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142 Publications visible to you, out of a total of 142
Modeling combined chemo- and immunotherapy of high-grade non-Hodgkin lymphoma.
LIFE - Leipzig Research Center for Civilization Diseases, Genetical Statistics and Systems Biology

Abstract (Expand)

Moderate, but not massive intensification of CHOP-21 improves outcome in aggressive non-Hodgkin lymphoma. Adding immunotherapy with Rituximab was a break-through, but levels differences in chemotherapy. … Ongoing trials attempt to optimize R-CHOP type regimens. We present a mathematical model of chemo-immunotherapy to explain published and aiming at predicting future trials comparing R-CHOP variants. We hypothesize that, for cure, the immune system must dominate residual tumor cells at the end of treatment. Chemotherapy reduces both tumor and immune cells. Rituximab immunotherapy boosts the immune response. We translate this reasoning into a differential equations model. Model parameters are estimated using data of randomized clinical trials in elderly patients. The model explains observed hazard ratios between treatments. It explains why too intense chemotherapy could be detrimental. The model is validated predicting six published independent studies. As an application, we varied treatment schedules and predict that current R-CHOP variants have only limited optimization potential.

Authors: K. Rosch, M. Scholz, D. Hasenclever

Date Published: 16th Dec 2015

Publication Type: Not specified

Human Diseases: lymphoma

The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer.
LIFE HNC - Head and Neck Cancer Group, Genetical Statistics and Systems Biology

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, M. Rosolowski, K. Krohn, M. Kreuz, A. Boehm, A. Reiche, U. Scharrer, D. Halama, J. Bertolini, U. Bauer, D. Holzinger, M. Pawlita, J. Hess, C. Engel, D. Hasenclever, M. Scholz, P. Ahnert, H. Kirsten, A. Hemprich, C. Wittekind, O. Herbarth, F. Horn, A. Dietz, M. Loeffler

Date Published: 15th Dec 2015

Publication Type: Not specified

Human Diseases: head and neck cancer

Incremental value of Veterans Specific Activity Questionnaire and the YMCA-step test for the assessment of cardiorespiratory fitness in population-based studies.
LIFE Heart

Abstract (Expand)

BACKGROUND: Cardiorespiratory fitness is a well-established independent predictor of cardiovascular health. However, the relevance of alternative exercise and non-exercise tests for cardiorespiratory … fitness assessment in large cohorts has not been studied in detail. We aimed to evaluate the YMCA-step test and the Veterans Specific Activity Questionnaire (VSAQ) for the estimation of cardiorespiratory fitness in the general population. METHODS: One hundred and five subjects answered the VSAQ, performed the YMCA-step test and a maximal cardiopulmonary exercise test (CPX) and gave BORG ratings for both exercise tests (BORGSTEP, BORGCPX). Correlations of peak oxygen uptake on a treadmill (VO2_PEAK) with VSAQ, BORGSTEP, one-minute, post-exercise heartbeat count, and peak oxygen uptake during the step test (VO2_STEP) were determined. Moreover, the incremental values of the questionnaire and the step test in addition to other fitness-related parameters were evaluated using block-wise hierarchical regression analysis. RESULTS: Eighty-six subjects completed the step test according to the protocol. For completers, correlations of VO2_PEAK with the age- and gender-adjusted VSAQ, heartbeat count and VO2_STEP were 0.67, 0.63 and 0.49, respectively. However, using hierarchical regression analysis, age, gender and body mass index already explained 68.8% of the variance of VO2_PEAK, while the additional benefit of VSAQ was rather low (3.4%). The inclusion of BORGSTEP, heartbeat count and VO2_STEP increased R(2) by a further 2.2%, 3.3% and 5.6%, respectively, yielding a total R(2) of 83.3%. CONCLUSIONS: Neither VSAQ nor the YMCA-step test contributes sufficiently to the assessment of cardiorespiratory fitness in population-based studies.

Authors: A. Teren, S. Zachariae, F. Beutner, R. Ubrich, M. Sandri, C. Engel, M. Loffler, S. Gielen

Date Published: 15th Dec 2015

Publication Type: Not specified

Identifying neural correlates of visual consciousness with ALE meta-analyses.
LIFE Adult

Abstract (Expand)

Neural correlates of consciousness (NCC) have been a topic of study for nearly two decades. In functional imaging studies, several regions have been proposed to constitute possible candidates for NCC, … but as of yet, no quantitative summary of the literature on NCC has been done. The question whether single (striate or extrastriate) regions or a network consisting of extrastriate areas that project directly to fronto-parietal regions are necessary and sufficient neural correlates for visual consciousness is still highly debated [e.g., Rees et al., 2002, Nat Rev. Neurosci 3, 261-270; Tong, 2003, Nat Rev. Neurosci 4, 219-229]. The aim of this work was to elucidate this issue and give a synopsis of the present state of the art by conducting systematic and quantitative meta-analyses across functional magnetic resonance imaging (fMRI) studies using several standard paradigms for conscious visual perception. In these paradigms, consciousness is operationalized via perceptual changes, while the visual stimulus remains invariant. An activation likelihood estimation (ALE) meta-analysis was performed, representing the best approach for voxel-wise meta-analyses to date. In addition to computing a meta-analysis across all paradigms, separate meta-analyses on bistable perception and masking paradigms were conducted to assess whether these paradigms show common or different NCC. For the overall meta-analysis, we found significant clusters of activation in inferior and middle occipital gyrus; fusiform gyrus; inferior temporal gyrus; caudate nucleus; insula; inferior, middle, and superior frontal gyri; precuneus; as well as in inferior and superior parietal lobules. These results suggest a subcortical-extrastriate-fronto-parietal network rather than a single region that constitutes the necessary NCC. The results of our exploratory paradigm-specific meta-analyses suggest that this subcortical-extrastriate-fronto-parietal network might be differentially activated as a function of the paradigms used to probe for NCC.

Authors: S. Bisenius, S. Trapp, J. Neumann, M. L. Schroeter

Date Published: 15th Nov 2015

Publication Type: Not specified

Neural synchrony indexes impaired motor slowing after errors and novelty following white matter damage.
LIFE Adult

Abstract (Expand)

In humans, action errors and perceptual novelty elicit activity in a shared frontostriatal brain network, allowing them to adapt their ongoing behavior to such unexpected action outcomes. Healthy and … pathologic aging reduces the integrity of white matter pathways that connect individual hubs of such networks and can impair the associated cognitive functions. Here, we investigated whether structural disconnection within this network because of small-vessel disease impairs the neural processes that subserve motor slowing after errors and novelty (post-error slowing, PES; post-novel slowing, PNS). Participants with intact frontostriatal circuitry showed increased right-lateralized beta-band (12-24 Hz) synchrony between frontocentral and frontolateral electrode sites in the electroencephalogram after errors and novelty, indexing increased neural communication. Importantly, this synchrony correlated with PES and PNS across participants. Furthermore, such synchrony was reduced in participants with frontostriatal white matter damage, in line with reduced PES and PNS. The results demonstrate that behavioral change after errors and novelty result from coordinated neural activity across a frontostriatal brain network and that such cognitive control is impaired by reduced white matter integrity.

Authors: J. R. Wessel, M. Ullsperger, H. Obrig, A. Villringer, E. Quinque, M. L. Schroeter, K. J. Bretschneider, K. Arelin, E. Roggenhofer, S. Frisch, T. A. Klein

Date Published: 14th Nov 2015

Publication Type: Not specified

Resting-state functional magnetic resonance imaging of the subthalamic microlesion and stimulation effects in Parkinson's disease: Indications of a principal role of the brainstem.
LIFE Adult

Abstract (Expand)

During implantation of deep-brain stimulation (DBS) electrodes in the target structure, neurosurgeons and neurologists commonly observe a "microlesion effect" (MLE), which occurs well before … initiating subthalamic DBS. This phenomenon typically leads to a transitory improvement of motor symptoms of patients suffering from Parkinson's disease (PD). Mechanisms behind MLE remain poorly understood. In this work, we exploited the notion of ranking to assess spontaneous brain activity in PD patients examined by resting-state functional magnetic resonance imaging in response to penetration of DBS electrodes in the subthalamic nucleus. In particular, we employed a hypothesis-free method, eigenvector centrality (EC), to reveal motor-communication-hubs of the highest rank and their reorganization following the surgery; providing a unique opportunity to evaluate the direct impact of disrupting the PD motor circuitry in vivo without prior assumptions. Penetration of electrodes was associated with increased EC of functional connectivity in the brainstem. Changes in connectivity were quantitatively related to motor improvement, which further emphasizes the clinical importance of the functional integrity of the brainstem. Surprisingly, MLE and DBS were associated with anatomically different EC maps despite their similar clinical benefit on motor functions. The DBS solely caused an increase in connectivity of the left premotor region suggesting separate pathophysiological mechanisms of both interventions. While the DBS acts at the cortical level suggesting compensatory activation of less affected motor regions, the MLE affects more fundamental circuitry as the dysfunctional brainstem predominates in the beginning of PD. These findings invigorate the overlooked brainstem perspective in the understanding of PD and support the current trend towards its early diagnosis.

Authors: S. Holiga, K. Mueller, H. E. Moller, D. Urgosik, E. Ruzicka, M. L. Schroeter, R. Jech

Date Published: 29th Oct 2015

Publication Type: Not specified

Human Diseases: Parkinson's disease

Brain Arousal Regulation in Carriers of Bipolar Disorder Risk Alleles.
LIFE Adult

Abstract (Expand)

OBJECTIVES: Recent genome-wide association studies identified a number of chromosomal risk loci for bipolar disorder (BD, 'manic-depressive illness'). According to the vigilance regulation … model, the regulation of brain arousal (referred to as 'vigilance') when assessed via EEG is an emerging biomarker linked to the pathogenesis of manic and depressive episodes. On this basis, the present study aimed to assess whether carriers of BD risk alleles differ in brain arousal regulation. METHODS: Healthy participants of the population-based Leipzig Health Care Study (LIFE) underwent a 20-min eyes-closed resting EEG paradigm. Brain arousal was assessed applying the computer-based Vigilance Algorithm Leipzig (VIGALL). The primary sample (n = 540) was genotyped for ten of the most reliable BD risk variants, of which two qualified for replication (n = 509). RESULTS: Primary sample analyses revealed Bonferroni-adjusted significance for rs1006737 in CACNA1C (encoding a calcium channel subunit), with risk allele carriers exhibiting relatively steep brain arousal declines. Further, carriers of two risk alleles of rs472913 at 1p32.1 showed generally lower brain arousal levels for the duration of the resting paradigm. However, both associations failed replication. CONCLUSION: Although our initial findings are in line with the vigilance regulation model and convincing in view of the previously reported notable role of ion channelopathies in BD, our results do not provide consistent evidence for a link between BD risk variants and brain arousal regulation. Several between-sample differences may account for this inconsistency. The molecular genetics of brain arousal regulation remain to be clarified.

Authors: P. Jawinski, C. Sander, N. Mauche, J. Spada, J. Huang, A. Schmidt, M. Hantzsch, R. Burkhardt, M. Scholz, U. Hegerl, T. Hensch

Date Published: 29th Oct 2015

Publication Type: Not specified

Human Diseases: bipolar disorder

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