Aim: The aim of this study was to investigate the hypothesis that the opioid system is involved in the development of hepatic fibrosis. Methods: The effect of naltrexone (an opioid receptor antagonist) on hepatic fibrosis in bile duct ligated (BDL) or sham rats was assessed by histology and hepatic hydroxyproline levels. Liver matrix metalloproteinase 2 (MMP-2) was measured by zymography, and a smooth muscle actin (a-SMA) and CD45 (leucocyte common antigen) by immunohistochemistry. The redox state of the liver was assessed by hepatic glutathione (GSH)/oxidised glutathione (GSSG) and S-nitrosothiol levels. Subtypes of opioid receptors in cultured hepatic stellate cells (HSCs) were characterised by reverse transcriptase-polymerase chain reaction, and the effects of selective d opioid receptor agonists on cellular proliferation, tissue inhibitor of metalloproteinase 1 (TIMP-1), and procollagen I expression in HSCs determined. Results: Naltrexone markedly attenuated the development of hepatic fibrosis as well as MMP-2 activity (p,0.01), and decreased the number of activated HSCs in BDL rats (p,0.05). The development of biliary cirrhosis altered the redox state with a decreased hepatic GSH/GSSG ratio and increased concentrations of hepatic S-nitrosothiols, which were partially or completely normalised by treatment with naltrexone, respectively. Activated rat HSCs exhibited expression of d1 receptors, with increased procollagen I expression, and increased TIMP-1 expression in response to d 1 and d 2 agonists, respectively. Conclusions: This is the first study to demonstrate that administration of an opioid antagonist prevents the development of hepatic fibrosis in cirrhosis. Opioids can influence liver fibrogenesis directly via the effect on HSCs and regulation of the redox sensitive mechanisms in the liver.
Ovarian cancer remains the most common cause of gynecologic cancer-related death among women in developed countries. Nevertheless, subgroups of ovarian cancer patients experience relatively longer survival. Efforts to identify prognostic factors that characterize such patients are ongoing, with investigational areas including tumor characteristics, surgical management, inheritance patterns, immunologic factors, and genomic patterns. This review discusses various demographic, clinical, and molecular factors implicating longevity and ovarian cancer survival. Continued efforts at identifying these prognosticators may result in invaluable adjuncts to the treatment of ovarian cancer, with the ultimate goal of advancing patient care.
microRNAs are small single-stranded non-coding RNA molecules which modify gene expression by silencing potential target genes. The aberrant expression of RhoA, a small GTPase protein of Rho family, is involved in gastric cancer tumorigenesis. Since miR-31 is a pleomorphic molecule, we evaluated the miR-31/RhoA axis in inducing the malignant phenotype of gastric cancer cells MKN-45. Also, the clinicopathological significance of RhoA was investigated in a well-defined collection of gastric carcinomas which were embedded in tissue microarray blocks. Induction of miR-31 in MKN-45 followed by suppression of RhoA expression resulted in increased sensitivity to 5-fluorouracil, inhibition of cell proliferation, and invasion compared to the control groups. Immunohistochemical analysis in gastric adenocarcinoma patients' samples showed significantly higher expression of RhoA in diffuse versus intestinal subtype tumors ( P = 0.009), poorly differentiated versus well and moderately differentiated tumors ( P = 0.03) and the presence of vascular invasion versus the absence of vascular invasion ( P = 0.04). Our findings suggest a critical role for miR-31, as a tumor suppressor gene, in gastric cancer tumorigenesis by targeting the RhoA. Impact statement Gastric cancer ranks as the third leading cause of cancer-associated deaths worldwide. The RhoA gene encodes a small GTPase protein of Rho family (RhoA) that its dysregulation is associated with cell motility and invasion. A strong line of evidence supports the regulation of RhoA by a number of miRs, including miR-31 in tumors. Our findings revealed that miR-31 is involved in gastric cancer tumorigenesis as a tumor suppressor gene. Through down-regulation of RhoA, miR-31 decreased cell proliferation, migration, and invasion in gastric cancer cells. In addition, induction of miR-31 increased sensitivity to 5-FU; thus, increasing its tissue concentrations could be a potential target for treatment of gastric cancer in the future.
Cancer stem cells (CSCs) are hypothesized to be the main culprit of lung cancer progression. Clinicopathological significance of stem cell markers CD133 and ALDH1 in a large group of lung cancer patients was evaluated. ALDH1 and CD133 had higher expression levels in the NSCLC compared to the SCLC. Over-expression of both ALDH1 and CD133 markers was exclusively found in SCC and ADC. Low level of ALDH1 expression was strongly correlated with poor differentiation in ADC cases. Thus, ALDH1(high)/CD133(high) phenotype can be considered as a CSC marker in some lung cancer subtypes.
The purpose of this study was to determine if there is a correlation between urine and/or stone cultures with postoperative sepsis in patients treated for renal and ureteral calculi. Three hundred and twenty-eight consecutive patients who underwent percutaneous nephrolithotomy (PCNL) or ureteroscopy from 2006 to 2009 were identified, all of whom had a stone culture obtained during surgery. All had a preoperative urine culture. Two hundred and seventy-four underwent ureteroscopy and 54 PCNL. All patients had either negative preoperative urine cultures or were given preoperative antibiotics for 1-7 days prior to surgery. Stone fragments were obtained during the procedure and sent for analysis. The primary endpoint was sepsis. Of 328 patients, 3 % (11/328) developed postoperative sepsis. 73 % (8/11) had positive stone cultures, while none had a positive preoperative urine culture. 8 % (8/96) with positive stone cultures and 1 % (3/232) with negative stone cultures developed sepsis (p = 0.003). The stone culture grew the same pathogen as the urine culture obtained on readmission in 64 % (7/11) of the patients, while 9 % (1/11) of preoperative urine cultures correlated with the readmission pathogen (p = 0.02). The pathogen causing infection had a significantly higher correlation with the organism grown on stone culture than the preoperative urine culture. The patients who developed sepsis did so despite preoperative antibiotics, and the pathogen grown on the preoperative urine culture was different from that seen post operatively. These results suggest that stone culture is more informative than preoperative urine culture for determining treatment of postoperative sepsis.
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