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Large histological serial sections for computational tissue volume reconstruction.
ProstataCA

Abstract (Expand)

OBJECTIVES: A proof of principle study was conducted for microscopic tissue volume reconstructions using a new image processing chain operating on alternately stained large histological serial sections. … METHODS: Digital histological images were obtained from conventional brightfield transmitted light microscopy. A powerful nonparametric nonlinear optical flow-based registration approach was used. In order to apply a simple but computationally feasible sum-of-squared-differences similarity measure even in case of differing histological stainings, a new consistent tissue segmentation procedure was placed upstream. RESULTS: Two reconstructions from uterine cervix carcinoma specimen were accomplished, one alternately stained with p16(INK4a) (surrogate tumor marker) and H&E (routine reference), and another with three different alternate stainings, H&E, p16(INK4a), and CD3 (a T-lymphocyte marker). For both cases, due to our segmentation-based reference-free nonlinear registration procedure, resulting tissue reconstructions exhibit utmost smooth image-to-image transitions without impairing warpings. CONCLUSIONS: Our combination of modern nonparametric nonlinear registration and consistent tissue segmentation has turned out to provide a superior tissue reconstruction quality.

Authors: U. D. Braumann, N. Scherf, J. Einenkel, L. C. Horn, N. Wentzensen, M. Loeffler, J. P. Kuska

Date Published: 17th Oct 2007

Publication Type: Not specified

Human Diseases: cervical cancer

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated … in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.

Authors: Michael T. Parsons, Emma Tudini, Hongyan Li, Eric Hahnen, Barbara Wappenschmidt, Lidia Feliubadaló, Cora M. Aalfs, Simona Agata, Kristiina Aittomäki, Elisa Alducci, María Concepción Alonso-Cerezo, Norbert Arnold, Bernd Auber, Rachel Austin, Jacopo Azzollini, Judith Balmaña, Elena Barbieri, Claus R. Bartram, Ana Blanco, Britta Blümcke, Sandra Bonache, Bernardo Bonanni, Åke Borg, Beatrice Bortesi, Joan Brunet, Carla Bruzzone, Karolin Bucksch, Giulia Cagnoli, Trinidad Caldés, Almuth Caliebe, Maria A. Caligo, Mariarosaria Calvello, Gabriele L. Capone, Sandrine M. Caputo, Ileana Carnevali, Estela Carrasco, Virginie Caux-Moncoutier, Pietro Cavalli, Giulia Cini, Edward M. Clarke, Paola Concolino, Elisa J. Cops, Laura Cortesi, Fergus J. Couch, Esther Darder, Miguel de La Hoya, Michael Dean, Irmgard Debatin, Jesús Del Valle, Capucine Delnatte, Nicolas Derive, Orland Diez, Nina Ditsch, Susan M. Domchek, Véronique Dutrannoy, Diana M. Eccles, Hans Ehrencrona, Ute Enders, D. Gareth Evans, Ulrike Faust, Ute Felbor, Irene Feroce, Miriam Fine, Henrique C. R. Galvao, Gaetana Gambino, Andrea Gehrig, Francesca Gensini, Anne-Marie Gerdes, Aldo Germani, Jutta Giesecke, Viviana Gismondi, Carolina Gómez, Encarna B. Gómez Garcia, Sara González, Elia Grau, Sabine Grill, Eva Gross, Aliana Guerrieri-Gonzaga, Marine Guillaud-Bataille, Sara Gutiérrez-Enríquez, Thomas Haaf, Karl Hackmann, Thomas v. O. Hansen, Marion Harris, Jan Hauke, Tilman Heinrich, Heide Hellebrand, Karen N. Herold, Ellen Honisch, Judit Horvath, Claude Houdayer, Verena Hübbel, Silvia Iglesias, Angel Izquierdo, Paul A. James, Linda A. M. Janssen, Udo Jeschke, Silke Kaulfuß, Katharina Keupp, Marion Kiechle, Alexandra Kölbl, Sophie Krieger, Torben A. Kruse, Anders Kvist, Fiona Lalloo, Mirjam Larsen, Vanessa L. Lattimore, Charlotte Lautrup, Susanne Ledig, Elena Leinert, Alexandra L. Lewis, Joanna Lim, Markus Loeffler, Adrià López-Fernández, Emanuela Lucci-Cordisco, Nicolai Maass, Siranoush Manoukian, Monica Marabelli, Laura Matricardi, Alfons Meindl, Rodrigo D. Michelli, Setareh Moghadasi, Alejandro Moles-Fernández, Marco Montagna, Gemma Montalban, Alvaro N. Monteiro, Eva Montes, Luigi Mori, Lidia Moserle, Clemens R. Müller, Christoph Mundhenke, Nadia Naldi, Katherine L. Nathanson, Matilde Navarro, Heli Nevanlinna, Cassandra B. Nichols, Dieter Niederacher, Henriette R. Nielsen, Kai-Ren Ong, Nicholas Pachter, Edenir I. Palmero, Laura Papi, Inge Sokilde Pedersen, Bernard Peissel, Pedro Pérez-Segura, Katharina Pfeifer, Marta Pineda, Esther Pohl-Rescigno, Nicola K. Poplawski, Berardino Porfirio, Anne S. Quante, Juliane Ramser, Rui M. Reis, Françoise Revillion, Kerstin Rhiem, Barbara Riboli, Julia Ritter, Daniela Rivera, Paula Rofes, Andreas Rump, Monica Salinas, Ana María Sánchez de Abajo, Gunnar Schmidt, Ulrike Schoenwiese, Jochen Seggewiß, Ares Solanes, Doris Steinemann, Mathias Stiller, Dominique Stoppa-Lyonnet, Kelly J. Sullivan, Rachel Susman, Christian Sutter, Sean V. Tavtigian, Soo H. Teo, Alex Teulé, Mads Thomassen, Maria Grazia Tibiletti, Silvia Tognazzo, Amanda E. Toland, Eva Tornero, Therese Törngren, Sara Torres-Esquius, Angela Toss, Alison H. Trainer, Christi J. van Asperen, Marion T. van Mackelenbergh, Liliana Varesco, Gardenia Vargas-Parra, Raymonda Varon, Ana Vega, Ángela Velasco, Anne-Sophie Vesper, Alessandra Viel, Maaike P. G. Vreeswijk, Sebastian A. Wagner, Anke Waha, Logan C. Walker, Rhiannon J. Walters, Shan Wang-Gohrke, Bernhard H. F. Weber, Wilko Weichert, Kerstin Wieland, Lisa Wiesmüller, Isabell Witzel, Achim Wöckel, Emma R. Woodward, Silke Zachariae, Valentina Zampiga, Christine Zeder-Göß, Conxi Lázaro, Arcangela de Nicolo, Paolo Radice, Christoph Engel, Rita K. Schmutzler, David E. Goldgar, Amanda B. Spurdle

Date Published: 1st Sep 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Leipziger \textquotedblFast-track\textquotedbl-Protokoll in der Kardioanästhesie. Effektiv, sicher und ökonomisch sinnvoll
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnIn November 2005 a complex, multimodal anesthesia fast-track protocol (FTP) was introduced for elective cardiac surgery patients in the Cardiac Center of the University … of Leipzig which included changing from an opioid regime to remifentanil and postoperative treatment in a special post-anesthesia recovery and care unit. The goal was to speed up recovery times while maintaining safety and improving costs.\backslashr\backslashnMETHOD\backslashr\backslashnA total of 421 patients who underwent the FTP and were treated in the special recovery room were analyzed retrospectively. These patients were compared with patients who had been treated by a standard protocol (SP) prior to instituting the FTP. Primary outcomes were time to extubation, length of stay in the intensive care unit (ICU) and treatment costs.\backslashr\backslashnRESULTS\backslashr\backslashnThe times to extubation were significantly shorter in the FTP group with 75 min (range 45-110 min) compared to 900 min (range 600-1140 min) in the SP group. Intensive care unit stay and hospital length of stay were also significantly shorter in the FTP group (p\textless0.01). The reduction of treatment costs of intensive care for FTP patients was 53.5% corresponding to savings of EUR 738 per patient in the FTP group compared with the SP group.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnThe Leipzig fast-track protocol for cardio-anesthesia including the central elements of switching opiate therapy to remifentanil and switching patient recovery to a special post-anesthesia recovery and care unit, shortened therapy times, is safe and economically effective. BACKGROUND In November 2005 a complex, multimodal anesthesia fast-track protocol (FTP) was introduced for elective cardiac surgery patients in the Cardiac Center of the University of Leipzig which included changing from an opioid regime to remifentanil and postoperative treatment in a special post-anesthesia recovery and care unit. The goal was to speed up recovery times while maintaining safety and improving costs. METHOD A total of 421 patients who underwent the FTP and were treated in the special recovery room were analyzed retrospectively. These patients were compared with patients who had been treated by a standard protocol (SP) prior to instituting the FTP. Primary outcomes were time to extubation, length of stay in the intensive care unit (ICU) and treatment costs. RESULTS The times to extubation were significantly shorter in the FTP group with 75 min (range 45-110 min) compared to 900 min (range 600-1140 min) in the SP group. Intensive care unit stay and hospital length of stay were also significantly shorter in the FTP group (p\textless0.01). The reduction of treatment costs of intensive care for FTP patients was 53.5% corresponding to savings of EUR 738 per patient in the FTP group compared with the SP group. CONCLUSIONS The Leipzig fast-track protocol for cardio-anesthesia including the central elements of switching opiate therapy to remifentanil and switching patient recovery to a special post-anesthesia recovery and care unit, shortened therapy times, is safe and economically effective.

Authors: D. Häntschel, Jens Fassl, Markus Scholz, Marcus Sommer, Anne-Kathrin Funkat, M. Wittmann, Joerg Ender

Date Published: 1st Apr 2009

Publication Type: Journal article

Lifestyle intervention in BRCA1/2 mutation carriers: study protocol for a prospective, randomized, controlled clinical feasibility trial (LIBRE-1 study)
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND Women with highly penetrant BRCA mutations have a 55-60% lifetime risk for breast cancer and a 16-59% lifetime risk for ovarian cancer. However, penetrance differs interindividually, indicating …g that environmental and behavioral factors may modify this risk. These include lifestyle factors such as physical activity status, dietary habits, and body weight. The modification of penetrance by changing lifestyle factors has not thus far been investigated in a randomized trial in BRCA mutation carriers. METHODS Therefore, we intend to enroll 60 BRCA1/2 mutation carriers in a pilot feasibility study (Lifestyle Intervention Study in Women with Hereditary Breast and Ovarian Cancer (LIBRE) pilot). This multi-center, prospective, controlled trial aims to randomize (1:1) participants into a (1) multi-factorial lifestyle intervention group (IG) versus (2) the control group with usual care (CG). The primary endpoint is feasibility and acceptance of a structured interdisciplinary lifestyle intervention program over 12 months (at least 70% of the patients to complete the 1-year intervention). Furthermore, the effects on physical fitness, BMI, quality of life, and stress coping capacity will be investigated. During the first 3 months, women in the IG will receive structured, individualized and mainly supervised endurance training of \geq18 MET*h/week (MET = metabolic equivalent task) and personal nutritional counseling based on the Mediterranean diet. During the subsequent 9 months, the IG will receive monthly group training sessions and regular telephone contacts for motivation, whereas the CG will only receive usual care (one general counseling on healthy nutrition and benefits of regular physical activity on health status). At randomization and subsequent time points (3, 6, 12 months), cardiopulmonary fitness will be assessed by spiroergometry and nutritional and psychological status by validated questionnaires. DISCUSSION This pilot study will investigate the optimal strategy to improve physical fitness, nutritional habits, and psychological factors in women at high risk for developing breast or ovarian cancer. The results of this pilot feasibility study will be the basis for a larger prospective randomized trial including clinical events (LIBRE). TRIAL REGISTRATION ClinicalTrials.gov, NCT02087592.

Authors: Marion Kiechle, Christoph Engel, Anika Berling, Katrin Hebestreit, Stephan Bischoff, Ricarda Dukatz, Wolf-Dieter Gerber, Michael Siniatchkin, Katharina Pfeifer, Sabine Grill, Maryam Yahiaoui-Doktor, Ellen Kirsch, Uwe Niederberger, Nicole Marter, Ute Enders, Markus Löffler, Alfons Meindl, Kerstin Rhiem, Rita Schmutzler, Nicole Erickson, Martin Halle

Date Published: 1st Dec 2016

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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

Limited role for extended maintenance temozolomide for newly diagnosed glioblastoma.
GGN - German Glioma Network

Abstract (Expand)

OBJECTIVE: To explore an association with survival of modifying the current standard of care for patients with newly diagnosed glioblastoma of surgery followed by radiotherapy plus concurrent and 6 … cycles of maintenance temozolomide chemotherapy (TMZ/RT --> TMZ) by extending TMZ beyond 6 cycles. METHODS: The German Glioma Network cohort was screened for patients with newly diagnosed glioblastoma who received TMZ/RT --> TMZ and completed >/=6 cycles of maintenance chemotherapy without progression. Associations of clinical patient characteristics, molecular markers, and residual tumor determined by magnetic resonance imaging after 6 cycles of TMZ with progression-free survival (PFS) and overall survival (OS) were analyzed with the log-rank test. Multivariate analyses using the Cox proportional hazards model were performed to assess associations of prolonged TMZ use with outcome. RESULTS: Sixty-one of 142 identified patients received at least 7 maintenance TMZ cycles (median 11, range 7-20). Patients with extended maintenance TMZ treatment had better PFS (20.5 months, 95% confidence interval [CI] 17.7-23.3, vs 17.2 months, 95% CI 10.2-24.2, p = 0.035) but not OS (32.6 months, 95% CI 28.9-36.4, vs 33.2 months, 95% CI 25.3-41.0, p = 0.126). However, there was no significant association of prolonged TMZ chemotherapy with PFS (hazard ratio [HR] = 0.8, 95% CI 0.4-1.6, p = 0.559) or OS (HR = 1.6, 95% CI 0.8-3.3, p = 0.218) adjusted for age, extent of resection, Karnofsky performance score, presence of residual tumor, O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation status, or isocitrate dehydrogenase (IDH) mutation status. CONCLUSION: These data may not support the practice of prolonging maintenance TMZ chemotherapy beyond 6 cycles. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in patients with newly diagnosed glioblastoma, prolonged TMZ chemotherapy does not significantly increase PFS or OS.

Authors: D. Gramatzki, P. Kickingereder, B. Hentschel, J. Felsberg, U. Herrlinger, G. Schackert, J. C. Tonn, M. Westphal, M. Sabel, U. Schlegel, W. Wick, T. Pietsch, G. Reifenberger, M. Loeffler, M. Bendszus, M. Weller

Date Published: 11th Apr 2017

Publication Type: Journal article

Human Diseases: brain glioblastoma multiforme

Limited role for transforming growth factor-beta pathway activation-mediated escape from VEGF inhibition in murine glioma models.
GGN - German Glioma Network

Abstract (Expand)

BACKGROUND: The vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta pathways regulate key biological features of glioblastoma. Here we explore whether the TGF-beta … pathway, which promotes angiogenesis, invasiveness, and immunosuppression, acts as an escape pathway from VEGF inhibition. METHODS: The role of the TGF-beta pathway in escape from VEGF inhibition was assessed in vitro and in vivo and by gene expression profiling in syngeneic mouse glioma models. RESULTS: We found that TGF-beta is an upstream regulator of VEGF, whereas VEGF pathway activity does not alter the TGF-beta pathway in vitro. In vivo, single-agent activity was observed for the VEGF antibody B20-4.1.1 in 3 and for the TGF-beta receptor 1 antagonist LY2157299 in 2 of 4 models. Reduction of tumor volume and blood vessel density, but not induction of hypoxia, correlated with benefit from B20-4.1.1. Reduction of phosphorylated (p)SMAD2 by LY2157299 was seen in all models but did not predict survival. Resistance to B20 was associated with anti-angiogenesis escape pathway gene expression, whereas resistance to LY2157299 was associated with different immune response gene signatures in SMA-497 and GL-261 on transcriptomic profiling. The combination of B20 with LY2157299 was ineffective in SMA-497 but provided prolongation of survival in GL-261, associated with early suppression of pSMAD2 in tumor and host immune cells, prolonged suppression of angiogenesis, and delayed accumulation of tumor infiltrating microglia/macrophages. CONCLUSIONS: Our study highlights the biological heterogeneity of murine glioma models and illustrates that cotargeting of the VEGF and TGF-beta pathways might lead to improved tumor control only in subsets of glioblastoma.

Authors: D. Mangani, M. Weller, E. Seyed Sadr, E. Willscher, K. Seystahl, G. Reifenberger, G. Tabatabai, H. Binder, H. Schneider

Date Published: 12th Jun 2016

Publication Type: Not specified

Human Diseases: glioblastoma multiforme

Lineage-Specific Changes in Biomarkers in Great Apes and Humans
Genetical Statistics and Systems Biology

Abstract (Expand)

Although human biomedical and physiological information is readily available, such information for great apes is limited. We analyzed clinical chemical biomarkers in serum samples from 277 wild- and … captive-born great apes and from 312 healthy human volunteers as well as from 20 rhesus macaques. For each individual, we determined a maximum of 33 markers of heart, liver, kidney, thyroid and pancreas function, hemoglobin and lipid metabolism and one marker of inflammation. We identified biomarkers that show differences between humans and the great apes in their average level or activity. Using the rhesus macaques as an outgroup, we identified human-specific differences in the levels of bilirubin, cholinesterase and lactate dehydrogenase, and bonobo-specific differences in the level of apolipoprotein A-I. For the remaining twenty-nine biomarkers there was no evidence for lineage-specific differences. In fact, we find that many biomarkers show differences between individuals of the same species in different environments. Of the four lineage-specific biomarkers, only bilirubin showed no differences between wild- and captive-born great apes. We show that the major factor explaining the human-specific difference in bilirubin levels may be genetic. There are human-specific changes in the sequence of the promoter and the protein-coding sequence of uridine diphosphoglucuronosyltransferase 1 (UGT1A1), the enzyme that transforms bilirubin and toxic plant compounds into water-soluble, excretable metabolites. Experimental evidence that UGT1A1 is down-regulated in the human liver suggests that changes in the promoter may be responsible for the human-specific increase in bilirubin. We speculate that since cooking reduces toxic plant compounds, consumption of cooked foods, which is specific to humans, may have resulted in relaxed constraint on UGT1A1 which has in turn led to higher serum levels of bilirubin in humans.   Although human biomedical and physiological information is readily available, such information for great apes is limited. We analyzed clinical chemical biomarkers in serum samples from 277 wild- and captive-born great apes and from 312 healthy human volunteers as well as from 20 rhesus macaques. For each individual, we determined a maximum of 33 markers of heart, liver, kidney, thyroid and pancreas function, hemoglobin and lipid metabolism and one marker of inflammation. We identified biomarkers that show differences between humans and the great apes in their average level or activity. Using the rhesus macaques as an outgroup, we identified human-specific differences in the levels of bilirubin, cholinesterase and lactate dehydrogenase, and bonobo-specific differences in the level of apolipoprotein A-I. For the remaining twenty-nine biomarkers there was no evidence for lineage-specific differences. In fact, we find that many biomarkers show differences between individuals of the same species in different environments. Of the four lineage-specific biomarkers, only bilirubin showed no differences between wild- and captive-born great apes. We show that the major factor explaining the human-specific difference in bilirubin levels may be genetic. There are human-specific changes in the sequence of the promoter and the protein-coding sequence of uridine diphosphoglucuronosyltransferase 1 (UGT1A1), the enzyme that transforms bilirubin and toxic plant compounds into water-soluble, excretable metabolites. Experimental evidence that UGT1A1 is down-regulated in the human liver suggests that changes in the promoter may be responsible for the human-specific increase in bilirubin. We speculate that since cooking reduces toxic plant compounds, consumption of cooked foods, which is specific to humans, may have resulted in relaxed constraint on UGT1A1 which has in turn led to higher serum levels of bilirubin in humans. //  Although human biomedical and physiological information is readily available, such information for great apes is limited. We analyzed clinical chemical biomarkers in serum samples from 277 wild- and captive-born great apes and from 312 healthy human volunteers as well as from 20 rhesus macaques. For each individual, we determined a maximum of 33 markers of heart, liver, kidney, thyroid and pancreas function, hemoglobin and lipid metabolism and one marker of inflammation. We identified biomarkers that show differences between humans and the great apes in their average level or activity. Using the rhesus macaques as an outgroup, we identified human-specific differences in the levels of bilirubin, cholinesterase and lactate dehydrogenase, and bonobo-specific differences in the level of apolipoprotein A-I. For the remaining twenty-nine biomarkers there was no evidence for lineage-specific differences. In fact, we find that many biomarkers show differences between individuals of the same species in different environments. Of the four lineage-specific biomarkers, only bilirubin showed no differences between wild- and captive-born great apes. We show that the major factor explaining the human-specific difference in bilirubin levels may be genetic. There are human-specific changes in the sequence of the promoter and the protein-coding sequence of uridine diphosphoglucuronosyltransferase 1 (UGT1A1), the enzyme that transforms bilirubin and toxic plant compounds into water-soluble, excretable metabolites. Experimental evidence that UGT1A1 is down-regulated in the human liver suggests that changes in the promoter may be responsible for the human-specific increase in bilirubin. We speculate that since cooking reduces toxic plant compounds, consumption of cooked foods, which is specific to humans, may have resulted in relaxed constraint on UGT1A1 which has in turn led to higher serum levels of bilirubin in humans.

Authors: Claudius Ronke, Michael Dannemann, Michel Halbwax, Anne Fischer, Christin Helmschrodt, Mathias Brügel, Claudine André, Rebeca Atencia, Lawrence Mugisha, Markus Scholz, Uta Ceglarek, Joachim Thiery, Svante Pääbo, Kay Prüfer, Janet Kelso

Date Published: 6th Aug 2015

Publication Type: Journal article

Linking stem cell function and growth pattern of intestinal organoids.
ProstataCA

Abstract (Expand)

Intestinal stem cells (ISCs) require well-defined signals from their environment in order to carry out their specific functions. Most of these signals are provided by neighboring cells that form a stem … cell niche, whose shape and cellular composition self-organize. Major features of this self-organization can be studied in ISC-derived organoid culture. In this system, manipulation of essential pathways of stem cell maintenance and differentiation results in well-described growth phenotypes. We here provide an individual cell-based model of intestinal organoids that enables a mechanistic explanation of the observed growth phenotypes. In simulation studies of the 3D structure of expanding organoids, we investigate interdependences between Wnt- and Notch-signaling which control the shape of the stem cell niche and, thus, the growth pattern of the organoids. Similar to in vitro experiments, changes of pathway activities alter the cellular composition of the organoids and, thereby, affect their shape. Exogenous Wnt enforces transitions from branched into a cyst-like growth pattern; known to occur spontaneously during long term organoid expansion. Based on our simulation results, we predict that the cyst-like pattern is associated with biomechanical changes of the cells which assign them a growth advantage. The results suggest ongoing stem cell adaptation to in vitro conditions during long term expansion by stabilizing Wnt-activity. Our study exemplifies the potential of individual cell-based modeling in unraveling links between molecular stem cell regulation and 3D growth of tissues. This kind of modeling combines experimental results in the fields of stem cell biology and cell biomechanics constituting a prerequisite for a better understanding of tissue regeneration as well as developmental processes.

Authors: T. Thalheim, M. Quaas, M. Herberg, U. D. Braumann, C. Kerner, M. Loeffler, G. Aust, J. Galle

Date Published: 15th Jan 2018

Publication Type: Not specified

Human Diseases: colonic disease

Longitudinal anthropometry of children and adolescents using 3D-body scanning.
LIFE - Leipzig Research Center for Civilization Diseases, LIFE Child

Abstract (Expand)

3D-body scanning anthropometry is a suitable method for characterization of physiological development of children and adolescents, and for understanding onset and progression of disorders like overweight … and obesity. Here we present a novel body typing approach to describe and to interpret longitudinal 3D-body scanning data of more than 800 children and adolescents measured in up to four follow-ups in intervals of 1 year, referring to an age range between 6 and 18 years. We analyzed transitions between body types assigned to lower-, normal- and overweight participants upon development of children and adolescents. We found a virtually parallel development of the body types with only a few transitions between them. Body types of children and adolescents tend to conserve their weight category. 3D body scanning anthropometry in combination with body typing constitutes a novel option to investigate onset and progression of obesity in children.

Authors: H. Loeffler-Wirth, M. Vogel, T. Kirsten, F. Glock, T. Poulain, A. Korner, M. Loeffler, W. Kiess, H. Binder

Date Published: 14th Sep 2018

Publication Type: Not specified

Human Diseases: obesity

Long-term ovarian function in women treated with CHOP or CHOP plus etoposide for aggressive lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: Chemotherapy-associated ovarian damage comprises not only infertility, but also premature menopause. The latter has been reported as a consequence of alkylating chemotherapy for breast … cancer or Hodgkin's lymphoma. In this study, we assessed the long-term impact of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimens on ovarian function in patients with aggressive non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: Long-term survivors after CHOP or CHOP plus etoposide (CHOEP) treatment within the Mabthera International Trial or the NHL-B1 trial of the German NHL Study Group were requested to respond to a questionnaire and to consent to blood sampling for hormone assessment. RESULTS: A total of 46 of 81 contacted patients with a median age of 32.5 years at the time of enrolment into the aforementioned clinical trials responded to the questionnaire. The median follow-up after completion of treatment was 14 years. Last menstrual bleeding occurred significantly earlier in patients compared with the general population (47 versus 51 years, P < 0.0001). In comparison to the distribution of menopausal symptoms in the general population, the percentage of women with moderate or severe menopausal symptoms was increased. In 23 patients who agreed to participate in laboratory analyses, anti-Muller hormone as a marker of ovarian reserve was decreased when compared with correspondent age groups of the general population. CONCLUSION: Although most female patients regain fertility after CHOP-like chemotherapy, late ovarian impairment occurs frequently. Therefore, awareness of such delayed side-effects at the time of counselling is of importance.

Authors: J. Meissner, D. Tichy, V. Katzke, T. Kuhn, S. Dietrich, T. Schmitt, M. Ziepert, E. Kuhnt, T. Rixecker, M. Zorn, M. Witzens-Harig, M. Pfreundschuh, A. D. Ho

Date Published: 13th May 2015

Publication Type: Not specified

Human Diseases: lymphoma

Long-term survival in primary glioblastoma with versus without isocitrate dehydrogenase mutations.
GGN - German Glioma Network

Abstract (Expand)

PURPOSE: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in World Health Organization (WHO) grades II … and III gliomas, but rare in primary glioblastomas, and associated with longer survival. EXPERIMENTAL DESIGN: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival >36 months (LTS-36), including 33 patients surviving >60 months (LTS-60), with 257 patients surviving <36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations, and IDH1/2 mutations were determined by standard techniques. RESULTS: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23 of 67 patients) as opposed to 4.3% in controls (11 of 257 patients). Long-term survivors with IDH1/2-mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Long-term survivors with IDH1/2 wild-type showed no distinguishing features from other patients with IDH1/2 wild-type glioblastomas except for a higher rate of MGMT promoter methylation. Similarly, among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less-frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had less frequently TP53 mutations and radiotherapy alone as initial treatment. CONCLUSIONS: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade II/III gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

Authors: C. Hartmann, B. Hentschel, M. Simon, M. Westphal, G. Schackert, J. C. Tonn, M. Loeffler, G. Reifenberger, T. Pietsch, A. von Deimling, M. Weller

Date Published: 15th Sep 2013

Publication Type: Not specified

Human Diseases: glioblastoma multiforme

Loss of HLA-DR expression and immunoblastic morphology predict adverse outcome in diffuse large B-cell lymphoma - analyses of cases from two prospective randomized clinical trials.
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: Research on prognostically relevant immunohistochemical markers in diffuse large B-cell lymphomas has mostly been performed on retrospectively collected clinical data. This is also true for … immunohistochemical classifiers that are thought to reflect the cell-of-origin subclassification of gene expression studies. In order to obtain deeper insight into the heterogeneous prognosis of diffuse large B-cell lymphomas and to validate a previously published immunohistochemical classifier, we analyzed data from a large set of cases from prospective clinical trials with long-term follow-up. DESIGN AND METHODS: We performed morphological and extensive immunohistochemical analyses in 414 cases of diffuse large B-cell lymphoma from two prospective randomized clinical trials (NHL-B1/B2, Germany). Classification into germinal center and non-germinal center subtypes of B-cell lymphoma was based on the expression pattern of CD10, BCL6, and IRF4. Multivariate analyses were performed adjusting for the factors in the International Prognostic Index. RESULTS: Analyzing 20 different epitopes on tissue microarrays, expression of HLA-DR, presence of CD23(+) follicular dendritic cell meshworks, and monotypic light chain expression emerged as International Prognostic Index-independent markers of superior overall survival. Immunoblastic morphology was found to be related to poor event-free survival. The non-germinal center subtype, according to the three-epitope classifier (CD10, BCL6, and IRF4) did not have prognostic relevance when adjusted for International Prognostic Index factors (relative risk=1.2, p=0.328 for overall survival; and relative risk=1.1, p=0.644 for event-free survival). CONCLUSIONS: The previously reported International Prognostic Index-independent prognostic value of stratification into germinal center/non-germinal center B-cell lymphoma using the expression pattern of CD10, BCL6, and IRF4 was not reproducible in our series. However, other markers and the morphological subtype appear to be of prognostic value.

Authors: H. W. Bernd, M. Ziepert, C. Thorns, W. Klapper, H. H. Wacker, M. Hummel, H. Stein, M. L. Hansmann, G. Ott, A. Rosenwald, H. K. Muller-Hermelink, T. F. Barth, P. Moller, S. B. Cogliatti, M. Pfreundschuh, N. Schmitz, L. Trumper, S. Holler, M. Loffler, A. C. Feller

Date Published: 3rd Nov 2009

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Low-Dose Irradiation Affects Expression of Inflammatory Markers in the Heart of ApoE -/- Mice
Genetical Statistics and Systems Biology

Abstract (Expand)

Epidemiological studies indicate long-term risks of ionizing radiation on the heart, even at moderate doses. In this study, we investigated the inflammatory, thrombotic and fibrotic late responses of … the heart after low-dose irradiation (IR) with specific emphasize on the dose rate. Hypercholesterolemic ApoE-deficient mice were sacrificed 3 and 6 months after total body irradiation (TBI) with 0.025, 0.05, 0.1, 0.5 or 2 Gy at low (1 mGy/min) or high dose rate (150 mGy/min). The expression of inflammatory and thrombotic markers was quantified in frozen heart sections (CD31, E-selectin, thrombomodulin, ICAM-1, VCAM-1, collagen IV, Thy-1, and CD45) and in plasma samples (IL6, KC, MCP-1, TNF\textgreeka, INF\textgreekg, IL-1\textgreekb, TGF\textgreekb, INF\textgreekg, IL-10, sICAM-1, sE-selectin, sVCAM-1 and fibrinogen) by fluorescence analysis and ELISA. We found that even very low irradiation doses induced adaptive late responses, such as increases of capillary density and changes in collagen IV and Thy-1 levels indicating compensatory regulation. Slight decreases of ICAM-1 levels and reduction of Thy 1 expression at 0.025-0.5 Gy indicate anti-inflammatory effects, whereas at the highest dose (2 Gy) increased VCAM-1 levels on the endocardium may represent a switch to a pro-inflammatory response. Plasma samples partially confirmed this pattern, showing a decrease of proinflammatory markers (sVCAM, sICAM) at 0.025-2.0 Gy. In contrast, an enhancement of MCP-1, TNF\textgreeka and fibrinogen at 0.05-2.0 Gy indicated a proinflammatory and prothrombotic systemic response. Multivariate analysis also revealed significant age-dependent increases (KC, MCP-1, fibrinogen) and decreases (sICAM, sVCAM, sE-selectin) of plasma markers. This paper represents local and systemic effects of low-dose irradiation, including also age- and dose rate-dependent responses in the ApoE-/- mouse model. These insights in the multiple inflammatory/thrombotic effects caused by low-dose irradiation might facilitate an individual evaluation and intervention of radiation related, long-term side effects but also give important implications for low dose anti-inflammatory radiotherapy.   Epidemiological studies indicate long-term risks of ionizing radiation on the heart, even at moderate doses. In this study, we investigated the inflammatory, thrombotic and fibrotic late responses of the heart after low-dose irradiation (IR) with specific emphasize on the dose rate. Hypercholesterolemic ApoE-deficient mice were sacrificed 3 and 6 months after total body irradiation (TBI) with 0.025, 0.05, 0.1, 0.5 or 2 Gy at low (1 mGy/min) or high dose rate (150 mGy/min). The expression of inflammatory and thrombotic markers was quantified in frozen heart sections (CD31, E-selectin, thrombomodulin, ICAM-1, VCAM-1, collagen IV, Thy-1, and CD45) and in plasma samples (IL6, KC, MCP-1, TNF\textgreeka, INF\textgreekg, IL-1\textgreekb, TGF\textgreekb, INF\textgreekg, IL-10, sICAM-1, sE-selectin, sVCAM-1 and fibrinogen) by fluorescence analysis and ELISA. We found that even very low irradiation doses induced adaptive late responses, such as increases of capillary density and changes in collagen IV and Thy-1 levels indicating compensatory regulation. Slight decreases of ICAM-1 levels and reduction of Thy 1 expression at 0.025-0.5 Gy indicate anti-inflammatory effects, whereas at the highest dose (2 Gy) increased VCAM-1 levels on the endocardium may represent a switch to a pro-inflammatory response. Plasma samples partially confirmed this pattern, showing a decrease of proinflammatory markers (sVCAM, sICAM) at 0.025-2.0 Gy. In contrast, an enhancement of MCP-1, TNF\textgreeka and fibrinogen at 0.05-2.0 Gy indicated a proinflammatory and prothrombotic systemic response. Multivariate analysis also revealed significant age-dependent increases (KC, MCP-1, fibrinogen) and decreases (sICAM, sVCAM, sE-selectin) of plasma markers. This paper represents local and systemic effects of low-dose irradiation, including also age- and dose rate-dependent responses in the ApoE-/- mouse model. These insights in the multiple inflammatory/thrombotic effects caused by low-dose irradiation might facilitate an individual evaluation and intervention of radiation related, long-term side effects but also give important implications for low dose anti-inflammatory radiotherapy. //  Epidemiological studies indicate long-term risks of ionizing radiation on the heart, even at moderate doses. In this study, we investigated the inflammatory, thrombotic and fibrotic late responses of the heart after low-dose irradiation (IR) with specific emphasize on the dose rate. Hypercholesterolemic ApoE-deficient mice were sacrificed 3 and 6 months after total body irradiation (TBI) with 0.025, 0.05, 0.1, 0.5 or 2 Gy at low (1 mGy/min) or high dose rate (150 mGy/min). The expression of inflammatory and thrombotic markers was quantified in frozen heart sections (CD31, E-selectin, thrombomodulin, ICAM-1, VCAM-1, collagen IV, Thy-1, and CD45) and in plasma samples (IL6, KC, MCP-1, TNF\textgreeka, INF\textgreekg, IL-1\textgreekb, TGF\textgreekb, INF\textgreekg, IL-10, sICAM-1, sE-selectin, sVCAM-1 and fibrinogen) by fluorescence analysis and ELISA. We found that even very low irradiation doses induced adaptive late responses, such as increases of capillary density and changes in collagen IV and Thy-1 levels indicating compensatory regulation. Slight decreases of ICAM-1 levels and reduction of Thy 1 expression at 0.025-0.5 Gy indicate anti-inflammatory effects, whereas at the highest dose (2 Gy) increased VCAM-1 levels on the endocardium may represent a switch to a pro-inflammatory response. Plasma samples partially confirmed this pattern, showing a decrease of proinflammatory markers (sVCAM, sICAM) at 0.025-2.0 Gy. In contrast, an enhancement of MCP-1, TNF\textgreeka and fibrinogen at 0.05-2.0 Gy indicated a proinflammatory and prothrombotic systemic response. Multivariate analysis also revealed significant age-dependent increases (KC, MCP-1, fibrinogen) and decreases (sICAM, sVCAM, sE-selectin) of plasma markers. This paper represents local and systemic effects of low-dose irradiation, including also age- and dose rate-dependent responses in the ApoE-/- mouse model. These insights in the multiple inflammatory/thrombotic effects caused by low-dose irradiation might facilitate an individual evaluation and intervention of radiation related, long-term side effects but also give important implications for low dose anti-inflammatory radiotherapy.

Authors: Daniel Mathias, Ronald E J Mitchel, Mirela Barclay, Heather Wyatt, Michelle Bugden, Nicholas D. Priest, Stewart C. Whitman, Markus Scholz, Guido Hildebrandt, Manja Kamprad, Annegret Glasow, Ronald E. J. Mitchel

Date Published: 23rd Mar 2015

Publication Type: Journal article

Low-risk variants FGFR2, TNRC9 and LSP1 in German familial breast cancer patients
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

To validate common low-risk variants predisposing for breast cancer (BC) in a large set of BRCA1/2 negative familial or genetically enriched cases from Germany, we genotyped 1,415 cases and 1,830 healthy … women by MALDI-TOF in 105 candidate SNPs. Significantly higher ORs than previously reported for heterozygous unselected cases were found for the minor allele in FGFR2 (OR = 1.43, 95% CI 1.30-1.59, p-value = 1.24 x 10(-12)) and for TNRC9 (OR = 1.33, 95% CI 1.19-1.46, p-value = 1.54 x 10(-7)). Most intriguing, however, were the ORs for homozygous carriers from high-risk families for FGFR2 (OR = 2.05, 95% CI 1.68-2.51, LSP1 (OR = 0.49, 95% CI 0.28-0.86) and TNRC9 (OR = 1.62, 95% CI 1.27-2.07). Moreover, the additional validation of 99 CGEMS-SNPs identified putative novel susceptibility alleles within the LSP1 gene (OR = 0.73, 95% CI 0.61-0.87, p-value = 5.23 x 10(-4)). Finally, we provide evidence for the first time that a low-risk variant located at 6q22.33 (rs6569479) is associated with estrogen receptor negative BC in familial cases (OR = 1.33, 95% CI 1.06-1.66; p-value = 0.012). Our data confirm the impact of the previously identified susceptibility loci and provide preliminary evidence for novel susceptibility loci in familial BC cases and correlate them to specific histopathological subtypes defined by estrogen receptor status.

Authors: Kari Hemminki, Bertram Müller-Myhsok, Peter Lichtner, Christoph Engel, Bowang Chen, Barbara Burwinkel, Asta Försti, Christian Sutter, Barbara Wappenschmidt, Heide Hellebrand, Thomas Illig, Norbert Arnold, Dieter Niederacher, Bernd Dworniczak, Helmut Deissler, Karin Kast, Dorothea Gadzicki, Thomas Meitinger, H-Erich Wichmann, Marion Kiechle, Claus R. Bartram, Rita K. Schmutzler, Alfons Meindl

Date Published: 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Low sphingosine-1-phosphate plasma levels are predictive for increased mortality in patients with liver cirrhosis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND & AIM: The association of circulating sphingosine-1-phosphate (S1P), a bioactive lipid involved in various cellular processes, and related metabolites such as sphinganine-1-phosphate … (SA1P) and sphingosine (SPH) with mortality in patients with end-stage liver disease is investigated in the presented study. S1P as a bioactive lipid mediator, is involved in several cellular processes, however, in end-stage liver disease its role is not understood. METHODS: The study cohort consisted of 95 patients with end-stage liver disease and available information on one-year outcome. The median MELD (Model for end-stage liver disease) score was 12.41 (Range 6.43-39.63). The quantification of sphingolipids in citrated plasma specimen was performed after methanolic protein precipitation followed by hydrophilic interaction liquid chromatography and tandem mass spectrometric detection. RESULTS: S1P and SA1P displayed significant correlations with the MELD score. Patients with circulating S1P levels below the lowest tertile (110.68 ng/ml) showed the poorest one-year survival rate of only 57.1%, whereas one-year survival rate in patients with S1P plasma levels above 165.67 ng/ml was 93.8%. In a multivariate cox regression analysis including platelet counts, concentrations of hemoglobin and MELD score, S1P remained a significant predictor for three-month and one-year mortality. CONCLUSIONS: Low plasma S1P concentrations are highly significantly associated with prognosis in end-stage liver disease. This association is independent of the stage of liver disease. Further studies should be performed to investigate S1P, its role in the pathophysiology of liver diseases and its potential for therapeutic interventions.

Authors: Susen Becker, Benedict Kinny-Koster, Michael Bartels, Markus Scholz, Daniel Seehofer, Thomas Berg, Cornelius Engelmann, Joachim Thiery, Uta Ceglarek, Thorsten Kaiser

Date Published: 23rd Mar 2017

Publication Type: Journal article

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