University Childrens Hospital Jena

Jena, Germany

University Childrens Hospital Jena

Jena, Germany

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Dubose S.N.,Jaeb Center for Health Research | Hermann J.M.,University of Ulm | Tamborlane W.V.,Yale University | Beck R.W.,Jaeb Center for Health Research | And 6 more authors.
Journal of Pediatrics | Year: 2015

Objective To examine the current extent of the obesity problem in 2 large pediatric clinical registries in the US and Europe and to examine the hypotheses that increased body mass index (BMI) z-scores (BMIz) are associated with greater hemoglobin A1c (HbA1c) and increased frequency of severe hypoglycemia in youth with type 1 diabetes (T1D). Study design International (World Health Organization) and national (Centers for Disease Control and Prevention/German Health Interview and Examination Survey for Children and Adolescents) BMI references were used to calculate BMIz in participants (age 2-<18 years and ≥1 year duration of T1D) enrolled in the T1D Exchange (n = 11 435) and the Diabetes Prospective Follow-up (n = 21 501). Associations between BMIz and HbA1c and severe hypoglycemia were assessed. Results Participants in both registries had median BMI values that were greater than international and their respective national reference values. BMIz was significantly greater in the T1D Exchange vs the Diabetes Prospective Follow-up (P <.001). After stratification by age-group, no differences in BMI between registries existed for children 2-5 years, but differences were confirmed for 6- to 9-, 10- to 13-, and 14- to 17-year age groups (all P <.001). Greater BMIz were significantly related to greater HbA1c levels and more frequent occurrence of severe hypoglycemia across the registries, although these associations may not be clinically relevant. Conclusions Excessive weight is a common problem in children with T1D in Germany and Austria and, especially, in the US. Our data suggest that obesity contributes to the challenges in achieving optimal glycemic control in children and adolescents with T1D. © 2015 Elsevier Inc.


Sonnemann J.,University Childrens Hospital Jena | Sonnemann J.,Friedrich - Schiller University of Jena | Palani C.D.,University Childrens Hospital Jena | Wittig S.,University Childrens Hospital Jena | And 4 more authors.
European Journal of Cancer | Year: 2011

Mutation of p53 is rare in Ewing's sarcoma (ES), suggesting that targeting and activation of wild-type p53 may be an effective therapeutic strategy for ES. The recently developed small-molecule MDM2 inhibitor nutlin-3 restores wild-type p53 function, resulting in the inhibition of cancer cell growth and the induction of apoptosis. In the present study, we explored the responsiveness of ES cell lines with wild-type or mutated p53 to nutlin-3. We found that treatment with nutlin-3 increased p53 level and induced p53 target gene expression (MDM2, p21, PUMA) in ES cells with wild-type p53, but not in ES cells with mutated p53. Consistently, nutlin-3 elicited apoptosis only in wild-type p53 cells, as assessed by caspase-3 activity assay and flow cytometric analyses of mitochondrial depolarisation and DNA fragmentation. In addition, we found nutlin-3 to evoke cellular senescence, indicating that nutlin-3 induces pleiotropic anticancer effects in ES. Furthermore, combined treatment with nutlin-3 and an inhibitor of NF-κB produced synergistic antineoplastic activity in ES cells. Our findings suggest that the direct activation of p53 by nutlin-3 treatment may be a useful new therapeutic approach for patients with ES. © 2011 Elsevier Ltd. All rights reserved.


Buscher A.K.,University of Duisburg - Essen | Kranz B.,University of Munster | Buscher R.,University of Duisburg - Essen | Hildebrandt F.,Howard Hughes Medical Institute | And 10 more authors.
Clinical Journal of the American Society of Nephrology | Year: 2010

Background and objectives: Mutations in podocyte genes are associated with steroid-resistant nephrotic syndrome (SRNS), mostly affecting younger age groups. To date, it is unclear whether these patients benefit from intensified immunosuppression with cyclosporine A (CsA). The aim of this study was to evaluate the influence of podocyte gene defects in congenital nephrotic syndrome (CNS) and pediatric SRNS on the efficacy of CsA therapy and preservation of renal function. Design, settings, participants, & measurements: Genotyping was performed in 91 CNS/SRNS patients, irrespective of age at manifestation or response to CsA. Results: Mutations were identified in 52% of families (11 NPHS1, 17 NPHS2, 11 WT1, 1 LAMB2, 3 TRPC6). Sixty-eight percent of patients with nongenetic SRNS responded to CsA, most of them achieved complete remission. In contrast, none of the patients with genetic CNS/SRNS experienced a complete remission and only two (17%) achieved a partial response, both affected by a WT1 mutation. Preservation of renal function was significantly better in children with nongenetic disease after a mean follow-up time of 8.6 years (ESRD in 29% versus 71%). Conclusions: The mutation detection rate in our population was high (52%). Most patients with genetic CNS/SRNS did not benefit from CsA with significantly lower response rates compared with nongenetic patients and showed rapid progression to end-stage renal failure. These data strongly support the idea not to expose CNS/SRNS patients with inherited defects related to podocyte function to intensified immunosuppression with CsA. Copyright © 2010 by the American Society of Nephrology.


Palani C.D.,University Childrens Hospital Jena | Beck J.F.,University Childrens Hospital Jena | Sonnemann J.,University Childrens Hospital Jena | Sonnemann J.,Friedrich - Schiller University of Jena
Investigational New Drugs | Year: 2012

Nutlin-3, a small-molecule MDM2 inhibitor, restores p53 function and is, thus, an appealing candidate for the treatment of cancers retaining wild-type p53. However, nutlin-3 applied as single agent may be insufficient for cancer therapy. Therefore, we explored whether the anticancer activity of nutlin-3 could be enhanced by combination with histone deacetylase inhibitors (HDACi), i.e. vorinostat, sodium butyrate, MS-275 and apicidin. We found that nutlin-3 and HDACi cooperated to induce cell death in the p53 wild-type cell lines A549 and A2780, but not in the p53 null cell line PC-3, as assessed by Alamar Blue assay and flow cytometric analyses of propidium iodide uptake and mitochondrial depolarization. Combination index analysis showed that the effect was synergistic. For comparison, we tested nutlin-3 in combination with paclitaxel, revealing that nutlin-3 antagonized the cytotoxic activity of paclitaxel. To shed light on the underlying mechanism of the synergistic action of nutlin-3 and HDACi, we determined the acetylation status of p53 by immunoblotting and the mRNA levels of MDM2 and MDM4 by real-time RT-PCR. We observed vorinostat to induce p53 hyperacetylation, to reduce the constitutive gene expression of MDM2 and MDM4, and to counteract the nutlin-3-induced upregulation of MDM2 gene expression. In conclusion, our study shows that HDACi amplify the antitumor activity of nutlin-3-possibly by inducing p53 hyperacetylation and/or MDM2 and/or MDM4 downregulation- suggesting that treatment with a combination of nutlin- 3 and HDACi may be an effective strategy for treating tumors with wild-type p53. © Springer Science+Business Media, LLC 2010.


Sonnemann J.,University Childrens Hospital Jena | Sonnemann J.,Friedrich - Schiller University of Jena | Gressmann S.,University Childrens Hospital Jena | Becker S.,University Childrens Hospital Jena | And 3 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2010

Purpose: It has recently been recognised that anticancer chemotherapy can elicit an immunogenic form of apoptosis characterised by the exposure of calreticulin (CRT) on the surface of dying tumour cells, entailing an immune response that contributes to the therapeutic outcome. CRT exposure has been found to be induced by anthracyclins and oxaliplatin, but not by other proapoptotic antineoplastic agents including etoposide, camptothecin and cisplatin. In this study, we examined the histone deacetylase inhibitor vorinostat for its capability to stimulate CRT exposure in tumour cells. Methods: Childhood tumour cells, i.e. the brain tumour cell lines PFSK and DAOY and the Ewing's sarcoma cell line CADO-ES-1, were treated with vorinostat, and CRT exposure was determined by flow cytometric analysis of CRT immunofluorescence. Combination effects of vorino-stat/TRAIL and vorinostat/bortezomib were also assessed. Results: Vorinostat treatment induced CRT exposure in PFSK and DAOY cells, but not in caspase-8-deficient CADO-ES-1 cells. CRT exposure could be prevented by the pan-caspase inhibitor z-VAD-fmk and by brefeldin A, an inhibitor of Golgi-mediated transport. Conclusion: Vorinostat has the capacity to elicit CRT exposure, suggesting its usefulness as immunogenic antitu-mour agent. © Springer-Verlag 2010.


Wolf G.,University of Greifswald | Aumann N.,University of Greifswald | Michalska M.,University of Greifswald | Bast A.,University of Greifswald | And 5 more authors.
Journal of Endocrinology | Year: 2010

Type 1 diabetes mellitus is characterized by a progressive autoimmune destruction of insulin-producing β cells. Macrophages and T lymphocytes release cytokines, which induce the synthesis of oxygen and nitrogen radicals in the pancreatic islets. The resulting cellular and mitochondrial damage promotes β cell death. β cells are very sensitive to the autoimmune free radical-dependent attack due to their low content of antioxidant enzymes such as glutathione peroxidase and catalase. A focal point of β cell protection should be the control of the mitochondrial redox status, which will result in the preservation of metabolic stimulus-secretion coupling. For this reason, there is a considerable interest in the mitochondrial peroxiredoxin III (PRX III), a thioredoxin-dependent peroxide reductase, which was shown to be able to protect against both oxidative and nitrosative stress. Using the Tet-On-system, we generated stably transfected rat insulinoma cells over- or under-expressing PRX III in a doxycyclin-dependent manner to analyze the effect of increased or decreased amounts of cellular PRX III, following treatment with several stressors. We provide evidence that PRX III protects pancreatic β cells from cell stress induced by accumulation of hydrogen peroxide, or the induction of inducible nitric oxide synthase or caspase-9 and -3 by pro-inflammatory cytokines or streptozotocin. Basal insulin secretion was markedly decreased in cells expressing lower levels of PRX III. We suggest PRX III may be a suitable target for promoting deceleration or even prevention of stress-associated apoptosis in pancreatic β cells and the manifestation of insulin-dependent diabetes mellitus. © 2010 Society for Endocrinology.


Schmudde M.,University of Greifswald | Friebe E.,University of Greifswald | Sonnemann J.,University Childrens Hospital Jena | Beck J.F.,University Childrens Hospital Jena | Broker B.M.,University of Greifswald
Cancer Letters | Year: 2010

Histone deacetylase inhibitors (HDIs) exert direct tumour-toxic activity and sensitise tumour cells for other therapeutic regimens as well as the cytotoxic effects of activated immune cells. However, the HDI suberoylanilide hydroxamic acid (SAHA; vorinostat) interfered with the IL-2 activation of human NK cells and the priming of human tumour-specific T cells. In contrast, NK or T cells which were activated in the absence of HDIs became resistant to their immunosuppressive action. Therefore, as a therapeutic strategy, first the patient's immune system might be stimulated and then HDIs could sensitise the tumours for the attack of the pre-activated immune effector cells. © 2010 Elsevier Ireland Ltd.


Kurtze I.,University Childrens Hospital Jena | Sonnemann J.,University Childrens Hospital Jena | Beck J.F.,University Childrens Hospital Jena
Oncology Reports | Year: 2011

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib provide significant clinical benefit for non-small cell lung cancer (NSCLC) patients whose tumors bear EGFR mutations/amplifications. However, anti-EGFR therapy is largely ineffective in NSCLC with activating KRAS mutations. In this study, we investigated the treatment efficacy of erlotinib and gefitinib in combination with the histone deacetylase inhibitors (HDACi) vorinostat and sodium butyrate in the KRAS-mutated NSCLC cell line A549. For comparison, we tested the combination of HDACi with the dual tyrosine kinase inhibitor lapatinib. A549 cells proved to be resistant to erlotinib and gefitinib, but could be sensitized by cotreatment with HDACi, as assessed by flow cytometric analyses of cell death and mitochondrial depolarization. In contrast, A549 cells were a priori responsive to lapatinib treatment, but responsiveness to lapatinib could not be enhanced by HDACi cotreatment. These divergent effects of the different combination regimens may be explained by dissimilar types of cell death induced by the treatments: The use of the pan-caspase inhibitor z-VAD-fmk in the cell death and mitochondrial depolarization assays as well as fluorescence microscopy analyses indicated that erlotinib or gefitinib combined with HDACi elicited apoptosis, whereas lapatinib treatment induced a non-apoptotic type of cell death. Our study suggests that both HDACi/EGFR inhibitor-combination treatment and lapatinib-single treatment may be effective options for the therapy of NSCLC with KRAS mutations.


PubMed | University Childrens Hospital Jena
Type: Journal Article | Journal: Investigational new drugs | Year: 2012

Nutlin-3, a small-molecule MDM2 inhibitor, restores p53 function and is, thus, an appealing candidate for the treatment of cancers retaining wild-type p53. However, nutlin-3 applied as single agent may be insufficient for cancer therapy. Therefore, we explored whether the anticancer activity of nutlin-3 could be enhanced by combination with histone deacetylase inhibitors (HDACi), i.e. vorinostat, sodium butyrate, MS-275 and apicidin. We found that nutlin-3 and HDACi cooperated to induce cell death in the p53 wild-type cell lines A549 and A2780, but not in the p53 null cell line PC-3, as assessed by Alamar Blue assay and flow cytometric analyses of propidium iodide uptake and mitochondrial depolarization. Combination index analysis showed that the effect was synergistic. For comparison, we tested nutlin-3 in combination with paclitaxel, revealing that nutlin-3 antagonized the cytotoxic activity of paclitaxel. To shed light on the underlying mechanism of the synergistic action of nutlin-3 and HDACi, we determined the acetylation status of p53 by immunoblotting and the mRNA levels of MDM2 and MDM4 by real-time RT-PCR. We observed vorinostat to induce p53 hyperacetylation, to reduce the constitutive gene expression of MDM2 and MDM4, and to counteract the nutlin-3-induced upregulation of MDM2 gene expression. In conclusion, our study shows that HDACi amplify the antitumor activity of nutlin-3-possibly by inducing p53 hyperacetylation and/or MDM2 and/or MDM4 downregulation-suggesting that treatment with a combination of nutlin-3 and HDACi may be an effective strategy for treating tumors with wild-type p53.


PubMed | University Childrens Hospital Jena
Type: Journal Article | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2011

Mutation of p53 is rare in Ewings sarcoma (ES), suggesting that targeting and activation of wild-type p53 may be an effective therapeutic strategy for ES. The recently developed small-molecule MDM2 inhibitor nutlin-3 restores wild-type p53 function, resulting in the inhibition of cancer cell growth and the induction of apoptosis. In the present study, we explored the responsiveness of ES cell lines with wild-type or mutated p53 to nutlin-3. We found that treatment with nutlin-3 increased p53 level and induced p53 target gene expression (MDM2, p21, PUMA) in ES cells with wild-type p53, but not in ES cells with mutated p53. Consistently, nutlin-3 elicited apoptosis only in wild-type p53 cells, as assessed by caspase-3 activity assay and flow cytometric analyses of mitochondrial depolarisation and DNA fragmentation. In addition, we found nutlin-3 to evoke cellular senescence, indicating that nutlin-3 induces pleiotropic anticancer effects in ES. Furthermore, combined treatment with nutlin-3 and an inhibitor of NF-B produced synergistic antineoplastic activity in ES cells. Our findings suggest that the direct activation of p53 by nutlin-3 treatment may be a useful new therapeutic approach for patients with ES.

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