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1.
Am J Physiol Cell Physiol ; 325(1): C129-C140, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37273239

RESUMO

Liver cirrhosis is the end stage of all chronic liver diseases and contributes significantly to overall mortality of 2% globally. The age-standardized mortality from liver cirrhosis in Europe is between 10 and 20% and can be explained by not only the development of liver cancer but also the acute deterioration in the patient's overall condition. The development of complications including accumulation of fluid in the abdomen (ascites), bleeding in the gastrointestinal tract (variceal bleeding), bacterial infections, or a decrease in brain function (hepatic encephalopathy) define an acute decompensation that requires therapy and often leads to acute-on-chronic liver failure (ACLF) by different precipitating events. However, due to its complexity and organ-spanning nature, the pathogenesis of ACLF is poorly understood, and the common underlying mechanisms leading to the development of organ dysfunction or failure in ACLF are still elusive. Apart from general intensive care interventions, there are no specific therapy options for ACLF. Liver transplantation is often not possible in these patients due to contraindications and a lack of prioritization. In this review, we describe the framework of the ACLF-I project consortium funded by the Hessian Ministry of Higher Education, Research and the Arts (HMWK) based on existing findings and will provide answers to these open questions.


Assuntos
Insuficiência Hepática Crônica Agudizada , Doença Hepática Terminal , Varizes Esofágicas e Gástricas , Humanos , Doença Hepática Terminal/complicações , Varizes Esofágicas e Gástricas/complicações , Hemorragia Gastrointestinal/complicações , Cirrose Hepática/complicações , Cirrose Hepática/terapia , Insuficiência Hepática Crônica Agudizada/terapia , Insuficiência Hepática Crônica Agudizada/etiologia
2.
Eur Heart J ; 37(21): 1659-66, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-26516172

RESUMO

AIMS: Regenerative therapies have evolved as a promising new option in the treatment of post-infarction heart failure. A major limitation of intracoronary application of autologous bone marrow-derived mononuclear cells (BM-MNCs) is that homing of the applied cells is profoundly reduced in patients with post-infarction heart failure compared with patients with acute myocardial infarction. However, early pilot and also randomized controlled trials have demonstrated significant improvements in overall cardiac function. The aim of the present analysis was to quantify a potential mortality risk reduction and reduced hospitalization in order to provide data for a prospective outcome trial. METHODS AND RESULTS: The results of an ongoing single-centre registry including 297 post-infarction heart failure patients suggest that repeated intracoronary application of autologous bone marrow-derived cells is associated with a significant better 2-year survival compared with a single BM-MNC application (2-year survival 93.6 vs. 84.0%, P = 0.03). Likewise, mortality is significantly lower at 2-year follow-up compared with the mortality estimated by the use of the Seattle Heart Failure Model (SHFM) in patients receiving repeated BM-MNC application (observed mortality 6.4%, predicted mortality 16.2%, P = 0.02). Although the trend persisted at 3-year follow-up, the mortality reduction was no longer statistically significant between single and repeated treatment (mortality 21.9 vs. 13.7%, P = 0.06). CONCLUSION: Repeated intracoronary administration of BM-MNC appears to be associated with improved clinical outcome compared with single treatment at 2 years. This registry provides the rationale for the design of the multicentre randomized, controlled, open-label REPEAT trial, which prospectively compares the effects of single vs. repeated intracoronary application of autologous BM-MNC on total and SHFM-predicted mortality in patients with chronic post-infarction heart failure.


Assuntos
Células da Medula Óssea , Transplante de Medula Óssea/métodos , Infarto do Miocárdio/terapia , Idoso , Transplante de Medula Óssea/mortalidade , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Resultado do Tratamento
3.
Oncol Res Treat ; 47(9): 430-433, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38754400

RESUMO

INTRODUCTION: Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL) is treated as standard of care (SoC) by imatinib-based treatment combined with induction and consolidation chemotherapy followed by allogeneic stem cell transplantation (SCT) in first remission. The German Multicenter ALL Study Group for Adult ALL (GMALL) reports about a trial to evaluate the impact of ponatinib-based therapy, blinatumomab treatment for suboptimal responders, and the possibility of omission of SoC Allo SCT in optimal responders entitled GMALL-EVOLVE. METHODS: Herein, imatinib is randomized versus ponatinib as frontline treatment combined with chemotherapy, optimal responders also get randomized between SCT and chemo-immunotherapy, and suboptimal responders receive immunotherapy before SCT. The trial is registered under the EudraCT number 2022-000760-21. CONCLUSION: This trial will answer several major questions in the treatment of Ph+ALL.


Assuntos
Anticorpos Biespecíficos , Protocolos de Quimioterapia Combinada Antineoplásica , Mesilato de Imatinib , Imidazóis , Leucemia-Linfoma Linfoblástico de Células Precursoras , Piridazinas , Humanos , Anticorpos Biespecíficos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Piridazinas/uso terapêutico , Imidazóis/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Mesilato de Imatinib/uso terapêutico , Feminino , Masculino , Cromossomo Filadélfia , Inibidores de Proteínas Quinases/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Resultado do Tratamento , Pessoa de Meia-Idade , Transplante de Células-Tronco , Adulto Jovem
4.
Mediators Inflamm ; 2013: 710239, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24381411

RESUMO

Neutrophil extracellular traps (NETs) have been suggested to play a pathophysiological role in several autoimmune diseases. Since NET-formation in response to several biological and chemical stimuli is mostly ROS dependent, in theory any substance that inhibits or scavenges ROS could prevent ROS-dependent NET release. Therefore, in the present comprehensive study, several antioxidative substances were assessed for their capacity to inhibit NET formation of primary human neutrophils in vitro. We could show that the flavonoids (-)-epicatechin, (+)-catechin hydrate, and rutin trihydrate as well as vitamin C and the pharmacological substances N-acetyl-L-cysteine and 5-aminosalicylic acid inhibited PMA induced ROS production and NET formation. Therefore, a broad spectrum of antioxidative substances that reduce ROS production of primary human neutrophils also inhibits ROS-dependent NET formation. It is tempting to speculate that such antioxidants can have beneficial therapeutic effects in diseases associated with ROS-dependent NET formation.


Assuntos
Antioxidantes/farmacologia , Flavonoides/farmacologia , Mesalamina/farmacologia , Neutrófilos/efeitos dos fármacos , Acetilcisteína/farmacologia , Apoptose/efeitos dos fármacos , Ácido Ascórbico/farmacologia , Células Cultivadas , Quimiotaxia de Leucócito/efeitos dos fármacos , Humanos , NADPH Oxidases/antagonistas & inibidores , Neutrófilos/imunologia , Peroxidase/metabolismo , Fagocitose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Acetato de Tetradecanoilforbol/farmacologia
5.
Inflamm Bowel Dis ; 13(1): 65-70, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17206641

RESUMO

BACKGROUND: Concentrations of proinflammatory cytokines are increased in the intestinal mucosa of patients with active Crohn's disease (CD). In a prospective study we investigated whether cytokines can predict long-term remission (>6 months) in patients with steroid-refractory CD receiving treatment with infliximab or cyclophosphamide, followed by azathioprine or methotrexate. METHODS: Cytokine transcripts were quantified using real-time polymerase chain reaction (PCR) in mucosal biopsies from 19 patients with active, steroid-refractory CD before and 8 weeks after initiation of therapy. Patients were treated with cyclophosphamide (monthly treatment of 750 mg cyclophosphamide intravenously) or infliximab (5 mg/kg body weight) and were followed until relapse of the disease. Statistical analysis was performed to identify predictive factors to discriminate between patients with or without long-term remission. RESULTS: Seventeen out of 19 patients achieved remission of the disease, two patients were nonresponders, while six out of 17 patients exhibited an early recurrence. Pretreatment TNF-alpha, IL-18, MRP-14, and IL-8 transcripts were significantly correlated with long-term remission. While several cytokines, most importantly MMP-1, determined after 8 weeks were able to predict patients achieving long-term remission, only a decrease of TNF-alpha levels after 8 weeks was predictive. Overall, statistical analysis identified lower pretreatment TNF-alpha levels as the strongest predictor of long-term remission among baseline variables. CONCLUSIONS: Quantification of mucosal TNF-alpha transcripts prior to therapy allows identification of patients achieving long-term remission upon immunosuppression with infliximab or cyclophosphamide. Real-time PCR might have considerable potential in the analysis of disease activity and subsequent clinical management of patients with immunosuppressive therapies.


Assuntos
Doença de Crohn/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Mucosa Intestinal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Anticorpos Monoclonais/uso terapêutico , Quimiocinas/metabolismo , Doença de Crohn/metabolismo , Citocinas/metabolismo , Resistência a Medicamentos , Feminino , Fármacos Gastrointestinais/uso terapêutico , Glucocorticoides/uso terapêutico , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Indução de Remissão , Fator de Necrose Tumoral alfa/genética
6.
Oncogene ; 22(1): 69-80, 2003 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-12527909

RESUMO

Increased expression of the cell proliferation-associated polo-like kinase 1 (PLK1) and apoptosis-associated BCL-2 genes has been observed in different human malignancies. Inhibition of cell proliferation and reactivation of apoptosis are basic principles in anticancer therapy. The efficiency of this approach is often limited by insuf-ficient targeting and delivery of anticancer drugs into the tumors. Phosphorothioate antisense oligodeoxynucleotides (ODNs) directed against PLK1 and BCL-2 were administered systemically via the tail vein into nude mice bearing A549, MDA-MB-435, and Detroit562 xenografts. To enhance tumor-specific uptake and to reduce systemic toxicity of antisense ODNs membrane electroporation transfer was applied in vivo. Northern and Western blot analyses were used to assess PLK1 and BCL-2 expression. Tumor mass was assessed after resection of tumors. All three cell lines and corresponding xenografts expressed high levels of PLK1 and were sensitive towards antisense PLK1 treatment. Antisense BCL-2 therapy was effective in tumors expressing high levels of BCL-2, but not in A549 cells and corresponding xenografts, which express low levels of BCL-2. Administration of antisense ODNs in a dose of 5 mg/kg, twice weekly during four weeks supported by the membrane electroporation transfer, eradicated 60-100% of the xenografted tumors. Antitumor effect in BCL-2 overexpressing MDA-MB-435 cells was synergistic for BCL-2 and PLK1 combination therapy. This study provides evidence that combined systemic administration of antisense ODNs against proliferation and pro- survival associated targets and in vivo electroporation of tumors represents a promising antitumor therapeutic approach.


Assuntos
Neoplasias/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Proteínas Quinases/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Tionucleotídeos/uso terapêutico , Animais , Sequência de Bases , Proteínas de Ciclo Celular , Regulação para Baixo , Eletroporação , Humanos , Camundongos , Camundongos Nus , Microscopia de Fluorescência , Transplante de Neoplasias , Neoplasias/patologia , Oligonucleotídeos Antissenso/genética , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas , Tionucleotídeos/genética , Células Tumorais Cultivadas , Quinase 1 Polo-Like
7.
Med Microbiol Immunol ; 196(1): 11-21, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16955308

RESUMO

The hepatitis C virus (HCV) non-structural (NS)5A protein is linked to interferon alpha resistance in vitro and higher numbers of NS5A amino acid (aa) variations in HCV 1a/b isolates are associated with virologic response to interferon alpha-based therapy in vivo. Here, we aimed to study NS5A aa variations in Indian patients undergoing interferon alpha/ribavirin treatment infected with HCV 3a. The NS5A region [aa 2194-2401, comprising interferon sensitivity determining region, protein kinase resource (PKR) binding domain, V3 region] was sequenced from pre-treatment sera of 24 patients with HCV 3a infection. Mean number and physicochemical properties of aa variations (conserved vs. non-conserved) were assessed. Additionally, published NS5A sequences [NS5A region (n = 61), PKR binding domain (n = 111)] of characterized HCV 3a isolates were analyzed. The mean number of NS5A aa variations was not correlated with treatment response in our cohort. When all available NS5A sequences were included, a higher number of non-conserved aa variations within PKR binding domain and an extended V3 region of NS5A was associated with virologic response (P = 0.004 and 0.05, respectively). Mutational analyses of a large number of NS5A sequences suggest, that a higher number of non-conserved aa variations within the PKR binding domain and the extended V3 region is correlated with virologic response in HCV 3a infected patients.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Interferon-alfa/uso terapêutico , Proteínas não Estruturais Virais/genética , Adulto , Sequência de Aminoácidos , Estudos de Coortes , Farmacorresistência Viral/genética , Feminino , Hepacivirus/efeitos dos fármacos , Hepacivirus/metabolismo , Antígenos da Hepatite C/metabolismo , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Estrutura Secundária de Proteína , Ribavirina/uso terapêutico , Alinhamento de Sequência , Proteínas não Estruturais Virais/metabolismo
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