13513 Background: MicroRNAs (miRNAs) are small non-cording RNAs (∼ 22 nucleotide) that regulate gene expression by suppressing their target mRNAs at post-transcriptional level. Previous studies from our group have identified a number of dis-regulated miRNAs due to the loss of p53 tumor suppressor in cancer cell lines. As part of the efforts to further investigate the in vivo biological significance of these miRNAs, the expression of both hsa-let-7g and hsa-miR-200c were investigated using formalin-fixed paraffin embedded (FFPE) colon cancer specimens to evaluate the potential correlation with chemosensitivity and tumorigenesis. Methods: Forty-six patients with recurrent or residual colon cancer lesion assessable were treated with 5-FU based antimetabolite S-1. This includes twenty-one pair of tumor and normal samples. Total RNAs were isolated from these samples FFPE specimens (contains either > 90% normal or > 90% tumor tissue). cDNAs were synthesized using primers specific for hsa-let-7g, hsa-miR-200c and internal control 5S. The expression levels of each particular miRNAs were quantified using real time qRT-PCR analysis. The expression level of each miRNAs was quantified by measuring the difference of threshold cycle (CT) of candidate miRNAs and internal control 5S (Δ-CT). Results: The expression level of hsa-let-7g was significantly higher in tumor tissues compare to normal tissues (p=0.0026; Wilcoxon test). In the forty-six tumor tissues, the expression level of hsa-let-7g in disease response group (patients group of complete response, partial response and no change after chemotherapy) was significantly lower than the disease progression group (p=0.03; Mann-Whitney test). The expression of hsa-miR-200c was significantly over-expressed in tumor tissues compare to normal tissues (p=0.0001; Wilcoxon test). Although hsa-let-7g is strongly associated with patient’s response to S-1 treatment, it is not a prognostic factor for predicting survival. Conclusion: hsa-let-7g and hsa-miR-200c may be associated with tumorigenesis in colon cancer. In addition, hsa-let-7g may be a significant indicator for chemoresponse to S-1 based chemotherapy. No significant financial relationships to disclose.
Because hepatic vasculatures exhibit variations, a preoperative evaluation of the vascular anatomy and an estimation of the volume of the liver graft are essential for successful adult living donor liver transplantation. Using 3-dimensional (3D) computed tomography (CT), we analyzed the volumetric and anatomical relationship of the hepatic vasculatures of liver grafts. The livers of 223 potential donors were analyzed by 3D CT. Volumetric analysis was performed for each hepatic vein and its tributaries. The anatomy of the portal vein and hepatic artery was assessed along with the biliary system via intraoperative cholangiography in 110 recipients. On the basis of the anatomical presentation of the inferior right hepatic vein (IRHV), the hepatic veins were classified as follows: in type I, the IRHV was absent; in type II, the IRHV was smaller than the right hepatic vein (RHV); and in type III, the IRHV was greater than or equal to the RHV in size. The drainage volume of the middle hepatic vein (MHV) and especially its tributaries in the right lobe increased with the size of the IRHV (P < 0.001). In type III hepatic veins with a large IRHV (17% of the donors), the MHV tributaries had the largest drainage volume in the right lobe (41.2% 6 11.8%). Furthermore, type III hepatic veins typically exhibited biliary variations in 75% of the donors. No correlation was observed between variations in the hepatic artery and portal vein. In conclusion, a right lobe graft with a large IRHV is accompanied by a large drainage volume via the MHV and by bile duct variations in 17% of livers. Therefore, anatomical and volumetric analysis is important for preoperative evaluations. Living donor liver transplantation (LDLT) is an alternative to deceased donor liver transplantation for the treatment of patients with end-stage liver disease. 1 However, its application in adult recipients has been complicated by the problems associated with anatomical variations of hepatic vasculatures 2 and insufficient graft volume caused by venous outflow disturbances. 3 This is particularly true when the right lobe is selected for transplantation.To successfully perform right lobe LDLT, the drainage volume of the middle hepatic vein (MHV) tributaries and the inferior right hepatic vein (IRHV) must be Abbreviations: 3D, 3-dimensional; A1, normal branching of the hepatic artery; A2, replacement of the left hepatic artery from the left gastric artery; A3, replacement of the right hepatic artery from the superior mesenteric artery; A4, middle hepatic artery arising from the left hepatic artery; A5, middle hepatic artery arising from the right hepatic artery; B1, normal branching of the biliary duct; B2, trifurcation of the biliary duct; B3, posterior branching from the left hepatic duct; B4, independent posterior branching from the common hepatic duct; B5, segment 3 or 4 bile duct from the right hepatic duct; CT, computed tomography; IRHV, inferior right hepatic vein; LDLT, living donor liver transplantation; LGA, left gastric artery; LHV, left hepatic vei...
Background & AimsMesalamine is a first-line drug for treatment of inflammatory bowel diseases (IBD). However, its mechanisms are not fully understood. CD4+ Foxp3+ regulatory T cells (Tregs) play a potential role in suppressing IBD. This study determined whether the anti-inflammatory activity of mesalamine is related to Treg induction in the colon.MethodsWe examined the frequencies of Tregs in the colons of wild-type mice, mice deficient for aryl hydrocarbon receptor (AhR-/- mice), and bone marrow–chimeric mice lacking AhR in hematopoietic cells (BM-AhR-/- mice), following oral treatment with mesalamine. We also examined the effects of mesalamine on transforming growth factor (TGF)-β expression in the colon.ResultsTreatment of wild-type mice with mesalamine increased the accumulation of Tregs in the colon and up-regulated the AhR target gene Cyp1A1, but this effect was not observed in AhR-/- or BM-AhR-/- mice. In addition, mesalamine promoted in vitro differentiation of naive T cells to Tregs, concomitant with AhR activation. Mice treated with mesalamine exhibited increased levels of the active form of TGF-β in the colon in an AhR-dependent manner and blockade of TGF-β signaling suppressed induction of Tregs by mesalamine in the colon. Furthermore, mice pretreated with mesalamine acquired resistance to dextran sodium sulfate–induced colitis.ConclusionsWe propose a novel anti-inflammatory mechanism of mesalamine for colitis: induction of Tregs in the colon via the AhR pathway, followed by TGF-β activation.
We present the case of a child who underwent a combined liver, pancreas and double kidney transplant following complications of Wolcott–Rallison syndrome (WRS) a rare genetic disorder that causes infantile insulin‐dependent diabetes mellitus (IDDM) and often death in childhood from fulminant liver and concomitant kidney failure. WRS is characterized clinically through infantile IDDM, propensity for liver failure following viral infections, bone dysplasia and growth failure and developmental delay. Fewer than 60 cases with WRS are reported in the literature, mostly from consanguineous parents. Future episodes of liver failure, the main contributor to the increased mortality in WRS, may be prevented through timely liver transplantation. To the best of our knowledge, transplantation has not been utilized to manage complications of WRS prior to this report.
In leukemogenesis, Notch signaling can be up and downregulated in a context-dependent manner. The transcription factor hairy and enhancer of split-1 (Hes1) is well-characterized as a downstream target of Notch signaling. Hes1 encodes a basic helix-loop-helix-type protein, and represses target gene expression. Here, we report that deletion of the Hes1 gene in mice promotes acute myeloid leukemia (AML) development induced by the MLL-AF9 fusion protein. We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity. FLT3 was consequently upregulated in MLL-AF9-expressing immortalized and leukemia cells with a Hes1- or RBPJ-null background. MLL-AF9-expressing Hes1-null AML cells showed enhanced proliferation and ERK phosphorylation following FLT3 ligand stimulation. FLT3 inhibition efficiently abrogated proliferation of MLL-AF9-induced Hes1-null AML cells. Furthermore, an agonistic anti-Notch2 antibody induced apoptosis of MLL-AF9-induced AML cells in a Hes1-wild type but not a Hes1-null background. We also accessed two independent databases containing messenger RNA (mRNA) expression profiles and found that the expression level of FLT3 mRNA was negatively correlated with those of HES1 in patient AML samples. These observations demonstrate that Hes1 mediates tumor suppressive roles of Notch signaling in AML development, probably by downregulating FLT3 expression.
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