Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related ...cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.
Chronic hepatitis C virus (HCV) infection affects 80-160 million people worldwide and is one of the leading causes of chronic liver disease. It is only a few years ago that standard treatment regimes ...were based on pegylated interferon alpha and ribavirin. However, treatment of HCV has undergone a revolutionary change in recent years. The admission of the nucleotide polymerase inhibitor Sofosbuvir enabled an interferon-free regimen with direct antiviral agents (DAA). Meanwhile seven DAAs are available and can be applied in several combinations for 8 to 24 wk depending on HCV genotype and patient characteristics such as cirrhosis and chronic renal failure. High rates of sustained virological response (SVR) rates can be achieved with these novel drugs. Even in difficult to treat populations such as patients with liver cirrhosis, HCV-human immunodeficiency virus co-infections, after liver transplantion, or with chronic kidney disease comparable high rates of SVR can be achieved. The anticipated 2(nd) generation DAAs are strikingly effective in patients so far classified as difficult to treat including decompensated liver cirrhosis or post-transplant patients. These 2(nd) generations DAAs will have higher resistance barriers, higher antiviral effects and a pan-genotypic spectrum. This review highlights the current state of the art of antiviral treatment in hepatitis C and gives an outlook for upcoming therapies.
Dye-less chromoendoscopy is an emerging technology for colorectal polyp characterization. Herein, we investigated whether the newly introduced I-scan optical enhancement (OE) can accurately predict ...polyp histology in vivo in real-time.
In this prospective three-phased study, 84 patients with 230 diminutive colorectal polyps were included. During the first two study phases, five endoscopists assessed whether analysis of polyp colour, surface and vascular pattern under i-scan OE can differentiate in vivo between adenomatous and hyperplastic polyps. Finally, junior and experienced endoscopists (JE, EE, each n = 4) not involved in the prior study phases made a post hoc diagnosis of polyp histology using a static i-scan OE image database. Histopathology was used as a gold-standard in all study phases.
The overall accuracy of i-scan OE for histology prediction was 90% with a sensitivity, specificity, positive (PPV) and negative prediction value (NPV) of 91%, 90%, 86% and 94%, respectively. In high confidence predictions, the diagnostic accuracy increased to 93% with sensitivity, specificity, PPV and NPV of 94%, 91%, 89% and 96%. Colonoscopy surveillance intervals were predicted correctly in ≥ 90% of patients. In the post hoc analysis EE predicted polyp histology under i-scan OE with an overall accuracy of 91%. After a single training session, JE achieved a comparable diagnostic performance for predicting polyp histology with i-scan OE.
The histology of diminutive colorectal polyps can be accurately predicted with i-scan OE in vivo in real-time. Furthermore, polyp differentiation with i-scan OE appears to require only a short learning curve.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hepatocellular carcinoma (HCC) still represents an unmet medical need. Epigenetic inactivation of tumor suppressor genes like RASSF1A or APC by overexpression of DNA methyltransferases (DNMTs) has ...been shown to be common in HCC and to be linked to the overall prognosis of patients. Inhibitors of protein and histone deacetylases (DACi) have been demonstrated to possess strong anti-tumor effects in HCC models.
We therefore investigated whether DACi also has any influence on the expression and activity of DNMTs and methylated target genes in HepG2 and Hep3B cell culture systems and in a xenograft model by immunohistochemistry, westernblotting, RT-qPCR and methylation-specific PCR.
Our findings demonstrate a rapid inhibition of DNMT activity 6 h after treatment with 0.1 μM of the pan-DACi panobinostat. A downregulation of DNMT mRNAs and protein were also observed at later points in time. This loss of DNMT activity and expression was paralleled by a diminished methylation of the target genes RASSF1A and APC and a concomitant re-expression of APC mRNA and protein. Analysis of HepG2 xenograft specimens confirmed these results in vivo.
We suggest a dual mode of action of DACi on DNA methylation status: a rapid inhibition of enzyme activity due to interference with posttranslational acetylation and a delayed effect on transcriptional control of DNMT genes by HDAC or miRNA mechanisms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
AIM：To evaluate the antitumoral effect of combined inhibitors of angiogenesis and histone deacetylases in an experimental rat hepatoma model.METHODS：MH7777A hepatoma cells were injected into the ...liver of male Buffalo rats.After 7 d treatment with the vascular endothelial growth factor receptor antagonist PTK787/ZK222584（PTK/ZK）,the histone deacetylase inhibitor MS-275,tamoxifen（TAM） and/or retinoic acid was initiated（n ≥ 8 animals/group）.Natural tumor development was shown in untreated control groups（control 1 with n = 12,control 2 with n = 8）.The control groups were initiated at different time points to demonstrate the stability of the hepatoma model.For documentation of possible side effects,we documented any change in body weight,loss of fur and diarrhea.After 21 d treatment,the rats were euthanized.Main target parameters were tumor size and metastasis rate.Additionally,immunohistochemistry for the proliferating cell nuclear antigen（PCNA） and TdT-mediated dUTP-biotin nick end labeling（TUNEL） assay were performed.RESULTS：The control groups developed large tumor nodules with extrahepatic tumor burden in the lung and abdominal organs（control 1：6.18 cm3 ± 4.14 cm3 and control 2：8.0 cm3 ± 4.44 cm3 28 d after tumor cell injection）.The tumor volume did not differ significantly in the control groups（P = 0.13）.As single agents MS-275 and PTK/ZK reduced tumor volume by 58.6% ± 2.6% and 48.7% ± 3.2% vs control group 1,which was significant only for MS-275（P = 0.025）.The combination of MS-275 and PTK/ZK induced a nearly complete and highly significant tumor shrinkage by 90.3% ± 1%（P = 0.005）.Addition of TAM showed no further efficacy,while quadruple therapy with retinoic acid increased antitumoral efficacy（tumor reduction by 93 ± 1%） and side effects.PCNA positive cells were not significantly reduced by the single agents,while dual therapy（MS-275 and PTK/ZK） and quadruple therapy reduced the PCNA-positive cell fraction significantly by 9.1 and 20.6% vs control 1（P 0.05）.The number of TUNEL-positive cells,markers for ongoing apoptosis,was increased significantly by the single agents（control 1：6.9%,PTK/ZK：11.4%,MS-275：12.2% with P 0.05 vs control 1）.The fraction of TUNEL-positive cells was upregulated highly significantly by dual therapy（18.4%） and quadruple therapy（24.8%,P 0.01 vs control 1）.For the proliferating（PCNA positive） and apoptotic cell fraction,quadruple therapy was significantly superior to dual therapy（P = 0.01）.CONCLUSION：Combined PTK/ZK and MS-275 were highly effective in this hepatoma model.Quadruple therapy enhanced the effects microscopically,but not macroscopically.These results should be investigated further.
Human cytomegalovirus (CMV) remains a major cause of mortality and morbidity in human liver transplant recipients. Anti-CMV therapeutics can be used to prevent or treat CMV in liver transplant ...recipients, but their toxicity needs to be balanced against the benefits. The choice of prevention strategy (prophylaxis or preemptive treatment) depends on the donor/recipient sero-status but may vary between institutions. We conducted a series of consultations and roundtable discussions with German liver transplant center representatives. Based on 20 out of 22 centers, we herein summarize the current approaches to CMV prevention and treatment in the context of liver transplantation in Germany. In 90% of centers, transient prophylaxis with ganciclovir or valganciclovir was standard of care in high-risk (donor CMV positive, recipient CMV naive) settings, while preemptive therapy (based on CMV viremia detected during (bi) weekly PCR testing for circulating CMV-DNA) was preferred in moderate- and low-risk settings. Duration of prophylaxis or intense surveillance was 3–6 months. In the case of CMV infection, immunosuppression was adapted. In most centers, antiviral treatment was initiated based on PCR results (median threshold value of 1000 copies/mL) with or without symptoms. Therefore, German transplant centers report similar approaches to the prevention and management of CMV infection in liver transplantation.
Objective. Pancreatic cancer continues to be an urgent clinical problem. We used the novel DNA methyltransferase inhibitor Zebularine and the histone deacetylase inhibitor SAHA to investigate the ...epigenetic influence on viability and differentiation of the pancreatic cancer cell lines YAP C, DAN G and Panc-89 in vitro and in vivo. Material and methods. Cell vitality, proliferation and expression of PDX-1, cytokeratin 7 and 20, chromogranin A, vimentin, bax and bcl-2 were determined on the protein and mRNA level in vitro and in a subcutaneous xenograft model. Results. A time- and dose-dependent increase of apoptosis, paralleled by decreased proliferation, was observed after incubation with single agents or a combination therapy with lower concentrations. This was associated with up-regulation of pro-apoptotic bax and a phenotypic stabilization by the enhanced expression of cytokeratin 7. In vivo, growth of xenografts was delayed with the most pronounced effect in Panc-89 after 1 week of daily intraperitoneal injections of Zebularine paralleled with CK7 up-regulation and down-regulation of dedifferentiation markers. Conclusions. Epigenetic modulation via inhibition of DNA methyltransferase and histone deacetylase induces apoptosis in human pancreatic cancer cells in vitro and delays xenograft growth in vivo, which is associated with a morphological/molecular phenotypic stabilization. These compounds may therefore be suitable as adjunctive therapeutic agents in the treatment of pancreatic cancer.
The incidence of hepatocellular carcinoma is rising. However, this is occurring not only in developing nations, but in industrial countries as well. Surveillance programmes, classification systems ...and therapeutic options have improved, but there is a lack of data regarding their impact on the prognosis of this difficult-to-treat cancer.
We evaluated 484 patients and reported on disease stage, therapeutic procedures and survival time. Data were compared with a historical cohort treated in the same centre 10 years before.
In this cohort, the main reason for liver disease was alcoholism, although hepatitis B remains the leading cause of hepatocellular carcinoma worldwide. Now, most patients have compensated liver function and hepatocellular carcinoma is diagnosed in the early tumour stages (it was diagnosed in the advanced disease stages in the previous cohort). Overall, median survival time was 62.4 weeks, 1-year survival was 58.6% and 3-year survival was 23.2%. Survival time correlated with the stage of liver disease, tumour stage and with therapeutic options.
Surveillance programmes lead to diagnosis in earlier tumour stages. Differentiated classification systems allow individualised therapeutic approaches. Earlier cancer stage and compensated liver function allow combination or sequential therapy, which was nearly impossible some years ago but is an option for most now. Primary liver cancer remains a difficult-to-treat malignancy, but the prognosis has improved remarkably, at least in the western world.
Advanced hepatocellular carcinoma still represents an unmet medical need that has only a limited overall survival despite the introduction of the multi-kinase inhibitor sorafenib. Recently, ...inhibitors of histone and other protein deacetylases have been established as novel therapeutic approaches to cancer diseases. We here review the molecular rationale for combining these two novel targeted therapies and report a patient with metastasized hepatocellular carcinoma who showed a partial remission of primary and metastatic lesions for five months after a combination therapy with sorafenib and the orally available pan-deacetylase inhibitor panobinostat.
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