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958 Publications visible to you, out of a total of 958
Optimization of rituximab for the treatment of DLBCL: increasing the dose for elderly male patients.
GLA - German Lymphoma Alliance

Abstract (Expand)

Male sex is associated with unfavourable pharmacokinetics and prognosis in elderly patients with diffuse large B-cell lymphoma (DLBCL). We investigated higher rituximab doses for elderly male DLBCL … patients. Elderly patients (61-80 years) received 6 cycles CHOP-14 (cyclophosphamide, doxorubicin, vincristine and prednisone at 14-day intervals) and were randomized to 8 cycles rituximab (males 500 mg/m(2) , females 375 mg/m(2) ) every 2 weeks or according to an upfront dose-dense schedule. In 268 (120 females, 148 males) no difference between the standard and the upfront dose-dense rituximab schedule was found (3-year PFS 72% vs. 74%; OS 74% vs. 77%; P = 0.651). The 500 mg/m(2) dose of rituximab for male patients was associated with serum levels and exposure times slightly better than in females and a male/female hazard ratio of 0.9 for progression-free survival (PFS) and 0.8 for overall survival. For elderly males, 500 mg/m(2) was not more toxic than 375 mg/m(2) rituximab, but improved PFS by 32.5% (P = 0.039), with a trend for a (30%) better overall survival (P = 0.076) in a planned subgroup analysis adjusting for International Prognostic Index risk factors. We conclude that the higher rituximab dose for elderly male patients abrogated the adverse prognosis of male sex without increasing toxicity. In the era of personalized medicine, sex-specific pharmacokinetics and toxicities should be investigated for all drugs where these parameters impact on outcome.

Authors: M. Pfreundschuh, N. Murawski, S. Zeynalova, M. Ziepert, M. Loeffler, M. Hanel, J. Dierlamm, U. Keller, M. Dreyling, L. Truemper, N. Frickhofen, A. N. Hunerliturkoglu, N. Schmitz, V. Poschel, T. Rixecker, C. Berdel, C. Rube, G. Held, C. Zwick

Date Published: 11th Oct 2017

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma, diffuse large B-cell lymphoma

Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease
Genetical Statistics and Systems Biology

Abstract (Expand)

Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O2). Regardless, the primary molecular driver of the disease … remains elusive. We discover significant enrichment for SNPs in the PDGF-R\textgreeka gene in preterms with nCLD and directly test the effect of PDGF-R\textgreeka haploinsufficiency on the development of nCLD using a preclinical mouse model of MV-O2 In the context of MV-O2, attenuated PDGF signaling independently contributes to defective septation and endothelial cell apoptosis stemming from a PDGF-R\textgreeka-dependent reduction in lung VEGF-A. TGF-\textgreekb contributes to the PDGF-R\textgreeka-dependent decrease in myofibroblast function. Remarkably, endotracheal treatment with exogenous PDGF-A rescues both the lung defects in haploinsufficient mice undergoing MV-O2 Overall, our results establish attenuated PDGF signaling as an important driver of nCLD pathology with provision of PDGF-A as a protective strategy for newborns undergoing MV-O2.

Authors: Prajakta Oak, Tina Pritzke, Isabella Thiel, Markus Koschlig, Daphne S. Mous, Anita Windhorst, Noopur Jain, Oliver Eickelberg, Kai Foerster, Andreas Schulze, Wolfgang Goepel, Tobias Reicherzer, Harald Ehrhardt, Robbert J. Rottier, Peter Ahnert, Ludwig Gortner, Tushar J. Desai, Anne Hilgendorff

Date Published: 9th Oct 2017

Publication Type: Journal article

TP53 mutation and survival in aggressive B cell lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

TP53 is mutated in 20-25% of aggressive B-cell lymphoma (B-NHL). To date, no studies have addressed the impact of TP53 mutations in prospective clinical trial cohorts. To evaluate the impact of TP53 … mutation to current risk models in aggressive B-NHL, we investigated TP53 gene mutations within the RICOVER-60 trial. Of 1,222 elderly patients (aged 61-80 years) enrolled in the study and randomized to six or eight cycles of CHOP-14 with or without Rituximab (NCT00052936), 265 patients were analyzed for TP53 mutations. TP53 mutations were demonstrated in 63 of 265 patients (23.8%). TP53 mutation was associated with higher LDH (65% vs. 37%; p < 0.001), higher international prognostic index-Scores (IPI 4/5 27% vs. 12%; p = 0.025) and B-symptoms (41% vs. 24%; p = 0.011). Patients with TP53 mutation were less likely to obtain a complete remission CR/CRu (CR unconfirmed) 61.9% (mut) vs. 79.7% (wt) (p = 0.007). TP53 mutations were associated with decreased event-free (EFS), progression-free (PFS) and overall survival (OS) (median observation time of 40.2 months): the 3 year EFS, PFS and OS were 42% (vs. 60%; p = 0.012), 42% (vs. 67.5%; p < 0.001) and 50% (vs. 76%; p < 0.001) for the TP53 mutation group. In a Cox proportional hazard analysis adjusting for IPI-factors and treatment arms, TP53 mutation was shown to be an independent predictor of EFS (HR 1.5), PFS (HR 2.0) and OS (HR 2.3; p < 0.001). TP53 mutations are independent predictors of survival in untreated patients with aggressive CD20+ lymphoma. TP53 mutations should be considered for risk models in DLBCL and strategies to improve outcome for patients with mutant TP53 must be developed.

Authors: T. Zenz, M. Kreuz, M. Fuge, W. Klapper, H. Horn, A. M. Staiger, D. Winter, H. Helfrich, J. Huellein, M. L. Hansmann, H. Stein, A. Feller, P. Moller, N. Schmitz, L. Trumper, M. Loeffler, R. Siebert, A. Rosenwald, G. Ott, M. Pfreundschuh, S. Stilgenbauer

Date Published: 1st Oct 2017

Publication Type: Journal article

Human Diseases: non-Hodgkin lymphoma, B-cell lymphoma

IRS1 DNA promoter methylation and expression in human adipose tissue are related to fat distribution and metabolic traits.
LHA - Leipzig Health Atlas

Abstract (Expand)

The SNP variant rs2943650 near IRS1 gene locus was previously associated with decreased body fat and IRS1 gene expression as well as an adverse metabolic profile in humans. Here, we hypothesize that … these effects may be mediated by an interplay with epigenetic alterations. We measured IRS1 promoter DNA methylation and mRNA expression in paired human subcutaneous and omental visceral adipose tissue samples (SAT and OVAT) from 146 and 41 individuals, respectively. Genotyping of rs2943650 was performed in all individuals (N = 146). We observed a significantly higher IRS1 promoter DNA methylation in OVAT compared to SAT (N = 146, P = 8.0 x 10(-6)), while expression levels show the opposite effect direction (N = 41, P = 0.011). OVAT and SAT methylation correlated negatively with IRS1 gene expression in obese subjects (N = 16, P = 0.007 and P = 0.010). The major T-allele is related to increased DNA methylation in OVAT (N = 146, P = 0.019). Finally, DNA methylation and gene expression in OVAT correlated with anthropometric traits (waist- circumference waist-to-hip ratio) and parameters of glucose metabolism in obese individuals. Our data suggest that the association between rs2943650 near the IRS1 gene locus with clinically relevant variables may at least be modulated by changes in DNA methylation that translates into altered IRS1 gene expression.

Authors: K. Rohde, M. Klos, L. Hopp, X. Liu, M. Keller, M. Stumvoll, A. Dietrich, M. R. Schon, D. Gartner, T. Lohmann, M. Dressler, P. Kovacs, H. Binder, M. Bluher, Y. Bottcher

Date Published: 28th Sep 2017

Publication Type: Not specified

Genome-Wide Association Analysis for Severity of Coronary Artery Disease Using the Gensini Scoring System
Genetical Statistics and Systems Biology

Abstract (Expand)

Coronary artery disease (CAD) has a complex etiology involving numerous environmental and genetic factors of disease risk. To date, the genetic 9p21 locus represents the most robust genetic finding for … prevalent and incident CAD. However, limited information is available on the genetic background of the severity and distribution of CAD. CAD manifests itself as stable CAD or acute coronary syndrome. The Gensini score quantifies the extent CAD but requires coronary angiography. Here, we aimed to identify novel genetic variants associated with Gensini score severity and distribution of CAD. A two-stage approach including a discovery and a replication stage was used to assess genetic variants. In the discovery phase, a meta-analysis of genome-wide association data of 4,930 CAD-subjects assessed by the Gensini score was performed. Selected single nucleotide polymorphisms (SNPs) were replicated in 2,283 CAD-subjects by de novo genotyping. We identified genetic loci located on chromosome 2 and 9 to be associated with Gensini score severity and distribution of CAD in the discovery stage. Although the loci on chromosome 2 could not be replicated in the second stage, the known CAD-locus on chromosome 9p21, represented by rs133349, was identified and, thus, was confirmed as risk locus for CAD severity.

Authors: Tanja Zeller, Moritz Seiffert, Christian Müller, Markus Scholz, Anna Schäffer, Francisco Ojeda, Heinz Drexel, Axel Mündlein, Marcus E. Kleber, Winfried März, Christoph Sinning, Fabian J. Brunner, Christoph Waldeyer, Till Keller, Christoph H. Saely, Karsten Sydow, Joachim Thiery, Daniel Teupser, Stefan Blankenberg, Renate Schnabel

Date Published: 20th Sep 2017

Publication Type: Journal article

Increased Level of Interleukin 6 Associates With Increased 90-Day and 1-Year Mortality in Patients With End-Stage Liver Disease.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND & AIMS: Organ allocation for liver transplantation is based on prognosis, using the model for end-stage liver disease (MELD) or MELD including serum sodium (MELD-Na) score. These scores … do not consider systemic inflammation and septic complications. Blood level of C-reactive protein (CRP), in addition to the MELD score, associates with mortality in patients with end-stage liver disease, whereas levels of interleukin 6 (IL6) have not been systematically studied. METHODS: We performed a retrospective observational cohort study of 474 patients with end-stage liver disease (63.5% male; median age, 56.9 years), evaluated for liver transplantation in Germany, with at least 1 year of follow up. Data were collected on blood levels of CRP, IL6, and white blood cell count (WBC). Findings were analyzed in relation to mortality and compared with patients' MELD scores and MELD-Na scores. For survival analysis, the cohort was divided into quartiles of IL6, CRP, and WBC levels, as well as MELD scores. Log-rank test and the Cox proportional hazards regression model were used to compare the groups, and area under the receiver operating characteristic (AUROC) values were calculated. RESULTS: Blood levels of IL6 and MELD scores associated with mortality: none of the patients with levels of IL6 below the first quartile (below 5.3 pg/mL) died within 1 year. In contrast, 67.7% of the patients in the highest quartile of IL6 level (37.0 pg/mL or more) died within 1 year. MELD score also correlated with mortality: among patients with MELD scores below 8.7, 0.9% died within 1 year, whereas in patients with MELD scores of 18.0 or more, 67.4% died within 1 year. The predictive value of level of IL6 (AUROC, 0.940) was higher than level of CRP (AUROC, 0.866) (P = .009) or WBC (AUROC, 0.773) (P < .001) for 90-day mortality. MELD scores associated with 90-day mortality (AUROC, 0.933) (P = .756) as did MELD-Na score (AUROC, 0.946) (P = .771). Level of IL6 associated with 1-year mortality (AUROC, 0.916) to a greater extent than liver synthesis or detoxification markers international normalized ratio (AUROC, 0.839) (P = .007) or bilirubin (AUROC 0.846) (P = .007). Level of IL6 was an independent, significant risk factor for mortality after adjustment for MELD score, MELD-Na score, level of CRP, or WBC. CONCLUSIONS: In a retrospective analysis, we found high blood levels of IL6 to associate with 90-day and 1-year mortality in patients with end-stage liver disease; its predictive value was comparable to that of MELD or MELD-Na score, and was higher than that of level of CRP or WBC. Further studies should be performed to confirm the results in different cohorts.

Authors: J. Remmler, C. Schneider, T. Treuner-Kaueroff, M. Bartels, D. Seehofer, M. Scholz, T. Berg, T. Kaiser

Date Published: 19th Sep 2017

Publication Type: Journal article

Light-Weighted Automatic Import of Standardized Ontologies into the Content Management System Drupal.
Onto-Med Research Group

Abstract (Expand)

The amount of ontologies, which are utilizable for widespread domains, is growing steadily. BioPortal alone, embraces over 500 published ontologies with nearly 8 million classes. In contrast, the vast … informative content of these ontologies is only directly intelligible by experts. To overcome this deficiency it could be possible to represent ontologies as web portals, which does not require knowledge about ontologies and their semantics, but still carries as much information as possible to the end-user. Furthermore, the conception of a complex web portal is a sophisticated process. Many entities must be analyzed and linked to existing terminologies. Ontologies are a decent solution for gathering and storing this complex data and dependencies. Hence, automated imports of ontologies into web portals could support both mentioned scenarios. The Content Management System (CMS) Drupal 8 is one of many solutions to develop web presentations with less required knowledge about programming languages and it is suitable to represent ontological entities. We developed the Drupal Upper Ontology (DUO), which models concepts of Drupal's architecture, such as nodes, vocabularies and links. DUO can be imported into ontologies to map their entities to Drupal's concepts. Because of Drupal's lack of import capabilities, we implemented the Simple Ontology Loader in Drupal (SOLID), a Drupal 8 module, which allows Drupal administrators to import ontologies based on DUO. Our module generates content in Drupal from existing ontologies and makes it accessible by the general public. Moreover Drupal offers a tagging system which may be amplified with multiple standardized and established terminologies by importing them with SOLID. Our Drupal module shows that ontologies can be used to model content of a CMS and vice versa CMS are suitable to represent ontologies in a user-friendly way. Ontological entities are presented to the user as discrete pages with all appropriate properties, links and tags.

Authors: C. Beger, A. Uciteli, H. Herre

Date Published: 9th Sep 2017

Publication Type: Journal article

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