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- Serum microRNA-21 as marker for necroinflammation in hepatitis C patients with and without hepatocellular carcinoma (2011)
- Background: MicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations of miR-21 have also been found in sera or plasma from patients with malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum miR-21 levels with clinical parameters in patients with different stages of chronic hepatitis C virus infection (CHC) and CHC-associated HCC. Methodology/Principal Findings: 62 CHC patients, 29 patients with CHC and HCC and 19 healthy controls were prospectively enrolled. RNA was extracted from the sera and miR-21 as well as miR-16 levels were analyzed by quantitative real-time PCR; miR-21 levels (normalized by miR-16) were correlated with standard liver parameters, histological grading and staging of CHC. The data show that serum levels of miR-21 were elevated in patients with CHC compared to healthy controls (P<0.001); there was no difference between serum miR-21 in patients with CHC and CHC-associated HCC. Serum miR-21 levels correlated with histological activity index (HAI) in the liver (r = −0.494, P = 0.00002), alanine aminotransferase (ALT) (r = −0.309, P = 0.007), aspartate aminotransferase (r = −0.495, P = 0.000007), bilirubin (r = −0.362, P = 0.002), international normalized ratio (r = −0.338, P = 0.034) and γ-glutamyltransferase (r = −0.244, P = 0.034). Multivariate analysis revealed that ALT and miR-21 serum levels were independently associated with HAI. At a cut-off dCT of 1.96, miR-21 discriminated between minimal and mild-severe necroinflammation (AUC = 0.758) with a sensitivity of 53.3% and a specificity of 95.2%. Conclusions/Significance: The serum miR-21 level is a marker for necroinflammatory activity, but does not differ between patients with HCV and HCV-induced HCC.
- N-terminus of hMLH1 confers interaction of hMutL{alpha} and hMutL{beta} with hMutS{alpha} (2003)
- Mismatch repair is a highly conserved system that ensures replication fidelity by repairing mispairs after DNA synthesis. In humans, the two protein heterodimers hMutS{alpha} (hMSH2-hMSH6) and hMutL{alpha} (hMLH1-hPMS2) constitute the centre of the repair reaction. After recognising a DNA replication error, hMutS{alpha} recruits hMutL{alpha}, which then is thought to transduce the repair signal to the excision machinery. We have expressed an ATPase mutant of hMutL{alpha} as well as its individual subunits hMLH1 and hPMS2 and fragments of hMLH1, followed by examination of their interaction properties with hMutS{alpha} using a novel interaction assay. We show that, although the interaction requires ATP, hMutL{alpha} does not need to hydrolyse this nucleotide to join hMutS{alpha} on DNA, suggesting that ATP hydrolysis by hMutL{alpha} happens downstream of complex formation. The analysis of the individual subunits of hMutL{alpha} demonstrated that the hMutS{alpha}–hMutL{alpha} interaction is predominantly conferred by hMLH1. Further experiments revealed that only the N-terminus of hMLH1 confers this interaction. In contrast, only the C-terminus stabilised and co-immunoprecipitated hPMS2 when both proteins were co-expressed in 293T cells, indicating that dimerisation and stabilisation are mediated by the C-terminal part of hMLH1. We also examined another human homologue of bacterial MutL, hMutL{beta} (hMLH1–hPMS1). We show that hMutL{beta} interacts as efficiently with hMutS{alpha} as hMutL{alpha}, and that it predominantly binds to hMutS{alpha} via hMLH1 as well.
- Portal vein thrombosis and arterioportal shunts: effects on tumor response after chemoembolization of hepatocellular carcinoma (2011)
- AIM: To evaluate the effect of portal vein thrombosis and arterioportal shunts on local tumor response in advanced cases of unresectable hepatocellular carcinoma treated by transarterial chemoembolization. METHODS: A retrospective study included 39 patients (mean age: 66.4 years, range: 45-79 years, SD: 7) with unresectable hepatocellular carcinoma (HCC) who were treated with repetitive transarterial chemoembolization (TACE) in the period between March 2006 and October 2009. The effect of portal vein thrombosis (PVT) (in 19 out of 39 patients), the presence of arterioportal shunt (APS) (in 7 out of 39), the underlying liver pathology, Child-Pugh score, initial tumor volume, number of tumors and tumor margin definition on imaging were correlated with the local tumor response after TACE. The initial and end therapy local tumor responses were evaluated according to the response evaluation criteria in solid tumors (RECIST) and magnetic resonance imaging volumetric measurements. RESULTS: The treatment protocols were well tolerated by all patients with no major complications. Local tumor response for all patients according to RECIST criteria were partial response in one patient (2.6%), stable disease in 34 patients (87.1%), and progressive disease in 4 patients (10.2%). The MR volumetric measurements showed that the PVT, APS, underlying liver pathology and tumor margin definition were statistically significant prognostic factors for the local tumor response (P = 0.018, P = 0.008, P = 0.034 and P = 0.001, respectively). The overall 6-, 12- and 18-mo survival rates from the initial TACE were 79.5%, 37.5% and 21%, respectively. CONCLUSION: TACE may be exploited safely for palliative tumor control in patients with advanced unresectable HCC; however, tumor response is significantly affected by the presence or absence of PVT and APS.
- SEMS vs cSEMS in duodenal and small bowel obstruction: High risk of migration in the covered stent group (2013)
- AIM: To compare clinical success and complications of uncovered self-expanding metal stents (SEMS) vs covered SEMS (cSEMS) in obstruction of the small bowel. METHODS: Technical success, complications and outcome of endoscopic SEMS or cSEMS placement in tumor related obstruction of the duodenum or jejunum were retrospectively assessed. The primary end points were rates of stent migration and overgrowth. Secondary end points were the effect of concomitant biliary drainage on migration rate and overall survival. The data was analyzed according to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. RESULTS: Thirty-two SEMS were implanted in 20 patients. In all patients, endoscopic stent implantation was successful. Stent migration was observed in 9 of 16 cSEMS (56%) in comparison to 0/16 SEMS (0%) implantations (P = 0.002). Stent overgrowth did not significantly differ between the two stent types (SEMS: 3/16, 19%; cSEMS: 2/16, 13%). One cSEMS dislodged and had to be recovered from the jejunum by way of laparotomy. Time until migration between SEMS and cSEMS in patients with and without concomitant biliary stents did not significantly differ (HR = 1.530, 95%CI 0.731-6.306; P = 0.556). The mean follow-up was 57 ± 71 d (range: 1-275 d). CONCLUSION: SEMS and cSEMS placement is safe in small bowel tumor obstruction. However, cSEMS is accompanied with a high rate of migration in comparison to uncovered SEMS.
- Anti-angiogenesis in hepatocellular carcinoma treatment: current evidence and future perspectives (2011)
- Hepatocellular carcinoma (HCC) is among the most common cancer diseases worldwide. Arterial hypervascularisation is an essential step for HCC tumorigenesis and can be targeted by transarterial chemoembolization (TACE). This interventional method is the standard treatment for patients with intermediate stage HCC, but is also applied as “bridging” therapy for patients awaiting liver transplantation in many centers worldwide. Usually the devascularization effect induced by TACE is transient, consequently resulting in repeated cycles of TACE every 4-8 wk. Despite documented survival benefits, TACE can also induce the up-regulation of proangiogenic and growth factors, which might contribute to accelerated progression in patients with incomplete response. In 2007, sorafenib, a multi-tyrosine kinase and angiogenesis inhibitor, was approved as the first systemic treatment for advanced stage HCC. Other active targeted compounds, either inhibitors of angiogenesis and/or growth factors, are currently being investigated in numerous clinical trials. To overcome revascularisation or tumor progression under TACE treatment it seems therefore attractive to combine TACE with systemic targeted agents, which might theoretically block the effects of proangiogenic and growth factors. Over the last 12 mo, several retrospecretrospective or prospective cohort studies combining TACE and sorafenib have been published. Nevertheless, robust results of the efficacy and tolerability of such combination strategies as proven by randomized, controlled trials are awaited in the next two years.
