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ABSTRACT: In patients with cirrhosis, bacterial DNA has been found in ascites reflecting bacterial translocation. However, the clinical relevance of this finding is ill-defined especially compared with the standard diagnostics for detection of spontaneous bacterial peritonitis (SBP). Furthermore, other DNA tests have not been sufficiently evaluated.
We prospectively included 151 patients with cirrhosis and ascites admitted to our department. The patients were evaluated for diagnosis of SBP (polymorphonuclear count > 250 cells/mm) or finding of bacterascites, defined by positive bacterial culture from ascites. To detect bacterial species of bacterial DNA fragments in ascites, broad-range polymerase chain reaction and nucleotide sequencing analysis with the LightCycler SeptiFast Kit Mgrade were performed. Routine parameters were correlated with these findings.
Eighteen of 151 patients (12%) had SBP according to the classic definition. Bacterial DNA was detected in five of these 18 patients (3%), whereas in 13 patients (9%), bacterial DNA was detected without standard SBP. Seven patients (5%) had culture-positive SBP, only in two of them bacterial DNA was detected. In multivariate analysis, C-reactive protein (P = 0.000), white blood cell count (P = 0.019), and lactic acid dehydrogenase in ascites (P = 0.000) were independently associated with SBP. In the DNA-positive ascites group, none of the assessed parameters was significantly associated with the bacterial DNA positivity.
We found no correlation between detection of bacterial DNA in ascites and SBP (polymorphonuclear count > 250/mm). In contrast to the patients with bacterial DNA in ascites, patients with SBP showed clinical signs of infection. This study provides no evidence that detection of bacterial DNA in ascites of patients with liver cirrhosis is of clinical or diagnostic relevance when using the panel of LightCycler SeptiFast Kit Mgrade.
European journal of gastroenterology & hepatology 12/2010; 22(12):1487-94. · 1.66 Impact Factor
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ABSTRACT: The aim of this study was to characterize patients and report outcome of diffuse alveolar hemorrhage (DAH) requiring intensive care unit support.
Thirty-seven patients were identified. Clinical characteristics and outcome were determined by chart review.
Eighty-nine percent of patients presented with shortness of breath, 23% with cough, and 3% with hemoptysis. In 9% of patients, a diagnosis of DAH was suspected on admission. Diagnosis was confirmed by finding a progressively hemorrhagic bronchoalveolar lavage fluid in 89% and by a positive iron stain in 11% of patients. Vasculitis was causative in 19%, drug toxicity in 11%, thrombocytopenia in 27%, stem-cell transplantation in 5%, sepsis-associated lung injury in 22%, and unknown mechanisms in 16%. Thirty-two patients were mechanically ventilated, 4 received noninvasive ventilation, and 1 received supplemental oxygen therapy. Overall, 18 (49%) of 37 patients survived the intensive care unit stay. Survival was markedly different between patients with an immunologic/unknown etiology (82%) and patients with thrombocytopenia and/or sepsis (22%).
Diffuse alveolar hemorrhage should be considered in all patients with persistent pulmonary infiltrates. Both bronchoalveolar lavage fluid and iron stain are mandatory diagnostic means. Patients with an immunologic/idiopathic pathogenetic mechanism have a relatively good prognosis, whereas the outcome in individuals with DAH secondary to cancer therapy or sepsis is poor.
Journal of critical care 08/2009; 25(2):230-5. · 2.13 Impact Factor
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ABSTRACT: Large-volume paracentesis in patients with cirrhosis and ascites induces arterial vasodilatation and decreases effective arterial blood volume, termed paracentesis-induced circulatory dysfunction (PICD), which can be prevented by costly intravenous albumin. Vasoconstrictors, e.g. terlipressin, may also prevent PICD. The aim was to compare the less expensive vasoconstrictor midodrine, an alpha-adrenoceptor agonist, with albumin in preventing PICD.
Twenty-four patients with cirrhosis and ascites were randomly assigned to be treated with either midodrine (n=11) (12.5 mg three times per day; over 2 days) or albumin (n=13) (8 g/L of removed ascites) after large-volume paracentesis. Effective arterial blood volume was assessed indirectly by measuring plasma renin and aldosterone concentration on days 0 and 6 after paracentesis; renal function and haemodynamic changes were also measured. PICD was defined as an increase in plasma renin concentration on day 6 by more than 50% of the baseline value.
PICD developed in six patients of the midodrine group (60%) and in only four patients (31%) of the albumin group. Six days after paracentesis, the aldosterone concentration increased significantly in the midodrine group, but not in the albumin group.
This pilot study suggests that midodrine is not as effective as albumin in preventing circulatory dysfunction after large-volume paracentesis in patients with cirrhosis and ascites.
Liver international: official journal of the International Association for the Study of the Liver 05/2008; 28(7):1019-25. · 3.82 Impact Factor
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ABSTRACT: Organophosphate poisoning is associated with a high mortality rate due to respiratory failure, dysrhythmias, and multi-organ failure. We report two cases of survival after "in-the field" antidote treatment of very severe organophosphate poisonings. Two patients orally ingested large amounts of the organophosphorous agent oxydemeton-methyl in suicide attempts, resulting in the hypercholinergic syndrome in both. Resuscitation included early administration of antidote by emergency medical personnel as well as high-dose atropine. Plasma levels of pseudo cholinesterase were initially very low in both patients. Long-term mechanical ventilation was necessary, and both patients developed aspiration pneumonia. At discharge, no major neurological deficits were present. Prompt antidote treatment and aggressive supportive emergency and intensive care unit therapy contribute to improved survival after acute organophosphate poisoning. We believe that in cases of mass poisonings--for example, terrorist activity--therapy must be available on the scene as soon as possible. This also may require decentralized antidote storage.
Journal of Emergency Medicine 03/2008; 37(3):279-82. · 1.31 Impact Factor
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Nephrology Dialysis Transplantation 02/2008; 23(1):385-6. · 3.40 Impact Factor
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ABSTRACT: The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, and new alternative treatments are needed.
To comparatively test the angiostatic and antitumour effects of adenoviral gene transfer of angiostatin (PlgK1-4, amino acids 1-440) and full kringles 1-5 (PlgK1-5, amino acids 1-546) in a model of subcutaneously transferred HCC in mice.
PlgK1-4 and PlgK1-5 were generated from human WtPlg cDNA and used for adenovirus construction. Vector function and angiostatic effects were confirmed in vitro and in vivo. Antitumoral efficacies of intratumoral vector injections were studied in a model of subcutaneously transferred HCC model.
Cell supernatants containing PlgK1-4 and PlgK1-5 reduced endothelial tube formation in vitro by about 30%, whereas WtPlg exerted no inhibitory effect. Endothelial cell infiltration in vivo was decreased by about 60%, but not in AdWtPlg-treated animals. Intratumoral treatment of subcutaneous HCC tumours inhibited growth by 40% for AdPlgK1-4 and 63% for AdPlgK1-5 in surviving mice 12 days after initiation of treatment, whereas treatment with AdWtPlg even led to accelerated growth. Although PlgK1-4 and PlgK1-5 have similar inhibitory effects on intratumoral microvessels, PlgK1-5 markedly improved the survival time compared with PlgK1-4.
PlgK1-5 and PlgK1-4 effectively inhibited HCC growth. As PlgK1-5 could also prolong the survival time, inducing complete tumour elimination in half of the AdPlgK1-5-treated mice, PlgK1-5 might be the most potential plasminogen fragment for treatment of experimental HCC.
Gut 03/2007; 56(2):271-8. · 10.11 Impact Factor
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ABSTRACT: High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) plays an important role in the treatment of aggressive non-Hodgkin's lymphoma (NHL). We report on a retrospective analysis of all patients with diffuse large B-cell lymphoma who were consecutively treated with HDT followed by ASCT at the University Hospital of Bonn, Germany, between 1996 and 2004.
A total of 25 patients were transplanted for biopsy-proven diffuse large B-cell lymphoma (DLBCL). Eight patients received up-front HDT as first-line therapy, four patients received HDT due to incomplete response to conventional induction chemotherapy, and six patients were treated for primary refractory disease. Seven patients had recurrent lymphoma.
A complete remission (CR) was achieved in 14 of 25 patients (56%). Estimated 3-year survival for patients treated with upfront HDT, chemosensitive patients with incomplete response to first line therapy, and patients with chemosensitive relapsed disease was 87.5%, 50.0% and 60.0%, respectively. In contrast, no patient with primary refractory disease or relapsed disease lacking chemosensitivity lived longer than 8 months. Chemosensitivity was the only significant prognostic factor for overall survival (OS) in multivariate analysis.
Our results confirm that HDT and ASCT is a highly effective therapy in patients with DLBCL leading to long-term survival in a substantial proportion of patients. Patients treated upfront for high-risk disease, incomplete response to conventional first-line therapy, or for chemosensitive relapse have a good prognosis. In contrast, patients with primary chemorefractory disease and patients with relapsed disease lacking chemosensitivity do not benefit from HDT with ASCT.
German medical science : GMS e-journal 02/2007; 5:Doc02.
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ABSTRACT: The addition of rituximab to chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) has been shown to improve outcome in first-line therapy. However, in patients with relapsed or refractory disease, the value of adding rituximab to salvage chemotherapy is less clearly defined. This study performed a matched-pair analysis of patients with relapsed or refractory DLBCL by comparing the combination of dexamethasone, high-dose cytarabine and cisplatin (DHAP) with rituximab to DHAP alone. Sixty-seven patients with relapsed or refractory DLBCL were collected from two prospective phase II trials from Germany and Italy. Twenty-three patient pairs treated with either DHAP in combination with rituximab or DHAP alone could be analysed after matching for important prognostic factors. The addition of rituximab to the DHAP regimen led to higher complete and similar overall remission rates. However, differences with regard to complete remission rates failed to reach statistical significance, thereby necessitating further evaluation of the role of combined immunochemotherapy in this patient population.
Leukemia and Lymphoma 01/2007; 47(12):2558-66. · 2.58 Impact Factor
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Ulrich J M Mey,
Katjana S Orlopp,
Dimitri Flieger,
John W Strehl,
Anthony D Ho,
Manfred Hensel,
Cordula Bopp,
Marcus Gorschlüter,
Martin Wilhelm,
Josef Birkmann,
Ulrich Kaiser,
Andreas Neubauer,
Axel Florschütz, Christian Rabe,
Corinna Hahn,
Axel G Glasmacher,
Ingo G H Schmidt-Wolf
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ABSTRACT: We designed a multicenter Phase II trial to prospectively evaluate the efficacy and safety of the combination of rituximab with the DHAP regimen (dexamethasone, high-dose cytarabine, cisplatin) in patients who relapsed after or were resistant to a CHOP-like regimen. A total of 53 patients with relapsed or resistant aggressive B-cell NHL were analyzed. The overall response rate was 62.3 percent. With a median follow-up of 24.9 months, median overall and progression-free survivals were 8.5 and 6.7 months, respectively. Immunochemotherapy with rituximab and DHAP proved to be feasible and effective in this patient population.
Cancer Investigation 11/2006; 24(6):593-600. · 1.85 Impact Factor
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ABSTRACT: The induction of liver fibrosis is difficult in mice. Here, we intended to improve fibrosis induction by combination of thioacetamide (TAA) injections and ethanol (EtOH) feeding and to characterize features of liver damage in this model. Most experimental therapeutic studies are performed in mice without pre-damaged livers.
C3H mice were injected three times/week (0.15 mg/g body weight) and fed with EtOH. Tissue and serum samples were collected and analysed.
Portal fibrosis was verified by van Gieson staining showing a mild fibrosis (score F2) in TAA-treated mice and liver fibrosis (score F4) in the combination group using TAA/EtOH. Consonant with the histological results, the fibrosis marker MMP-2 and alpha 1 procollagen (I) were elevated at week 10 and 15 after treatment initiation in the combination group, whereas tissue protective proteinase, TIMP-1, was 18.5-fold increased only at week 10 but normalized until week 15. Fibrosis development was associated with elevated ICAM-1 expression.
Taken together, TAA/EtOH application was suitable to induce liver fibrosis characterized by typical bio-markers in C3H/He.
Journal of Hepatology 10/2006; 45(3):370-6. · 9.26 Impact Factor
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Nephrology Dialysis Transplantation 03/2006; 21(2):526-9. · 3.40 Impact Factor
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ABSTRACT: Neutropenic enterocolitis is a life-threatening complication most frequently occurring after intensive chemotherapy in acute leukaemias. Gramnegative bacteria constitute the most important group of causative pathogens. Fungi have also been reported, but their practical relevance remains unclear. The guidelines do not address concrete treatment recommendations for fungal neutropenic enterocolitis.
Here, we conducted a metaanalysis to answer the questions: What are frequency and mortality of fungal neutropenic enterocolitis? Do frequencies and microbiological distribution of causative fungi support empirical antimycotic therapy? Do reported results of antimycotic therapy in documented fungal neutropenic enterocolitis help with the selection of appropriate drugs? Following a systematic search, we extracted and summarised all detail data from the complete literature.
Among 186 articles describing patients with neutropenic enterocolitis, we found 29 reports describing 53 patients with causative fungal pathogens. We found no randomised controlled trial, no good quality cohort study and no good quality case control study on the role of antifungal treatment. The pooled frequency of fungal neutropenic enterocolitis was 6.2% calculated from all 860 reported patients and 3.4% calculated from selected representative studies only. In 94% of the patients, Candida spp. were involved. The pooled mortality rate was 81.8%. Most authors did not report or perform antifungal therapy.
In patients with neutropenic enterocolitis, fungal pathogens play a relevant, but secondary role compared to bacteria. Evidence concerning therapy is very poor, but epidemiological data from this study may provide helpful clues to select empiric antifungal therapy in neutropenic enterocolitis.
BMC Infectious Diseases 02/2006; 6:35. · 3.12 Impact Factor
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ABSTRACT: Pseudomembranous and obstructive Aspergillus tracheobronchitis (PMATB/OATB) are still considered to be refractory to therapy and to have a fatal outcome. To evaluate the optimal diagnostic strategy and to describe factors affecting the outcome of PMATB and OATB. Retrospective analysis of four new cases of PMATB and OATB combined with 16 previously reported cases over a 10-year period (1995-2004). Among the four new cases reported and the 16 published cases, four patients survived their infection. The mortality rate was significantly higher in the group of ventilated patients [94% (15 of 16 patients)] than in the group of non-ventilated patients [25% (1 of 4 patients), P < 0.05, Fisher's exact test]. In all 20 patients, diagnosis was established by bronchoscopy. Culture examination of mucous plugs was positive in 8 of 10, culture of the tracheobronchial aspirate was positive in 8 of 12, and bronchoalveolar lavage was diagnostic in 7 of 13 patients. All bronchoscopic techniques were complementary in improving the yield of bronchoscopy. However, microscopy of mucous plugs and/or necrotic material was the best diagnostic modality [positive in 94% (17 of 18 patients)]. Prognosis of PMATB and OATB remains poor. Microscopy of respiratory specimens is the most sensitive tool to confirm the diagnosis. The characteristic appearance of the disease makes it possible to start antifungal therapy immediately.
Mycoses 02/2006; 49(1):37-42. · 2.25 Impact Factor
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ABSTRACT: We applied an experimental approach employing two recombinant adenoviral vectors (Ad) that express interleukin-12 (IL-12) and angiostatin-like molecule (K1-3) respectively to a subcutaneous hepatoma model in mice.
Injection of AdK1-3 into tumour nodules established by subcutaneous (s.c.) implantation of Hepa129 hepatoma cells in C3H mice resulted in a significant dose-dependent reduction in tumour growth by 57% in the high dosage group (5x10(9) plaque-forming units [pfu], n=8) 10 days after treatment initiation. Similar antitumoural effects were found for the intratumoural mono-therapy with IL-12 (2.5x10(9) pfu, n=8) resulting in 60% tumour inhibition at the same time point. The survival rate was significantly (p=0.009) improved in the IL-12 but not in the K1-3 treatment group. A combination therapy of AdK1-3 and AdIL-12 was also effective, but did not further improve antitumour efficacy compared with the monotherapy.
In conclusion, both mono- and combination therapy of K1-3 and IL-12 significantly inhibited tumour progression in this experimental tumour model. The co-administration of both compounds did not result in additive antitumour effects. We hypothesise that the lack of additive antitumour effects of the combination treatment might be attributed to partially counteracting antitumour effects and further studies are needed to illustrate the interference of tumour angiogenesis and tumour inflammation in this tumour model.
International Journal of Colorectal Disease 12/2005; 20(6):494-501. · 2.38 Impact Factor
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Liver Transplantation 09/2005; 11(8):990-2. · 3.39 Impact Factor
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ABSTRACT: Tumor angiogenesis has been shown to be promoted by vascular endothelial growth factor (VEGF) via stimulating endothelial cell proliferation, migration, and survival. Blockade of VEGF signaling by different means has been demonstrated to result in reduced tumor growth and suppression of tumor angiogenesis in distinct tumor entities. Here, we tested a recombinant adenovirus, AdsFlt1-3, that encodes an antagonistically acting fragment of the VEGF receptor 1 (Flt-1), for systemic antitumor effects in pre-established subcutaneous CRC tumors in mice.
Murine colorectal carcinoma cells (CT26) were inoculated subcutaneously into Balb/c mice for in vivo studies. Tumor size and survival were determined. 293 cell line was used for propagation of the adenoviral vectors. Human lung cancer line A549 and human umbilical vein endothelial cells were transfected for in vitro experiments.
Infection of tumor cells with AdsFlt1-3 resulted in protein secretion into cell supernatant, demonstrating correct vector function. As expected, the secreted sFlt1-3 protein had no direct effect on CT26 tumor cell proliferation in vitro, but endothelial cell function was inhibited by about 46% as compared to the AdLacZ control in a tube formation assay. When AdsFlt1-3 (5 x 10(9) PFU/animal) was applied to tumor bearing mice, we found a tumor inhibition by 72% at d 12 after treatment initiation. In spite of these antitumoral effects, the survival time was not improved. According to reduced intratumoral microvessel density in AdsFlt1-3-treated mice, the antitumor mechanism can be attributed to angiostatic vector effects. We did not detect increased systemic VEGF levels after AdsFlt1-3 treatment and liver toxicity was low as judged by serum alanine aminotransferase determination.
In this study we confirmed the value of a systemic administration of AdsFlt1-3 to block VEGF signaling as antitumor therapy in an experimental metastatic colorectal carcinoma model in mice.
World Journal of Gastroenterology 08/2005; 11(28):4332-6. · 2.47 Impact Factor
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Esther Raskopf,
Christian Dzienisowicz,
Tobias Hilbert, Christian Rabe,
Ludger Leifeld,
Nicolas Wernert,
Tilman Sauerbruch,
Jesús Prieto,
Cheng Qian,
Wolfgang H Caselmann,
Volker Schmitz
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ABSTRACT: Vascular endothelial growth factor (VEGF) activity is correlated with a progressive tumor disease in patients with hepatocellular carcinoma (HCC). In spite of the well-recognized role of VEGF in HCC, there are few data available regarding therapeutic strategies to block VEGF activity. Therefore, we employed a recombinant adenoviral vector encoding a soluble dominant negative fragment of VEGF receptor 2 (Flk-1), AdsFlk-1, to control pre-established murine orthotopic and metastatic hepatomas. Vector function was confirmed via reverse-transcriptase polymerase chain reaction and ELISA, and angiostatic effects were analyzed in vitro and in vivo. Antitumoral effects of systemic AdsFlk-1 application were studied in a subcutaneous and orthotopic Hepa129 HCC model. Cell supernatant containing the truncated form of Flk-1 had no direct effect on cell proliferation of Hepa129 cells in vitro but reduced endothelial tube formation on matrigel matrix by approximately 80% in vitro. Endothelial-like cell infiltration into matrigel plugs in vivo was also decreased by 80%. Systemic treatment of tumor-bearing mice inhibited tumor growth by 84% compared with the corresponding control group within 16 days after vector application. Likewise, the survival rate was significantly improved in the AdsFlk-1 group compared with control. Orthotopic tumor growth was reduced by 82%, and development of malignant ascites was also retarded. In conclusion, systemic adenoviral-mediated gene transfer of an Flk-1 fragment significantly inhibited tumor growth in orthotopic and metastatic murine HCC. The data support the value of VEGF blockade as an effective target for HCC treatment.
Hepatology 07/2005; 41(6):1233-40. · 11.66 Impact Factor
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ABSTRACT: Complicated parapneumonic effusions (PPE) and pleural empyemas (PE) are associated with increased morbidity and mortality. Intrapleural fibrinolytic therapy (IFT) has been established, besides video-assisted thoracoscopy (VATS), in the management of PPE and PE. Combination of IFT and small-bore catheter drainage has previously not been investigated.
15 patients consecutively referred for PPE and PE were managed with simultaneous IFT via small-bore catheter drainage (9, 12, 14 F). In addition to evaluation of primary outcome, lung function testing and radiologic studies were obtained after 3 months to predict potential pulmonary restrictive impairment and residual pleural thickening.
Primary outcome of all 15 patients was positive. Only one patient showed a significant residual pleural thickening. None of the patients showed a restrictive lung function pattern.
Proven applicability of IFT via small-bore catheter drainage seems to be effective in the face of long-term outcome. Further prospective and multicentric studies should be initiated to investigate the practicability of IFT via small-bore catheter drainage.
Medizinische Klinik 05/2005; 100(4):181-5. · 0.34 Impact Factor
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ABSTRACT: Hintergrund und Ziel:
Komplizierte parapneumonische Pleuraergsse (PPE) und Pleuraempyeme (PE) sind mit einer erhhten Morbiditt und Mortalitt assoziiert. Die intrapleurale Fibrinolytikatherapie (IFT) hat sich neben der videoassistierten Thorakoskopie (VATS) als Therapieoption etabliert. Inwieweit kleinlumige Drainagen in Kombination mit einer IFT ber den akuten Krankheitsverlauf hinaus auch im Langzeitverlauf ohne relevante funktionelle Einschrnkungen anwendbar sind, war Gegenstand der Untersuchung.
Patienten und Methodik:
In einer prospektiven Untersuchung wurden 15 konsekutive Flle komplizierter PPE und PE mittels IFT ber kleinlumige Drainagen (9, 12, 14 F) behandelt. Neben dem unmittelbaren Therapieerfolg wurden im Langzeitverlauf (3 Monate) funktionelle und morphologische Vernderungen mittels Bildgebung und Lungenfunktionsuntersuchungen beurteilt.
Ergebnisse:
In allen 15 Fllen konnte die Akutbehandlung erfolgreich abgeschlossen werden. Im Langzeitverlauf wies lediglich eine Patientin eine relevante residuelle pleurale Verdickung auf; in keinem Fall zeigte sich eine restriktive Ventilationsstrung oder eine respiratorische Insuffizienz.
Schlussfolgerung:
Die durch vielfltige Studien belegte Anwendbarkeit der IFT ber kleinlumige Drainagen in der Akutbehandlung von komplizierten PPE und PE erscheint auch im Hinblick auf den Langzeitverlauf besttigt. Multizentrische, kontrollierte Studien zur Anwendung der IFT ber kleinlumige Drainagen sollten initiiert werden.
Background and Purpose:
Complicated parapneumonic effusions (PPE) and pleural empyemas (PE) are associated with increased morbidity and mortality. Intrapleural fibrinolytic therapy (IFT) has been established, besides video-assisted thoracoscopy (VATS), in the management of PPE and PE. Combination of IFT and small-bore catheter drainage has previously not been investigated.
Patients and Methods:
15 patients consecutively referred for PPE and PE were managed with simultaneous IFT via small-bore catheter drainage (9, 12, 14 F). In addition to evaluation of primary outcome, lung function testing and radiologic studies were obtained after 3 months to predict potential pulmonary restrictive impairment and residual pleural thickening.
Results:
Primary outcome of all 15 patients was positive. Only one patient showed a significant residual pleural thickening. None of the patients showed a restrictive lung function pattern.
Conclusion:
Proven applicability of IFT via small-bore catheter drainage seems to be effective in the face of long-term outcome. Further prospective and multicentric studies should be initiated to investigate the practicability of IFT via small-bore catheter drainage.
03/2005; 100(4):181-185.
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ABSTRACT: Hepatocellular carcinomas (HCC) often show resistance to the effects of transforming growth factor-beta (TGF-beta). This study focuses on molecular mechanisms of this resistance to explore ways to overcome it.
Transcription and protein expression of TGF-beta type I and type II receptors (TGF-betaRI/RII) were analyzed in clinical HCCs and the human hepatoma cell lines HuH-7 and HepG2. HuH-7 cells were transiently and stably transfected with a constitutively active TGF-betaRI mutant (CA TGF-betaRI). Resulting growth kinetics, integrin expression, invasiveness, TGF-beta-mediated activation of human plasminogen activator inhibitor type-1 (PAI-1) promoter and Smad expression were determined.
In clinical HCCs, there was less TGF-betaRII (6/10 cases) and more TGF-betaRI (8/10 cases) protein expression detectable in tumor compared to adjacent liver tissue. In HuH-7 cells, TGF-betaRII expression was likewise decreased. Cells transiently transfected with CA TGF-betaRI exhibited strong TGF-beta-related PAI-1 promoter activation. Stably transfected cells showed an attenuated response of the PAI-1 promoter, but increased Smad7 expression. Proliferation of stable clones was decreased. There was no change in integrin expression or invasiveness.
Decreased TGF-betaRII protein expression might cause TGF-beta resistance in a subset of clinical HCCs. Stable transfection with CA TGF-betaRI reverses this in HuH-7 cells without increasing invasiveness.
Digestion 02/2005; 71(2):78-91. · 2.05 Impact Factor
