Abstract (Expand)

PURPOSE: The aim of this study was to test psychometric properties of the Satisfaction with Life Scale (SWLS), to provide normative values, and to analyze associations between life satisfaction and sociodemographic and behavioral data. METHODS: A German community sample (n = 9711) with an age range of 18-80 years was surveyed using the SWLS and several other questionnaires. Confirmatory factor analysis (CFA) was used to test the dimensionality of the SWLS. Invariance across gender and age groups was tested with multiple-group CFA. Associations between SWLS, sociodemographic variables, and behavioral variables were tested with ANOVAs. RESULTS: Confirmatory factorial analysis results confirmed that the SWLS is a one-dimensional scale. Measurement invariance across gender was completely confirmed, while concerning age strict measurement invariance was confirmed. The effects of gender and age on satisfaction with life were weak. Satisfaction with life was associated with fatigue (r = - .49), the mental component of quality of life (r = .45), anxiety (r = - .42), dispositional optimism (r = .41), pessimism (r = - .34), sleep quality (r = - .32), and sociodemographic factors such as marital status, income, and occupational status. Non-smokers reported higher life satisfaction than smokers. CONCLUSIONS: Because of the good psychometric properties, the SWLS can be recommended for use in epidemiological research. Normative values based on a large community sample are provided.

Authors: Andreas Hinz, I. Conrad, M. L. Schroeter, H. Glaesmer, E. Brahler, M. Zenger, R. D. Kocalevent, P. Y. Herzberg

Date Published: 29th Mar 2018

Journal: Qual Life Res

Human Diseases: Not specified

Abstract (Expand)

PURPOSE: The Sniffin' Sticks Screening 12 test is a test of olfactory performance based on pen-like odor dispensing devices. The aims of this study were to analyze the performance of this test in a general population sample and to explore associations between olfactory dysfunction and quality of life. METHODS: A large community sample (n = 7267) completed the Sniffin' Sticks Screening 12 test and several questionnaires measuring quality of life, anxiety, dispositional optimism, social support, and satisfaction with life. RESULTS: According to the criteria recommended by the test manufacturer, 5.1% of the participants were anosmic (score </= 6), 52.4% were dysosmic (7 </= score </= 10), and 42.5% were normosmic (score >/= 11). While frequencies of correct identification differed between the 12 sticks, all sticks contributed positively to the test results. The associations between olfactory functioning and quality of life variables were negligible. In the multivariate analyses, none of the associations reached the 1% significance level. CONCLUSIONS: While studies with patients in otorhinolaryngological clinics often report substantial detriments to their quality of life in relation to olfactory dysfunction, the present epidemiological study cannot confirm this association for the general population.

Authors: Andreas Hinz, Tobias Luck, Steffi Gerlinde Riedel-Heller, P. Y. Herzberg, C. Rolffs, K. Wirkner, Christoph Engel

Date Published: 21st Nov 2018

Journal: Eur Arch Otorhinolaryngol

Human Diseases: Not specified

Abstract (Expand)

AIM: We present here a novel method that enables unraveling the interplay between gene expression and DNA methylation in complex diseases such as cancer. MATERIALS & METHODS: The method is based on self-organizing maps and allows for analysis of data landscapes from 'governed by methylation' to 'governed by expression'. RESULTS: We identified regulatory modules of coexpressed and comethylated genes in high-grade gliomas: two modes are governed by genes hypermethylated and underexpressed in IDH-mutated cases, while two other modes reflect immune and stromal signatures in the classical and mesenchymal subtypes. A fifth mode with proneural characteristics comprises genes of repressed and poised chromatin states active in healthy brain. Two additional modes enrich genes either in active or repressed chromatin states. CONCLUSION: The method disentangles the interplay between gene expression and methylation. It has the potential to integrate also mutation and copy number data and to apply to large sample cohorts.

Authors: Lydia Hopp, Henry Löffler-Wirth, J. Galle, Hans Binder

Date Published: 12th Jun 2018

Journal: Epigenomics

Human Diseases: glioblastoma multiforme

Abstract (Expand)

BACKGROUND: Haematotoxicity of conventional chemotherapies often results in delays of treatment or reduction of chemotherapy dose. To ameliorate these side-effects, patients are routinely treated with blood transfusions or haematopoietic growth factors such as erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF). For the latter ones, pharmaceutical derivatives are available, which differ in absorption kinetics, pharmacokinetic and -dynamic properties. Due to the complex interaction of cytotoxic effects of chemotherapy and the stimulating effects of different growth factor derivatives, optimal treatment is a non-trivial task. In the past, we developed mathematical models of thrombopoiesis, granulopoiesis and erythropoiesis under chemotherapy and growth-factor applications which can be used to perform clinically relevant predictions regarding the feasibility of chemotherapy schedules and cytopenia prophylaxis with haematopoietic growth factors. However, interactions of lineages and growth-factors were ignored so far. RESULTS: To close this gap, we constructed a hybrid model of human granulopoiesis and erythropoiesis under conventional chemotherapy, G-CSF and EPO applications. This was achieved by combining our single lineage models of human erythropoiesis and granulopoiesis with a common stem cell model. G-CSF effects on erythropoiesis were also implemented. Pharmacodynamic models are based on ordinary differential equations describing proliferation and maturation of haematopoietic cells. The system is regulated by feedback loops partly mediated by endogenous and exogenous EPO and G-CSF. Chemotherapy is modelled by depletion of cells. Unknown model parameters were determined by fitting the model predictions to time series data of blood counts and cytokine profiles. Data were extracted from literature or received from cooperating clinical study groups. Our model explains dynamics of mature blood cells and cytokines after growth-factor applications in healthy volunteers. Moreover, we modelled 15 different chemotherapeutic drugs by estimating their bone marrow toxicity. Taking into account different growth-factor schedules, this adds up to 33 different chemotherapy regimens explained by the model. CONCLUSIONS: We conclude that we established a comprehensive biomathematical model to explain the dynamics of granulopoiesis and erythropoiesis under combined chemotherapy, G-CSF, and EPO applications. We demonstrate how it can be used to make predictions regarding haematotoxicity of yet untested chemotherapy and growth-factor schedules.

Authors: S. Schirm, Christoph Engel, Markus Löffler, Markus Scholz

Date Published: 26th May 2014

Journal: Theor Biol Med Model

Human Diseases: leukemia, anemia

Abstract (Expand)

Anaemia is a common haematologic side effect of dose-dense multi-cycle cytotoxic polychemotherapy requiring erythrocyte transfusions or erythropoietin (EPO) administration. To simulate the effectiveness of different EPO application schedules, we performed both modelling of erythropoiesis under chemotherapy and pharmacokinetic and dynamic modelling of EPO applications in the framework of a single comprehensive biomathematical model. For this purpose, a cell kinetic model of bone marrow erythropoiesis was developed that is based on a set of differential compartment equations describing proliferation and maturation of erythropoietic cell stages. The system is regulated by several feedback loops comprising those mediated by EPO. We added a model of EPO absorption after injection at different sites and a pharmacokinetic model of EPO derivatives to account for the effects of external EPO applications. Chemotherapy is modelled by a transient depletion of bone marrow cell stages. Unknown model parameters were determined by fitting the predictions of the model to data sets of circulating erythrocytes, haemoglobin, haematocrit, percentage of reticulocytes or EPO serum concentrations derived from the literature or cooperating clinical study groups. Parameter fittings resulted in a good agreement of model and data. Depending on site of injection and derivative (Alfa, Beta, Delta, Darbepoetin), nine groups of EPO applications were distinguished differing in either absorption kinetics or pharmacokinetics. Finally, eight different chemotherapy protocols were modelled. The model was validated on the basis of scenarios not used for parameter fitting. Simulations were performed to analyze the impact of EPO applications on the risk of anaemia during chemotherapy. We conclude that we established a model of erythropoiesis under chemotherapy that explains a large set of time series data under EPO and chemotherapy applications. It allows predictions regarding yet untested EPO schedules. Prospective clinical studies are needed to validate model predictions and to explore the feasibility and effectiveness of the proposed schedules.

Authors: S. Schirm, Christoph Engel, Markus Löffler, Markus Scholz

Date Published: 12th Jun 2013

Journal: PLoS One

Human Diseases: anemia

Abstract (Expand)

Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.

Authors: G. Wichmann, Maciej Rosolowski, K. Krohn, Markus Kreuz, A. Boehm, A. Reiche, U. Scharrer, D. Halama, J. Bertolini, U. Bauer, D. Holzinger, M. Pawlita, J. Hess, Christoph Engel, D. Hasenclever, Markus Scholz, P. Ahnert, Toralf Kirsten, A. Hemprich, C. Wittekind, O. Herbarth, F. Horn, A. Dietz, Markus Löffler

Date Published: 15th Dec 2015

Journal: Int J Cancer

Human Diseases: head and neck cancer

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, Markus Löffler

Date Published: 1st Dec 2009

Journal: J Clin Oncol

Human Diseases: brain glioma, glioblastoma multiforme

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