JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
Predictive Scores in Primary Biliary Cirrhosis: A Retrospective Single Center Analysis of 204 Patients.
J. Clin. Gastroenterol.
PUBLISHED: 07-12-2014
Show Abstract
Hide Abstract
The aim of this study was to assess the long-term outcome of primary biliary cirrhosis (PBC) patients and to test the clinical value of various outcome models, such as the Mayo Risk Score (MRS), in a large single-center cohort in Germany.
Related JoVE Video
SILEN-C3, a phase 2 randomized trial with faldaprevir plus pegylated interferon ?-2a and ribavirin in treatment-naive hepatitis C virus genotype 1-infected patients.
Antimicrob. Agents Chemother.
PUBLISHED: 04-07-2014
Show Abstract
Hide Abstract
Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon ?-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143-2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of <25 IU/ml at week 4 and undetectable at weeks 8 and 12) stopped all treatment at week 24, otherwise they continued PegIFN/RBV to week 48. SVR was achieved by 67% and 74% of patients in the 12-week and 24-week groups, respectively. Virologic response rates were lower in the 12-week group from weeks 2 to 12, during which both groups received identical treatment. SVR rates were similar in both groups for patients achieving undetectable HCV RNA. Most adverse events were mild or moderate, and 6% of patients in each treatment group discontinued treatment due to adverse events. Once-daily faldaprevir at 120 mg for 12 or 24 weeks with PegIFN/RBV resulted in high SVR rates, and the regimen was well tolerated. Differences in the overall SVR rates between the 12-week and 24-week groups were not statistically significant and possibly were due to IL28B genotype imbalances; IL28B genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620).
Related JoVE Video
Efficacy of SpyGlass(TM)-directed biopsy compared to brush cytology in obtaining adequate tissue for diagnosis in patients with biliary strictures.
World J Gastrointest Endosc
PUBLISHED: 03-04-2014
Show Abstract
Hide Abstract
To evaluate the diagnostic yield (inflammatory activity) and efficiency (size of the biopsy specimen) of SpyGlass(TM)-guided biopsy vs standard brush cytology in patients with and without primary sclerosing cholangitis (PSC).
Related JoVE Video
Faldaprevir and deleobuvir for HCV genotype 1 infection.
N. Engl. J. Med.
PUBLISHED: 08-16-2013
Show Abstract
Hide Abstract
Interferon-free regimens would be a major advance in the treatment of patients with chronic hepatitis C virus (HCV) infection.
Related JoVE Video
Cellular FLICE-Like Inhibitory Protein Secures Intestinal Epithelial Cell Survival and Immune Homeostasis by Regulating Caspase-8.
Gastroenterology
PUBLISHED: 08-01-2013
Show Abstract
Hide Abstract
The intestinal epithelium generates a barrier that protects mammals from potentially harmful intestinal contents, such as pathogenic bacteria. Dysregulation of epithelial cell death has been implicated in barrier dysfunction and in the pathogenesis of intestinal inflammation. We investigated mechanisms of cell-death regulation in the intestinal epithelium of mice.
Related JoVE Video
Defer or treat? Reasons for treatment decisions in patients with chronic hepatitis C genotype 1 in the early era of directly acting antiviral agents.
Dig Liver Dis
PUBLISHED: 05-20-2013
Show Abstract
Hide Abstract
In chronic genotype 1 hepatitis C, telaprevir or boceprevir plus peginterferon and ribavirin have become the new standard of care. Aim of this study was to identify factors contributing to the decision whether to defer or treat with the current triple regimens.
Related JoVE Video
Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis.
Immunity
PUBLISHED: 05-17-2013
Show Abstract
Hide Abstract
Liver fibrosis is a consequence of chronic liver diseases and thus a major cause of mortality and morbidity. Clinical evidence and animal studies suggest that local tissue homeostasis is disturbed due to immunological responses to chronic hepatocellular stress. Poorly defined stress-associated inflammatory networks are thought to mediate gradual accumulation of extracellular-matrix components, ultimately leading to fibrosis and liver failure. Here we have reported that hepatic expression of interleukin-33 (IL-33) was both required and sufficient for severe hepatic fibrosis in vivo. We have demonstrated that IL-33s profibrotic effects related to activation and expansion of liver resident innate lymphoid cells (ILC2). We identified ILC2-derived IL-13, acting through type-II IL-4 receptor-dependent signaling via the transcription factor STAT6 and hepatic stellate-cell activation, as a critical downstream cytokine of IL-33-dependent pathologic tissue remodeling and fibrosis. Our data reveal key immunological networks implicated in hepatic fibrosis and support the concept of modulation of IL-33 bioactivity for therapeutic purposes.
Related JoVE Video
How to decide about liver transplantation in patients with hepatocellular carcinoma: size and number of lesions or response to TACE?
J. Hepatol.
PUBLISHED: 04-03-2013
Show Abstract
Hide Abstract
Liver transplantation is a curative treatment option for patients with hepatocellular carcinoma (HCC) and liver cirrhosis. To date, patient selection for transplantation is based on size and number of nodules as assessed by imaging before listing. We hypothesized that changes in tumour features resulting from pre-transplant transarterial chemoembolisation (TACE) is a superior criterion to predict tumour recurrence.
Related JoVE Video
Faldaprevir (BI 201335), deleobuvir (BI 207127) and ribavirin oral therapy for treatment-naive HCV genotype 1: SOUND-C1 final results.
Antivir. Ther. (Lond.)
PUBLISHED: 03-17-2013
Show Abstract
Hide Abstract
Faldaprevir (BI 201335) and deleobuvir (BI 207127) are direct-acting antiviral agents under development for the treatment of chronic HCV infection. This article describes the final results of the Phase Ib SOUND-C1 study that evaluated the interferon-free oral combination of faldaprevir, deleobuvir and ribavirin in 32 treatment-naive patients infected with HCV genotype 1.
Related JoVE Video
Downregulation of organic cation transporter 1 (SLC22A1) is associated with tumor progression and reduced patient survival in human cholangiocellular carcinoma.
Int. J. Oncol.
PUBLISHED: 01-11-2013
Show Abstract
Hide Abstract
Cholangiocellular carcinoma (CCA) is a primary hepatic malignancy derived from cholangiocytes. The prognosis for CCA patients is very poor and conventional chemotherapy has been proven ineffective in improving long?term patient survival rates. Organic cation transporters (OCTs) mediate the transport of a broad spectrum of endogenous substrates and the detoxification of xenobiotics. Moreover, OCTs are considered responsible for the responsiveness towards platinum?based chemotherapies. Currently, there are no data available regarding the role of OCTs in CCA. Therefore, the aim of this study was to investigate the expression of OCT1 and OCT3 in CCA and the corresponding non-neoplastic tumor?surrounding tissue (TST). OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human CCA by real-time PCR (n=27). Protein expression was determined by western blot analysis and immunohistochemistry. Data were correlated with the clinicopathological parameters of CCA. Real-time PCR demonstrated a downregulation of the expression of SLC22A1 and SLC22A3 in CCA, compared to that in TST (p<0.001). A low SLC22A1 expression was associated with a worse patient survival (p<0.05). The downregulation of SLC22A1 was significantly associated with advanced CCA stages, since tumors with a low SLC22A1 mRNA expression presented with larger tumor diameters (p=0.02). There were no significant differences in tumor characteristics or patient survival in relation to the level of SLC22A3 expression. Western blot analysis and immunohistochemistry confirmed the downregulation of OCT1 and OCT3 protein levels in cancerous tissue compared to those in TST. In conclusion, the downregulation of OCT1 is associated with tumor progression and worse overall patient survival rates.
Related JoVE Video
Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells.
Hepatology
PUBLISHED: 01-10-2013
Show Abstract
Hide Abstract
Alternatively polarized macrophages (M?) shape the microenvironment of hepatocellular carcinoma (HCC) and temper anticancer immune responses. We investigated if sorafenib alters the HCC microenvironment by restoring classical macrophage polarization and triggering tumor-directed natural killer (NK) cell responses. In vivo experiments were conducted with sorafenib (25 mg/kg)-treated C57BL/6 wildtype as well as hepatitis B virus (HBV) and lymphotoxin transgenic mice with and without HCC. Monocyte-derived M? or tumor-associated macrophages (TAM) isolated from HCC tissue were treated with sorafenib (0.07-5.0 ?g/mL) and cocultured with autologous NK cells. M? and NK cell activation was analyzed by flow cytometry and killing assays, respectively. Cytokine and growth factor release was measured by enzyme-linked immunosorbent assay. Short-term administration of sorafenib triggered activation of hepatic NK cells in wildtype and tumor-bearing mice. In vitro, sorafenib sensitized M? to lipopolysaccharide, reverted alternative M? polarization and enhanced IL12 secretion (P = 0.0133). NK cells activated by sorafenib-treated M? showed increased degranulation (15.3 ± 0.2% versus 32.0 ± 0.9%, P < 0.0001) and interferon-gamma (IFN-?) secretion (2.1 ± 0.2% versus 8.0 ± 0.2%, P < 0.0001) upon target cell contact. Sorafenib-triggered NK cell activation was verified by coculture experiments using TAM. Sorafenib-treated M? increased cytolytic NK cell function against K562, Raji, and HepG2 target cells in a dose-dependent manner. Neutralization of interleukin (IL)12 or IL18 as well as inhibition of the nuclear factor kappa B (NF-?B) pathway reversed NK cell activation in M?/NK cocultures. Conclusion: Sorafenib triggers proinflammatory activity of TAM and subsequently induces antitumor NK cell responses in a cytokine- and NF-?B-dependent fashion. This observation is relevant for HCC therapy, as sorafenib is a compound in clinical use that reverts alternative polarization of TAM in HCC. (HEPATOLOGY 2013;57:2358-2368).
Related JoVE Video
AFP measurement in monitoring treatment response of advanced hepatocellular carcinoma to sorafenib: case report and review of the literature.
Onkologie
PUBLISHED: 09-16-2011
Show Abstract
Hide Abstract
The multi-targeted tyrosine kinase inhibitor sorafenib was the first agent to demonstrate a significant improvement in overall survival in patients with advanced hepatocellular carcinoma (HCC). However, survival under sorafenib treatment is still lower than 1 year in most patients in clinical practice. Sorafenib rarely produces radiological tumor regression, pointing out limitations in using conventional radiological assessment of response to targeted therapy. Serial alpha-fetoprotein (AFP) measurement may be useful in monitoring treatment response in patients with advanced HCC undergoing systemic therapy; however, this approach is poorly defined for the case of sorafenib.
Related JoVE Video
The recipient CYP2D6 allele 4-associated poor metabolizer status correlates with an early fibrosis development after liver transplantation.
Transpl. Int.
PUBLISHED: 07-28-2011
Show Abstract
Hide Abstract
CYP2D6 is part of the cytochrome P450 system, which catalyzes biotransformation of endogenous substrates and xenobiotics. Approximately 10% of the Caucasian population has two null alleles, resulting in a poor metabolizer (PM) status. Mostly, allele four (CYP2D6*4) is responsible for the PM status, which is suspected to be associated with an accelerated fibrosis progression (FP). The aim of the present study was to analyze the role of the CYP2D6*4 genotype for FP after liver transplantation (LT). Genotypes were determined in liver biopsies (donor) and peripheral blood (recipient) by fluorescence resonance energy transfer. Data were correlated with clinical variables and risk factors for fibrosis. We analyzed 517 LTs performed between 1997 and 2009. Overall donor and recipient allele frequencies were comparable (18.0%, 20.5%; P = 0.43). The donor genotype did not correlate with FP. In contrast, recipients carrying CYP2D6*4, showed a significant higher risk for an accelerated FP (P = 0.011) in HCV positive (P = 0.038) and HCV negative patients (P = 0.033). Results were confirmed by multivariate analysis (Hazard ratio 1.65; P = 0.001). The CYP2D6*4-associated PM status of the donor liver seems to have no influence on FP after LT. Recipients, carrying the allele, have an elevated risk for an accelerated FP.
Related JoVE Video
In vivo real-time imaging of the liver with confocal endomicroscopy permits visualization of the temporospatial patterns of hepatocyte apoptosis.
Am. J. Physiol. Gastrointest. Liver Physiol.
PUBLISHED: 07-21-2011
Show Abstract
Hide Abstract
Apoptosis is a dynamic process of programmed cell death and is involved in multiple diseases. However, its mechanisms and sequence of events are still incompletely understood, partly because of the inability to visualize single cells continuously in vivo. The aim of the present study was to monitor hepatocyte apoptosis with confocal endomicroscopy in living rodents. In 73 anaesthetized mice, apoptotic liver injury was induced by injection of the CD95-agonistic antibody Jo2. Individual hepatocytes were followed for up to 240 min with a handheld confocal probe (FIVE1; Optiscan) providing 0.7 ?m resolution (1,000-fold magnification). Different fluorescence staining protocols were used for cellular staining, vascular and cellular barrier function imaging, and caspase activation visualization. The time course of apoptosis could be visualized in vivo while liver perfusion and tissue integrity were maintained. In contrast to most ex vivo studies, initial cell swelling was observed that coincided with early defects in barrier function of sinusoids and hepatocytes. Cytoplasmic vesicle formation, nuclear condensation, cellular disintegration, and macrophage infiltration were captured sequentially. Labeling of caspases allowed molecular imaging. Our study allowed for the first time to continuously follow distinct morphological, functional, and molecular features of apoptosis in a solid organ in vivo and at high resolution. Intravital confocal microscopy may be a valuable tool to study the effects of therapeutic intervention on apoptosis in animal models and humans.
Related JoVE Video
Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection.
Gastroenterology
PUBLISHED: 06-03-2011
Show Abstract
Hide Abstract
Therapeutic regimens are being developed for patients with hepatitis C virus (HCV) infection that do not include the combination of peginterferon alfa and ribavirin. We investigated the antiviral effect and safety of BI 201335 (an inhibitor of the NS3/4A protease) and BI 207127 (an inhibitor of the NS5B non-nucleoside polymerase) with ribavirin.
Related JoVE Video
Down-regulation of CYLD as a trigger for NF-?B activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells.
Int. J. Oncol.
PUBLISHED: 05-25-2011
Show Abstract
Hide Abstract
The cylindromatosis gene (CYLD) was identified as a tumor suppressor gene, which is mutated in familial cylindromatosis (Brooke-Spiegler syndrome), an autosomal-dominant predisposition to multiple tumors of the skin appendages. CYLD is a deubiquitinating enzyme acting as a negative regulator of the nuclear factor ?B (NF-?B) signaling pathway by removing lysine-63-linked polyubiquitin chains from NF-?B activating proteins. In order to investigate the role of CYLD in apoptotic signaling in human hepatocellular carcinoma (HCC) cells, we first studied the expression levels of CYLD in HCC tissues. CYLD expression was lower in HCC both at protein and mRNA levels compared to the surrounding non-malignant tissue. In order to further study the role of CYLD in the apoptotic sensitivity of HCC cells, CYLD was specifically down-regulated in HCC cell lines via RNA interference. The specific down-regulation of CYLD resulted in increased resistance towards treatment with doxorubicin, 5-fluorouracil and cisplatin. In addition, the down-regulation of CYLD in HCC cells decreased the sensitivity towards tumor necrosis factor-?-induced apoptosis. The CYLD knockdown also led to the degradation of the NF-?B inhibitor, I?B-?, resulting in enhanced NF-?B activity in HCC cells. Finally, we found that CYLD expression was triggered by the multikinase inhibitor, sorafenib, by the inhibition of Raf-1, as well as by the blockage of the pro-survival kinases, MEK (U0126) and the epidermal growth factor receptor (AG1478). In summary, we show that CYLD is down-regulated in human HCC and is involved in the apoptotic resistance of HCC cells. Our data identify the reconstitution of CYLD expression as an attractive approach for overcoming resistance to treatment in HCC.
Related JoVE Video
Ablation of c-FLIP in hepatocytes enhances death-receptor mediated apoptosis and toxic liver injury in vivo.
J. Hepatol.
PUBLISHED: 03-07-2011
Show Abstract
Hide Abstract
Apoptosis is crucially involved in acute and chronic liver injury, including viral, cholestatic, toxic, and metabolic liver disease. Additionally, dysregulation of apoptosis signaling pathways has been implicated in hepatocarcinogenesis. The most prominent members of the apoptosis-mediating tumor necrosis factor receptor superfamily are the TNF-R1 (CD120a) and the CD95 (Apo-1/Fas) receptor. Although extensively studied, the intracellular signaling events in hepatocytes are only incompletely understood.
Related JoVE Video
Posttransplant lymphoproliferative disease in liver transplant patients.
Curr Infect Dis Rep
PUBLISHED: 02-11-2011
Show Abstract
Hide Abstract
Posttransplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation. Many posttransplant lymphomas develop from the uncontrolled proliferation of Epstein-Barr virus (EBV)-infected B-cells, whereas EBV-negative PTLDs were increasingly recognized within the past decade. Major risk factors for the development of PTLDs after liver transplantation are immunosuppressive therapy and the type of underlying disease: viral hepatitis, autoimmune liver disease, or alcoholic liver cirrhosis contribute to an increased risk for PTLD. Therapeutic regimens include reduction of immunosuppression, the anti-CD20 antibody rituximab, and chemotherapy, as well as new approaches using interferon-? and anti-interleukin-6 antibodies. Despite the different therapeutic regimens, mortality from PTLD remains high. Therefore, it is of major importance to identify patients at risk at an early stage of the disease. In this review, risk factors for PTLD development after liver transplantation, clinical presentation, diagnosis, and therapy are discussed.
Related JoVE Video
Mini-laparoscopy in the endoscopy unit: Safety and outcomes in over one thousand patients.
World J Gastrointest Endosc
PUBLISHED: 01-25-2011
Show Abstract
Hide Abstract
To investigate the safety of consecutive mini-laparoscopy guided liver biopsies for the diagnosis and staging of liver diseases.
Related JoVE Video
Alterations in lipid, carbohydrate and iron metabolism in patients with non-alcoholic steatohepatitis (NASH) and metabolic syndrome.
Eur. J. Intern. Med.
PUBLISHED: 01-14-2011
Show Abstract
Hide Abstract
NASH (non-alcoholic steatohepatitis) is considered the hepatic manifestation of the metabolic syndrome (MS). We aimed to analyze lipid, carbohydrate, and iron metabolism in NASH.
Related JoVE Video
Cell death and hepatocarcinogenesis: Dysregulation of apoptosis signaling pathways.
J. Gastroenterol. Hepatol.
PUBLISHED: 01-05-2011
Show Abstract
Hide Abstract
Hepatocellular carcinoma (HCC) remains a disease with a poor prognosis despite recent advances in the pathophysiology and treatment. Although the disease is biologically heterogeneous, dysregulation of cellular proliferation and apoptosis both occur frequently and contribute to the malignant phenotype. Chronic liver disease is associated with intrahepatic inflammation which promotes dysregulation of cellular signaling pathways; this triggers proliferation and thus lays the ground for expansion of premalignant cells. Cancer emerges when immunological control fails and transformed cells develop resistance against cell death signaling pathways. The same mechanisms underlie the poor responsiveness of HCC towards chemotherapy. Only recently advances in understanding the signaling pathways involved has led to the development of an effective pharmacological therapy for advanced disease. The current review will discuss apoptosis signaling pathways and focus on apoptosis resistance of HCC involving derangements in cell death receptors (e.g. tumor necrosis factor-alpha [TNF], CD95/Apo-1, TNF-related apoptosis-inducing ligand [TRAIL]) and associated adapter molecules (e.g. FADD and FLIP) of apoptotic signaling pathways. In addition, the role of the transcription factor nuclear factor-kappaB (NF?B) and members of the B cell leukemia-2 (Bcl-2) family that contribute to the regulation of apoptosis in hepatocytes are discussed. Eventually, the delineation of cell death signaling pathways could contribute to the implementation of new therapeutic strategies to treat HCC.
Related JoVE Video
Sunitinib in patients with advanced hepatocellular carcinoma after progression under sorafenib treatment.
Oncology
PUBLISHED: 05-10-2010
Show Abstract
Hide Abstract
To evaluate the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) after progression under sorafenib treatment.
Related JoVE Video
Liver transplanted patients with preoperative autoimmune hepatitis and immunological disorders are at increased risk for Post-Transplant Lymphoproliferative Disease (PTLD).
Eur. J. Intern. Med.
PUBLISHED: 01-31-2010
Show Abstract
Hide Abstract
Long term immunosuppression and therapy of acute rejections result in a 20-120-fold increased risk to develop Non Hodgkin lymphoma (NHL). Since immunosuppressive therapy and immunological disorders are major risk factors for the development of NHL in the non-transplant population we aimed to analyze risk factors for PTLD in our cohort of liver transplanted (LT) patients.
Related JoVE Video
Hepatocyte-specific deletion of the antiapoptotic protein myeloid cell leukemia-1 triggers proliferation and hepatocarcinogenesis in mice.
Hepatology
PUBLISHED: 01-26-2010
Show Abstract
Hide Abstract
Regulation of hepatocellular apoptosis is crucial for liver homeostasis. Increased sensitivity of hepatocytes toward apoptosis results in chronic liver injury, whereas apoptosis resistance is linked to hepatocarcinogenesis and nonresponsiveness to therapy-induced cell death. Recently, we have demonstrated an essential role of the antiapoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) in hepatocyte survival. In mice lacking Mcl-1 specifically in hepatocytes (Mcl-1(Deltahep)), spontaneous apoptosis caused severe liver damage. Here, we demonstrate that chronically increased apoptosis of hepatocytes coincides with strong hepatocyte proliferation resulting in hepatocellular carcinoma (HCC). Liver cell tumor formation was observed in >50% of Mcl-1(Deltahep) mice already by the age of 8 months, whereas 12-month-old wild-type (wt) and heterozygous Mcl-1(flox/wt) mice lacked tumors. Tumors revealed a heterogenous spectrum ranging from small dysplastic nodules to HCC. The neoplastic nature of the tumors was confirmed by histology, expression of the HCC marker glutamine synthetase and chromosomal aberrations. Liver carcinogenesis in Mcl-1(Deltahep) mice was paralleled by markedly increased levels of Survivin, an important regulator of mitosis which is selectively overexpressed in common human cancers. Conclusion: This study provides in vivo evidence that increased apoptosis of hepatocytes not only impairs liver homeostasis but is also accompanied by hepatocyte proliferation and hepatocarcinogenesis. Our findings might have implications for understanding apoptosis-related human liver diseases.
Related JoVE Video
TRAIL-induced apoptosis of hepatocellular carcinoma cells is augmented by targeted therapies.
World J. Gastroenterol.
PUBLISHED: 12-17-2009
Show Abstract
Hide Abstract
To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors, in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand (TRAIL), on overcoming TRAIL resistance in hepatocellular carcinoma (HCC) and to study the efficacy of agonistic TRAIL antibodies, as well as the commitment of antiapoptotic BCL-2 proteins, in TRAIL-induced apoptosis.
Related JoVE Video
Diabetes and apoptosis: liver.
Apoptosis
PUBLISHED: 06-23-2009
Show Abstract
Hide Abstract
The liver is a central regulator of glucose homeostasis and stores or releases glucose according to metabolic demands. In insulin resistant states or diabetes the dysregulation of hepatic glucose release contributes significantly to the pathophysiology of these conditions. Acute or chronic liver disease can aggravate insulin resistance and the physiological effects of insulin on hepatocytes are disturbed. Insulin resistance has also been recognized as an independent risk factor for the development of liver injury. In the healthy liver tissue homeostasis is achieved through cell turnover by apoptosis and dysregulation of the physiological process resulting in too much or too little cell death can have potentially devastating effects on liver tissue. The delineation of the signaling pathways that mediate apoptosis changed the paradigms of understanding of many liver diseases. These signaling events include cell surface based receptor-ligand systems and intracellular signaling pathways that are regulated through kinases on multiple levels. The dissection of these signaling pathways has shown that the regulators of apoptosis signaling events in hepatocytes can also modulate insulin signaling pathways and that mediators of insulin resistance in turn influence liver cell apoptosis. This review will summarize the potential crosstalk between apoptosis and insulin resistance signaling events and discuss the involved mediators.
Related JoVE Video
Systemic therapies in hepatocellular carcinoma.
Dig Dis
PUBLISHED: 06-22-2009
Show Abstract
Hide Abstract
Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors worldwide in the human population. Due to late diagnosis and/or advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefit are available in up to 70% of patients. During the last decades, no effective conventional cytotoxic systemic therapy was available contributing to the dismal prognosis in patients with advanced disease. However, a better knowledge of molecular hepatocarcinogenesis provides today the opportunity for targeted therapy. Positive data from the pivotal phase III SHARP trial assessing the efficacy and safety of the multikinase inhibitor sorafenib broadened the horizon for patients with advanced disease. After years of therapeutic nihilism, sorafenib was the first agent to demonstrate a statistically significant improvement in overall survival for patients with advanced HCC. This article reviews the historical perspective of systemic therapy in HCC and provides a brief overview of molecular hepatocarcinogenesis and potential targets in HCC. Most promising molecular targeted agents tested within clinical trials in advanced HCC are summarized, with a special attention to sorafenib, sunitinib, bevacizumab, and erlotinib.
Related JoVE Video
Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study.
Cardiovasc Intervent Radiol
PUBLISHED: 06-09-2009
Show Abstract
Hide Abstract
Transcatheter arterial chemoembolization (TACE) offers a survival benefit to patients with intermediate hepatocellular carcinoma (HCC). A widely accepted TACE regimen includes administration of doxorubicin-oil emulsion followed by gelatine sponge-conventional TACE. Recently, a drug-eluting bead (DC Bead) has been developed to enhance tumor drug delivery and reduce systemic availability. This randomized trial compares conventional TACE (cTACE) with TACE with DC Bead for the treatment of cirrhotic patients with HCC. Two hundred twelve patients with Child-Pugh A/B cirrhosis and large and/or multinodular, unresectable, N0, M0 HCCs were randomized to receive TACE with DC Bead loaded with doxorubicin or cTACE with doxorubicin. Randomization was stratified according to Child-Pugh status (A/B), performance status (ECOG 0/1), bilobar disease (yes/no), and prior curative treatment (yes/no). The primary endpoint was tumor response (EASL) at 6 months following independent, blinded review of MRI studies. The drug-eluting bead group showed higher rates of complete response, objective response, and disease control compared with the cTACE group (27% vs. 22%, 52% vs. 44%, and 63% vs. 52%, respectively). The hypothesis of superiority was not met (one-sided P = 0.11). However, patients with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease showed a significant increase in objective response (P = 0.038) compared to cTACE. DC Bead was associated with improved tolerability, with a significant reduction in serious liver toxicity (P < 0.001) and a significantly lower rate of doxorubicin-related side effects (P = 0.0001). TACE with DC Bead and doxorubicin is safe and effective in the treatment of HCC and offers a benefit to patients with more advanced disease.
Related JoVE Video
Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma in consideration of concomitant stage of liver cirrhosis.
J. Clin. Gastroenterol.
PUBLISHED: 02-28-2009
Show Abstract
Hide Abstract
The multikinase inhibitor sorafenib provides survival benefit for patients with advanced hepatocellular carcinoma (HCC) and liver cirrhosis (LCI) Child-Pugh A. We report our experiences with sorafenib in advanced HCC, particularly in patients with LCI Child-Pugh B/C, where only limited data are available in regard to safety and efficacy of sorafenib.
Related JoVE Video
Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes.
Hepatology
PUBLISHED: 01-08-2009
Show Abstract
Hide Abstract
Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. It interacts with proapoptotic Bcl-2 family members, thereby inhibiting mitochondrial activation and induction of apoptosis. Mcl-1 is essential for embryonal development and the maintenance of B cells, T cells, and hematopoietic stem cells. We have recently shown that induction of Mcl-1 by growth factors rescues primary human hepatocytes from CD95-mediated apoptosis. This prompted us to further analyze the relevance of Mcl-1 for hepatocellular homeostasis. Therefore, we generated a hepatocyte-specific Mcl-1 knockout mouse (Mcl-1(flox/flox)-AlbCre). Deletion of Mcl-1 in hepatocytes results in liver cell damage caused by spontaneous induction of apoptosis. Livers of Mcl-1(flox/flox)-AlbCre mice are smaller compared to control littermates, due to higher apoptosis rates. As a compensatory mechanism, proliferation of hepatocytes is enhanced in the absence of Mcl-1. Importantly, hepatic pericellular fibrosis occurs in Mcl-1 negative livers in response to chronic liver damage. Furthermore, Mcl-1(flox/flox)-AlbCre mice are more susceptible to hepatocellular damage induced by agonistic anti-CD95 antibodies or concanavalin A. Conclusion: The present study provides in vivo evidence that Mcl-1 is a crucial antiapoptotic factor for the liver, contributing to hepatocellular homeostasis and protecting hepatocytes from apoptosis induction.
Related JoVE Video
Evaluation of portal vein thrombosis in liver graft ten years after liver transplantation due to budd-Chiari syndrome using Doppler ultrasound.
Acta Inform Med
Show Abstract
Hide Abstract
Budd-Chiari syndrome is a rare but life-threatening disorder characterized by obstruction of the hepatic venous outflow. Treatment depends on underlying cause, extent of the obstruction and functional capacity of the liver. When all other therapy options are unsuccessful, liver transplant should be considered. Portal vein thrombosis (PVT) is a frequent event in patients with cirrhosis which can be treated with anticoagulants, but there are limited data regarding safety and efficacy of this approach.
Related JoVE Video
The impact of patient and tumour baseline characteristics on the overall survival of patients with advanced hepatocellular carcinoma treated with sorafenib.
Dig Liver Dis
Show Abstract
Hide Abstract
Impact of patient and tumour baseline characteristics on the overall survival is not well characterized in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib.
Related JoVE Video
Metabolic syndrome and its association with fatty liver disease after orthotopic liver transplantation.
Transpl. Int.
Show Abstract
Hide Abstract
The metabolic syndrome (MetS) might contribute to morbidity after orthotopic liver transplantation (OLT). For this reason, we searched for MetS-associated risk factors and analyzed the link with nonalcoholic fatty liver disease (NAFLD) in OLT recipients. De novo MetS affected 32.9% of our cohort (n = 170) within 2 years after OLT. Multivariate analysis identified glycosylated hemoglobin (HbA1c) levels ?5% [odds ratio (OR) = 3.5; 95% confidence interval (CI) = 1.56-8.13, P = 0.003], diabetes mellitus (OR = 4.31, CI = 1.69-10.99, P = 0.002), and arterial hypertension (OR = 4.59, CI = 1.46-14.49, P = 0.009) as independent risk factors for de novo MetS. MetS incidence correlated with steroid dosage after OLT (5.2 ± 2.4 mg/day vs. 7.1 ± 4.7 mg/day, P = 0.014), and was linked to NAFLD (P = 0.001) via obesity (OR = 4.67, CI = 1.55-14.1, P = 0.006) and dyslipidemia (OR = 4.23, CI = 1.35-13.3, P = 0.013) post-OLT. In conclusion, we were able to identify low threshold HbA1c as a novel risk factor for MetS after OLT and described a link of MetS with NAFLD in transplant organs. This study also indicated that steroid treatment is associated with MetS rates after OLT.
Related JoVE Video
Clinicopathologic features and prognosis of young patients with hepatocellular carcinoma in a large German cohort.
J. Clin. Gastroenterol.
Show Abstract
Hide Abstract
Hepatocellular carcinoma in non-hepatitis B virus endemic areas is rare in patients younger than 40 years of age. The aim of this study was to characterize young patients in a large German cohort in comparison with older patients with regard to underlying liver disease, clinical management, and survival.
Related JoVE Video
Liver specific deletion of CYLDexon7/8 induces severe biliary damage, fibrosis and increases hepatocarcinogenesis in mice.
J. Hepatol.
Show Abstract
Hide Abstract
CYLD is a tumor suppressor gene that is mutated in familial cylindromatosis, an autosomal dominant predisposition to tumors of skin appendages. Reduced CYLD expression has been observed in other tumor entities, including hepatocellular carcinoma. In the present study, we analyzed the role of CYLD in liver homeostasis and hepatocarcinogenesis in vivo.
Related JoVE Video
Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP.
Am. J. Physiol. Gastrointest. Liver Physiol.
Show Abstract
Hide Abstract
Chronic liver disease promotes hepatocellular injury involving apoptosis and triggers compensatory regeneration that leads to the activation of quiescent stellate cells in the liver. The deposition of extracellular matrix from activated myofibroblasts promotes hepatic fibrosis and the progression to cirrhosis with deleterious effects on liver physiology. The role of apoptosis signaling pathways in the development of fibrosis remains undefined. The aim of the current study was to determine the involvement of the caspase-8 homologue cellular FLICE-inhibitory protein (cFLIP) during the initiation and progression of fibrosis. Liver injury and fibrosis from carbon tetrachloride (CCl(4)) and thioacetamide (TAA) were examined in mice exhibiting a hepatocyte-specific deletion of cFLIP (flip(-/-)). Acute liver injury from CCl(4) and TAA were enhanced in flip(-/-) mice. This was accompanied by increased activation of caspase-3 and -9, pronounced phosphorylation of JNK, and decreased phosphorylation of Erk. Deletion of the cJun NH(2)-terminal kinase 2 (JNK2) in flip(-/-) mice protected from injury. Hepatic fibrosis was increased at baseline in 12-wk-old flip(-/-) mice, and progression of fibrosis from TAA was accelerated compared with the wild type. In conclusion, deletion of cFLIP in hepatocytes leads to increased fibrosis and accelerated fibrosis progression. This is accompanied by increased injury involving the activation of caspases and JNK2. Thus predisposition to liver injury involving increased hepatocellular apoptosis is a critical mediator of accelerated fibrogenesis, and prevention of liver injury will be a most important measure for patients with chronic liver disease.
Related JoVE Video
Histological examination and evaluation of donor bile ducts received during orthotopic liver transplantation--a morphological clue to ischemic-type biliary lesion?
Virchows Arch.
Show Abstract
Hide Abstract
Ischemic-type biliary lesions (ITBL) belong to a group of biliary disorders that are regarded as the major complication in patients with orthotopic liver transplantation (OLT). We performed histological evaluation of donor common bile ducts received during OLT to find morphological clues to the pathomechanisms of ITBL. We investigated 93 grafts of 92 patients (recipients: mean age, 56.5 years; underlying disease: hepatocellular carcinoma (n?=?45), alcoholic cirrhosis (n?=?16), viral hepatitis with cirrhosis (n?=?9), retransplantations (n?=?9), others (n?=?14); donors: mean age, 53.2 years). Donor common bile ducts were received after recirculation of the hepatic artery prior to biliary end-to-end anastomosis and routinely processed. Statistical evaluation was performed by chi-square analysis and multivariate analysis using a logistic regression model. With regard to ITBL (observed in 19.4 %), the following phenomena were found to be statistically relevant: necrosis of the bile duct wall, arteriolonecrosis, vascular lesions (such as subintimal edema), and intramural bleeding (P?
Related JoVE Video
Prognostic factors and outcomes of patients with hepatocellular carcinoma in non-cirrhotic liver.
Scand. J. Gastroenterol.
Show Abstract
Hide Abstract
To report the outcome of patients with hepatocellular carcinoma (HCC) in non-cirrhotic liver depending on the mode of primary treatment and to define clinicopathological factors influencing patients prognosis.
Related JoVE Video
Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance.
BMC Cancer
Show Abstract
Hide Abstract
Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC).
Related JoVE Video
The role of death effector domain-containing proteins in acute oxidative cell injury in hepatocytes.
Free Radic. Biol. Med.
Show Abstract
Hide Abstract
Apoptosis is a mechanism that regulates hepatic tissue homeostasis and contributes to both acute and chronic injury in liver disease. The apoptotic signaling cascade involves activation of the death-inducing signaling complex (DISC) and subsequent recruitment of proteins containing death effector domains (DED), which regulate downstream effector molecules. Prominent among these are the Fas-associated death domain (FADD) and the cellular caspase 8-like inhibitory protein (cFLIP), and alterations in these proteins can lead to severe disruption of physiological processes, including acute liver failure or hepatocellular carcinoma. Their role in cell signaling events independent of the DISC remains undetermined. Oxidative stress can cause cell injury from direct effects on molecules or by activating intracellular signaling pathways including the mitogen-activated protein kinases (MAPKs). In this context, prolonged activation of the cJun N-terminal kinase (JNK)/AP-1/cJun signaling pathway promotes hepatocellular apoptosis, whereas activation of the extracellular signal-regulated kinase (Erk) exerts protection. We investigated the roles of FADD and cFLIP in acute oxidant stress induced by the superoxide generator menadione in hepatocytes. Menadione resulted in dose-dependent predominantly necrotic cell death. Hepatocytes expressing a truncated, dominant-negative FADD protein were partially protected, whereas cFLIP-deficient hepatocytes displayed increased cell death from menadione. In parallel, Erk phosphorylation was enhanced in hepatocytes expressing dnFADD and decreased in cFLIP-deficient hepatocytes. Hepatocyte injury was accompanied by increased release of proapoptotic factors and increased JNK/cJun activation. Thus, FADD and cFLIP contribute to the regulation of cell death from acute oxidant stress in hepatocytes involving MAPK signaling. This implies that DED-containing proteins are involved in the regulation of cellular survival beyond their role in cell death receptor-ligand-mediated apoptosis.
Related JoVE Video
Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.
Dig Liver Dis
Show Abstract
Hide Abstract
Recurrence of hepatocellular carcinoma after orthotopic liver transplantation not amenable to surgical approaches is associated with poor outcome.
Related JoVE Video
Trends in Epidemiology, Treatment, and Survival of Hepatocellular Carcinoma Patients Between 1998 and 2009: An Analysis of 1066 Cases of a German HCC Registry.
J. Clin. Gastroenterol.
Show Abstract
Hide Abstract
The aim of this study was to analyze clinical presentation, course of disease, and management of patients with hepatocellular carcinoma (HCC) in a German referral center between 1998 and 2009.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

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.