7 results on '"Holdenrieder, Stefan"'
Search Results
2. A liposomal formulation of the synthetic curcumin analog EF24 (Lipo-EF24) inhibits pancreatic cancer progression: towards future combination therapies.
- Author
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Bisht, Savita, Schlesinger, Martin, Rupp, Alexander, Schubert, Rolf, Nolting, Jens, Wenzel, Jörg, Holdenrieder, Stefan, Brossart, Peter, Bendas, Gerd, and Feldmann, Georg
- Subjects
CURCUMIN ,RISK factors of pancreatic cancer ,PIPERIDONES ,LIPOSOMES ,CANCER cells ,CANCER treatment - Abstract
Background: Pancreatic cancer is one of the most lethal of human malignancies known to date and shows relative insensitivity towards most of the clinically available therapy regimens. 3,5-bis(2-fluorobenzylidene)-4-piperidone (EF24), a novel synthetic curcumin analog, has shown promising in vitro therapeutic efficacy in various human cancer cells, but insufficient water solubility and systemic bioavailability limit its clinical application. Here, we describe nanoencapsulation of EF24 into pegylated liposomes (Lipo-EF24) and evaluation of these particles in preclinical in vitro and in vivo model systems of pancreatic cancer. Results: Transmission electron microscopy and size distribution studies by dynamic light scattering confirmed intact spherical morphology of the formed liposomes with an average diameter of less than 150 nm. In vitro, treatment with Lipo-EF24 induced growth inhibition and apoptosis in MIAPaCa and Pa03C pancreatic cancer cells as assessed by using cell viability and proliferation assays, replating and soft agar clonogenicity assays as well as western blot analyses. Lipo-EF24 potently suppressed NF-kappaB nuclear translocation by inhibiting phosphorylation and subsequent degradation of its inhibitor I-kappa-B-alpha. In vivo, synergistic tumor growth inhibition was observed in MIAPaCa xenografts when Lipo-EF24 was given in combination with the standard-of-care cytotoxic agent gemcitabine. In line with in vitro observations, western blot analysis revealed decreased phosphorylation of I-kappa-B-alpha in excised Lipo-EF24-treated xenograft tumor tissues. Conclusion: Due to its promising therapeutic efficacy and favorable toxicity profile Lipo-EF24 might be a promising starting point for development of future combinatorial therapeutic regimens against pancreatic cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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3. Individualized versus standardized risk assessment in patients at high risk for adverse drug reactions (IDrug) - study protocol for a pragmatic randomized controlled trial.
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Stingl, Julia Carolin, Kaumanns, Katharina Luise, Claus, Katrin, Lehmann, Marie-Louise, Kastenmüller, Kathrin, Bleckwenn, Markus, Hartmann, Gunther, Steffens, Michael, Wirtz, Dorothee, Leuchs, Ann-Kristin, Benda, Norbert, Meier, Florian, Schöffski, Oliver, Holdenrieder, Stefan, Coch, Christoph, and Weckbecker, Klaus
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THROMBOEMBOLISM risk factors ,HEMORRHAGE risk factors ,DRUG therapy ,WARFARIN ,DRUG side effects ,CONFIDENCE intervals ,DISEASES ,DRUG labeling ,CLINICAL drug trials ,FAMILY medicine ,PATIENT aftercare ,KIDNEY diseases ,MEDICAL needs assessment ,RESEARCH protocols ,PATIENT education ,PHARMACOLOGY ,RISK assessment ,EVIDENCE-based medicine ,DATA analysis ,RANDOMIZED controlled trials ,POLYPHARMACY - Abstract
Background: Elderly patients are particularly vulnerable to adverse drug reactions, especially if they are affected by additional risk factors such as multimorbidity, polypharmacy, impaired renal function and intake of drugs with high risk potential. Apart from these clinical parameters, drug safety and efficacy can be influenced by pharmacogenetic factors. Evidence-based recommendations concerning drug-gene-combinations have been issued by international consortia and in drug labels. However, clinical benefit of providing information on individual patient factors in a comprehensive risk assessment aiming to reduce the occurrence and severity of adverse drug reactions is not evident. Purpose of this randomized controlled trial is to compare the effect of a concise individual risk information leaflet with standard information on risk factors for side effects. Methods/Design: The trial was designed as a prospective, two-arm, randomized, controlled, multicenter, pragmatic study. 960 elderly, multimorbid outpatients in general medicine are included if they take at least one high risk and one other long-term drug (polymedication). As high risk "index drugs" oral anticoagulants and antiplatelets were chosen because of their specific, objectively assessable side effects. Following randomization, test group patients receive an individualized risk assessment leaflet evaluating their personal data concerning bleeding- and thromboembolic-risk-scores, potential drug-drug-interactions, age, renal function and pharmacogenetic factors. Control group patients obtain a standardized leaflet only containing general information on these criteria. Follow-up period is 9 months for each patient. Primary endpoint is the occurrence of a thromboembolic/bleeding event or death. Secondary endpoints are other adverse drug reactions, hospital admissions, specialist referrals and medication changes due to adverse drug reactions, the patients' adherence to medication regimen as well as health related quality of life, mortality and resulting costs. Discussion: Despite extensive evidence of risk factors for adverse drug reactions, there are few prospective trial data about an individualized risk assessment including pharmacogenetic information to increase patient safety. By conducting a health economic analysis, we will evaluate if the application of an individualized drug therapy in daily routine is cost-effective. [ABSTRACT FROM AUTHOR]
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- 2016
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4. Immune- and miRNA-response to recombinant interferon beta-1a: a biomarker evaluation study to guide the development of novel type I interferon- based therapies.
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Coenen, Martin, Hinze, Annette Viktoria, Mengel, Martin, Fuhrmann, Christine, Lüdenbach, Bastian, Zimmermann, Julian, Dykstra, Verena, Fimmers, Rolf, Viviani, Roberto, Stingl, Julia, Holdenrieder, Stefan, Müller, Marcus, Hartmann, Gunther, and Coch, Christoph
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MICRORNA ,IMMUNE response ,INTERFERON beta-1a ,BIOMARKERS ,TYPE I interferons ,TUMOR growth ,ANTIVIRAL agents - Abstract
Background: The innate immune receptor RIG-I detects viral RNA within the cytosol of infected cells. Activation of RIG-I leads to the induction of antiviral cytokines, in particular type I interferon, the inhibition of a T(H)17 response as well as to the suppression of tumor growth. Therefore, RIG-I is a promising drug target for the treatment of cancer as well as multiple sclerosis. A specific ligand for RIG-I is currently in preclinical testing. The first-in-human trial will need to be carefully designed to avoid an overshooting cytokine response. Therefore, the ResI study was set up to analyze the human immune response to standard treatment with recombinant interferon-beta to establish biomarkers for safety and efficacy of the upcoming first-in-human trial investigating the RIG-I ligand. Methods/Design: ResI is a single center, prospective, open label, non-randomized phase I clinical trial. Three different cohorts (20 healthy volunteers, 20 patients with RRMS and ongoing interferon-beta treatment and 10 patients starting on interferon-beta) will receive standard interferon-beta-1a therapy for nine days. The study will be conducted according to the principles of the german medicinal products act, ICH-GCP, and the Declaration of Helsinki on the phase I unit of the Institute of Clinical Chemistry and Clinical Pharmacology and in the Department of Neurology, both University Hospital Bonn. Interferon-beta-induced cytokine levels, surface marker on immune cells, mRNA- and miRNA-expression as well as psychometric response will be investigated as target variables. Discussion: The ResI study will assess biomarkers in response to interferon-β treatment to guide the dose steps within the first-in-human trial with a newly developed RIG-I ligand. Thus, ResI is a biomarker study to enhance the safety of the clinical development of a first-in-class compound. The data can additionally be used for the development of other therapies based on type I interferon induction such as TLR ligands. Moreover, it will help to understand the interferon-beta induced immune response in a controlled in vivo setting in the human system. [ABSTRACT FROM AUTHOR]
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- 2015
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5. Relevance of circulating nucleosomes and oncological biomarkers for predicting response to transarterial chemoembolization therapy in liver cancer patients.
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Kohles, Nikolaus, Nagel, Dorothea, Jüngst, Dietrich, Durner, Jürgen, Stieber, Petra, and Holdenrieder, Stefan
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BIOMARKERS ,ONCOLOGY ,LIVER cancer ,ALPHA fetoproteins ,C-reactive protein - Abstract
Background: Transarterial chemoembolization (TACE) therapy is an effective locoregional treatment in hepatocellular cancer (HCC) patients. For early modification of therapy, markers predicting therapy response are urgently required. Methods: Here, sera of 50 prospectively and consecutively included HCC patients undergoing 71 TACE therapies were taken before and 3 h, 6 h and 24 h after TACE application to analyze concentrations of circulating nucleosomes, cytokeratin-19 fragments (CYFRA 21-1), alpha fetoprotein (AFP), C-reactive protein (CRP) and several liver biomarkers, and to compare these with radiological response to therapy. Results: While nucleosomes, CYFRA 21-1, CRP and some liver biomarkers increased already 24 h after TACE, percental changes of nucleosome concentrations before and 24 h after TACE and pre- and posttherapeutic values of AFP, gamma-glutamyl-transferase (GGT) and alkaline phosphatase (AP) significantly indicated the later therapy response (39 progression versus 32 no progression). In multivariate analysis, nucleosomes (24 h), AP (24 h) and TACE number were independent predictive markers. The risk score of this combination model achieved an AUC of 81.8% in receiver operating characteristic (ROC) curves and a sensitivity for prediction of non-response to therapy of 41% at 97% specificity, and of 72% at 78% specificity. Conclusion: Circulating nucleosomes and liver markers are valuable tools for early estimation of the efficacy of TACE therapy in HCC patients. [ABSTRACT FROM AUTHOR]
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- 2011
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6. Early prediction of therapy response in patients with acute myeloid leukemia by nucleosomal DNA fragments.
- Author
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Mueller, Susanne, Holdenrieder, Stefan, Stieber, Petra, Haferlach, Torsten, Schalhorn, Andreas, Braess, Jan, Nagel, Dorothea, and Seidel, Dietrich
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MYELOID leukemia , *DNA , *TUMORS , *ONCOLOGY , *CANCER - Abstract
Background: Elevated levels of nucleosomal DNA fragments can be detected in plasma and sera of patients with malignant diseases. Methods: We investigated the course of nucleosomal DNA, thymidine kinase, lactate dehydrogenase and leukocytes in sera of 25 patients with acute myeloid leukemia during the first cycle of induction chemotherapy and tested their power to distinguish between patients with complete remission and those with no remission. Results: Almost all patients showed strongly decreasing levels of nucleosomal DNA during the first week, in some cases after initial peaks. In overall analysis of variance, DNA levels could clearly distinguish between patients with complete remission, who had higher DNA values, and those with insufficient response (p = 0.017). The area under the curve of DNA values of days 2-4 after start of therapy (AUC 2-4) discriminated between both groups with a sensitivity of 56% at a specificity of 100%. Further, pretherapeutic levels and AUC 2-4 of nucleosomal DNA correlated significantly with blast reduction after 16 days. A tendency to higher levels in patients with complete response was also found for thymidine kinase, lactate dehydrogenase and leukocytes, however the difference did not reach the level of significance (p = 0.542, p = 0.260, and p = 0.144, respectively). Conclusion: Our results indicate that nucleosomal DNA fragments are valuable markers for the early prediction of therapeutic efficacy in patients with acute myeloid leukemia. [ABSTRACT FROM AUTHOR]
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- 2006
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7. SMAD4 Y353C promotes the progression of PDAC.
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Wang, Zusen, Li, Yongxing, Zhan, Shixiong, Zhang, Lu, Zhang, Shun, Tang, Qian, Li, Miaomiao, Tan, Zhen, Liu, Shiguo, and Xing, Xiaoming
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MISSENSE mutation ,CELL migration ,CELL proliferation ,SEQUENCE analysis ,LYMPH nodes ,LYMPHATIC metastasis - Abstract
Background: SMAD4 is frequently inactivated and associated with a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Abnormal SMAD4 expression also plays an important role in the malignant progression of PDAC.Methods: We investigated SMAD4 status in PDAC by immunohistochemical methods to explore the relationships between SMAD4 expression and clinicopathological features and then detected SMAD4 mutations by Sanger sequencing in 95 patients with PDAC to identify new mutation sites in PDAC. We further evaluated the effects of a missense mutation, Y353C, in the SMAD4 MH2 domain, on cell proliferation and migration in vitro.Results: Immunohistochemistry showed that the expression of SMAD4 in PDAC carcinoma tissue was significantly lower than that in normal pancreatic tissue, and negative SMAD4 expression was closely related to tumour diameter, staging, lymph node metastasis and differentiation. Sanger sequencing analysis showed that the rate of SMAD4 mutation was 11.8% in 85 PDAC cases, and the novel SMAD4 Y353C missense mutation identified in this study promoted cell migration and invasion without affecting cell proliferation in vitro. Furthermore, SMAD4 Y353C resulted in reduced expression of E-cadherin and increased expression of Vimentin compared with wild-type SMAD4 overexpression.Conclusion: This study supports the key role of SMAD4 as a tumour suppressor gene in PDAC and shows that SMAD4 Y353C is associated with poor progression of PDAC. [ABSTRACT FROM AUTHOR]- Published
- 2019
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