35 results on '"Ginzel, S"'
Search Results
2. POS0994 DEVELOPMENT OF AN AUTOMATED ALGORITHM BASED ON METHODS OF ARTIFICIAL INTELLIGENCE TO ASSIST IN THE PREDICTION OF CORRECT REFERRALS OF PSORIATIC ARTHRITIS AND AXIAL SPONDYLOARTHRITIS BY USING PATIENT HISTORY TEXTS
- Author
-
Kratz, H., primary, Ginzel, S., additional, Ohrndorf, S., additional, Baraliakos, X., additional, Tsiami, S., additional, Haedecke, E., additional, Doll, N., additional, Holz-Müller, J., additional, Rüping, S., additional, Behrens, F., additional, and Köhm, M., additional
- Published
- 2022
- Full Text
- View/download PDF
3. Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases
- Author
-
Linka, R M, Risse, S L, Bienemann, K, Werner, M, Linka, Y, Krux, F, Synaeve, C, Deenen, R, Ginzel, S, Dvorsky, R, Gombert, M, Halenius, A, Hartig, R, Helminen, M, Fischer, A, Stepensky, P, Vettenranta, K, Köhrer, K, Ahmadian, M R, Laws, H-J, Fleckenstein, B, Jumaa, H, Latour, S, Schraven, B, and Borkhardt, A
- Published
- 2012
- Full Text
- View/download PDF
4. Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G>A
- Author
-
Auer, F, Rüschendorf, F, Gombert, M, Husemann, P, Ginzel, S, Izraeli, S, Harit, M, Weintraub, M, Weinstein, O Y, Lerer, I, Stepensky, P, Borkhardt, A, and Hauer, J
- Published
- 2014
- Full Text
- View/download PDF
5. Specific antibody deficiency and autoinflammatory disease extend the clinical and immunological spectrum of heterozygous NFKB1 loss-of-function mutations in humans
- Author
-
Schipp, C., primary, Nabhani, S., additional, Bienemann, K., additional, Simanovsky, N., additional, Kfir-Erenfeld, S., additional, Assayag-Asherie, N., additional, Oommen, P. T., additional, Revel-Vilk, S., additional, Honscheid, A., additional, Gombert, M., additional, Ginzel, S., additional, Schafer, D., additional, Laws, H.-J., additional, Yefenof, E., additional, Fleckenstein, B., additional, Borkhardt, A., additional, Stepensky, P., additional, and Fischer, U., additional
- Published
- 2016
- Full Text
- View/download PDF
6. Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease
- Author
-
Nabhani, S., primary, Ginzel, S., additional, Miskin, H., additional, Revel-Vilk, S., additional, Harlev, D., additional, Fleckenstein, B., additional, Honscheid, A., additional, Oommen, P. T., additional, Kuhlen, M., additional, Thiele, R., additional, Laws, H.-J., additional, Borkhardt, A., additional, Stepensky, P., additional, and Fischer, U., additional
- Published
- 2015
- Full Text
- View/download PDF
7. Constitutional Mismatch Repair-deficiency and Whole-exome Sequencing as the Means of the Rapid Detection of the Causative MSH6 Defect
- Author
-
Hoell, J., additional, Gombert, M., additional, Ginzel, S., additional, Loth, S., additional, Landgraf, P., additional, Käfer, V., additional, Streiter, M., additional, Prokop, A., additional, Weiss, M., additional, Thiele, R., additional, and Borkhardt, A., additional
- Published
- 2014
- Full Text
- View/download PDF
8. Multi-Cluster Text Mining on the Grid using the D-Grid UNICORE environment
- Author
-
Kumpf, K., Mevissen, T., Wäldrich, O., Ziegler, W., Ginzel, S., and Weuffel, T.
- Abstract
Text mining is inherently more computation-intensive than information retrieval on pre-structured data and requires transfer and filtering of huge amounts of data. Grid environments provide a suitable infrastructure for accomplishing these tasks. We present the mapping and implementation of a standard text mining (TM) workflow for analysis of biomedical text data from PubMed to a D-Grid UNICORE environment with multiple PC-clusters. We discuss the gain in applicability, the open issues of our solution and possible future enhancements.
- Published
- 2007
9. Runtime Prediction von Textmining-Applikationen im Grid am Beispiel von ProMiner
- Author
-
Ginzel, S.
- Published
- 2007
- Full Text
- View/download PDF
10. Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G>A
- Author
-
Auer, F, primary, Rüschendorf, F, additional, Gombert, M, additional, Husemann, P, additional, Ginzel, S, additional, Izraeli, S, additional, Harit, M, additional, Weintraub, M, additional, Weinstein, O Y, additional, Lerer, I, additional, Stepensky, P, additional, Borkhardt, A, additional, and Hauer, J, additional
- Published
- 2013
- Full Text
- View/download PDF
11. The impact of TEL-AML1 (ETV6-RUNX1) expression in precursor B cells and implications for leukaemia using three different genome-wide screening methods
- Author
-
Linka, Y, primary, Ginzel, S, additional, Krüger, M, additional, Novosel, A, additional, Gombert, M, additional, Kremmer, E, additional, Harbott, J, additional, Thiele, R, additional, Borkhardt, A, additional, and Landgraf, P, additional
- Published
- 2013
- Full Text
- View/download PDF
12. Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27
- Author
-
Salzer, E., primary, Daschkey, S., additional, Choo, S., additional, Gombert, M., additional, Santos-Valente, E., additional, Ginzel, S., additional, Schwendinger, M., additional, Haas, O. A., additional, Fritsch, G., additional, Pickl, W. F., additional, Forster-Waldl, E., additional, Borkhardt, A., additional, Boztug, K., additional, Bienemann, K., additional, and Seidel, M. G., additional
- Published
- 2012
- Full Text
- View/download PDF
13. Short-term predictor for COVID-19 severity from a longitudinal multi-omics study for practical application in intensive care units.
- Author
-
Kugler S, Hahnefeld L, Kloka JA, Ginzel S, Nürenberg-Goloub E, Zinn S, Vehreschild MJ, Zacharowski K, Lindau S, Ullrich E, Burmeister J, Kohlhammer J, Schwäble J, Gurke R, Dorochow E, Bennett A, Dauth S, Campe J, Knape T, Laux V, Kannt A, Köhm M, Geisslinger G, Resch E, and Behrens F
- Subjects
- Humans, SARS-CoV-2, Pandemics, Multiomics, Intensive Care Units, Disease Progression, COVID-19 diagnosis
- Abstract
Background: The COVID-19 pandemic challenged the management of technical and human resources in intensive care units (ICU) across the world. Several long-term predictors for COVID-19 disease progression have been discovered. However, predictors to support short-term planning of resources and medication that can be translated to future pandemics are still missing. A workflow was established to identify a predictor for short-term COVID-19 disease progression in the acute phase of intensive care patients to support clinical decision-making., Methods: Thirty-two patients with SARS-CoV-2 infection were recruited on admission to the ICU and clinical data collected. During their hospitalization, plasma samples were acquired from each patient on multiple occasions, excepting one patient for which only one time point was possible, and the proteome (Inflammation, Immune Response and Organ Damage panels from Olink® Target 96), metabolome and lipidome (flow injection analysis and liquid chromatography-mass spectrometry) analyzed for each sample. Patient visits were grouped according to changes in disease severity based on their respiratory and organ function, and evaluated using a combination of statistical analysis and machine learning. The resulting short-term predictor from this multi-omics approach was compared to the human assessment of disease progression. Furthermore, the potential markers were compared to the baseline levels of 50 healthy subjects with no known SARS-CoV-2 or other viral infections., Results: A total of 124 clinical parameters, 271 proteins and 782 unique metabolites and lipids were assessed. The dimensionality of the dataset was reduced, selecting 47 from the 1177 parameters available following down-selection, to build the machine learning model. Subsequently, two proteins (C-C motif chemokine 7 (CCL7) and carbonic anhydrase 14 (CA14)) and one lipid (hexosylceramide 18:2; O2/20:0) were linked to disease progression in the studied SARS-CoV-2 infections. Thus, a predictor delivering the prognosis of an upcoming worsening of the patient's condition up to five days in advance with a reasonable accuracy (79 % three days prior to event, 84 % four to five days prior to event) was found. Interestingly, the predictor's performance was complementary to the clinicians' capabilities to foresee a worsening of a patient., Conclusion: This study presents a workflow to identify omics-based biomarkers to support clinical decision-making and resource management in the ICU. This was successfully applied to develop a short-term predictor for aggravation of COVID-19 symptoms. The applied methods can be adapted for future small cohort studies., Competing Interests: Declaration of competing interest ☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
14. Symptom diaries as a digital tool to detect SARS-CoV-2 infections and differentiate between prevalent variants.
- Author
-
Grüne B, Kugler S, Ginzel S, Wolff A, Buess M, Kossow A, Küfer-Weiß A, Rüping S, and Neuhann F
- Subjects
- Humans, Infant, Newborn, Pandemics, Artificial Intelligence, SARS-CoV-2, Public Health, COVID-19 diagnosis, COVID-19 epidemiology
- Abstract
The COVID-19 pandemic and the high numbers of infected individuals pose major challenges for public health departments. To overcome these challenges, the health department in Cologne has developed a software called DiKoMa. This software offers the possibility to track contact and index persons, but also provides a digital symptom diary. In this work, the question of whether these can also be used for diagnostic purposes will be investigated. Machine learning makes it possible to identify infections based on early symptom profiles and to distinguish between the predominant dominant variants. Focusing on the occurrence of the symptoms in the first week, a decision tree is trained for the differentiation between contact and index persons and the prevailing dominant variants (Wildtype, Alpha, Delta, and Omicron). The model is evaluated, using sex- and age-stratified cross-validation and validated by symptom profiles of the first 6 days. The variants achieve an AUC-ROC from 0.89 for Omicron and 0.6 for Alpha. No significant differences are observed for the results of the validation set (Alpha 0.63 and Omicron 0.87). The evaluation of symptom combinations using artificial intelligence can determine the individual risk for the presence of a COVID-19 infection, allows assignment to virus variants, and can contribute to the management of epidemics and pandemics on a national and international level. It can help to reduce the number of specific tests in times of low labor capacity and could help to early identify new virus variants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Grüne, Kugler, Ginzel, Wolff, Buess, Kossow, Küfer-Weiß, Rüping and Neuhann.)
- Published
- 2022
- Full Text
- View/download PDF
15. [Spatio-temporal distribution of COVID-19 in Cologne and associated socio-economic factors in the period from February 2020 to October 2021].
- Author
-
Neuhann F, Ginzel S, Buess M, Wolff A, Kugler S, Schlanstedt G, Kossow A, Nießen J, and Rüping S
- Subjects
- Economic Factors, Germany epidemiology, Humans, Pandemics, Risk Factors, Socioeconomic Factors, COVID-19 epidemiology
- Abstract
Background and Goals: Even in the early phase of the COVID-19 pandemic, which took a very different course globally, there were indications that socio-economic factors influenced the dynamics of disease spread, which from the second phase (September 2020) onwards particularly affected people with a lower socio-economic status. Such effects can also be seen within a large city. The present study visualizes and examines the spatio-temporal spread of all COVID-19 cases reported in Cologne, Germany (February 2020-October 2021) at district level and their possible association with socio-economic factors., Methods: Pseudonymized data of all COVID-19 cases reported in Cologne were geo-coded and their distribution was mapped in an age-standardized way at district level over four periods and compared with the distribution of social factors. The possible influence of the selected factors was also examined in a regression analysis in a model with case growth rates., Results: The small-scale local infection process changed during the pandemic. Neighborhoods with weaker socio-economic indices showed higher incidence over a large part of the pandemic course, with a positive correlation between poverty risk factors and age-standardized incidence. The strength of this correlation changed over time., Conclusion: The timely observation and analysis of the local spread dynamics reveals the positive correlation of disadvantaging socio-economic factors on the incidence rate of COVID-19 at the level of a large city and can help steer local containment measures in a targeted manner., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
16. Uncovering chains of infections through spatio-temporal and visual analysis of COVID-19 contact traces.
- Author
-
Antweiler D, Sessler D, Rossknecht M, Abb B, Ginzel S, and Kohlhammer J
- Abstract
A major challenge for departments of public health (DPHs) in dealing with the ongoing COVID-19 pandemic is tracing contacts in exponentially growing SARS-CoV-2 infection clusters. Prevention of further disease spread requires a comprehensive registration of the connections between individuals and clusters. Due to the high number of infections with unknown origin, the healthcare analysts need to identify connected cases and clusters through accumulated epidemiological knowledge and the metadata of the infections in their database. Here we contribute a visual analytics dashboard to identify, assess and visualize clusters in COVID-19 contact tracing networks. Additionally, we demonstrate how graph-based machine learning methods can be used to find missing links between infection clusters and thus support the mission to get a comprehensive view on infection events. This work was developed through close collaboration with DPHs in Germany. We argue how our dashboard supports the identification of clusters by public health experts, discuss ongoing developments and possible extensions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
17. Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets.
- Author
-
Hoell JI, Ginzel S, Kuhlen M, Kloetgen A, Gombert M, Fischer U, Hein D, Demir S, Stanulla M, Schrappe M, Zur Stadt U, Bader P, Babor F, Schuster F, Strahm B, Alten J, Moericke A, Escherich G, von Stackelberg A, Thiele R, McHardy AC, Peters C, Bornhauser B, Bourquin JP, Krause S, Enczmann J, Meyer LH, Eckert C, Borkhardt A, and Meisel R
- Subjects
- Child, Child, Preschool, Computational Biology methods, DNA Repair, Female, Hematopoietic Stem Cell Transplantation methods, Humans, Immunophenotyping, Infant, Male, Mutation, Polymorphism, Single Nucleotide, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Recurrence, Transplantation, Homologous, Tumor Suppressor Protein p53 genetics, Biomarkers, Tumor, Clonal Evolution genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma etiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Selection, Genetic
- Abstract
Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post-allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post-allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions. Moreover, mutational cluster analysis showed substantial clonal dynamics during leukemia progression from initial diagnosis to relapse after allo-SCT. Only very few alterations stayed constant over time. This dynamic clonality was exemplified by the detection of thiopurine resistance-mediating mutations in the nucleotidase NT5C2 in 3 patients' first relapses, which disappeared in the post-allo-SCT relapses on relief of selective pressure of maintenance chemotherapy. Moreover, we identified TP53 mutations in 4 of 10 patients after allo-SCT, reflecting acquired chemoresistance associated with selective pressure of prior antineoplastic treatment. Finally, in 9 of 10 children's post-allo-SCT relapse, we found alterations in genes for which targeted therapies with novel agents are readily available. We could show efficient targeting of leukemic blasts by APR-246 in 2 patients carrying TP53 mutations. Our findings shed light on the genetic basis of post-allo-SCT relapse and may pave the way for unraveling novel therapeutic strategies in this challenging situation., (© 2019 by The American Society of Hematology.)
- Published
- 2019
- Full Text
- View/download PDF
18. Mutated SON putatively causes a cancer syndrome comprising high-risk medulloblastoma combined with café-au-lait spots.
- Author
-
Chiu C, Loth S, Kuhlen M, Ginzel S, Schaper J, Rosenbaum T, Pietsch T, Borkhardt A, and Hoell JI
- Subjects
- Child, Preschool, Consanguinity, Fatal Outcome, Humans, Male, Pedigree, Point Mutation, Syndrome, Cafe-au-Lait Spots genetics, Cerebellar Neoplasms genetics, DNA-Binding Proteins genetics, Medulloblastoma genetics, Minor Histocompatibility Antigens genetics
- Abstract
Medulloblastoma is the most frequent malignant brain tumor in childhood. This highly malignant neoplasm occurs usually before 10 years of age and more frequently in boys. The 5-year event-free survival rate for high-risk medulloblastoma is low at 62% despite a multimodal therapy including surgical resection, radiation therapy and chemotherapy. We report the case of a boy, who was born to consanguineous parents. Prominently, he had multiple café-au-lait spots. At the age of 3 years he was diagnosed with a high-risk metastatic medulloblastoma. The patient died only 11 months after diagnosis of a fulminant relapse presenting as meningeal and spinal dissemination. Whole-exome sequencing of germline DNA was employed to detect the underlying mutation for this putative cancer syndrome presenting with the combination of medulloblastoma and skin alterations. After screening all possible homozygous gene SNVs, we identified a mutation of SON, an essential protein in cell cycle regulation and cell proliferation, as the most likely genetic cause.
- Published
- 2019
- Full Text
- View/download PDF
19. EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency.
- Author
-
Schipp C, Schlütermann D, Hönscheid A, Nabhani S, Höll J, Oommen PT, Ginzel S, Fleckenstein B, Stork B, Borkhardt A, Stepensky P, and Fischer U
- Subjects
- Autoimmune Lymphoproliferative Syndrome diagnosis, Case-Control Studies, Computational Biology methods, DNA Mutational Analysis, Epstein-Barr Virus Infections virology, Female, Humans, Immunologic Deficiency Syndromes diagnosis, Intracellular Signaling Peptides and Proteins, Lymphoma diagnosis, Male, Mutation, Pedigree, Exome Sequencing, Autoimmune Lymphoproliferative Syndrome etiology, Epstein-Barr Virus Infections complications, Herpesvirus 4, Human, Immunologic Deficiency Syndromes etiology, Lymphoma etiology, Phenotype, Protein Serine-Threonine Kinases deficiency
- Abstract
Serine/threonine kinase 4 (STK4) deficiency is an autosomal recessive genetic condition that leads to primary immunodeficiency (PID) typically characterized by lymphopenia, recurrent infections and Epstein Barr Virus (EBV) induced lymphoproliferation and -lymphoma. State-of-the-art treatment regimens consist of prevention or treatment of infections, immunoglobulin substitution (IVIG) and restoration of the immune system by hematopoietic stem cell transplantation. Here, we report on two patients from two consanguineous families of Turkish (patient P1) and Moroccan (patient P2) decent, with PID due to homozygous STK4 mutations. P1 harbored a previously reported frameshift (c.1103 delT, p.M368RfsX2) and P2 a novel splice donor site mutation (P2; c.525+2 T>G). Both patients presented in childhood with recurrent infections, CD4 lymphopenia and dysregulated immunoglobulin levels. Patient P1 developed a highly malignant B cell lymphoma at the age of 10 years and a second, independent Hodgkin lymphoma 5 years later. To our knowledge she is the first STK4 deficient case reported who developed lymphoma in the absence of detectable EBV or other common viruses. Lymphoma development may be due to the lacking tumor suppressive function of STK4 or the perturbed immune surveillance due to the lack of CD4+ T cells. Our data should raise physicians' awareness of [1] lymphoma proneness of STK4 deficient patients even in the absence of EBV infection and [2] possibly underlying STK4 deficiency in pediatric patients with a history of recurrent infections, CD4 lymphopenia and lymphoma and unknown genetic make-up. Patient P2 experienced recurrent otitis in childhood, but when she presented at the age of 14, she showed clinical and immunological characteristics similar to patients suffering from Autoimmune Lymphoproliferative Syndrome (ALPS): elevated DNT cell number, non-malignant lymphadenopathy and hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia. Also patient P1 presented with ALPS-like features (lymphadenopathy, elevated DNT cell number and increased Vitamin B12 levels) and both were initially clinically diagnosed as ALPS-like. Closer examination of P2, however, revealed active EBV infection and genetic testing identified a novel STK4 mutation. None of the patients harbored typically ALPS-associated mutations of the Fas receptor mediated apoptotic pathway and Fas-mediated apoptosis was not affected. The presented case reports extend the clinical spectrum of STK4 deficiency.
- Published
- 2018
- Full Text
- View/download PDF
20. Loss of Pax5 Exploits Sca1-BCR-ABL p190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL.
- Author
-
Martín-Lorenzo A, Auer F, Chan LN, García-Ramírez I, González-Herrero I, Rodríguez-Hernández G, Bartenhagen C, Dugas M, Gombert M, Ginzel S, Blanco O, Orfao A, Alonso-López D, Rivas JL, García-Cenador MB, García-Criado FJ, Müschen M, Sánchez-García I, Borkhardt A, Vicente-Dueñas C, and Hauer J
- Subjects
- Animals, B-Lymphocytes metabolism, Cell Line, Energy Metabolism genetics, Fusion Proteins, bcr-abl genetics, Glucose metabolism, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, PAX5 Transcription Factor metabolism, Preleukemia pathology, Fusion Proteins, bcr-abl metabolism, Gene Expression Regulation, Leukemic genetics, PAX5 Transcription Factor genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology
- Abstract
Preleukemic clones carrying BCR-ABL
p190 oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here, we model a BCR-ABLp190 preleukemic state and show that limiting BCR-ABLp190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABLp190 ) causes pB-ALL at low penetrance, which resembles the human disease. pB-ALL blast cells were BCR-ABL-negative and transcriptionally similar to pro-B/pre-B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABLp190 + Pax5+/- mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type Pax5 allele. Mechanistically, the Pax5-deficient leukemic pro-B cells exhibited a metabolic switch toward increased glucose utilization and energy metabolism. Transcriptome analysis revealed that metabolic genes ( IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1 ) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first in vivo evidence that the combination between Sca1-BCR-ABLp190 and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development. These findings might help to prevent conversion of BCR-ABLp190 preleukemic cells. Significance: Loss of Pax5 drives metabolic reprogramming, which together with Sca1-restricted BCR-ABL expression enables leukemic transformation. Cancer Res; 78(10); 2669-79. ©2018 AACR ., (©2018 American Association for Cancer Research.)- Published
- 2018
- Full Text
- View/download PDF
21. Diagnostic challenges in a child with early onset desmoplastic medulloblastoma and homozygous variants in MSH2 and MSH6.
- Author
-
Taeubner J, Wimmer K, Muleris M, Lascols O, Colas C, Fauth C, Brozou T, Felsberg J, Riemer J, Gombert M, Ginzel S, Hoell JI, Borkhardt A, and Kuhlen M
- Subjects
- Cell Line, Tumor, Cells, Cultured, Cerebellar Neoplasms pathology, DNA-Binding Proteins metabolism, Diagnosis, Differential, Female, Homozygote, Humans, Infant, Medulloblastoma pathology, MutS Homolog 2 Protein metabolism, Cerebellar Neoplasms genetics, DNA-Binding Proteins genetics, Genetic Testing methods, Medulloblastoma genetics, MutS Homolog 2 Protein genetics, Phenotype
- Abstract
Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessively inherited childhood cancer susceptibility syndrome caused by biallelic germline mutations in one of the mismatch repair (MMR) genes. The spectrum of CMMRD-associated tumours is very broad and many CMMRD patients additionally display signposting non-neoplastic features, most frequently café-au-lait macules and other pigmentation alterations. We report on a 13-month-old girl suspected of having CMMRD due to a desmoplastic medulloblastoma and a striking skin pigmentation that included multiple café-au-lait macules, hypopigmented areas and Mongolian spots. Whole-exome sequencing revealed homozygosity for MSH2 variant p.(Leu92Val) and MSH6 variant p.(Val809del), both variants of uncertain significance (VUS). Immunohistochemical analysis of the tumour tissue showed expression of all four MMR proteins and gMSI testing was negative. However, functional assays demonstrated that the cells of the patient displayed methylation tolerance and ex vivo microsatellite instability, which unequivocally confirmed the diagnosis of CMMRD. Taken together, the results render the MSH2 variant unlikely to be responsible for the phenotype, while they are compatible with MSH6-associated CMMRD. This case illustrates the diagnostic strategy of confirming CMMRD syndrome in patients with VUS.
- Published
- 2018
- Full Text
- View/download PDF
22. Congenital embryonal rhabdomyosarcoma caused by heterozygous concomitant PTCH1 and PTCH2 germline mutations.
- Author
-
Taeubner J, Brozou T, Qin N, Bartl J, Ginzel S, Schaper J, Felsberg J, Fulda S, Vokuhl C, Borkhardt A, and Kuhlen M
- Subjects
- Humans, Infant, Newborn, Male, Rhabdomyosarcoma, Embryonal pathology, Germ-Line Mutation, Patched-1 Receptor genetics, Patched-2 Receptor genetics, Rhabdomyosarcoma, Embryonal genetics
- Abstract
The sonic hedgehog (SHH) signaling pathway has been shown to play important roles in embryogenesis, cell proliferation as well as in cell differentiation. It is aberrantly activated in various common cancers in adults, but also in pediatric neoplasms, such as rhabdomyosarcoma (RMS) and atypical teratoid/rhabdoid tumors (AT/RTs). Dysregulation and germline mutation in PATCHED1 (PTCH1), a receptor for SHH, is responsible for the Gorlin Syndrome, a familial cancer predisposing syndrome including RMS. Here, we report a newborn diagnosed with congenital embryonal RMS. Whole-exome sequencing (WES) identified the presence of two heterozygous germline mutations in two target genes of the SHH signaling pathway. The PTCH1 mutation p.(Gly38Glu) is inherited from the mother, whereas the PTCH2 p.(His622Tyr) mutation is transmitted from the father. Quantitative RT-PCR expression analysis of GLI and SMO, key players of the SHH pathway, showed significantly increase in the tumor tissue of the patient and also enrichment in the germline sample in comparison to the parents indicating activation of the SHH pathway in the patient. These findings demonstrate that SHH pathway activity seems to play a role in eRMS as evidenced by high expression levels of GLI1 RNA transcripts. We speculate that PTCH2 modulates tumorigenesis linked to the PTCH1 mutation and is likely associated with the congenital onset of the RMS observed in our patient.
- Published
- 2018
- Full Text
- View/download PDF
23. STAT3 gain-of-function mutations associated with autoimmune lymphoproliferative syndrome like disease deregulate lymphocyte apoptosis and can be targeted by BH3 mimetic compounds.
- Author
-
Nabhani S, Schipp C, Miskin H, Levin C, Postovsky S, Dujovny T, Koren A, Harlev D, Bis AM, Auer F, Keller B, Warnatz K, Gombert M, Ginzel S, Borkhardt A, Stepensky P, and Fischer U
- Subjects
- Biphenyl Compounds, Butylated Hydroxytoluene analogs & derivatives, Case-Control Studies, Child, Preschool, Enzyme-Linked Immunosorbent Assay, Family, Fas Ligand Protein metabolism, Female, Gene Expression Profiling, Germ-Line Mutation, Humans, Immunoblotting, Immunophenotyping, Leukocytes, Mononuclear, Lymphocytes, Nitrophenols, Piperazines, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2 metabolism, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA, Sulfonamides, T-Lymphocytes drug effects, T-Lymphocytes metabolism, fas Receptor metabolism, Apoptosis genetics, Autoimmune Lymphoproliferative Syndrome genetics, STAT3 Transcription Factor genetics
- Abstract
Autoimmune lymphoproliferative syndrome (ALPS) is typically caused by mutations in genes of the extrinsic FAS mediated apoptotic pathway, but for about 30% of ALPS-like patients the genetic diagnosis is lacking. We analyzed 30 children with ALPS-like disease of unknown cause and identified two dominant gain-of-function mutations of the Signal Transducer And Activator Of Transcription 3 (STAT3, p.R278H, p.M394T) leading to increased transcriptional activity. Hyperactivity of STAT3, a known repressor of FAS, was associated with decreased FAS-mediated apoptosis, mimicking ALPS caused by FAS mutations. Expression of BCL2 family proteins, further targets of STAT3 and regulators of the intrinsic apoptotic pathway, was disturbed. Cells with hyperactive STAT3 were consequently more resistant to intrinsic apoptotic stimuli and STAT3 inhibition alleviated this effect. Importantly, STAT3-mutant cells were more sensitive to death induced by the BCL2-inhibitor ABT-737 indicating a dependence on anti-apoptotic BCL2 proteins and potential novel therapeutic options., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
24. Human RAD52 - a novel player in DNA repair in cancer and immunodeficiency.
- Author
-
Ghosh S, Hönscheid A, Dückers G, Ginzel S, Gohlke H, Gombert M, Kempkes B, Klapper W, Kuhlen M, Laws HJ, Linka RM, Meisel R, Mielke C, Niehues T, Schindler D, Schneider D, Schuster FR, Speckmann C, and Borkhardt A
- Subjects
- Adolescent, Cell Cycle drug effects, DNA Breaks, Double-Stranded, Fibroblasts drug effects, Fibroblasts immunology, Fibroblasts pathology, Herpesvirus 4, Human pathogenicity, Herpesvirus 4, Human physiology, Humans, Infectious Mononucleosis immunology, Infectious Mononucleosis pathology, Male, Mitomycin pharmacology, Models, Molecular, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Rad52 DNA Repair and Recombination Protein chemistry, Rad52 DNA Repair and Recombination Protein immunology, Severe Combined Immunodeficiency immunology, Severe Combined Immunodeficiency pathology, DNA Repair, Infectious Mononucleosis genetics, Rad52 DNA Repair and Recombination Protein genetics, Severe Combined Immunodeficiency genetics
- Published
- 2017
- Full Text
- View/download PDF
25. A novel homozygous mutation in UNC13D presenting as Epstein-Barr-virus-associated lymphoproliferative disease at 9 years of age.
- Author
-
Bienemann K, Daschkey S, Sörensen J, Schwabe D, Klingebiel T, Hönscheid A, Gombert M, Ginzel S, and Borkhardt A
- Subjects
- Amino Acid Substitution, Child, Consanguinity, Epstein-Barr Virus Infections diagnosis, Epstein-Barr Virus Infections pathology, Female, Herpesvirus 4, Human pathogenicity, Humans, Lymphoproliferative Disorders diagnosis, Polymorphism, Single Nucleotide, Turkey, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections genetics, Homozygote, Lymphoproliferative Disorders genetics, Lymphoproliferative Disorders virology, Membrane Proteins genetics, Mutation, Missense
- Published
- 2016
- Full Text
- View/download PDF
26. A novel approach to detect resistance mechanisms reveals FGR as a factor mediating HDAC inhibitor SAHA resistance in B-cell lymphoma.
- Author
-
Joosten M, Ginzel S, Blex C, Schmidt D, Gombert M, Chen C, Linka RM, Gräbner O, Hain A, Hirsch B, Sommerfeld A, Seegebarth A, Gruber U, Maneck C, Zhang L, Stenin K, Dieks H, Sefkow M, Münk C, Baldus CD, Thiele R, Borkhardt A, Hummel M, Köster H, Fischer U, Dreger M, and Seitz V
- Subjects
- Cell Line, Tumor, Gene Knockout Techniques, Gene Regulatory Networks drug effects, Humans, Mass Spectrometry, Mutation genetics, Reproducibility of Results, Vorinostat, Drug Resistance, Neoplasm drug effects, Histone Deacetylase Inhibitors pharmacology, Hydroxamic Acids pharmacology, Lymphoma, B-Cell pathology, Proto-Oncogene Proteins metabolism, src-Family Kinases metabolism
- Abstract
Histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) are not commonly used in clinical practice for treatment of B-cell lymphomas, although a subset of patients with refractory or relapsed B-cell lymphoma achieved partial or complete remissions. Therefore, the purpose of this study was to identify molecular features that predict the response of B-cell lymphomas to SAHA treatment. We designed an integrative approach combining drug efficacy testing with exome and captured target analysis (DETECT). In this study, we tested SAHA sensitivity in 26 B-cell lymphoma cell lines and determined SAHA-interacting proteins in SAHA resistant and sensitive cell lines employing a SAHA capture compound (CC) and mass spectrometry (CCMS). In addition, we performed exome mutation analysis. Candidate validation was done by expression analysis and knock-out experiments. An integrated network analysis revealed that the Src tyrosine kinase Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog (FGR) is associated with SAHA resistance. FGR was specifically captured by the SAHA-CC in resistant cells. In line with this observation, we found that FGR expression was significantly higher in SAHA resistant cell lines. As functional proof, CRISPR/Cas9 mediated FGR knock-out in resistant cells increased SAHA sensitivity. In silico analysis of B-cell lymphoma samples (n = 1200) showed a wide range of FGR expression indicating that FGR expression might help to stratify patients, which clinically benefit from SAHA therapy. In conclusion, our comprehensive analysis of SAHA-interacting proteins highlights FGR as a factor involved in SAHA resistance in B-cell lymphoma., (Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
27. Fatal Lymphoproliferative Disease in Two Siblings Lacking Functional FAAP24.
- Author
-
Daschkey S, Bienemann K, Schuster V, Kreth HW, Linka RM, Hönscheid A, Fritz G, Johannes C, Fleckenstein B, Kempkes B, Gombert M, Ginzel S, and Borkhardt A
- Subjects
- Amino Acid Substitution, Cell Cycle, Codon, Consanguinity, DNA Damage, DNA Repair, DNA-Binding Proteins metabolism, Fanconi Anemia Complementation Group D2 Protein metabolism, Fanconi Anemia Complementation Group Proteins, Fatal Outcome, Female, Genotype, Homozygote, Humans, Lymphocyte Count, Lymphoproliferative Disorders virology, Male, Pedigree, Phenotype, Receptors, Antigen, T-Cell metabolism, Signal Transduction, Sister Chromatid Exchange, T-Lymphocytes immunology, T-Lymphocytes metabolism, Ubiquitination, Exome Sequencing, DNA-Binding Proteins genetics, Lymphoproliferative Disorders diagnosis, Lymphoproliferative Disorders genetics, Mutation, Siblings
- Abstract
Hereditary defects in several genes have been shown to disturb the normal immune response to EBV and to give rise to severe EBV-induced lymphoproliferation in the recent years. Nevertheless, in many patients, the molecular basis of fatal EBV infection still remains unclear. The Fanconi anemia-associated protein 24 (FAAP24) plays a dual role in DNA repair. By association with FANCM as component of the FA core complex, it recruits the FA core complex to damaged DNA. Additionally, FAAP24 has been shown to evoke ATR-mediated checkpoint responses independently of the FA core complex. By whole exome sequencing, we identified a homozygous missense mutation in the FAAP24 gene (cC635T, pT212M) in two siblings of a consanguineous Turkish family who died from an EBV-associated lymphoproliferative disease after infection with a variant EBV strain, expressing a previously unknown EBNA2 allele.In order to analyze the functionality of the variant FAAP24 allele, we used herpes virus saimiri-transformed patient T cells to test endogenous cellular FAAP24 functions that are known to be important in DNA damage control. We saw an impaired FANCD2 monoubiquitination as well as delayed checkpoint responses, especially affecting CHK1 phosphorylation in patient samples in comparison to healthy controls. The phenotype of this FAAP24 mutation might have been further accelerated by an EBV strain that harbors an EBNA2 allele with enhanced activities compared to the prototype laboratory strain B95.8. This is the first report of an FAAP24 loss of function mutation found in human patients with EBV-associated lymphoproliferation.
- Published
- 2016
- Full Text
- View/download PDF
28. Infection Exposure is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5-Inherited Susceptibility.
- Author
-
Martín-Lorenzo A, Hauer J, Vicente-Dueñas C, Auer F, González-Herrero I, García-Ramírez I, Ginzel S, Thiele R, Constantinescu SN, Bartenhagen C, Dugas M, Gombert M, Schäfer D, Blanco O, Mayado A, Orfao A, Alonso-López D, Rivas Jde L, Cobaleda C, García-Cenador MB, García-Criado FJ, Sánchez-García I, and Borkhardt A
- Subjects
- Animals, Bone Marrow Transplantation, Cell Line, Tumor, Cell Transformation, Neoplastic, Cluster Analysis, Disease Models, Animal, Drug Resistance, Neoplasm genetics, Exome, Female, Gene Expression Profiling, Genotype, High-Throughput Nucleotide Sequencing, Interleukin-7 metabolism, Interleukin-7 pharmacology, Janus Kinase 3 antagonists & inhibitors, Janus Kinase 3 genetics, Male, Mice, Mice, Knockout, Mutation, Phenotype, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma therapy, Protein Kinase Inhibitors pharmacology, Receptors, Interleukin-7 genetics, STAT5 Transcription Factor genetics, Virus Integration, Disease Susceptibility, Host-Pathogen Interactions, PAX5 Transcription Factor genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma etiology
- Abstract
Unlabelled: Earlier in the past century, infections were regarded as the most likely cause of childhood B-cell precursor acute lymphoblastic leukemia (pB-ALL). However, there is a lack of relevant biologic evidence supporting this hypothesis. We present in vivo genetic evidence mechanistically connecting inherited susceptibility to pB-ALL and postnatal infections by showing that pB-ALL was initiated in Pax5 heterozygous mice only when they were exposed to common pathogens. Strikingly, these murine pB-ALLs closely resemble the human disease. Tumor exome sequencing revealed activating somatic, nonsynonymous mutations of Jak3 as a second hit. Transplantation experiments and deep sequencing suggest that inactivating mutations in Pax5 promote leukemogenesis by creating an aberrant progenitor compartment that is susceptible to malignant transformation through accumulation of secondary Jak3 mutations. Thus, treatment of Pax5(+/-) leukemic cells with specific JAK1/3 inhibitors resulted in increased apoptosis. These results uncover the causal role of infection in pB-ALL development., Significance: These results demonstrate that delayed infection exposure is a causal factor in pB-ALL. Therefore, these findings have critical implications for the understanding of the pathogenesis of leukemia and for the development of novel therapies for this disease., (©2015 American Association for Cancer Research.)
- Published
- 2015
- Full Text
- View/download PDF
29. Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.
- Author
-
Fischer U, Forster M, Rinaldi A, Risch T, Sungalee S, Warnatz HJ, Bornhauser B, Gombert M, Kratsch C, Stütz AM, Sultan M, Tchinda J, Worth CL, Amstislavskiy V, Badarinarayan N, Baruchel A, Bartram T, Basso G, Canpolat C, Cario G, Cavé H, Dakaj D, Delorenzi M, Dobay MP, Eckert C, Ellinghaus E, Eugster S, Frismantas V, Ginzel S, Haas OA, Heidenreich O, Hemmrich-Stanisak G, Hezaveh K, Höll JI, Hornhardt S, Husemann P, Kachroo P, Kratz CP, Te Kronnie G, Marovca B, Niggli F, McHardy AC, Moorman AV, Panzer-Grümayer R, Petersen BS, Raeder B, Ralser M, Rosenstiel P, Schäfer D, Schrappe M, Schreiber S, Schütte M, Stade B, Thiele R, von der Weid N, Vora A, Zaliova M, Zhang L, Zichner T, Zimmermann M, Lehrach H, Borkhardt A, Bourquin JP, Franke A, Korbel JO, Stanulla M, and Yaspo ML
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Coculture Techniques, Cohort Studies, DNA Mutational Analysis, Drug Resistance, Neoplasm, Female, Gene Expression, Genetic Association Studies, Genomics, Humans, Immunoglobulin Light Chains, Surrogate genetics, Inhibitory Concentration 50, Kaplan-Meier Estimate, Male, Mice, Inbred NOD, Mice, SCID, Mutation, Oncogene Proteins, Fusion metabolism, PAX5 Transcription Factor genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Sequence Deletion, Xenograft Model Antitumor Assays, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease.
- Published
- 2015
- Full Text
- View/download PDF
30. Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients.
- Author
-
Chen C, Bartenhagen C, Gombert M, Okpanyi V, Binder V, Röttgers S, Bradtke J, Teigler-Schlegel A, Harbott J, Ginzel S, Thiele R, Husemann P, Krell PF, Borkhardt A, Dugas M, Hu J, and Fischer U
- Subjects
- Antineoplastic Agents therapeutic use, Base Sequence, Child, Preschool, DNA Repair genetics, Female, High-Throughput Nucleotide Sequencing, Humans, Karyotype, Male, Molecular Sequence Data, Ploidies, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Recurrence, Risk Factors, Signal Transduction, Apoptosis Regulatory Proteins genetics, Epigenesis, Genetic, Gene Expression Regulation, Leukemic, Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Proto-Oncogene Proteins genetics, Transcription Factors genetics
- Abstract
20% of children suffering from high hyperdiploid acute lymphoblastic leukemia develop recurrent disease. The molecular mechanisms are largely unknown. Here, we analyzed the genetic landscape of five patients at relapse, who developed recurrent disease without prior high-risk indication using whole-exome- and whole-genome-sequencing. Oncogenic mutations of RAS pathway genes (NRAS, KRAS, FLT3, n=4) and deactivating mutations of major epigenetic regulators (CREBBP, EP300, each n=2 and ARID4B, EZH2, MACROD2, MLL2, each n=1) were prominent in these cases and virtually absent in non-recurrent cases (n=6) or other pediatric acute lymphoblastic leukemia cases (n=18). In relapse nucleotide variations were detected in cell fate determining transcription factors (GLIS1, AKNA). Structural genomic alterations affected genes regulating B-cell development (IKZF1, PBX1, RUNX1). Eleven novel translocations involved the genes ART4, C12orf60, MACROD2, TBL1XR1, LRRN4, KIAA1467, and ELMO1/MIR1200. Typically, patients harbored only single structural variations, except for one patient who displayed massive rearrangements in the context of a germline tumor suppressor TP53 mutation and a Li-Fraumeni syndrome-like family history. Another patient harbored a germline mutation in the DNA repair factor ATM. In summary, the relapse patients of our cohort were characterized by somatic mutations affecting the RAS pathway, epigenetic and developmental programs and germline mutations in DNA repair pathways., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
31. Identification of TEL-AML1 (ETV6-RUNX1) associated DNA and its impact on mRNA and protein output using ChIP, mRNA expression arrays and SILAC.
- Author
-
Linka Y, Ginzel S, Borkhardt A, and Landgraf P
- Abstract
The contribution of the most common reciprocal translocation in childhood B-cell precursor leukemia t(12;21)(p13;q22) to leukemia development is still under debate. Direct as well as secondary indirect effects of the TEL-AML1 fusion protein are commonly recorded by using cell lines and patient samples, often bearing the TEL-AML1 fusion protein for decades. To identify direct targets of the fusion protein a short-term induction of TEL-AML1 is needed. We here describe in detail the experimental procedure, quality controls and contents of the ChIP, mRNA expression and SILAC datasets associated with the study published by Linka and colleagues in the Blood Cancer Journal [1] utilizing a short term induction of TEL-AML1 in an inducible precursor B-cell line model.
- Published
- 2014
- Full Text
- View/download PDF
32. Whole-genome paired-end analysis confirms remarkable genomic stability of atypical teratoid/rhabdoid tumors.
- Author
-
Hoell JI, Gombert M, Bartenhagen C, Ginzel S, Husemann P, Felsberg J, Reifenberger G, Eggert A, Dugas M, Schönberger S, Borkhardt A, and Fischer U
- Subjects
- Female, Humans, Male, Chromosomal Proteins, Non-Histone genetics, DNA-Binding Proteins genetics, Mutation, Rhabdoid Tumor genetics, Transcription Factors genetics
- Published
- 2013
- Full Text
- View/download PDF
33. Next-generation-sequencing-based risk stratification and identification of new genes involved in structural and sequence variations in near haploid lymphoblastic leukemia.
- Author
-
Chen C, Bartenhagen C, Gombert M, Okpanyi V, Binder V, Röttgers S, Bradtke J, Teigler-Schlegel A, Harbott J, Ginzel S, Thiele R, Fischer U, Dugas M, Hu J, and Borkhardt A
- Subjects
- Adolescent, Child, Preschool, Chromosome Aberrations, Female, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Male, Oligonucleotide Array Sequence Analysis, Precursor Cell Lymphoblastic Leukemia-Lymphoma classification, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Risk Assessment, Tumor Cells, Cultured, Biomarkers, Tumor genetics, Exome genetics, Gene Expression Profiling, Haploidy, High-Throughput Nucleotide Sequencing, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Near haploidy (23-29 chromosomes) is a numerical cytogenetic aberration in childhood acute lymphoblastic leukemia (ALL) associated with particularly poor outcome. In contrast, high hyperdiploidy (51-67 chromosomes) has a favorable prognosis. Correct classification and appropriate risk stratification of near haploidy is frequently hampered by the presence of apparently high hyperdiploid clones that arise by endoreduplication of the original near haploid clone. We evaluated next-generation-sequencing (NGS) to distinguish between "high hyperdiploid" leukemic clones of near haploid and true high hyperdiploid origin. Five high hyperdiploid ALL cases and the "high hyperdiploid" cell line MHH-CALL-2, derived from a near haploid clone, were tested for uniparental isodisomy. NGS showed that all disomic chromosomes of MHH-CALL-2, but none of the patients, were of uniparental origin, thus reliably discriminating these subtypes. Whole-exome- and whole-genome-sequencing of MHH-CALL-2 revealed homozygous non-synonymous coding mutations predicted to be deleterious for the protein function of 63 genes, among them known cancer-associated genes, such as FANCA, NF1, TCF7L2, CARD11, EP400, histone demethylases, and transferases (KDM6B, KDM1A, PRDM11). Only eight of these were also, but heterozygously, mutated in the high hyperdiploid patients. Structural variations in MHH-CALL-2 include a homozygous deletion (MTAP/CDKN2A/CDKN2B/ANRIL), a homozygous inversion (NCKAP5), and an unbalanced translocation (FAM189A1). Together, the sequence variations provide MHH-CALL-2 with capabilities typically acquired during cancer development, e.g., loss of cell cycle control, enhanced proliferation, lack of DNA repair, cell death evasion, and disturbance of epigenetic gene regulation. Poorer prognosis of near haploid ALL most likely results from full penetrance of a large array of detrimental homozygous mutations., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2013
- Full Text
- View/download PDF
34. Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27.
- Author
-
Salzer E, Daschkey S, Choo S, Gombert M, Santos-Valente E, Ginzel S, Schwendinger M, Haas OA, Fritsch G, Pickl WF, Förster-Waldl E, Borkhardt A, Boztug K, Bienemann K, and Seidel MG
- Subjects
- Epstein-Barr Virus Infections immunology, Female, Humans, Infant, Lymphoproliferative Disorders immunology, Male, Pedigree, Phenotype, Severe Combined Immunodeficiency immunology, Tumor Necrosis Factor Receptor Superfamily, Member 7 metabolism, Epstein-Barr Virus Infections complications, Herpesvirus 4, Human immunology, Lymphoproliferative Disorders genetics, Lymphoproliferative Disorders virology, Severe Combined Immunodeficiency complications, Severe Combined Immunodeficiency genetics, Tumor Necrosis Factor Receptor Superfamily, Member 7 deficiency
- Abstract
CD27, a tumor necrosis factor receptor family member, interacts with CD70 and influences T-, B- and NK-cell functions. Disturbance of this axis impairs immunity and memory generation against viruses including Epstein Barr virus (EBV), influenza, and others. CD27 is commonly used as marker of memory B cells for the classification of B-cell deficiencies including common variable immune deficiency. Flow cytometric immunophenotyping including expression analysis of CD27 on lymphoid cells was followed by capillary sequencing of CD27 in index patients, their parents, and non-affected siblings. More comprehensive genetic analysis employed single nucleotide polymorphism-based homozygosity mapping and whole exome sequencing. Analysis of exome sequencing data was performed at two centers using slightly different data analysis pipelines, each based on the Genome Analysis ToolKit Best Practice version 3 recommendations. A comprehensive clinical characterization was correlated to genotype. We report the simultaneous confirmation of human CD27 deficiency in 3 independent families (8 patients) due to a homozygous mutation (p. Cys53Tyr) revealed by whole exome sequencing, leading to disruption of an evolutionarily conserved cystein knot motif of the transmembrane receptor. Phenotypes varied from asymptomatic memory B-cell deficiency (n=3) to EBV-associated hemophagocytosis and lymphoproliferative disorder (LPD; n=3) and malignant lymphoma (n=2; +1 after LPD). Following EBV infection, hypogammaglobulinemia developed in at least 3 of the affected individuals, while specific anti-viral and anti-polysaccharide antibodies and EBV-specific T-cell responses were detectable. In severely affected patients, numbers of iNKT cells and NK-cell function were reduced. Two of 8 patients died, 2 others underwent allogeneic hematopoietic stem cell transplantation successfully, and one received anti-CD20 (rituximab) therapy repeatedly. Since homozygosity mapping and exome sequencing did not reveal additional modifying factors, our findings suggest that lack of functional CD27 predisposes towards a combined immunodeficiency associated with potentially fatal EBV-driven hemo-phagocytosis, lymphoproliferation, and lymphoma development.
- Published
- 2013
- Full Text
- View/download PDF
35. Concomitant treatment with urodilatin (ularitide) does not improve renal function in patients with acute renal failure after major abdominal surgery--a randomized controlled trial.
- Author
-
Herbert MK, Ginzel S, Mühlschlegel S, and Weis KH
- Subjects
- Acute Kidney Injury etiology, Adult, Aged, Atrial Natriuretic Factor adverse effects, Critical Care, Diuretics adverse effects, Dopamine administration & dosage, Dopamine adverse effects, Double-Blind Method, Drug Therapy, Combination, Female, Furosemide administration & dosage, Furosemide adverse effects, Humans, Kidney Function Tests, Male, Middle Aged, Peptide Fragments adverse effects, Postoperative Complications etiology, Prospective Studies, Renal Replacement Therapy, Treatment Failure, Abdomen surgery, Acute Kidney Injury drug therapy, Atrial Natriuretic Factor therapeutic use, Diuretics therapeutic use, Peptide Fragments therapeutic use, Postoperative Complications drug therapy
- Abstract
Acute renal failure after major abdominal surgery is a severe complication in critically ill patients in intensive care units (ICU). The aim of the study was to investigate the effect of urodilatin on the peak value and course of serum creatinine in patients with acute renal insufficiency after major abdominal surgery and the necessity of apparatus-based renal replacement treatment. Furthermore, the incidence and nature of adverse events under urodilatin was documented. In a prospective randomized double-blind placebo-controlled study, 12 critically ill patients after major abdominal surgery with acute renal failure in an intensive care unit (ICU) received 20 ng/kg b.w./min urodilatin (ularitide, INN) or placebo in addition to the standard diuretic therapy or low-dose dopamine (2.5 micrograms/kg b.w./min) and furosemide (1000 mg/24 hr) for a minimum of 96 hours. All patients received mechanical ventilation. Both groups had similar serum creatinine values on the day before the onset of urodilatin/placebo infusion (2.80 +/- 0.24 mg/dl, 2.93 +/- 0.48 mg/dl). Peak serum creatinine was lower in the urodilatin group (4.65 +/- 0.57 mg/dl) compared to vehicle treatment (5.78 +/- 1.58 mg/dl), although the difference did not reach statistical significance (P = 0.148). The total number of hemodialyses due to oligo-/anuria and/or hyperkalemia was the same in both groups during the study. In 4 patients of the placebo group, diuresis was reduced to anuria, whereas only 1 of the patients treated with urodilatin became anuric. No hemodynamic side effects or adverse events due to urodilatin were observed. This clinical study under double blind conditions revealed that the addition of urodilatin to the standard diuretic therapy of low-dose dopamine and furosemide failed to improve renal function in patients with established acute renal failure and that urodilatin did not eliminate the need for apparatus-based renal replacement treatment.
- Published
- 1999
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.