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Liu L.,Xijing Hospital of Digestive Diseases | Wang W.,Xijing Hospital of Digestive Diseases | Chen H.,Xijing Hospital of Digestive Diseases | Zhao Y.,Xijing Hospital of Digestive Diseases | And 7 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Published studies have not investigated the suitability of Response Evaluation Criteria in Solid Tumors (RECIST), European Association for the Study of the Liver (EASL) criteria, and modified RECIST (mRECIST) for assessing the response of patients with hepatocellular carcinoma to treatment with sorafenib combined with transarterial chemoembolization. Here, we aimed to define the earliest time at which the response to combination therapy could be accurately assessed and validate the prognostic value of these criteria at this early posttherapy time point. Experimental Design: A total of 114 consecutive patients with hepatocellular carcinoma receiving combination therapy were retrospectively enrolled. The therapy response at different time points was assessed using RECIST, EASL, and mRECIST. Cox regression analysis and Kaplan-Meier curves were used to assess overall survival (OS) in the responders and nonresponders. Results: At the third follow-up (median, 94 days; range, 89-102 days) after therapy, the response rates obtained using EASL (50.6%) and mRECIST (51.6%) were greater than that obtained using RECIST (16.5%). The agreement was strong between the mRECIST and EASL results (k 1/4 0.9) but weak between mRECIST and RECIST (k 1/4 0.3). The EASL and mRECIST responses significantly correlated with survival. Risk reductions of 52% and 50% were observed for EASL and mRECIST responders, respectively, compared with nonresponders. However, no significant association between the treatment response and survival was observed using RECIST. Conclusions: The earliest time to evaluate the response to combination therapy is 3 months (median, 94 days) after therapy. EASL and mRECIST responses are independent predictors for OS at this early time point. © 2014 American Association for Cancer Research.

Hong L.,Xijing Hospital of Digestive Diseases | Hong L.,PLA Fourth Military Medical University | Han Y.,PLA Fourth Military Medical University | Brain L.,Johns Hopkins University
Expert Review of Gastroenterology and Hepatology | Year: 2014

Despite tremendous efforts to reduce deaths due to gastric cancer, it represents the second leading cause of cancer-related deaths worldwide. EGF receptor (EGFR) plays important roles in gastric carcinogenesis by regulation of cell cycle, angiogenesis and apoptosis. This review evaluates the functions, mechanisms and clinical uses of EGFR in gastric cancer. Although EGFR targeted single therapy shows limited effect, the combination of EGFR targeted agents with traditional chemotherapy regimens may bring about important progress in cancer therapy. More clinical trials should be performed to clarify both the prognostic and therapeutic value of EGFR in gastric cancer. © 2014 Informa UK Ltd.

Qi X.,PLA Fourth Military Medical University | Tang Y.,No 463 Hospital Of Chinese Pla | An D.,Xi'an Jiaotong University | Bai M.,PLA Fourth Military Medical University | And 5 more authors.
Journal of Clinical Gastroenterology | Year: 2014

Background and Goals: Whether radiofrequency ablation or hepatic resection is superior for improving the survival in patients with small hepatocellular carcinoma (HCC) remains controversial. A meta-analysis of randomized controlled trials was performed to examine this issue. Methods: PubMed, EMBASE, and Cochrane Library databases were used to identify all randomized controlled trials comparing the survival between small HCC patients receiving radiofrequency ablation and hepatic resection. The hazard ratio (HR) was pooled to compare the overall survival and recurrence-free survival rates. The odds ratio was pooled to compare the incidence of treatment-related complications. The mean difference was pooled to compare the hospitalization duration. Heterogeneity among studies was assessed. Results: Three randomized controlled trials were included in this meta-analysis. All patients met the Milan criteria. Hepatic resection was superior to radiofrequency ablation for the improvement of overall survival [HR=1.41; 95% confidence interval (CI), 1.06-1.89; P=0.02] and recurrence-free survival (HR=1.41; 95% CI, 1.14-1.74; P=0.001). Heterogeneity among studies was not significant (overall survival: P=0.14; recurrence-free survival: P=0.28). Patients treated with hepatic resection had a significantly higher incidence of treatment-related complications (odds ratio=0.12; 95% CI, 0.03-0.47; P=0.002) and a significantly longer hospitalization duration (mean difference:-8.77; 95% CI,-10.36 to-7.18; P<0.00001) than those treated with radiofrequency ablation. Heterogeneity among studies was significant (treatment-related complications: P=0.006; hospitalization duration: P=0.003). No hospital death occurred in the 2 groups. Conclusions: Evidence from the meta-analysis of randomized controlled trials suggested that hepatic resection might improve the overall survival and recurrence-free survival in small HCC patients, whereas increase the complications and hospitalization duration. However, this conclusion should be explained with caution, due to the absence of further subgroup analysis with respect to the outcome in patients with different tumor size (<3 and 3 to 5 cm). © 2013 Lippincott Williams & Wilkins.

Xie K.,Tianjin Medical University | Yu Y.,Tianjin Medical University | Huang Y.,PLA Fourth Military Medical University | Zheng L.,Shanxi Provincial Peoples Hospital | And 6 more authors.
Shock | Year: 2012

Acute lung injury (ALI) is still a leading cause of morbidity and mortality in critically ill patients. Recently, our and other studies have found that hydrogen gas (H2) treatment can ameliorate the lung injury induced by sepsis, ventilator, hyperoxia, and ischemia-reperfusion. However, the molecular mechanisms by which H2 ameliorates lung injury remain unclear. In the current study, we investigated whether H2 or hydrogen-rich saline (HS) could exert protective effects in a mouse model of ALI induced by intratracheal administration of lipopolysaccharide (LPS) via inhibiting the nuclear factor κB (NF-κB) signaling pathway-mediated inflammation and apoptosis. Two percent of H2 was inhaled for 1 h beginning at 1 and 6 h after LPS administration, respectively. We found that LPS-challenged mice exhibited significant lung injury characterized by the deterioration of histopathology and histologic scores, wet-to-dry weight ratio, and oxygenation index (PaO2/FIO2), as well as total protein in the bronchoalveolar lavage fluid (BALF), which was attenuated by H2 treatment. Hydrogen gas treatment inhibited LPS-induced pulmonary early and late NF-κB activation. Moreover, H2 treatment dramatically prevented the LPS-induced pulmonary cell apoptosis in LPS-challenged mice, as reflected by the decrease in TUNEL (deoxynucleotidyl transferase dUTP nick end labeling) staining-positive cells and caspase 3 activity. Furthermore, H2 treatment markedly attenuated LPS-induced lung neutrophil recruitment and inflammation, as evidenced by downregulation of lung myeloperoxidase activity, total cells, and polymorphonuclear neutrophils in BALF, as well as proinflammatory cytokines (tumor necrosis factor α, interleukin 1β, interleukin 6, and high-mobility group box 1) and chemokines (keratinocyte-derived chemokine, macrophage inflammatory protein [MIP] 1α, MIP-2, and monocyte chemoattractant protein 1) in BALF. In addition, i.p. injection of 10 mL/kg hydrogen-rich saline also significantly attenuated the LPS-induced ALI. Collectively, these results demonstrate that molecular hydrogen treatment ameliorates LPS-induced ALI through reducing lung inflammation and apoptosis, which may be associated with the decreased NF-κB activity. Hydrogen gas may be useful as a novel therapy to treat ALI. © 2012 by the Shock Society.

Hong L.,Xijing Hospital of Digestive Diseases | Han Y.,PLA Fourth Military Medical University | Liu J.,Xijing Hospital of Digestive Diseases | Brain L.,Johns Hopkins University
Expert Review of Gastroenterology and Hepatology | Year: 2013

Gastric cancer remains a leading cause of cancer-related death in the world. FGF receptor 2 (FGFR2) is preferentially amplified and overexpressed in the diffuse type of gastric cancer. This review evaluates the expression and function of FGFR2 in gastric cancer, and analyzes the use of its inhibitors for gastric cancer therapy. This review also discusses the limitations of FGFR2-based therapy, and envisages future developments toward the clinical applications of FGFR2. © 2013 Informa UK Ltd.

Wang B.,PLA Fourth Military Medical University | Cai Z.,PLA Fourth Military Medical University | Lu F.,PLA Fourth Military Medical University | Li C.,Ningxia Medical University | And 4 more authors.
Journal of Neurochemistry | Year: 2014

Progressive loss of dopaminergic (DA) neurons in the substantial nigra pars compacta (SNc) is an important pathological feature in Parkinson's disease (PD). Loss of transcription factor myocyte enhancer factor 2D (MEF2D), a key neuronal survival factor, has been shown to underlie the loss of DA neurons in SNc and the pathogenic process of PD. It is known that PD-associated neurotoxins reduce the level of MEF2D protein to trigger neuronal death. Although neurotoxins clearly destabilize MEF2D by post-translational mechanisms, it is not known whether regulation of MEF2D mRNA contributes to neurotoxin-induced decrease in MEF2D protein. In this work, we showed that MPP+, the toxic metabolite of MPTP, caused a significant decrease in the half-life and total level of MEF2D mRNA in a DA neuronal cell line, SN4741 cells. Quantitative PCR analysis of the SNc DA neurons captured by immune-laser capture microdissection showed that exposure to MPTP led to a marked reduction in the level of MEF2D mRNA in SNc DA neurons compared to controls. Down-regulation of MEF2D mRNA alone reduced the viability of SN4741 cells and sensitized the cells to MPP+-induced toxicity. These results suggest that destabilization and reduction in MEF2D mRNA is in part responsible for neurotoxin-induced decrease in MEF2D protein and neuronal viability. Myocyte enhancer factor 2D (MEF2D) plays an important role in neuronal survival. How MEF2D mRNA is deregulated under toxic stress is unclear. We found that PD-associated neurotoxins destabilize MEF2D mRNA and reduce its level in vitro and in vivo. Reduction in MEF2D mRNA is sufficient to sensitize model cells to neurotoxin-induced toxicity, suggesting that destabilization of MEF2D mRNA is part of the mechanism by which neurotoxins trigger deregulation of neuronal survival. Myocyte enhancer factor 2D (MEF2D) plays an important role in neuronal survival. How MEF2D mRNA is deregulated under toxic stress is unclear. We found that PD-associated neurotoxins destabilize MEF2D mRNA and reduce its level in vitro and in vivo. Reduction in MEF2D mRNA is sufficient to sensitize model cells to neurotoxin-induced toxicity, suggesting that destabilization of MEF2D mRNA is part of the mechanism by which neurotoxins trigger deregulation of neuronal survival. © 2014 International Society for Neurochemistry.

Liang S.,Xijing Hospital of Digestive Diseases | He L.,Xijing Hospital of Digestive Diseases | He L.,PLA Fourth Military Medical University | Zhao X.,Xijing Hospital of Digestive Diseases | And 10 more authors.
PLoS ONE | Year: 2011

Background: MicroRNAs (miRNAs) are important regulators that play key roles in tumorigenesis and tumor progression. A previous report has shown that let-7 family members can act as tumor suppressors in many cancers. Through miRNA array, we found that let-7f was downregulated in the highly metastatic potential gastric cancer cell lines GC9811-P and SGC7901-M, when compared with their parental cell lines, GC9811 and SGC7901-NM; however, the mechanism was not clear. In this study, we investigate whether let-7f acts as a tumor suppressor to inhibit invasion and metastasis in gastric cancers. Methodology/Principal: Real-time PCR showed decreased levels of let-7f expression in metastatic gastric cancer tissues and cell lines that are potentially highly metastatic. Cell invasion and migration were significantly impaired in GC9811-P and SGC7901-M cell lines after transfection with let-7f-mimics. Nude mice with xenograft models of gastric cancer confirmed that let-7f could inhibit gastric cancer metastasis in vivo after transfection by the lentivirus pGCsil-GFP- let-7f. Luciferase reporter assays demonstrated that let-7f directly binds to the 3′UTR of MYH9, which codes for myosin IIA, and real-time PCR and Western blotting further indicated that let-7f downregulated the expression of myosin IIA at the mRNA and protein levels. Conclusions/Significance: Our study demonstrated that overexpression of let-7f in gastric cancer could inhibit invasion and migration of gastric cancer cells through directly targeting the tumor metastasis-associated gene MYH9. These data suggest that let-7f may be a novel therapeutic candidate for gastric cancer, given its ability to reduce cell invasion and metastasis. © 2011 Liang et al.

Nagahashi M.,Virginia Commonwealth University | Nagahashi M.,Niigata University | Takabe K.,Virginia Commonwealth University | Liu R.,Virginia Commonwealth University | And 13 more authors.
Hepatology | Year: 2015

Bile acids are important hormones during the feed/fast cycle, allowing the liver to coordinately regulate nutrient metabolism. How they accomplish this has not been fully elucidated. Conjugated bile acids activate both the ERK1/2 and AKT signaling pathways via sphingosine 1-phosphate receptor 2 (S1PR2) in rodent hepatocytes and in vivo. Here, we report that feeding mice a high-fat diet, infusion of taurocholate into the chronic bile fistula rat, or overexpression of the gene encoding S1PR2 in mouse hepatocytes significantly upregulated hepatic sphingosine kinase 2 (SphK2) but not SphK1. Key genes encoding nuclear receptors/enzymes involved in nutrient metabolism were significantly downregulated in livers of S1PR2-/- and SphK2-/- mice. In contrast, overexpression of the gene encoding S1PR2 in primary mouse hepatocytes differentially increased SphK2, but not SphK1, and mRNA levels of key genes involved in nutrient metabolism. Nuclear levels of sphingosine-1-phosphate, an endogenous inhibitor of histone deacetylases 1 and 2, as well as the acetylation of histones H3K9, H4K5, and H2BK12 were significantly decreased in hepatocytes prepared from S1PR2-/- and SphK2-/- mice. Conclusion: Both S1PR2-/- and SphK2-/- mice rapidly developed fatty livers on a high-fat diet, suggesting the importance of conjugated bile acids, S1PR2, and SphK2 in regulating hepatic lipid metabolism. (Hepatology 2015;61:1216-1226). © 2014 by the American Association for the Study of Liver Diseases.

Li T.,Xijing Hospital of Digestive Diseases | Lu Y.Y.,Xijing Hospital of Digestive Diseases | Zhao X.D.,Xijing Hospital of Digestive Diseases | Guo H.Q.,Xijing Hospital of Digestive Diseases | And 8 more authors.
Oncogene | Year: 2014

Caudal-related homeobox 1 (CDX1), an intestinal-specific transcription factor, has been reported to have vital roles in gastric intestinal metaplasia (IM). Although IM is a high-risk factor for gastric cancer (GC), the specific role of CDX1 in GC is largely unknown. In this study, we investigated the expression of CDX1 and its functional roles in GC, and its upstream regulatory mechanisms at the microRNA (miRNA) level were further explored. We found that CDX1 is lost in GC when compared with adjacent IM tissues. Gain-of-function studies showed that CDX1 significantly inhibited GC cell growth by inducing cell cycle arrest and apoptosis. Interestingly, we identified and verified an onco-mir, miR-296-5p, as a direct upstream regulator of CDX1. miR-296-5p overexpression significantly promoted GC cell growth and attenuated the CDX1-induced anti-growth effects by recurring cell cycle distribution and apoptotic status, whereas knockdown of miR-296-5p decreased GC cell growth. Furthermore, we found that the extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation and the subsequent downstream changes in protein levels related to cell cycle and apoptosis partly account for the miR-296-5p-CDX1- induced GC growth promotion. In addition, the detection of miR-296-5p and expression of CDX1 in primary GC tissues and adjacent IM tissues revealed that miR-296-5p is inversely correlated with CDX1, further supporting our in vitro results. Our results showed an anti-growth effect of CDX1 and identified its miRNA regulatory mechanism in GC. The identification of this novel miR-296-5p-CDX1-ERK1/2 axis sheds new light on the understanding of the process from IM to GC and may provide therapeutic targets for the treatment of GC. © 2014 Macmillan Publishers Limited.

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