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Find video protocols related to scientific articles indexed in Pubmed.
Lymph node ratio as an independent prognostic indicator in stage III colorectal cancer: especially for fewer than 12 lymph nodes examined.
Tumour Biol.
PUBLISHED: 08-21-2014
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Although nodal invasion represents one of the most powerful prognostic indicators in colorectal cancer (CRC), marked heterogeneity exists within stage III patients. Lymph node ratio (LNR) may offer more precise prognostication in stage III CRC. The aim of this study is to investigate the prognostic impact of LNR on survival in stage III CRC patients. We retrospectively reviewed the data of 288 consecutive patients who underwent radical resection for stage III CRC between January 2000 and December 2008 in the Gastrointestinal Surgery Department, Peking University People's Hospital. The patients were divided into three groups according to LNR quartiles: LNR?
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Proposal of a new lymph node staging system for gastric cancer: study from two institutions in China.
Med. Oncol.
PUBLISHED: 07-22-2014
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The aim of this study was to identify the best cutoff points for lymph node classification to improve the prognostic prediction of gastric cancer in China. Patients who had undergone surgery for gastric cancer were retrospectively evaluated in two high-volume institutions from Peking University People's Hospital (PKUPH, N=503) and Affiliated Hospital of Qingdao University (AHQU, N=1,003). The prognosis of these patients was assessed according to the number of metastatic lymph nodes with an increment of one node at one time. A new lymph node classification was proposed based on the relation between prognosis and the number of metastatic lymph nodes. According to the prognostic value, the proposed node (N) stage was categorized as N0 (no regional LNs metastasis), N1 (1-3 involved regional LNs), N2 (4-6 involved regional LNs), and N3 (?7 involved regional LNs). The hazard ratio for the proposed N classification increased steadily and reasonably compared with the 7th edition. Moreover, the Cox regression multivariate analysis showed that the proposed N classification was superior to the 7th N classification as an independent prognostic factor. The proposed N category was superior to 7th edition N category of the American Joint Committee on Cancer (AJCC) for assessing the prognosis for gastric cancer patients in China.
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Expression QTL-based analyses reveal the mechanisms underlying colorectal cancer predisposition.
Tumour Biol.
PUBLISHED: 07-14-2014
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Genome-wide association studies have identified many risk loci associated with colorectal cancer. Strategies integrating biological data sets with GWAS results will provide insights into the roles of risk single-nucleotide polymorphisms. We performed expression quantitative trait locus-based analyses using the information provided in The Cancer Genome Atlas. Analysis of the cis-expression quantitative trait loci (eQTLs) of 18 previously reported colorectal cancer risk loci resulted in the discovery of five variants that were significantly associated with gene expressions. Analysis of the trans-eQTLs identified three risk loci that affect the expression levels of a neighboring transcription factor, MYC. These findings provide a more comprehensive picture of gene expression determinants in colorectal cancer and insights into the underlying biology of risk loci.
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Risk assessment of butyltins based on a fugacity-based food web bioaccumulation model in the Jincheng Bay mariculture area: II. Risk assessment.
Environ Sci Process Impacts
PUBLISHED: 06-21-2014
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A fugacity-based food web bioaccumulation model was constructed, and the biotic concentrations of butyltins in the food web of the Jincheng Bay mariculture area were estimated accordingly, using the water and sediment concentrations described in the accompanying paper (Part I). This paper presents an ecological risk assessment (ERA) and a human health risk assessment (HHRA) of the butyltins, based on the estimated tissue residues in the marine life in this area. The results showed that the ecological risk probability was greater than 0.05. At this level, management control is critical since sensitive marine species would be profoundly endangered by butyltin contamination. Few if any detrimental effects, however, would be generated for humans from exposure to butyltins through seafood consumption. The fugacity-based model can refine the ERA and HHRA of pollutants in marine areas, provide a basis for protecting marine ecology and the security of fishery products, and thus help determine the feasibility of a proposed aquaculture project.
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Risk assessment of butyltins based on a fugacity-based food web bioaccumulation model in the Jincheng Bay mariculture area: I. Model development.
Environ Sci Process Impacts
PUBLISHED: 06-20-2014
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A fugacity-based model was developed to simulate the bioaccumulation of butyltins in the food web of the Jincheng Bay mariculture area. The predicted biological tissue residues of tributyltin (TBT), dibutyltin (DBT), and monobutyltin (MBT) were 0.04-17.09, 0.14-53.54, and 0.27-108.77 ng-Sn g(-1), respectively, and the predicted values in six mollusca agreed well with the measured ones. The lipid-normalized concentrations did not significantly increase across trophic levels, indicating no biomagnification across aquatic food webs. These results were highly consistent with those observed both in the laboratory and field, which had been reported in numerous references. The explanation, from calculating their flux equilibrium in the food web, was that butyltins were primarily taken in via respiration from the water column by marine organisms. The sensitivities of the model parameters were analyzed, revealing that the hydrophobicity of butyltins played the dominant role in their bioaccumulation phenomena. The verified model predictions of the biotic tissue concentrations of the butyltins could be readily applied to perform internal ecological risk and human health risk assessments in this area.
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Therapeutic experience with primary liposarcoma from the sigmoid mesocolon accompanied with well-differentiated liposarcomas in the pelvis.
Surg. Today
PUBLISHED: 05-15-2014
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Multifocal liposarcoma with different histological types is rare, especially that originating from the mesentery. We herein report a case of primary myxoid liposarcoma from the sigmoid mesocolon that was accompanied with well-differentiated liposarcomas in the pelvis. The location, the fat signal and the relationship with adjacent organs of the liposarcomas were well shown in the axial, coronal and sagittal dimensions of MRI, giving a comprehensive and specific image before surgery. To alleviate the patient's symptoms and mental stress, a laparotomy was performed. The tumors were all completely excised with macroscopic free margins. The final histopathological report showed that the tumor in the sigmoid mesocolon was a pure myxoid liposarcoma, while the pelvic tumors were spindle cell liposarcomas, a special type of well-differentiated liposarcoma. According to the AJCC staging system, they were all stage IIB. No further adjuvant therapy was performed. Close follow-up after the surgery has been performed, and the patient has remained healthy without any evidence of recurrence or metastasis for 17 months after the surgery.
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Clinicopathological significance of SIRT1 expression in colorectal adenocarcinoma.
Med. Oncol.
PUBLISHED: 04-12-2014
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Sirtuin 1 (SIRT1) has been reported to have diverse roles in various biological processes through deacetylation of histone and nonhistone proteins. However, the correlations between SIRT1 protein expression, clinicopathological parameters, and survival of colorectal cancer patients remain unclear. SIRT1 protein expression in a paraffin-embedded tissue microarray, including 13 benign adenomas, nine liver metastasis tissues, and 120 paired colorectal cancer and normal mucosa tissues, was measured by immunohistochemistry. SIRT1 mRNA and protein expression in colon cancer cell lines with different metastatic potential and normal colon cells were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. The correlations between SIRT1 protein expression, clinicopathological features, and prognosis were analyzed. All samples (100 %) were positive for SIRT1, with variable staining in the cytoplasm rather than the nucleus. There was significant difference in SIRT1 overexpression between adenocarcinomas and normal mucosal tissues (P < 0.01, ?(2) test). SIRT1 overexpression was more frequently observed in advanced-stage tumors and lymph node or liver metastases (P = 0.046, 0.002, and 0.004, respectively, ?(2) test). SIRT1 expression was also significantly elevated in the more aggressive colon cancer cell line SW620. SIRT1 overexpression was significantly correlated with poor overall survival (P = 0.013, log-rank test) and disease-free survival (P = 0.012, log-rank test). SIRT1 overexpression was correlated with advanced-stage and poor prognosis. SIRT1 may play an important role in the progression of colorectal cancer.
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Mice deleted for GPAT3 have reduced GPAT activity in white adipose tissue and altered energy and cholesterol homeostasis in diet-induced obesity.
Am. J. Physiol. Endocrinol. Metab.
PUBLISHED: 04-08-2014
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Glycerol-3-phosphate acyltransferases (GPATs) catalyze the first step in the synthesis of glycerolipids and glycerophospholipids. Microsomal GPAT, the major GPAT activity, is encoded by at least two closely related genes, GPAT3 and GPAT4. To investigate the in vivo functions of GPAT3, we generated Gpat3-deficient (Gpat3(-/-)) mice. Total GPAT activity in white adipose tissue of Gpat3(-/-) mice was reduced by 80%, suggesting that GPAT3 is the predominant GPAT in this tissue. In liver, GPAT3 deletion had no impact on total GPAT activity but resulted in a 30% reduction in N-ethylmaleimide-sensitive GPAT activity. The Gpat3(-/-) mice were viable and fertile and exhibited no obvious metabolic abnormalities on standard laboratory chow. However, when fed a high-fat diet, female Gpat3(-/-) mice showed decreased body weight gain and adiposity and increased energy expenditure. Increased energy expenditure was also observed in male Gpat3(-/-) mice, although it was not accompanied by a significant change in body weight. GPAT3 deficiency lowered fed, but not fasted, glucose levels and tended to improve glucose tolerance in diet-induced obese male and female mice. On a high-fat diet, Gpat3(-/-) mice had enlarged livers and displayed a dysregulation in cholesterol metabolism. These data establish GPAT3 as the primary GPAT in white adipose tissue and reveal an important role of the enzyme in regulating energy, glucose, and lipid homeostasis.
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Evaluation of the seventh AJCC TNM staging system for gastric cancer: a meta-analysis of cohort studies.
Tumour Biol.
PUBLISHED: 04-03-2014
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The AJCC seventh edition TNM classification for gastric cancer was released in 2010 and included major revision. Large-volume gastric cancer centers have evaluated the prognostic significance of the new system and obtained paradoxical results. The authors performed a meta-analysis of these studies to evaluate the new classification. Fifteen eligible studies with 38,972 patients were included in the analysis. Hazard ratios (HRs) and associated 95 % confidence intervals were extracted from identified studies. The primary outcome was overall survival. The HRs for the seventh edition T classification and N classification were found to increase steadily and reasonably. The cumulative survival rates of the seventh edition subgroups of T classifications demonstrated obvious differences; meanwhile, the differences between subgroups of N classifications including N3a and N3b categories were also significant. The 5-year survival rates according to the seventh edition TNM staging system were 94.71 % (stage IA), 88.72 % (stage IB), 80.45 % (stage IIA), 67.24 % (stage IIB), 53.68 % (stage IIIA), 37.56 % (stage IIIB), and 21.26 % (stage IIIC), respectively. The results of this study indicate that the seventh edition of the TNM classification was considered valid, although further evaluation was needed for N3a and N3b categories.
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[Application of sacral nerve stimulation in patients with fecal incontinence].
Zhonghua Wei Chang Wai Ke Za Zhi
PUBLISHED: 03-28-2014
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Fecal incontinence is one of diseases effecting the quality of life and mental health. Germany surgeon used sacral nerve stimulation(SNS) to treat fecal incontinence at first in 1995. The aim of SNS is to mobilize the ability to control the feces through stimulating the nerves of dominating the sphincter muscles and pelvic floor muscles. Standard SNS includes two stages: evaluation stage of SNS and permanent implantation stage. Preoperative evaluation plays important role in guaranteeing the success of treatment. SNS is the primary treatment of choice for severe fecal incontinence. The complications of SNS include pain, shift of electronic probe, wound dehiscence, bowel dysfunction and infection.
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[Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): Chinese subgroup analysis].
Zhonghua Wei Chang Wai Ke Za Zhi
PUBLISHED: 03-01-2014
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To evaluate the efficacy and safety profile of XELOX (capecitabine/oxaliplatin) in patients with locally advanced gastric cancer who underwent curative D2 resection in China.
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[Research progress of circumferential resection margin of colon cancer].
Zhonghua Wei Chang Wai Ke Za Zhi
PUBLISHED: 02-13-2014
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Circumferential resection margin(CRM) is the closest distance from the deepest of tumor invasion to the surgical margin of mesentery. It has been well known that CRM has significant impact on the prognosis and treatment of rectal cancer. However, the significance of CRM of colon cancer is just brought to the forefront recently. Current evidence showed positive rate of CRM is 10%, and the patients with positive CRM have worse survival. The factors influencing CRM include tumor stage, differentiation, vascular cancer embolus, etc. Standard surgical procedure can lower the positive rate of colon CRM, and adjuvant therapy applied to the patients with positive colon CRM can improve the survival of colon cancer patients. CRM may become a new factor guiding the treatment in colon cancer patients.
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IRS1(Ser307) phosphorylation does not mediate mTORC1-induced insulin resistance.
Biochem. Biophys. Res. Commun.
PUBLISHED: 12-03-2013
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Increased mammalian target of rapamycin complex 1 (mTORC1) activity has been suggested to play important roles in development of insulin resistance in obesity. mTORC1 hyperactivity also increases endoplasmic reticulum (ER) stress, which in turn contributes to development of insulin resistance and glucose intolerance. Increased IRS1 phosphorylation at Ser307 in vitro is correlated with mTORC1- and ER stress-induced insulin resistance. This phosphorylation site correlates strongly with impaired insulin receptor signaling in diabetic mice and humans. In contrast, evidence from knock-in mice suggests that phosphorylation of IRS1 at Ser307 is actually required to maintain insulin sensitivity. To study the involvement of IRS1(Ser307) phosphorylation in mTORC1-mediated glucose intolerance and insulin sensitivity in vivo, we investigated the effects of liver specific TSC1 depletion in IRS1(Ser307Ala) mice and controls. Our results demonstrate that blockade of IRS1(Ser307) phosphorylation in vivo does not prevent mTORC1-mediated glucose intolerance and insulin resistance.
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A novel molecular marker of prognosis in colorectal cancer: Vasohibin-1.
Med. Oncol.
PUBLISHED: 11-08-2013
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Vasohibin-1 has been recently detected in endothelial cells and identified as a negative feedback regulator of angiogenesis induced by VEGF-A. However, the expression of Vasohibin-1 in colorectal cancer and its correlations with VEGF-A, microvessel density (MVD), and the prognosis of the patients remain unclear. In this study, Vasohibin-1 and VEGF-A expression were measured in 132 paraffin-embedded tissues of colorectal cancer by immunohistochemistry and Western blot, as well as in colon cancer cell lines with different metastatic potential and in normal colon cell by Western blot and real-time PCR. MVD was measured by counting CD34 positive clusters in a single field of view with the most intensive neovascularization of colon cancer tissues. The correlation between the expression of Vasohibin-1, VEGF-A, MVD, clinicopathological features, and prognosis was analyzed. We found that Vasohibin-1 and VEGF-A proteins were expressed in 88.64 % (117/132) and 84.09 % (111/132) colorectal cancer tissues, respectively. Strongly positive correlations were found between Vasohibin-1, VEGF-A expression, and MVD in the colorectal cancer tissues (Vasohibin-1 vs.
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Comparison of metastatic lymph node ratio staging system with the 7th AJCC system for colorectal cancer.
J. Cancer Res. Clin. Oncol.
PUBLISHED: 09-06-2013
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To evaluate the prognostic value and staging accuracy of the metastatic lymph node ratio (rN) staging system for colorectal cancer.
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Vasohibin-1 expression is regulated by transforming growth factor-?/bone morphogenic protein signaling pathway between tumor-associated macrophages and pancreatic cancer cells.
J. Interferon Cytokine Res.
PUBLISHED: 05-07-2013
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Vasohibin-1 has been detected in endothelial cells as an intrinsic angiogenesis inhibitor. Both tumor-associated macrophages (TAMs) and transforming growth factor-? (TGF-?)/bone morphogenic protein (BMP) signaling have been reported to promote angiogenesis in cancer. However, whether vasohibin-1 expression is regulated by TGF-?/BMP signaling between TAMs and cancer cells remains unclear. The expression of TGF-?1, TGF-?2, BMP-4, and BMP-7 in TAMs and the expression of vasohibin-1, vascular endothelial growth factor-A (VEGF-A), and VEGF-C in two pancreatic cancer cell lines (a nonmetastatic cell line Panc-1 and a distant metastatic cell line HPAF-II) were measured by real-time reverse transcription-polymerase chain reaction (RT-PCR). The TGF-? receptor 1 and BMP receptor 1 were inhibited by the inhibitor SB-431542 and LDN193189, respectively. Thereafter, vasohibin-1, VEGF-A, and VEGF-C expression was detected by real-time RT-PCR. We found that the expression of TGF-?1, TGF-?2, BMP-4, and BMP-7 was upregulated in TAMs cocultured with pancreatic cancer cells. Vasohibin-1, VEGF-A, and VEGF-C mRNA expression in pancreatic cancer cells was upregulated by TAMs. Vasohibin-1 expression in pancreatic cancer cells cocultured with TAMs was upregulated significantly when TGF-? receptors or BMP receptors were inhibited, but VEGF-C expression was downregulated. Therefore, Vasohibin-1 expression is regulated by the TGF-?/BMP signaling between TAMs and pancreatic cancer cells. These results might shed a new light on the antiangiogenesis therapy in the pancreatic cancer.
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An anatomical, histopathological, and molecular biological function study of the fascias posterior to the interperitoneal colon and its associated mesocolon: their relevance to colonic surgery.
J. Anat.
PUBLISHED: 05-06-2013
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The study aim was to explore the anatomy, histopathology, and molecular biological function of the fascias posterior to the interperitoneal colon and its mesocolon to provide information for improving complete mesocolic excision. To accomplish this aim, we performed intraoperative observations in 60 interperitoneal colon-cancer patients accepted for complete mesocolic excision and conducted local anatomy observations for five embalmed cadavers. An additional two embalmed child cadaver specimens were studied with large slices and paraffin sections. Ten of the 60 patients were examined with a lymph node tracer technique in vivo, while fresh specimens from these patients were assessed by histopathological examination and transwell cell migration assays in vitro. The anatomical and histopathological findings showed that the fascias posterior to the interperitoneal colon and its associated mesocolon were composed of two independent layers: the visceral and parietal fascias. These two fascias were primarily composed of collagen fibers, with the parietal fascia containing a small amount of muscle fiber. The in vivo test showed that the visceral fascia surrounded the colon and its associated mesocolon, including vessels and lymphatics, and that it had no lymphatic flow through it into the rear tissues. Moreover, the in vitro assays showed the visceral fascia was able to block tumor cell migration. Although many surgical scholars have known of the existence of fascia tissue posterior to the intraperitoneal colon, the detailed structure has been ignored and been unclear. As shown by our findings, the visceral and parietal fascias are truly formed structures that have not been previously reported. A thorough understanding of fascial structures and the function of the visceral fascia barrier in blocking tumor cells will facilitate surgeons when performing high-quality complete mesocolic excision procedures.
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Novel focal adhesion protein kindlin-2 promotes the invasion of gastric cancer cells through phosphorylation of integrin ?1 and ?3.
J Surg Oncol
PUBLISHED: 04-23-2013
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We have found that the expression of the novel focal adhesion protein kindlin-2 had a significant positive correlation with poor survival in gastric cancer. However, the mechanism by which kindlin-2 acts in gastric cancer warrants further evaluation.
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Identification of two new HLA-A*0201-restricted cytotoxic T lymphocyte epitopes from colorectal carcinoma-associated antigen PLAC1/CP1.
J. Gastroenterol.
PUBLISHED: 04-02-2013
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BACKGROUND: To explore the potential application of placenta-specific PLAC1/Cancer Placenta (CP) 1 antigen for immunotherapy in CRC patients, further identification of the cytotoxic T lymphocyte epitopes from this antigen is necessary. METHODS: We assessed the protein expression of PLAC1/CP1 using a tissue chip and immunochemistry staining in CRC samples. Simultaneously, we predicted four PLAC1/CP1-derived HLA-A*0201-restricted peptides by using reverse immunology methods. Peptide-specific CD8(+) T cell responses were assessed by an IFN-? release ELISPOT assay. Effector CD8(+) T cells lyse HLA-A*0201 CRC cell line SW620 was detected in a granzyme-B release ELISPOT cytotoxicity assay. RESULTS: Our results indicated that PLAC1/CP1 was highly expressed in 56.7 % (55/97) of adenocarcinomas. PLAC1/CP1 protein expression was associated with CRC tumor differentiation, the tumor/node/metastasis stage, and lymph node metastasis. Two of four peptides showed high affinities in an HLA-A2 binding assay. In 66.7 % (6/9) of peripheral blood mononuclear cells of CRC samples with PLAC1/CP1 protein-positive expression, these two peptides, PLAC1/CP1 p41-50 (FMLNNDVCV) and PLAC1/CP1 p69-77 (HAYQFTYRV), were immunogenic in the induction of peptide-specific CD8(+) T cell responses as assessed by an IFN-? release ELISPOT assay. Furthermore, the generated effector CD8(+) T cells could specifically lyse the PLAC1/CP1 HLA-A*0201 CRC cell line SW620 in a granzyme-B release ELISPOT cytotoxicity assay. CONCLUSIONS: These results show that the PLAC1/CP1 antigen is a possible prognostic marker of CRC and that PLAC1/CP1 p41-50 and PLAC1/CP1 p69-77 are novel HLA-A*0201-restricted CD8(+) T cell epitopes and potential targets for peptide-based immunotherapy in CRC patients.
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Macrophage coculture enhanced invasion of gastric cancer cells via TGF-? and BMP pathways.
Scand. J. Gastroenterol.
PUBLISHED: 03-23-2013
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Transforming growth factor ? (TGF-?) superfamily plays an important role in regulating gastric cancer progression. As previously demonstrated, tumor-associated macrophages (TAMs) promoted the invasion of gastric cancer cells in Matrigel. However, the role of TGF-? superfamily signaling between TAMs and gastric cancer remains unclear.
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Lipocalin 13 regulation of glucose and lipid metabolism in obesity.
Vitam. Horm.
PUBLISHED: 02-05-2013
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Lipocalin (LCN) family members are small secreted proteins that bind to small hydrophobic molecules via their characteristic central ?-barrels. A couple of LCN family members, including major urinary protein 1, retinol-binding protein 4, LCN2, and LCN13, have been reported to regulate insulin sensitivity and nutrient metabolism. LCN13 is expressed by multiple tissues, including the liver, pancreas, epididymis, and skeletal muscle, and is secreted into the bloodstream in mice. Obesity is associated with a downregulation of LCN13 expression and lower levels of circulating LCN13. LCN13 therapies overcome LCN13 deficiency in mice with either genetic or dietary obesity, leading to an improvement in hyperglycemia, hyperinsulinemia, insulin resistance, glucose intolerance, and hepatic steatosis. In hepatocytes, LCN13 directly suppresses hepatic gluconeogenesis and lipogenesis but increases fatty acid ? oxidation. LCN13 also enhances insulin sensitivity in adipocytes. The potential mechanisms of the antidiabetes and antisteatosis actions of LCN13 are discussed.
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Leptin signaling and leptin resistance.
Front Med
PUBLISHED: 01-24-2013
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Leptin is secreted into the bloodstream by adipocytes and is required for the maintenance of energy homeostasis and body weight. Leptin deficiency or genetic defects in the components of the leptin signaling pathways cause obesity. Leptin controls energy balance and body weight mainly through leptin receptor b (LEPRb)-expressing neurons in the brain, particularly in the hypothalamus. These LEPRb-expressing neurons function as the first-order neurons that project to the second-order neurons located within and outside the hypothalamus, forming a neural network that controls the energy homeostasis and body weight. Multiple factors, including inflammation and endoplasmic reticulum (ER) stress, contribute to leptin resistance. Leptin resistance is the key risk factor for obesity. This review is focused on recent advance about leptin action, leptin signaling, and leptin resistance.
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Hepatic SH2B1 and SH2B2 Regulate Liver Lipid Metabolism and VLDL Secretion in Mice.
PLoS ONE
PUBLISHED: 01-01-2013
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SH2B1 is an SH2 and PH domain-containing adaptor protein. Genetic deletion of SH2B1 results in obesity, type 2 diabetes, and fatty liver diseases in mice. Mutations in SH2B1 are linked to obesity in humans. SH2B1 in the brain controls energy balance and body weight at least in part by enhancing leptin sensitivity in the hypothalamus. SH2B1 in peripheral tissues also regulates glucose and lipid metabolism, presumably by enhancing insulin sensitivity in peripheral metabolically-active tissues. However, the function of SH2B1 in individual peripheral tissues is unknown. Here we generated and metabolically characterized hepatocyte-specific SH2B1 knockout (HKO) mice. Blood glucose and plasma insulin levels, glucose tolerance, and insulin tolerance were similar between HKO, albumin-Cre, and SH2B1(f/f) mice fed either a normal chow diet or a high fat diet (HFD). Adult-onset deletion of SH2B1 in the liver either alone or in combination with whole body SH2B2 knockout also did not exacerbate HFD-induced insulin resistance and glucose intolerance. Adult-onset, but not embryonic, deletion of SH2B1 in the liver attenuated HFD-induced hepatic steatosis. In agreement, adult-onset deletion of hepatic SH2B1 decreased the expression of diacylglycerol acyltransferase-2 (DGAT2) and increased the expression of adipose triglyceride lipase (ATGL). Furthermore, deletion of liver SH2B1 in SH2B2 null mice attenuated very low-density lipoprotein (VLDL) secretion. These data indicate that hepatic SH2B1 is not required for the maintenance of normal insulin sensitivity and glucose metabolism; however, it regulates liver triacylglycerol synthesis, lipolysis, and VLDL secretion.
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Targeting Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) with small molecule inhibitors for the treatment of metabolic diseases.
J. Biol. Chem.
PUBLISHED: 10-11-2011
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Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final step in triglyceride synthesis. Findings from genetically modified mice as well as pharmacological studies suggest that inhibition of DGAT1 is a promising strategy for the treatment of obesity and type 2 diabetes. Here we characterize a tool DGAT1 inhibitor compound, T863. We found that T863 is a potent inhibitor for both human and mouse DGAT1 in vitro, which acts on the acyl-CoA binding site of DGAT1 and inhibits DGAT1-mediated triacylglycerol formation in cells. In an acute lipid challenge model, oral administration of T863 significantly delayed fat absorption and resulted in lipid accumulation in the distal small intestine of mice, mimicking the effects of genetic ablation of DGAT1. In diet-induced obese mice, oral administration of T863 for 2 weeks caused weight loss, reduction in serum and liver triglycerides, and improved insulin sensitivity. In addition to the expected triglyceride-lowering activity, T863 also lowered serum cholesterol. Hepatic IRS2 protein was dramatically up-regulated in mice treated with T863, possibly contributing to improved insulin sensitivity. In differentiated 3T3-L1 adipocytes, T863 enhanced insulin-stimulated glucose uptake, suggesting a possible role for adipocytes to improve insulin sensitivity upon DGAT1 inhibition. These results reveal novel mechanistic insights into the insulin-sensitizing effects of DGAT1 inhibition in mouse models. Taken together, our study provides a comprehensive evaluation of a small molecule inhibitor for DGAT1 and suggests that pharmacological inhibition of DGAT1 holds promise in treating diverse metabolic disorders.
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[Pathological observation after MRI guided high intensity focused ultrasound therapy for ablating the liver tissues adjacent to goat portal vein].
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi
PUBLISHED: 09-23-2011
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The present study was aimed to investigate the pathological changes after magnetic resonance imaging (MRI) guided high intensity focused ultrasound (MRgHIFU) therapy for ablating the liver tissue adjacent to goat portal vein. Fifty goats were involved in this study. Normal liver tissues at 0, 5, and 10 mm distance from portal vein, respectively, were ablated with MRgHIFU. Among the 50 tested subjects, 40 goats were sacrificed immediately after the operations, and the other 10 were sacrificed 7 days after the procedure for pathological examination of the targeted areas and the contiguous portal veins. Coagulation necrosis was observed in all the treated liver tissues. Collagen swelling (CS) and vessel wall fracture (VWF) emerged more frequently in the 0 mm group than that in the 5mm group: CS [0 mm group VS 5mm group = 27/40 (67.5%) VS 7/40 (17.5%), P < 0.05], VWF [0 mm group VS 5mm group = 8/40 (20%) VS 0/40 (0%), P < 0.05]. Seven days after ablation, no portal vein damages (CS and VWF) were observed under light microscope. The results indicated that MRgHIFU could be used to ablate the liver tissue adjacent to goat portal vein effectively, which may cause blood vessel damage when the focus is on the wall of blood vessels (0 mm). However, the pathological results indicated that these damages are reversible.
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microRNA-320a inhibits tumor invasion by targeting neuropilin 1 and is associated with liver metastasis in colorectal cancer.
Oncol. Rep.
PUBLISHED: 09-13-2011
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MicroRNAs (miRNAs) have been implicated in regulating diverse cellular pathways. Although there is emerging evidence that various miRNAs function as oncogenes or tumor suppressors in colorectal cancer (CRC), the role of miRNAs in mediating liver metastasis remains unexplored. The expression profile of miRNAs in liver metastasis and primary CRC tissues was analyzed by miRNA microarrays and verified by real-time polymerase chain reaction (PCR). In 62 CRC patients, the expression levels of miR-320a were determined by real-time PCR, and the effects on migration and invasion of miR-320a were determined using a transwell assay. miR-320a target genes were confirmed by luciferase assay, real-time PCR and western blot analysis. A set of miRNAs was found to be dysregulated in the liver metastasis tissues compared to matched primary CRC tissues, and the expression levels of miR-320a were significantly decreased in the liver metastasis tissues examined. miR-320a was correlated with tumor progression in CRC. miR-320a was downregulated in liver metastatic colon cancer cells and inhibited liver metastatic colon cancer cell migration and invasion. miR-320a directly binds to the 3UTR of neuropilin 1 (NRP-1), a protein that functions as a co-receptor of vascular epithelial growth factor. miR-320a downregulated the expression of NRP-1 at both the mRNA and protein levels. These data demonstrated that miR-320a may be useful for identifying CRC patients that are at an elevated risk for developing liver metastasis. Our findings suggest that miR-320a may be a novel therapeutic candidate for the treatment of colorectal cancer.
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Lipocalin 13 protein protects against hepatic steatosis by both inhibiting lipogenesis and stimulating fatty acid ?-oxidation.
J. Biol. Chem.
PUBLISHED: 09-09-2011
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Obesity is associated with hepatic steatosis, partially due to increased lipogenesis and decreased fatty acid ?-oxidation in the liver; however, the underlying mechanism of abnormal lipid metabolism is not fully understood. We reported previously that obesity is associated with LCN13 (lipocalin 13) deficiency. LCN13 is a lipocalin family member involved in glucose metabolism, and LCN13 deficiency appears to contribute to hyperglycemia in obese mice. Here, we show that LCN13 is also an important regulator of lipogenesis and ?-oxidation in the liver. In primary hepatocytes, recombinant LCN13 directly suppressed lipogenesis and increased fatty acid ?-oxidation, whereas neutralization of endogenous LCN13 had an opposite effect. Transgenic overexpression of LCN13 protected against hepatic steatosis in mice with either dietary or genetic (ob/ob) obesity. LCN13 transgenic overexpression also improved hyperglycemia, glucose intolerance, and insulin resistance in ob/ob mice. Short-term LCN13 overexpression via an adenovirus-mediated gene transfer similarly attenuated hepatic steatosis in db/db mice. LCN13 inhibited the expression of important lipogenic genes and stimulated the genes that promote ?-oxidation. These results suggest that LCN13 decreases liver lipid levels by both inhibiting hepatic lipogenesis and stimulating ?-oxidation. LCN13 deficiency is likely to contribute to fatty liver disease in obese mice.
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Targeted gene delivery to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption.
Exp. Neurol.
PUBLISHED: 07-31-2011
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This study aimed to investigate the feasibility of targeted gene transfer into central nervous system (CNS) by MRI-guided focused ultrasound-induced blood-brain barrier (BBB) disruption. Before each sonication, T2-weighted images were obtained to select the target region. Followed by injecting DNA-loaded microbubbles into the tail vein, sonication was performed. The state of local BBB, distribution of plasmid DNA through the opened BBB, the ultrastructural changes of neurons and BDNF expression were detected. The results showed that MRI-guided focused ultrasound (FUS) could accomplish noninvasive, transient, and local BBB disruption, at 1h after sonication, plasmid DNA across the opened BBB had been internalized into the neurons presenting heterogeneous distribution and numerous transparent vesicles were observed in the cytoplasm of the neurons at the sonicated region, suggesting vesicle-mediated endocytosis. At 48 h after sonication, the expressions of exogenous gene pBDNF-EGFP were observed in the cytoplasm of some neurons, and BDNF expressions were markedly enhanced by the combination of ultrasound and pBDNF-EGFP-loaded microbubbles about 20-fold than that of the control group (P<0.01). The method by using MRI-guided FUS to induce the local BBB disruption could accomplish effective targeted exogenous gene transfer in CNS. This technique may provide a new option for the treatment of various CNS diseases.
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p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis.
Nat. Med.
PUBLISHED: 05-11-2011
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Here we show that p38 mitogen-activated protein kinase (p38 MAPK) phosphorylates the spliced form of X-box binding protein 1 (Xbp1s) on its Thr48 and Ser61 residues and greatly enhances its nuclear migration in mice, whereas mutation of either residue to alanine substantially reduces its nuclear translocation and activity. We also show that p38 MAPK activity is markedly reduced in the livers of obese mice compared with lean mice. Further, we show that activation of p38 MAPK by expression of constitutively active MAP kinase kinase 6 (MKK6Glu) greatly enhances nuclear translocation of Xbp1s, reduces endoplasmic reticulum stress and establishes euglycemia in severely obese and diabetic mice. Hence, our results define a crucial role for phosphorylation on Thr48 and Ser61 of Xbp1s in the maintenance of glucose homeostasis in obesity, and they suggest that p38 MAPK activation in the livers of obese mice could lead to a new therapeutic approach to the treatment of type 2 diabetes.
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Kindlin-2: a novel adhesion protein related to tumor invasion, lymph node metastasis, and patient outcome in gastric cancer.
Am. J. Surg.
PUBLISHED: 04-03-2011
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Kindlin-2 has been confirmed as an essential element of bidirectional integrin signaling. In recent years, the relationship between Kindlin-2 expression and cancers has been a focus of interest. However, the relationship between Kindlin-2 expression in gastric cancer and tumor invasion, metastasis, and the outcome of patients have not been studied.
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The role of caveolin-1 in blood-brain barrier disruption induced by focused ultrasound combined with microbubbles.
J. Mol. Neurosci.
PUBLISHED: 03-25-2011
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This research was designed to determine whether disrupting the blood-brain barrier (BBB) in rats by applying focused ultrasound (FUS) combined with microbubbles induced changes in the density of caveolae and/or the expression of the structural protein caveolin-1. To this end, two approaches were utilized. First, using enhanced magnetic resonance imaging, characteristics of BBB disruption induced by our specific FUS parameters and dose of microbubble were recorded, and the time after treatment when the BBB was the most permeable was determined. Second, rats were treated with FUS or microbubbles alone, both or neither, and a combination of Evans blue (EB) BBB permeability assays, streptavidin-peroxidase (SP) immunohistochemistry, western blot, and transmission electron microscopy (TEM) was employed to detect any changes in caveolae density and caveolin-1 expression at the previously determined time point when the BBB was the most permeable. The first set of studies revealed that our specific FUS parameters and dose of microbubbles were able to induce a transient, targeted, and reversible BBB opening in rats, and that the BBB was the most permeable 1 h after treatment with FUS and microbubbles. In the second set of experiments, the results of the SP immunohistochemistry, western blot, and TEM, taken together, revealed that caveolae and caveolin-1 were primarily localized in the brain microvascular endothelial cells of all of the rats regardless of treatment, and that caveolin-1 expression was highest in the rats treated with both FUS and microbubbles. In summary, treatment with FUS, in combination with a dose of microbubbles, can enhance BBB permeability through a caveolae-mediated transcellular approach by upregulating the expression level of caveolin-1 and, consequently, the amount of caveolae. This caveolin-1-mediated transcellular transport pathway may cooperate with other transport pathways to induce opening of the BBB. This research sheds light on the mechanism of a transient, targeted, and reversible opening of the BBB induced by FUS combined with microbubbles.
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Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction.
Nat. Med.
PUBLISHED: 02-13-2011
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To date, the only known role of the spliced form of X-box-binding protein-1 (XBP-1s) in metabolic processes has been its ability to act as a transcription factor that regulates the expression of genes that increase the endoplasmic reticulum (ER) folding capacity, thereby improving insulin sensitivity. Here we show that XBP-1s interacts with the Forkhead box O1 (FoxO1) transcription factor and directs it toward proteasome-mediated degradation. Given this new insight, we tested modest hepatic overexpression of XBP-1s in vivo in mouse models of insulin deficiency or insulin resistance and found it improved serum glucose concentrations, even without improving insulin signaling or ER folding capacity. The notion that XBP-1s can act independently of its role in the ER stress response is further supported by our finding that in the severely insulin resistant ob/ob mouse strain a DNA-binding-defective mutant of XBP-1s, which does not have the ability to increase ER folding capacity, is still capable of reducing serum glucose concentrations and increasing glucose tolerance. Our results thus provide the first evidence to our knowledge that XBP-1s, through its interaction with FoxO1, can bypass hepatic insulin resistance independent of its effects on ER folding capacity, suggesting a new therapeutic approach for the treatment of type 2 diabetes.
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Lipocalin-13 regulates glucose metabolism by both insulin-dependent and insulin-independent mechanisms.
Mol. Cell. Biol.
PUBLISHED: 12-06-2010
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Insulin sensitivity is impaired in obesity, and insulin resistance is the primary risk factor for type 2 diabetes. Here we show that lipocalin-13 (LCN13), a lipocalin superfamily member, is a novel insulin sensitizer. LCN13 was secreted by multiple cell types. Circulating LCN13 was markedly reduced in mice with obesity and type 2 diabetes. Three distinct approaches were used to increase LCN13 levels: LCN13 transgenic mice, LCN13 adenoviral infection, and recombinant LCN13 administration. Restoration of LCN13 significantly ameliorated hyperglycemia, insulin resistance, and glucose intolerance in mice with obesity. LCN13 enhanced insulin signaling not only in animals but also in cultured adipocytes. Recombinant LCN13 increased the ability of insulin to stimulate glucose uptake in adipocytes and to suppress hepatic glucose production (HGP) in primary hepatocyte cultures. Additionally, LCN13 alone was able to suppress HGP, whereas neutralization of LCN13 increased HGP in primary hepatocyte cultures. These data suggest that LCN13 regulates glucose metabolism by both insulin-dependent and insulin-independent mechanisms. LCN13 and LCN13-related molecules may be used to treat insulin resistance and type 2 diabetes.
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Sarco(endo)plasmic reticulum Ca2+-ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 10-25-2010
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Increased endoplasmic reticulum (ER) stress is one of the central mechanisms that lead to dysregulated metabolic homeostasis in obesity. It is thus crucial to understand the underpinnings of the mechanisms that lead to the development of ER stress. A high level of ER Ca(2+) is imperative for maintenance of normal ER function and this high Ca(2+) concentration of ER is maintained by sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA). Here, we show that SERCA2b protein and mRNA levels are dramatically reduced in the liver of obese mice and restoration of SERCA2b in the liver of obese and diabetic mice alleviates ER stress, increases glucose tolerance, and significantly reduces the blood glucose levels. Furthermore, overexpression of SERCA2b in the liver of obese mice significantly reduces the lipogenic gene expression and the triglyceride content in the liver. Our results document the importance of SERCA2b in dysregulated glucose and lipid homeostasis in the liver of obese mice and suggest development of drugs to increase SERCA2b activity for treatment of type 2 diabetes and nonalcoholic steatohepatitis.
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Major urinary protein regulation of chemical communication and nutrient metabolism.
Vitam. Horm.
PUBLISHED: 09-14-2010
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The major urinary protein (MUP) family members contain a conserved ?-barrel structure with a characteristic central hydrophobic pocket. They are secreted by the liver and excreted into the urine. MUPs bind via their central pockets to volatile pheromones or other lipophilic molecules, and regulate pheromone transportation in the circulation, excretion in the kidney, and release into the air from urine marks. MUPs are highly polymorphic, and the MUP profiles in urine function as individual identity signatures of the owners. The MUP signatures are detected by the main and accessory olfactory systems and trigger adaptive behavioral responses and/or developmental processes. Circulating MUPs serve as a metabolic signal to regulate glucose and lipid metabolism. Recombinant MUP1 markedly ameliorates hyperglycemia and glucose intolerance in mice with type 2 diabetes. MUP1 suppresses hepatic gluconeogenesis and promotes energy expenditure in skeletal muscle by stimulating mitochondrial biogenesis and function. MUPs are unique members of the lipocalin superfamily that mediate both chemical and metabolic signaling.
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Sodium butyrate induces differentiation of gastric cancer cells to intestinal cells via the PTEN/phosphoinositide 3-kinase pathway.
Cell Biol. Int.
PUBLISHED: 08-20-2010
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NaB (sodium butyrate) inhibits cell proliferation and induces differentiation in a variety of tumour cells. In this study, we aimed to determine whether NaB induced differentiation and regulated the expression of the mucosal factor MUC2 through the PTEN/PI3K (phosphoinositide 3-kinase) pathway. BGC823 cells treated with NaB for 24-72 h showed marked inhibition of cell proliferation and alteration in cellular morphology. NaB treatment markedly increased the expression of PTEN and MUC2, but it decreased the expression of PI3K. These effects were enhanced by intervention with PI3K inhibitors and were reduced by intervention with PTEN siRNA. Hence, we conclude that NaB increased PTEN expression, promoted the expression of MUC2 and induced the differentiation of gastric cancer cells through the PTEN/PI3K signalling pathway.
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Clinical study on the correlation between metabolic syndrome and colorectal carcinoma.
ANZ J Surg
PUBLISHED: 06-19-2010
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Although metabolic syndrome (MS) has received a lot of attention in recent years, the correlation between MS and colorectal carcinoma is still not very clear. This study aims at exploring the relationship between MS and colorectal carcinoma.
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[Research on thermal dose for high intensity focused ultrasound treatment based on the temperature-map of magnetic resonance imaging].
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi
PUBLISHED: 05-21-2010
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Based on the T-map of MRI, this research sought to address the relationship between the simulated threshold thermal dose of coagulation and actual the coagulation on histological slides. The MR imaging guided HIFU system was used, the parameters of therapeutic transducer were: frequency--1 MHz, diameter--150 mm, and focal length--150 mm. In fresh beef liver tissue in vitro, sonications were delivered at a fixed depth of 20 mm and at varying powers. The temperature-sensitive MR images obtained during the sonications were used to estimate the temperature, and the thermal dosage of each voxel in the target region was calculated. The thermal dosage of each voxel was compared with the reference threshold thermal dosage, so as to calculate the boundary and area of the coagulated tissue. After the exposure, the tissue was dissected along the maximal section of the coagulation necrosis, and the area of the biological focal region was measured.
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A novel molecular marker for early detection and evaluating prognosis of gastric cancer: N-myc downstream regulated gene-1 (NDRG1).
Scand. J. Gastroenterol.
PUBLISHED: 04-15-2010
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N-myc downstream regulated gene-1 (NDRG1) is known as a differentiation-related gene that plays important roles in cell differentiation, organ formation, and embryonic development. NDRG1 was recently found to significantly down regulate in a variety of different neoplasms. Its significance in gastric cancer has not been studied.
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Proteomics-based identification of a group of apoptosis-related proteins and biomarkers in gastric cancer.
Int. J. Oncol.
PUBLISHED: 02-09-2010
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Gastric cancer (GC) is the one of the most common types of cancer in Asia. To better understand the molecular mechanisms underlying GC, and to seek new markers of tumor progression, we used a proteomics strategy to analyze the protein expression patterns in matched pairs of GC tissue and normal gastric mucosa of 8 GC patients. Comparative proteomic analysis, using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), revealed that 32 protein spots showed a >2-fold difference in intensity between tumor and normal tissues. Twenty-six proteins were up-regulated and 6 proteins were down-regulated in tumor tissue compared to control. Western blot analysis confirmed differential expression for 9 proteins, including AGR2, ENO1, GDI2, GRP78, GRP94, PPIA, PRDX1, PTEN and VDAC1. Immunohistochemical staining of a tissue microarray, derived from 145 GC patients, with antibodies for each of the 9 proteins demonstrated a significant association between the level of protein immunostaining and the clinical features of the disease in the donor. The identified proteins were functionally classified using bioinformatics methods, showing that the 9 proteins identified were related to BCL2, BAX, ERBB2 and CASP3 proteins and involved in the process of apoptosis. These proteomic data provide potentially valuable insights into both the biology of GC and the identity of biomarkers for tumor progression. We propose ENO1, GRP78, GRP94, PPIA, PRDX1 and PTEN as potential GC biomarkers.
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Metabolic syndrome is an important factor for the evolution of prognosis of colorectal cancer: survival, recurrence, and liver metastasis.
Am. J. Surg.
PUBLISHED: 01-15-2010
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Several studies have shown that metabolic syndrome (MS) was a risk factor for colorectal cancer, but few studies have reported the relationship between MS and the prognosis of colorectal cancer.
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The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation.
Nat. Med.
PUBLISHED: 01-04-2010
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Despite the fact that X-box binding protein-1 (XBP-1) is one of the main regulators of the unfolded protein response (UPR), the modulators of XBP-1 are poorly understood. Here, we show that the regulatory subunits of phosphotidyl inositol 3-kinase (PI3K), p85alpha (encoded by Pik3r1) and p85beta (encoded by Pik3r2) form heterodimers that are disrupted by insulin treatment. This disruption of heterodimerization allows the resulting monomers of p85 to interact with, and increase the nuclear translocation of, the spliced form of XBP-1 (XBP-1s). The interaction between p85 and XBP-1s is lost in ob/ob mice, resulting in a severe defect in XBP-1s translocation to the nucleus and thus in the resolution of endoplasmic reticulum (ER) stress. These defects are ameliorated when p85alpha and p85beta are overexpressed in the liver of ob/ob mice. Our results define a previously unknown insulin receptor signaling pathway and provide new mechanistic insight into the development of ER stress during obesity.
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Identification of transgelin-2 as a biomarker of colorectal cancer by laser capture microdissection and quantitative proteome analysis.
Cancer Sci.
PUBLISHED: 11-03-2009
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To search for potential protein markers of colorectal cancer (CRC), the changes in protein expression levels between microdissected tumor cells and normal mucosa epithelia were analyzed by an acetylation stable isotopic labeling method coupled with linear quadrupole ion trap fourier transform mass spectrometry (LTQ-FTMS). In total, 137 proteins were up-regulated or down-regulated significantly in cancer by at least two-fold. Based on gene ontology analysis, the largest part of differential proteins were unknown for both subcellular localization and biological process. In particular, the significant up-regulation of transgelin-2 (TAGLN2) in CRC was validated by Western blot analysis and further evaluated by immunohistochemistry in paired tumor and normal mucosa samples from 120 consecutive CRC patients, 20 adenomas, and eight synchronous hepatic metastases of CRC. TAGLN2 expression was frequently observed in cancer cells, precancerous lesions, and hepatic metastases, whereas in normal epithelia expression was rarely observed. The overexpression of TAGLN2 was associated with lymph node and distant metastasis, advanced clinical stage (P < 0.001), and shorter overall survival in CRCs. Cox regression analysis indicated that high tumor-TAGLN2 expression represents an independent prognostic factor. Consequently, over-expression of TAGLN2 may serve as a new biomarker for predicting progression and prognosis of CRC.
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Focused ultrasound microbubble destruction-mediated changes in blood-brain barrier permeability assessed by contrast-enhanced magnetic resonance imaging.
J Ultrasound Med
PUBLISHED: 10-27-2009
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The purpose of this study was to use enhanced magnetic resonance imaging (MRI) to evaluate the changes of blood-brain barrier (BBB) permeability in target and nontarget areas of rabbit brains after BBB disruption induced by focused ultrasound-mediated microbubble destruction.
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Experimental study on targeted methotrexate delivery to the rabbit brain via magnetic resonance imaging-guided focused ultrasound.
J Ultrasound Med
PUBLISHED: 06-24-2009
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The purpose of this study was to investigate the effects of targeted and reversible disruption of the blood-brain barrier (BBB) by magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) and delivery of methotrexate (MTX) to the rabbit brain.
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SH2B1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins.
Diabetes
PUBLISHED: 06-19-2009
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SH2B1 is a SH2 domain-containing adaptor protein expressed in both the central nervous system and peripheral tissues. Neuronal SH2B1 controls body weight; however, the functions of peripheral SH2B1 remain unknown. Here, we studied peripheral SH2B1 regulation of insulin sensitivity and glucose metabolism.
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Pilot postoperative ileus study of escin in cancer patients after colorectal surgery.
World J Surg
PUBLISHED: 04-17-2009
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Postoperative ileus, a common complication in patients after abdominal surgery, brings no benefit to the recovery of postoperative patients, and treatment targeted at restoring gastrointestinal motility may shorten the hospital stay. Studies have shown that escin accelerates gastrointestinal transit in mice and improves gastrointestinal motility in patients after abdominal surgery. A pilot study of escins effect on the recovery of gastrointestinal motility was conducted in colorectal cancer patients in anticipation of a multiple-center randomized controlled trial.
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Identification of MUP1 as a regulator for glucose and lipid metabolism in mice.
J. Biol. Chem.
PUBLISHED: 03-03-2009
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Major urinary protein (MUP) 1 is a lipocalin family member abundantly secreted into the circulation by the liver. MUP1 binds to lipophilic pheromones and is excreted in urine. Urinary MUP1/pheromone complexes mediate chemical communication in rodents. However, it is unclear whether circulatory MUP1 has additional physiological functions. Here we show that MUP1 regulates glucose and lipid metabolism. MUP1 expression was markedly reduced in both genetic and dietary fat-induced obesity and diabetes. Mice were infected with MUP1 adenoviruses via tail vein injection, and recombinant MUP1 was overexpressed in the liver and secreted into the bloodstream. Recombinant MUP1 markedly attenuated hyperglycemia and glucose intolerance in genetic (db/db) and dietary fat-induced type 2 diabetic mice as well as in streptozotocin-induced type 1 diabetic mice. MUP1 inhibited the expression of both gluconeogenic genes and lipogenic genes in the liver. Moreover, recombinant MUP1 directly decreased glucose production in primary hepatocyte cultures by inhibiting the expression of gluconeogenic genes. These data suggest that MUP1 regulates systemic glucose and/or lipid metabolism through the paracrine/autocrine regulation of the hepatic gluconeogenic and/or lipogenic programs, respectively.
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Surgical treatment of Chiari I malformation complicated with syringomyelia.
Exp Ther Med
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The aim of this study was to evaluate the curative effects of various surgical procedures on Chiari I malformation (CMI) complicated with syringomyelia. A total of 185 patients with CMI complicated with syringomyelia who received treatment between January 1997 and December 2011 were recruited. All patients underwent posterior fossa decompression in which the lamina of the first cervical vertebra was removed, with the removal of the second or third depending on the severity of the cerebellar tonsil herniation. Of the patients, 76 underwent large-bone-window decompression and duraplasty, while 109 underwent small-bone-window decompression, displaced cerebellar tonsil resection and duraplasty. The curative effects of the different surgical procedures were analyzed retrospectively. Clinical symptoms were eliminated or improved in 156 patients (84.3%) by the time of discharge from hospital. A total of 148 patients were evaluated using magnetic resonance imaging (MRI) which revealed that the cisterna magna was reconstructed in 92 patients and spinal syrinx was reduced in 75. Follow-up was performed on 147 patients (79.5%) for between 3 months and 12 years. During the follow-up, symptoms were eliminated or improved in 110 patients (74.8%), not improved in 26 (17.7%) and deteriorated in 11 (7.5%). MRI was performed on 95 patients during follow-up examinations and the cisterna magna was reconstructed in 87 patients and spinal syrinx was reduced in 79. Small-bone-window decompression plus duraplasty is an effective surgical procedure for treating CMI complicated with syringomyelia and intraoperative cerebellar tonsillectomy significantly aids patient recovery.
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Both macrophages and hypoxia play critical role in regulating invasion of gastric cancer in vitro.
Acta Oncol
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As previously demonstrated, tumor associated macrophages (TAMs) infiltration is associated with some cancers invasion and metastasis. However, the role of TAMs in the gastric cancer remains unclear.
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Discrimination of metastatic lymph nodes in patients with gastric carcinoma using diffusion-weighted imaging.
J Magn Reson Imaging
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To determine the accuracy of diffusion-weighted imaging (DWI) in discrimination of metastatic lymph nodes (LNs) in gastric carcinoma with rigorous histopathological correlation.
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The novel focal adhesion gene kindlin-2 promotes the invasion of gastric cancer cells mediated by tumor-associated macrophages.
Oncol. Rep.
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Kindlin-2 is a novel focal adhesion gene mediating the cell-extracellular matrix (ECM) adhesion. Tumor-associated macrophages (TAMs) play an important role in linking chronic inflammation to cancer progression. Both kindlin-2 and TAMs have been found to promote the invasion of gastric cancer cells in our previous studies. However, the correlation between kindlin-2 and TAMs remains unclear. Real-time RT-PCR was used to investigate kindlin-2 expression in the AGS, NCI and Hs-746T gastric cancer cell lines co-cultured with TAMs under normal or hypoxic conditions. IL8, IL10, IL11, IL17b, IL18, IL22 and IL24 expressions were measured by real-time RT-PCR in the gastric cancer lines with varying levels of kindlin-2 expression, as well as after downregulation of kindlin-2 mRNA expression by the siRNA method. We found that kindlin-2 was upregulated in all three gastric cancer cell lines when co-cultured with TAMs under normal conditions. Under hypoxic conditions, the induction of kindlin-2 expression induced by macrophages was significantly downregulated in the Hs-746T cell line. IL8, IL11, IL17b, IL22 and IL24 expression was significantly higher in gastric cell lines with high kindlin-2 expression. Downregulation of kindlin-2 mRNA decreased IL10, IL11, IL17b, IL22 and IL24 expression but IL8 and IL18 expression was upregulated. Therefore, the novel focal adhesion gene kindlin-2 may play an important role in promoting the invasion of gastric cancer cells mediated by TAMs through regulating interleukin expression.
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Analysis of colistin A and B in fishery products by ultra performance liquid chromatography with positive electrospray ionization tandem mass spectrometry.
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
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A rapid and simple method for the determination of colistin A and B in fishery products by reversed phase ultra performance liquid chromatography with positive electrospray ionization tandem spectrometry (UPLC-ESI-MS/MS) method was described. The samples were extracted with 1.0 mol/L of hydrochloric acid in methanol-water and then purified on the PLS solid phase extraction columns. Then the eluate was evaporated to less than 1 mL under a gentle stream of nitrogen at 40 °C and formic acid-acetonitrile-water (0.2/10/90, v/v/v) was added to adjust volume to 1 mL final volume. An aliquot (10 ?L) was injected onto the LC column for analysis with the mobile phase of 0.2% formic acid in acetonitrile and 0.2% formic acid in water at 0.20 mL min?¹. Multiple reaction monitoring was performed using precursor-product ion combinations. Calibration curves were linear from 200 ng/mL to 2000 ng/mL for colistin A and B. Mean recoveries were between 72.9% and 82.9%. The LOD was 10.0 ?g/kg and LOQ was 40.0 ?g/kg. The intra-day assay precision values for QC samples were between 2.17% and 9.00%, and inter-day values were between 2.80% and 6.97%. The method has merits of simplicity, sensitivity and rapidity, and it can be used for the determination of colistin A and B in fishery products.
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IL10, IL11, IL18 are differently expressed in CD14+ TAMs and play different role in regulating the invasion of gastric cancer cells under hypoxia.
Cytokine
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Recent evidence shows that chronic inflammation mediated by tumor-associated macrophage (TAM) play an important role in malignant tumor formation and progression. Interleukins expressed in TAMs regulate this progress. Hypoxia is a salient feature of solid tumors and has a profound influence on the biology of TAMs However, the role of interleukins in the gastric cancer progression under hypoxia is not clear.
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NF-?B–inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action.
Nat. Med.
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The canonical inhibitor of nuclear factor ?B kinase subunit ? (IKK-?)–nuclear factor of ? light polypeptide gene enhancer in B cells 1 (NF-?B1) pathway has been well documented to promote insulin resistance; however, the noncanonical NF-?B–inducing kinase (NIK)–NF-?B2 pathway is not well understood in obesity. Additionally, the contribution of counter-regulatory hormones, particularly glucagon, to hyperglycemia in obesity is unclear. Here we show that NIK promotes glucagon responses in obesity. Hepatic NIK was abnormally activated in mice with dietary or genetic obesity. Systemic deletion of Map3k14, encoding NIK, resulted in reduced glucagon responses and hepatic glucose production (HGP). Obesity is associated with high glucagon responses, and liver-specific inhibition of NIK led to lower glucagon responses and HGP and protected against hyperglycemia and glucose intolerance in obese mice. Conversely, hepatocyte-specific overexpression of NIK resulted in higher glucagon responses and HGP. In isolated mouse livers and primary hepatocytes, NIK also promoted glucagon action and glucose production, at least in part by increasing cAMP response element-binding (CREB) stability. Therefore, overactivation of liver NIK in obesity promotes hyperglycemia and glucose intolerance by increasing the hyperglycemic response to glucagon and other factors that activate CREB.
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Laparoscopic appendectomy for acute appendicitis versus chronic appendicitis.
J Invest Surg
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The advantage or disadvantage of laparoscopic appendectomy for acute appendicitis remains unclear.
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Vasohibin-1 and vasohibin-2 expression in gastric cancer cells and TAMs.
Med. Oncol.
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Accumulating evidence suggests that TAMs contribute to tumor progression. Recently, vasohibin-1 and vasohibin-2 were detected in endothelial cells and considered as intrinsic angiogenesis inhibitors. However, it is not known whether they are also expressed in cancer cells or tumor-associated macrophages (TAMs). Realtime RT-PCR was used to investigate the vasohibin-1 and vasohibin-2 expression in four gastric cancer cell lines, including a non-metastatic cell line AGS, and metastatic cell lines HGC-27, Hs-746T and NCI-N87, co-cultured with or without TAMs. The effect of hypoxic conditions on vasohibin expression was evaluated as well, and the correlation between vasohibin-1, vasohibin-2 and VEGF-A expression under different culture conditions was analyzed. We found that both vasohibin-1 and vasohibin-2 were expressed in the four gastric cancer cell lines and in TAMs. Under normal conditions, vasohibin-1 and vasohibin-2 expressions were significantly upregulated by TAMs in all the gastric cancer cell lines. Under hypoxia, both vasohibin-1 and vasohibin-2 expressions were significantly decreased in the distant metastasis cancer cell line Hs-746T, cultured with or without TAMs (P<0.001). After induction by TAMs or hypoxia, the vasohibin-1 and vasohibin-2 expressions correlated with that of VEGF-A. In addition, TAMs, when co-cultured with the metastatic cancer cell lines, showed hypoxia-induced vasohibin-1 upregulation (P<0.05). In conclusion, both vasohibin-1 and vasohibin-2 mRNA are expressed in gastric cancer cells and in TAMs, and their expressions are altered by hypoxia.
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Epinephrine deficiency results in intact glucose counter-regulation, severe hepatic steatosis and possible defective autophagy in fasting mice.
Int. J. Biochem. Cell Biol.
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Epinephrine is one of the major hormones involved in glucose counter-regulation and gluconeogenesis. However, little is known about its importance in energy homeostasis during fasting. Our objective is to study the specific role of epinephrine in glucose and lipid metabolism during starvation. In our experiment, we subject regular mice and epinephrine-deficient mice to a 48-h fast then we evaluate the different metabolic responses to fasting. Our results show that epinephrine is not required for glucose counter-regulation: epinephrine-deficient mice maintain their blood glucose at normal fasting levels via glycogenolysis and gluconeogenesis, with normal fasting-induced changes in the peroxisomal activators: peroxisome proliferator activated receptor ? coactivator ? (PGC-1?), fibroblast growth factor 21 (FGF-21), peroxisome proliferator activated receptor ? (PPAR-?), and sterol regulatory element binding protein (SREBP-1c). However, fasted epinephrine-deficient mice develop severe ketosis and hepatic steatosis, with evidence for inhibition of hepatic autophagy, a process that normally provides essential energy via degradation of hepatic triglycerides during starvation. We conclude that, during fasting, epinephrine is not required for glucose homeostasis, lipolysis or ketogenesis. Epinephrine may have an essential role in lipid handling, possibly via an autophagy-dependent mechanism.
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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.