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1.
Cell Death Differ ; 23(4): 576-82, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26470729

RESUMO

Hepatocellular carcinoma (HCC) develops as a consequence of chronic inflammatory liver diseases such as chronic hepatitis B virus (HBV) infection. The transcription factor c-Jun/activator protein 1 (AP-1) is strongly expressed in response to inflammatory stimuli, promotes hepatocyte survival during acute hepatitis and acts as an oncogene during chemically induced liver carcinogenesis in mice. Here, we therefore aimed to characterize the functions of c-Jun during HBV-related liver tumorigenesis. To this end, transgenic mice expressing all HBV envelope proteins (HBV(+)), an established model of HBV-related HCC, were crossed with knockout mice lacking c-Jun specifically in hepatocytes and tumorigenesis was analyzed. Hepatic expression of c-Jun was strongly induced at several time points during tumorigenesis in HBV(+) mice, whereas expression of other AP-1 components remained unchanged. Importantly, formation of premalignant foci and tumors was strongly reduced in HBV(+) mice lacking c-Jun. This phenotype correlated with impaired hepatocyte proliferation and increased expression of the cell cycle inhibitor p21, whereas hepatocyte survival was not affected. Progression and prognosis of HBV-related HCC correlates with the expression of the cytokine osteopontin (Opn), an established AP-1 target gene. Opn expression was strongly reduced in HBV(+) livers and primary mouse hepatocytes lacking c-Jun, demonstrating that c-Jun regulates hepatic Opn expression in a cell-autonomous manner. These findings indicate that c-Jun has important functions during HBV-associated tumorigenesis by promoting hepatocyte proliferation as well as progression of dysplasia. Therefore, targeting c-Jun may be a useful strategy to prevent hepatitis-associated tumorigenesis.


Assuntos
Carcinoma Hepatocelular/metabolismo , Transformação Celular Viral , Vírus da Hepatite B/metabolismo , Neoplasias Hepáticas/metabolismo , Fígado/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Proliferação de Células/genética , Vírus da Hepatite B/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatócitos/virologia , Fígado/patologia , Fígado/virologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-jun/genética , Fator de Transcrição AP-1/genética
6.
Transpl Infect Dis ; 14(5): 445-51, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22970743

RESUMO

BACKGROUNDS AND AIMS: Organ shortage is a major problem in transplantation. The use of organs from hepatitis B surface antigen (HBsAg)-negative and hepatitis B core antibody (HBcAb)-positive donors could significantly increase the donor pool. However, little information is available about the impact of HBcAb status of renal donors on viral transmission to recipients. To address this issue, the present quantitative review of relevant studies has been performed. MATERIALS AND METHODS: Electronic databases including Medline, EMBASE, ISI, and Scopus were systematically searched for studies that evaluated risk of hepatitis B virus (HBV) transmission through renal transplantation from HBsAg-/HBcAb+ donors. Eligible studies were identified according to predefined criteria. The final outcome was one of HBV markers seroconversion defined as HBsAg, hepatitis B surface antibody (HBsAb), or HBcAb detection in previously seronegative end-stage renal disease (ESRD) patients after transplantation, and without other identified major sources of infection. RESULTS: Nine studies with 1385 eligible kidney recipients were included. In total, 45 subjects showed seroconversion of HBV markers as follows: HBsAg (n = 4) (0.28%; 95% confidence interval [CI] 0.006; 0.57), HBcAb (n = 32), HBsAb (n = 5), and either HBcAb or HBsAb (n = 4). The total rate of seroconversion after renal transplantation was calculated to be 3.24% (95% CI: 2.31-4.18). CONCLUSION: Our review indicates that the risk of HBV transmission from HBcAb-positive kidney donors is extremely low. Therefore, kidneys from these donors can be transplanted safely into ESRD patients.


Assuntos
Anticorpos Anti-Hepatite B/sangue , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Hepatite B/transmissão , Falência Renal Crônica/terapia , Transplante de Rim , Doadores de Tecidos , Hepatite B/imunologia , Hepatite B/virologia , Vírus da Hepatite B , Humanos
7.
Dtsch Med Wochenschr ; 137(25-26): 1360-5, 2012 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-22653493

RESUMO

The standard antiviral therapy for chronic hepatitis C is pegylated interferon-alfa (PegIFN) and ribavirin since about 10 years. This treatment regimen leads to a sustained virological response (SVR) in 40-50 % of patients infected with HCV genotype 1 and in approx. 80 % of those infected with HCV genotype 2 or 3. In recent years, many direct antiviral agents (DAA) have been developed and are being explored in clinical studies. These antiviral agents target different viral proteins that are central for HCV replication, incl. the NS3/4A protease, NS5B polymerase, and the NS5A protein. The protease inhibitors telaprevir and boceprevir have recently been approved for the treatment of chronic HCV genotype 1 infection in combination with PegIFN and ribavirin. These triple therapies increase the SVR rates in HCV genotype 1 patients from 40-50 % to approx. 70 %. Other DAAs will likely be approved in the near future and may result in an IFN-free antiviral therapy.


Assuntos
Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/prevenção & controle , Interferon-alfa/uso terapêutico , Inibidores de Proteases/uso terapêutico , Ribavirina/uso terapêutico , Humanos , Resultado do Tratamento
8.
Z Gastroenterol ; 49(9): 1267-9, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21887664

RESUMO

BACKGROUND: Thyrotoxicosis may significantly alter hepatic function and is associated with autoimmune disorders of the liver. CASE REPORT: We report the case of a thyrotoxic patient with Graves' disease and histologically established cholestatic hepatitis. Medical treatment of hyperthyroidism normalized liver function tests. CONCLUSIONS: In patients with elevated liver function parameters and jaundice of unknown origin, thyroid function should generally be tested. Moreover, medical treatment of hyperthyroidism with thyrostatics may cause severe hepatitis whereas untreated hyperthyroid patients are at risk of developing chronic liver failure.


Assuntos
Doença de Graves/complicações , Icterícia Obstrutiva/etiologia , Redução de Peso , Doença de Graves/fisiopatologia , Humanos , Icterícia Obstrutiva/fisiopatologia , Testes de Função Hepática , Masculino , Adulto Jovem
9.
Clin Med Insights Oncol ; 5: 201-11, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21836816

RESUMO

Constipation, one of the major side effects of opiates used in palliative care, can impair patients' quality of life to a point where it prevents sufficient pain control. Methylnaltrexone is a novel µ-receptor antagonist, which does not pass the blood brain barrier. It is licensed to treat opiate induced constipation for patients with advanced diseases. This review article presents an overview of pharmacology and safety of its application, evidence of its efficacy and economic aspects of its use in clinical practice. Available data are limited but strongly suggest that methylnaltrexone causes laxation in less than 24 hours for at least half of those patients over the first two weeks of usage without impairing pain control or causing serious adverse effects. To avoid danger of gastrointestinal perforation it is contraindicated for patients at risk for that complication. More research is needed to evaluate its long-term efficacy and economic impact.

11.
Dtsch Med Wochenschr ; 136(23): 1251-4, 2011 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-21630171

RESUMO

HISTORY: A 76-year-old woman was admitted with a two-months history of pain in the right upper abdomen and nausea. There was no disease or premedication in her history. INVESTIGATIONS: Labaratory tests revealed a normocytic anemia, elevated liver enzymes and signs of cholestasis. An MR of the abdomen showed a hyperperfused tumor in the liver segments IV, V and VIII, likely to be a hepatocellular carcinoma. However, tumor markers including AFP were not elevated. A liver biopsy revealed the final diagnosis of angiosarcoma. THERAPY AND COURSE: Because the tumor was not resectable transarterial chemoembolisation (TACE) with doxorubicin was performed with palliative intent. Six weeks later a CT scan revealed extensive tumor progression. Therefore no further causal tretament was performed. With best supportive care the patient died within 4 weeks after she had been discharged. Occupational history revealed that the woman had been exposed to polyvinylchloride for six years when she had worked in a factory producing varnish aerosol cans 44 years ago. CONCLUSION: Angiosarcomas of the liver are rare, highly malignant and diffuse infiltrating vascular tumors with rapid growth and poor prognosis. In patients who have been exposed to polyvinylchloride and present with an indistinct lesion of the liver an angiosarcoma should be considered.


Assuntos
Exposição Ambiental , Hemangiossarcoma/induzido quimicamente , Hemangiossarcoma/diagnóstico , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/diagnóstico , Cloreto de Polivinila , Idoso , Quimioembolização Terapêutica , Doxorrubicina/uso terapêutico , Evolução Fatal , Feminino , Hemangiossarcoma/terapia , Humanos , Neoplasias Hepáticas/terapia , Cuidados Paliativos
13.
Dtsch Med Wochenschr ; 136(10): 459-60, 2011 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-21365521

RESUMO

Molecular and cell biology have not only greatly advanced our understanding of the pathogenesis of numerous human diseases but at the same time contributed to their diagnosis, therapy and prevention. Based on modern genetic as well as epigenetic and biochemical analyses it is possible to identify on the one hand point mutations and single nucleotide polymporphisms (SNPs) as well as epigenetic modifications. On the other hand, using high throughput array technologies, it is possible to analyze thousands of genes simultaneously, resulting in an individual gene or gene expression profile (signature). These data increasingly allow to define the individual risk for a given disease and to predict the individual prognosis of a disease as well as the efficacy of therapeutic strategies (personalized medicine).


Assuntos
Predisposição Genética para Doença/genética , Testes Genéticos/tendências , Técnicas de Sonda Molecular/tendências , Medicina de Precisão/tendências , Humanos
14.
Praxis (Bern 1994) ; 100(3): 159-66, 2011 Feb 02.
Artigo em Alemão | MEDLINE | ID: mdl-21290373

RESUMO

Molecular and cell biology have revolutionized not only diagnosis, therapy and prevention of human diseases but have also greatly contributed to the understanding of their pathogenesis. Based on modern molecular and biochemical methods it is possible to identify on the one hand point mutations and single nucleotide polymorphisms. On the other hand, using high throughput array technologies, it is possible to analyze thousands of genes simultaneously, resulting in an individual gene or gene expression profile (signature). These data increasingly allow to define the individual risk for a given disease and to predict the individual prognosis of a disease as well as the efficacy of therapeutic strategies (personalized medicine). In this review recent advances of predictive medicine and its clinical relevance will be addressed.


Assuntos
Medicina de Precisão/tendências , Análise Mutacional de DNA , Sistemas de Liberação de Medicamentos , Feminino , Previsões , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Projeto Genoma Humano , Humanos , Masculino , Metabolômica/tendências , MicroRNAs/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos/tendências , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Proteômica/tendências , Suíça
15.
Dtsch Med Wochenschr ; 136(3): 95-8, 2011 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-21225557

RESUMO

Genome-wide association studies (GWAS) are aimed to identify genetic markers of complex human diseases and individual traits. In this context more than 150 gene loci have been found to be associated with about 60 different diseases and personal characteristics. A recent example is the relevance of a polymorphism in the interleukin 28B gene for the natural course of hepatitis C virus infection and the efficacy of antiviral therapy. It is to be expected that GWAS will increasingly contribute to the understanding of the pathogenesis and consquently improve prediction, prevention, diagnosis and therapy of human diseases and eventually will become part of clinical practice.


Assuntos
Marcadores Genéticos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Antivirais/uso terapêutico , Cromossomos Humanos Par 19/genética , Genótipo , Haplótipos/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Interferons , Interleucinas/genética , Fenótipo , Polietilenoglicóis/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Proteínas Recombinantes , Ribavirina/uso terapêutico
19.
Dtsch Med Wochenschr ; 135(8): 339-42, 2010 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-20165997

RESUMO

HISTORY AND FINDINGS ON ADMISSION: A 70-year-old man with a 14 month history of chronic severe diarrhea treated with budenosid and mesalazin was admitted because of peripheral oedema and weight loss of about 26 kg. INVESTIGATIONS AND DIAGNOSIS: A general pigmentation of the skin, especially on scull and hands, as well as dystrophic nail changes and alopecia of scalp and facial hair were seen. The tests showed a slight macrocytotic, normochromic anemia. Total protein and the clotting factors were decreased. Endoscopy revealed multiple sessile polyps in the stomach and duodenum in appearance to colon and rectum. Endoscopic removal of a polyp showed histologically cystic dilatation of foveolae and oedematous mucosa. The histological features, the wide distribution of the polyps together with the skin changes, lead to the diagnosis of Cronkhite-Canada syndrome (CCS). TREATMENT AND COURSE: The patient was initially treated with prednisolon 60 mg/d i. v. for 2 weeks, resulting in a marked improvement of symptoms and weight gain. He is at present in good health under prednisolon 20 mg/d per os and is followed up in our outpatient department. CONCLUSION: CCS is in up to 14 % of the cases associated with a carcinoma of the gastrointestinal tract. At present there are only reports about a successful treatment by steroids, prophylactic gastrectomy and proctocolectomy. Typical myopathic lesions of CCS have not been described to date, but the demonstrated improvement of creatinin kinase with successful treatment suggests a common pathophysiological mechanism.


Assuntos
Alopecia/etiologia , Diarreia/etiologia , Polipose Intestinal/diagnóstico , Transtornos da Pigmentação/etiologia , Administração Oral , Idoso , Alopecia/tratamento farmacológico , Doença Crônica , Diarreia/tratamento farmacológico , Esquema de Medicação , Edema/etiologia , Endoscopia Gastrointestinal , Humanos , Infusões Intravenosas , Polipose Intestinal/tratamento farmacológico , Masculino , Transtornos da Pigmentação/tratamento farmacológico , Prednisolona/administração & dosagem , Redução de Peso
20.
Gut ; 58(12): 1644-53, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19710032

RESUMO

BACKGROUND AND AIMS: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and is associated with significant morbidity and mortality. Since there is evidence for an interaction of NS5A with c-Raf we studied whether the c-Raf inhibitor sorafenib affects HCV replication. METHODS: HCV replicating HuH7.5 cells were treated with sorafenib and examined for HCV RNA titres by northern blotting or real time polymerase chain reaction (PCR), for core, NS3 and NS5A expression by immunostaining, and for replication by luciferase reporter assays. RESULTS: Here we demonstrate that in cells replicating infectious HCV particles, NS5A recruits c-Raf to the replicon complex resulting in the activation of c-Raf. Therefore, we studied the effect of inhibition of c-Raf on HCV replication using the anti-tumour drug sorafenib that is known to inhibit c-Raf with high specificity. Sorafenib efficiently blocks HCV replication and viral gene expression. In addition, in HCV-replicating cells sorafenib decreased the hyperphosphorylated form of NS5A and resulted in the formation of additional hypophosphorylated forms. Further, sorafenib caused a rapid dissociation of lipid droplets. We provide evidence that the antiviral effect of sorafenib indeed is caused by inhibition of c-Raf. By contrast, inhibition of targets downstream of c-Raf or inhibition of tyrosine kinases by sunitinib did not affect HCV replication. CONCLUSION: Our data demonstrate that the well-characterised anti-tumour drug sorafenib efficiently blocks HCV replication in vitro. This novel effect of sorafenib should be further explored as an antiviral strategy for patients with chronic HCV infection.


Assuntos
Antivirais/farmacologia , Benzenossulfonatos/farmacologia , Hepacivirus/efeitos dos fármacos , Piridinas/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Hepacivirus/enzimologia , Hepacivirus/fisiologia , Hepatócitos/virologia , Humanos , Niacinamida/análogos & derivados , Compostos de Fenilureia , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Replicon/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Sorafenibe , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
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