL or greater were the most relevant predictors of poor survival. Multivariate analysis showed that chemotherapy and Chinese herbal medicine were protective factors. CONCLUSIONS: Multimodality treatment is well tolerated by patients with PCLM and may be effective in prolonging their survival. Awareness of the implications of these prognostic factors may assist in evaluating the survival potential of patients and selecting the most appropriate treatments.

AIMS: This study aimed to detect alterations of brain functional connectivity (FC) in acute mild traumatic brain injury (mTBI) and to estimate the extent to which these FC differences predicted the characteristics of posttraumatic cognitive impairment. METHODS: Resting-state fMRI data were acquired from acute mTBI patients (n = 50) and healthy controls (HCs) (n = 43). Resting-state networks (RSNs) were established based on independent component analysis (ICA), and functional network connectivity (FNC) analysis was performed. Subsequently, we analyzed the correlations between FNC abnormalities and cognitive impairment outcomes. RESULTS: Altered FC within the salience network (SN), sensorimotor network (SMN), default mode network (DMN), executive control network (ECN), visual network (VN), and cerebellum network (CN) was found in the mTBI group relative to the HC group. Moreover, different patterns of altered network interactions were found between the mTBI patients and HCs, including the SN-CN, VN-SMN, and ECN-DMN connections. Correlations between functional disconnection and cognitive impairment measurements in acute mTBI patients were also found. CONCLUSION: This study indicated that widespread FNC impairment and altered integration existed in mTBI patients at acute stage, suggesting that FNC disruption as a biomarker may be applied for the early diagnosis and prediction of cognitive impairment in mTBI.