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Das Drei-Ebenen-Metamodell für die Modellierung und Beschreibung von Informationssystemen (3LGM^2 V3)
Management of health information systems

Abstract

Not specified

Authors: Alfred Winter, L. Ißler, Franziska Jahn, A. Strübing, T. Wendt

Date Published: 2010

Publication Type: Misc

Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

PURPOSE To estimate the risk for contralateral breast cancer in members of BRCA1- and BRCA2-positive families and to determine predictive risk factors. PATIENTS AND METHODS A retrospective, multicenter, …er, cohort study was performed from 1996 until 2008 and comprised 2,020 women with unilateral breast cancer (index patients, n = 978; relatives, n = 1.42) from 978 families who had a BRCA1 or BRCA2 mutation. Cox regression analysis was applied to assess the association of age at first breast cancer with time from first to contralateral breast cancer, stratified by the affected BRCA gene. RESULTS The cumulative risk for contralateral breast cancer 25 years after first breast cancer was 47.4% (95% CI, 38.8% to 56.0%) for patients from families with BRCA1 or BRCA2 mutations. Members of families with BRCA1 mutations had a 1.6-fold (95% CI, 1.2-fold to 2.3-fold) higher risk of contralateral breast cancer than members of families with BRCA2 mutations. Younger age at first breast cancer was associated with a significantly higher risk of contralateral breast cancer in patients with BRCA1 mutation, and a trend was observed in patients with BRCA2 mutation. After 25 years, 62.9% (95% CI, 50.4% to 75.4%) of patients with BRCA1 mutation who were younger than 40 years of age at first breast cancer developed contralateral breast cancer, compared with only 19.6% (95% CI, 5.3% to 33.9%) of those who were older than 50 years of age at first breast cancer. CONCLUSION Contralateral breast cancer risk depends on age at first breast cancer and on the affected BRCA gene, and this risk should be considered in treatment planning.

Authors: Monika K. Graeser, Christoph Engel, Kerstin Rhiem, Dorothea Gadzicki, Ulrich Bick, Karin Kast, Ursula G. Froster, Bettina Schlehe, Astrid Bechtold, Norbert Arnold, Sabine Preisler-Adams, Carolin Nestle-Kraemling, Mohammad Zaino, Markus Loeffler, Marion Kiechle, Alfons Meindl, Dominic Varga, Rita K. Schmutzler

Date Published: 10th Dec 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network.
GGN - German Glioma Network

Abstract (Expand)

PURPOSE: The prognostic value of genetic alterations characteristic of glioblastoma in patients treated according to present standards of care is unclear. PATIENTS AND METHODS: Three hundred one patients … with glioblastoma were prospectively recruited between October 2004 and December 2006 at the clinical centers of the German Glioma Network. Two hundred fifty-eight patients had radiotherapy, 199 patients had temozolomide, 189 had both, and seven had another chemotherapy as the initial treatment. The tumors were investigated for TP53 mutation, p53 immunoreactivity, epidermal growth factor receptor, cyclin-dependent kinase CDK 4 or murine double minute 2 amplification, CDKN2A homozygous deletion, allelic losses on chromosome arms 1p, 9p, 10q, and 19q, O(6)-methylguanine methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutations. RESULTS: Median progression-free (PFS) and overall survival (OS) were 6.8 and 12.5 months. Multivariate analysis revealed younger age, higher performance score, MGMT promoter methylation, and temozolomide radiochemotherapy as independent factors associated with longer OS. MGMT promoter methylation was associated with longer PFS (relative risk [RR], 0.5; 95% CI, 0.38 to 0.68; P < .001) and OS (RR, 0.39; 95% CI, 0.28 to 0.54; P < .001) in patients receiving temozolomide. IDH1 mutations were associated with prolonged PFS (RR, 0.42; 95% CI, 0.19 to 0.91; P = .028) and a trend for prolonged OS (RR, 0.43; 95% CI, 0.15 to 1.19; P = .10). No other molecular factor was associated with outcome. CONCLUSION: Molecular changes associated with gliomagenesis do not predict response to therapy in glioblastoma patients managed according to current standards of care. MGMT promoter methylation and IDH1 mutational status allow for stratification into prognostically distinct subgroups.

Authors: M. Weller, J. Felsberg, C. Hartmann, H. Berger, J. P. Steinbach, J. Schramm, M. Westphal, G. Schackert, M. Simon, J. C. Tonn, O. Heese, D. Krex, G. Nikkhah, T. Pietsch, O. Wiestler, G. Reifenberger, A. von Deimling, M. Loeffler

Date Published: 1st Dec 2009

Publication Type: Not specified

Human Diseases: brain glioma, glioblastoma multiforme

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general …l population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

Authors: A. Osorio, R. L. Milne, G. Pita, P. Peterlongo, T. Heikkinen, J. Simard, G. Chenevix-Trench, A. B. Spurdle, J. Beesley, X. Chen, S. Healey, S. L. Neuhausen, Y. C. Ding, F. J. Couch, X. Wang, N. Lindor, S. Manoukian, M. Barile, A. Viel, L. Tizzoni, C. I. Szabo, L. Foretova, M. Zikan, K. Claes, M. H. Greene, P. Mai, G. Rennert, F. Lejbkowicz, O. Barnett-Griness, I. L. Andrulis, H. Ozcelik, N. Weerasooriya, A-M Gerdes, M. Thomassen, D. G. Cruger, M. A. Caligo, E. Friedman, B. Kaufman, Y. Laitman, S. Cohen, T. Kontorovich, R. Gershoni-Baruch, E. Dagan, H. Jernström, M. S. Askmalm, B. Arver, B. Malmer, S. M. Domchek, K. L. Nathanson, J. Brunet, T. Ramón Y Cajal, D. Yannoukakos, U. Hamann, F. B. L. Hogervorst, S. Verhoef, E. B. Gómez García, J. T. Wijnen, A. van den Ouweland, D. F. Easton, S. Peock, M. Cook, C. T. Oliver, D. Frost, C. Luccarini, D. G. Evans, F. Lalloo, R. Eeles, G. Pichert, J. Cook, S. Hodgson, P. J. Morrison, F. Douglas, A. K. Godwin, O. M. Sinilnikova, L. Barjhoux, D. Stoppa-Lyonnet, V. Moncoutier, S. Giraud, C. Cassini, L. Olivier-Faivre, F. Révillion, J-P Peyrat, D. Muller, J-P Fricker, H. T. Lynch, E. M. John, S. Buys, M. Daly, J. L. Hopper, M. B. Terry, A. Miron, Y. Yassin, D. Goldgar, C. F. Singer, D. Gschwantler-Kaulich, G. Pfeiler, A-C Spiess, Thomas v. O. Hansen, O. T. Johannsson, T. Kirchhoff, K. Offit, K. Kosarin, M. Piedmonte, G. C. Rodriguez, K. Wakeley, J. F. Boggess, J. Basil, P. E. Schwartz, S. V. Blank, A. E. Toland, M. Montagna, C. Casella, E. N. Imyanitov, A. Allavena, R. K. Schmutzler, B. Versmold, C. Engel, A. Meindl, N. Ditsch, N. Arnold, D. Niederacher, H. Deissler, B. Fiebig, R. Varon-Mateeva, D. Schaefer, U. G. Froster, T. Caldes, M. de La Hoya, L. McGuffog, A. C. Antoniou, H. Nevanlinna, P. Radice, J. Benítez

Date Published: 1st Dec 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide-induced granulocytopaenia
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES\backslashr\backslashnRecombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used as treatment for granulocytopaenia during cytotoxic chemotherapy; however, optimal … scheduling of this pharmaceutical is unknown. Biomathematical models can help to pre-select optimal application schedules but precise pharmacokinetic properties of the pharmaceuticals are required at first. In this study, we have aimed to construct a pharmacokinetic model of G-CSF derivatives filgrastim and pegfilgrastim in mice.\backslashr\backslashnMETHODS\backslashr\backslashnHealthy CD-1 mice and those with cyclophosphamide-induced granulocytopaenia were studied after administration of filgrastim and pegfilgrastim in different dosing and timing schedules. Close meshed time series of granulocytes and G-CSF plasma concentrations were determined. An ordinary differential equations model of pharmacokinetics was constructed on the basis of known mechanisms of drug distribution and degradation.\backslashr\backslashnRESULTS\backslashr\backslashnPredictions of the model fit well with all experimental data for both filgrastim and pegfilgrastim. We obtained a unique parameter setting for all experimental scenarios. Differences in pharmacokinetics between filgrastim and pegfilgrastim can be explained by different estimates of model parameters rather than by different model mechanisms. Parameter estimates with respect to distribution and clearance of the drug derivatives are in agreement with qualitative experimental results.\backslashr\backslashnCONCLUSION\backslashr\backslashnDynamics of filgrastim and pegfilgrastim plasma levels can be explained by the same pharmacokinetic model but different model parameters. Beause of a strong clearance mechanism mediated by granulocytes, granulocytotic and granulocytopaenic conditions must be studied simultaneously to construct a reliable model. The pharmacokinetic model will be extended to a murine model of granulopoiesis under chemotherapy and G-CSF application.

Authors: Markus Scholz, Manuela Ackermann, Christoph Engel, Frank Emmrich, Markus Loeffler, Manja Kamprad

Date Published: 1st Dec 2009

Publication Type: Journal article

Pharmacokinetic and pharmacodynamic modelling of the novel human granulocyte colony-stimulating factor derivative Maxy-G34 and pegfilgrastim in rats
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES\backslashr\backslashnThis study aims to compare pharmacokinetics and pharmacodynamics of pegfilgrastim, a pharmaceutical recombinant human granulocyte colony-stimulating factor (rhG-CSF), … with that of a newly developed reagent, Maxy-G34. This comparison was performed using rat experiments and biomathematical modelling of granulopoiesis.\backslashr\backslashnMETHODS\backslashr\backslashnHealthy rats and those with cyclophosphamide-induced neutropenia were treated with either pegfilgrastim or Maxy-G34 under various schedules. Time courses of absolute neutrophil count (ANC) and G-CSF serum level were measured and we constructed a combined pharmacokinetic/pharmacodynamic model of both drugs. Neutropenic episodes were assessed by experimental data and model simulations.\backslashr\backslashnRESULTS\backslashr\backslashnBoth Pegfilgrastim and Maxy-G34 showed strong dose-dependent efficacy in reducing neutropenic episodes. However, time courses of ANC and G-CSF serum levels were markedly different. The biomathematical model showed good agreement with these data. We estimated that differences between the two drugs could be explained by lower bioavailability and reduced elimination of Maxy-G34. Based on the data and model interpolations, we estimated that Maxy-G34 is superior in reducing neutropenic episodes. Also, we predicted that G-CSF administration 48 h after cyclophosphamide would be superior to its administration after 2 or 24 h, for both derivatives.\backslashr\backslashnCONCLUSION\backslashr\backslashnMaxy-G34 is a highly potent drug for stimulation of neutrophil production in rats. By our modelling approach, we quantified differences between Maxy-G34 and pegfilgrastim, related to pharmacokinetic parameters. Model simulations can be used to estimate optimal dosing and timing options in the present preclinical rat model.

Authors: Markus Scholz, Christoph Engel, D. Apt, S. L. Sankar, E. Goldstein, Markus Loeffler

Date Published: 1st Dec 2009

Publication Type: Journal article

Genetic variation and recent positive selection in worldwide human populations: evidence from nearly 1 million SNPs
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnGenome-wide scans of hundreds of thousands of single-nucleotide polymorphisms (SNPs) have resulted in the identification of new susceptibility variants to common diseases … and are providing new insights into the genetic structure and relationships of human populations. Moreover, genome-wide data can be used to search for signals of recent positive selection, thereby providing new insights into the genetic adaptations that occurred as modern humans spread out of Africa and around the world.\backslashr\backslashnMETHODOLOGY\backslashr\backslashnWe genotyped approximately 500,000 SNPs in 255 individuals (5 individuals from each of 51 worldwide populations) from the Human Genome Diversity Panel (HGDP-CEPH). When merged with non-overlapping SNPs typed previously in 250 of these same individuals, the resulting data consist of over 950,000 SNPs. We then analyzed the genetic relationships and ancestry of individuals without assigning them to populations, and we also identified candidate regions of recent positive selection at both the population and regional (continental) level.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnOur analyses both confirm and extend previous studies; in particular, we highlight the impact of various dispersals, and the role of substructure in Africa, on human genetic diversity. We also identified several novel candidate regions for recent positive selection, and a gene ontology (GO) analysis identified several GO groups that were significantly enriched for such candidate genes, including immunity and defense related genes, sensory perception genes, membrane proteins, signal receptors, lipid binding/metabolism genes, and genes involved in the nervous system. Among the novel candidate genes identified are two genes involved in the thyroid hormone pathway that show signals of selection in African Pygmies that may be related to their short stature.

Authors: David López Herráez, Marc Bauchet, Kun Tang, Christoph Theunert, Irina Pugach, Jing Li, Madhusudan R. Nandineni, Arnd Gross, Markus Scholz, Mark Stoneking

Date Published: 18th Nov 2009

Publication Type: Journal article

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