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Favorable impact of the interleukin-4 receptor allelic variant I75 on the survival of diffuse large B-cell lymphoma patients demonstrated in a large prospective clinical trial.
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: Recently published data indicate that host germline variations in immune genes can influence the outcome of lymphoma patients. Interleukin (IL)-4 and IL13 are crucial immune factors and may … influence the course of the disease. Both cytokines signal through the interleukin-4 receptor (IL4R). Therefore, we investigated whether polymorphisms of IL4, IL13 and IL4R genes could predict the outcome of diffuse large B-cell lymphoma (DLBCL) patients. METHODS: In 228 DLBCL samples of the German High-Grade Non-Hodgkin's Lymphoma Study Group, the polymorphisms of IL4 (-524CT, rs2243250), IL13 (-1069CT, rs1800925) and IL4R (I75V, rs1805010; S503P, rs1805015; Q576R, rs1801275) were analyzed and the soluble interleukin-4 receptor (sIL4R) serum level was measured before the start of chemotherapy. RESULTS: Patients harboring IL4R V75 (IL4R(I75V-AG) and IL4R(I75V-GG)) had shorter overall survival (OS) (P = 0.044) and event-free survival (EFS) (P = 0.056) periods compared with I75 carriers (IL4R(I75V-AA)). Multivariate analysis adjusted to the International Prognostic Index revealed a relative risk of 1.9 for carriers of the IL4R V75 (P = 0.011) in relation to OS. DLBCL patients homozygous for the IL4R I75 and low sIL4R serum levels have the most favorable OS and EFS. CONCLUSIONS: These data support the role for host germline gene variations of immunologically important factors like the IL4R I75V gene variation to predict the survival in DLBCL patients.

Authors: N. Schoof, F. von Bonin, S. Zeynalova, M. Ziepert, W. Jung, M. Loeffler, M. Pfreundschuh, L. Trumper, D. Kube

Date Published: 12th Jun 2009

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

fcGENE: a versatile tool for processing and transforming SNP datasets
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Modern analysis of high-dimensional SNP data requires a number of biometrical and statistical methods such as pre-processing, analysis of population structure, association analysis and …d genotype imputation. Software used for these purposes often rely on specific and incompatible input and output data formats. Therefore extensive data management including multiple format conversions is necessary during analyses. METHODS In order to support fast and efficient management and bio-statistical quality control of high-dimensional SNP data, we developed the publically available software fcGENE using C++ object-oriented programming language. This software simplifies and automates the use of different existing analysis packages, especially during the workflow of genotype imputations and corresponding analyses. RESULTS fcGENE transforms SNP data and imputation results into different formats required for a large variety of analysis packages such as PLINK, SNPTEST, HAPLOVIEW, EIGENSOFT, GenABEL and tools used for genotype imputation such as MaCH, IMPUTE, BEAGLE and others. Data Management tasks like merging, splitting, extracting SNP and pedigree information can be performed. fcGENE also supports a number of bio-statistical quality control processes and quality based filtering processes at SNP- and sample-wise level. The tool also generates templates of commands required to run specific software packages, especially those required for genotype imputation. We demonstrate the functionality of fcGENE by example workflows of SNP data analyses and provide a comprehensive manual of commands, options and applications. CONCLUSIONS We have developed a user-friendly open-source software fcGENE, which comprehensively supports SNP data management, quality control and analysis workflows. Download statistics and corresponding feedbacks indicate that software is highly recognised and extensively applied by the scientific community.

Authors: Nab Raj Roshyara, Markus Scholz

Date Published: 22nd Jul 2014

Publication Type: Journal article

Feasibility of structured endurance training and Mediterranean diet in BRCA1 and BRCA2 mutation carriers - an interventional randomized controlled multicenter trial (LIBRE-1).
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND: Women with pathogenic BRCA germline mutations have an increased risk for breast and ovarian cancer that seems to be modified by life-style factors. Though, randomized trials investigating … the impact of lifestyle interventions on cancer prevention and prognosis in BRCA carriers are still missing. METHODS: We implemented a multicenter, prospective randomized controlled trial in BRCA1/2 patients, comparing a lifestyle intervention group (IG) with a control group (CG) with the primary aim to prove feasibility. Intervention comprised a structured, individualized endurance training alongside nutrition education based on the Mediterranean diet (MD) for 3 months, plus monthly group training and regular telephone contact during the subsequent 9 months. The CG attended one session on healthy nutrition and the benefits of physical activity. Primary endpoints were feasibility, acceptance and satisfaction over 12 months. Furthermore, effects on physical fitness, diet profile, body mass index (BMI), quality of life and perceived stress were investigated. RESULTS: Sixty-eight participants (mean age 41, mean BMI 23.2 kg/m(2)) were enrolled, of whom 55 (81%, 26 IG, 29 CG) completed 12 months. 73% (n = 26) participated in at least 70% of all intervention sessions. Predictors for drop-outs (19%; n = 13) or non-adherence (27%; n = 7) were not found. 73% rated the program highly and 80% would participate again. Severe adverse events did not occur. Positive effects in the IG compared to the CG were observed for secondary endpoints: BMI, MD eating pattern and stress levels. CONCLUSIONS: This lifestyle intervention was feasible, safe and well accepted. Positive results on eating habits, physical fitness and stress levels warrant a larger randomized trial. TRIAL REGISTRATION: The study has been retrospectively registered at ClinicalTrials.gov (reference: NCT02087592 ) on March 12, 2014. The first patient was included on February 24, 2014.

Authors: M. Kiechle, R. Dukatz, M. Yahiaoui-Doktor, A. Berling, M. Basrai, V. Staiger, U. Niederberger, N. Marter, J. Lammert, S. Grill, K. Pfeifer, K. Rhiem, R. K. Schmutzler, M. Laudes, M. Siniatchkin, M. Halle, S. C. Bischoff, C. Engel

Date Published: 10th Nov 2017

Publication Type: Not specified

Human Diseases: hereditary breast ovarian cancer syndrome

Fibrinogen is not a prognostic factor for response to HELP-apheresis in sudden sensorineural hearing loss (SSHL)
Genetical Statistics and Systems Biology

Abstract (Expand)

Higher levels of fibrinogen or cholesterol were associated with improved hearing recovery in SSHL patients after treatment with HELP-apheresis (Heparin-induced extracorporeal LDL precipitation apheresis). … The present trial was performed to demonstrate HELP-related effects on relevant metabolic and inflammatory parameters in the context of SSHL treatment. In the framework of a single arm non-controlled trial, we investigated the variation of metabolic and inflammatory parameters using HELP-apheresis for a defined group of 100 patients with SSHL. Based on cut off inclusion criteria (Serum LDL-cholesterol >1.6 g/l and/or fibrinogen >2.0 g/l, SSHL in minimum three frequencies more than 30 dB, time after event not longer than 6 days), the protocol followed a strict time line with one single shot HELP-apheresis and follow-up monitoring including laboratory parameters at six defined time points. If HELP-apheresis could not effect improvement of hearing on day 5, additional corticosteroid treatment was applied. Concentration of anti-inflammatory IL-10 increased while other proinflammatory parameters declined. Serum levels of all measured sterols and apolipoproteins decreased significantly. None of the investigated parameters were suitable to predict hearing improvement of the patients. Levels of fibrinogen and LDL-cholesterol were not prognostic for outcome after HELP-apheresis. A significant (p < 0.001) increase of anti-inflammatory IL-10 after apheresis was notable, while most of the proinflammatory parameters declined. Despite the limited validity of a single arm non-controlled trial, these alterations on immune modulating factors indicate possible secondary pleiotropic effects caused by HELP-apheresis.

Authors: T. Berger, T. Kaiser, M. Scholz, A. Bachmann, U. Ceglarek, G. Hesse, B. Hagemeyer, M. Stumvoll, J. Thiery, A. Dietz

Date Published: 1st Dec 2015

Publication Type: Journal article

[Final Report Evaluation Metadata Repository (MDR-Eval)]
Evaluation Metadata Repository

Abstract (Expand)

Metadata Repositories sind Datenbanken für Datenelemente, die sowohl in der Forschung, z.B. in klinischen Studien oder epidemiologischen Kohorten, wie auch in der Versorgung, z.B. in Informationssystemen … des Krankenhauses genutzt werden (können). Bei diesen Datenelementen handelt es sich nicht um die eigentlichen Patientendaten (Fakten), sondern um eine vollständige Definition der verwendeten Variablen bzw. Merkmale inklusive der Kodierung, der Maßeinheit, des Datentyps und anderer Aspekte. In einem BMBF-geförderten und TMF-koordinierten Projekt wurde neben konzeptionellen Grundlagen ein Softwareprototyp für den Aufbau eines Nationalen Metadata Repositories für die klinische und epidemiologische Forschung in Deutschland (MDR) erarbeitet. Der Prototyp implementiert ein Datenmodell nach der aktualisierten Version 3 der ISO/IEC-Norm 11179/3 und steht unter einer Open-Source-Lizenz zur Verfügung . Basis für die realisierten Funktionalitäten des MDRs waren die in einem TMF-Vorprojekt analysierten funktionalen Anforderungen (TMF V063-01 Arbeitspaket 2), welche aber aufgrund der begrenzten Projektmittel nicht vollumfänglich umgesetzt werden konnten. Wesentliche Funktionen wie das Erstellen/Modifizieren/Importieren/Klassifizieren von Datenelementen und Formularen sowie einige der avisierten Community-Funktionen stehen jedoch zur Verfügung. Ziel des hier beschriebenen Projekts MDR-Evaluation war eine Evaluation der möglichen Anwendungsszenarien für Metadata Repositories durch eine größere Gruppe von Fachexperten. Dabei stand nicht eine konkrete Software im Vordergrund, sondern die prinzipielle Erwartung der Community an eine webbasierte Datenbank von Datenelementen. Zur Erreichung des Ziels wurde ein Fragebogen entworfen, der sowohl Fragen zu generellen Aspekten des Aufbaus einer zentralen Bibliothek für Datenelemente der biomedizinischen Forschung wie auch konkretere Punkte im Hinblick auf notwendige Funktionalitäten, gewünschte Inhalte, Werkzeuge zur Communityarbeit und zur Güte von Datenelementen enthielt. Der Fragebogen wurde im Rahmen einer Web-Umfrage einer breiten Community präsentiert. Aus den Antworten lassen sich strategische Erfolgskriterien für die Implementierung eines communityorientierten Metadata Repositories gewinnen.

Author: Matthias Löbe

Date Published: 1st Feb 2015

Publication Type: Not specified

Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining … association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

Authors: Laura Fachal, Hugues Aschard, Jonathan Beesley, Daniel R. Barnes, Jamie Allen, Siddhartha Kar, Karen A. Pooley, Joe Dennis, Kyriaki Michailidou, Constance Turman, Penny Soucy, Audrey Lemaçon, Michael Lush, Jonathan P. Tyrer, Maya Ghoussaini, Mahdi Moradi Marjaneh, Xia Jiang, Simona Agata, Kristiina Aittomäki, M. Rosario Alonso, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Adalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Bernd Auber, Paul L. Auer, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Alicia Beeghly-Fadiel, Javier Benitez, Marina Bermisheva, Katarzyna Białkowska, Amie M. Blanco, Carl Blomqvist, William Blot, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Ake Borg, Kristin Bosse, Hiltrud Brauch, Hermann Brenner, Ignacio Briceno, Ian W. Brock, Angela Brooks-Wilson, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Qiuyin Cai, Trinidad Caldés, Maria A. Caligo, Nicola J. Camp, Ian Campbell, Federico Canzian, Jason S. Carroll, Brian D. Carter, Jose E. Castelao, Jocelyne Chiquette, Hans Christiansen, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, J. Margriet Collée, Sten Cornelissen, Fergus J. Couch, Angela Cox, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Miguel de La Hoya, Peter Devilee, Orland Diez, Yuan Chun Ding, Gillian S. Dite, Susan M. Domchek, Thilo Dörk, Isabel Dos-Santos-Silva, Arnaud Droit, Stéphane Dubois, Martine Dumont, Mercedes Duran, Lorraine Durcan, Miriam Dwek, Diana M. Eccles, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Olivia Fletcher, Giuseppe Floris, Henrik Flyger, Lenka Foretova, William D. Foulkes, Eitan Friedman, Lin Fritschi, Debra Frost, Marike Gabrielson, Manuela Gago-Dominguez, Gaetana Gambino, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, José A. García-Sáenz, Mia M. Gaudet, Vassilios Georgoulias, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Maria Grazia Tibiletti, Mark H. Greene, Mervi Grip, Jacek Gronwald, Anne Grundy, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Jaana M. Hartikainen, Mikael Hartman, Wei He, Catherine S. Healey, Bernadette A. M. Heemskerk-Gerritsen, Jane Heyworth, Peter Hillemanns, Frans B. L. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, John L. Hopper, Anthony Howell, Guanmengqian Huang, Peter J. Hulick, Evgeny N. Imyanitov, Claudine Isaacs, Motoki Iwasaki, Agnes Jager, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Daehee Kang, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Michael J. Kerin, Elza Khusnutdinova, Johanna I. Kiiski, Judy Kirk, Cari M. Kitahara, Yon-Dschun Ko, Irene Konstantopoulou, Veli-Matti Kosma, Stella Koutros, Katerina Kubelka-Sabit, Ava Kwong, Kyriacos Kyriacou, Yael Laitman, Diether Lambrechts, Eunjung Lee, Goska Leslie, Jenny Lester, Fabienne Lesueur, Annika Lindblom, Wing-Yee Lo, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Jan Lubiński, Robert J. MacInnis, Tom Maishman, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Keitaro Matsuo, Tabea Maurer, Dimitrios Mavroudis, Rebecca Mayes, Lesley McGuffog, Catriona McLean, Noura Mebirouk, Alfons Meindl, Austin Miller, Nicola Miller, Marco Montagna, Fernando Moreno, Kenneth Muir, Anna Marie Mulligan, Victor M. Muñoz-Garzon, Taru A. Muranen, Steven A. Narod, Rami Nassir, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Finn C. Nielsen, Liene Nikitina-Zake, Aaron Norman, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Nick Orr, Ana Osorio, V. Shane Pankratz, Janos Papp, Sue K. Park, Tjoung-Won Park-Simon, Michael T. Parsons, James Paul, Inge Sokilde Pedersen, Bernard Peissel, Beth Peshkin, Paolo Peterlongo, Julian Peto, Dijana Plaseska-Karanfilska, Karolina Prajzendanc, Ross Prentice, Nadege Presneau, Darya Prokofyeva, Miquel Angel Pujana, Katri Pylkäs, Paolo Radice, Susan J. Ramus, Johanna Rantala, Rohini Rau-Murthy, Gad Rennert, Harvey A. Risch, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Estela Sánchez-Herrero, Dale P. Sandler, Marta Santamariña, Christobel Saunders, Elinor J. Sawyer, Maren T. Scheuner, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Ben Schöttker, Peter Schürmann, Christopher Scott, Rodney J. Scott, Leigha Senter, Caroline M. Seynaeve, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Xiao-Ou Shu, Christian F. Singer, Thomas P. Slavin, Snezhana Smichkoska, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Jennifer Stone, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony J. Swerdlow, Rulla M. Tamimi, Yen Yen Tan, William J. Tapper, Jack A. Taylor, Manuel R. Teixeira, Maria Tengström, Soo Hwang Teo, Mary Beth Terry, Alex Teulé, Mads Thomassen, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Rob A. E. M. Tollenaar, Ian Tomlinson, Diana Torres, Gabriela Torres-Mejía, Melissa A. Troester, Thérèse Truong, Nadine Tung, Maria Tzardi, Hans-Ulrich Ulmer, Celine M. Vachon, Christi J. van Asperen, Lizet E. van der Kolk, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Joseph Vijai, Maartje J. Vogel, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Hans Wildiers, Robert Winqvist, Alicja Wolk, Anna H. Wu, Drakoulis Yannoukakos, Yan Zhang, Wei Zheng, David Hunter, Paul D. P. Pharoah, Jenny Chang-Claude, Montserrat García-Closas, Marjanka K. Schmidt, Roger L. Milne, Vessela N. Kristensen, Juliet D. French, Stacey L. Edwards, Antonis C. Antoniou, Georgia Chenevix-Trench, Jacques Simard, Douglas F. Easton, Peter Kraft, Alison M. Dunning

Date Published: 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in … case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ER\textgreeka to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease.

Authors: Kerstin B. Meyer, Martin O’Reilly, Kyriaki Michailidou, Saskia Carlebur, Stacey L. Edwards, Juliet D. French, Radhika Prathalingham, Joe Dennis, Manjeet K. Bolla, Qin Wang, Ines de Santiago, John L. Hopper, Helen Tsimiklis, Carmel Apicella, Melissa C. Southey, Marjanka K. Schmidt, Annegien Broeks, Laura J. van ’t Veer, Frans B. Hogervorst, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A. Fasching, Michael P. Lux, Arif B. Ekici, Matthias W. Beckmann, Julian Peto, Isabel Dos Santos Silva, Olivia Fletcher, Nichola Johnson, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Florence Menegaux, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Roger L. Milne, M. Pilar Zamora, Jose I. Arias, Javier Benitez, Susan Neuhausen, Hoda Anton-Culver, Argyrios Ziogas, Christina C. Dur, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Alfons Meindl, Rita K. Schmutzler, Christoph Engel, Nina Ditsch, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, Heli Nevanlinna, Taru A. Muranen, Kristiina Aittomäki, Carl Blomqvist, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Thilo Dörk, Sonja Helbig, Natalia V. Bogdanova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Georgia Chenevix-Trench, Anna H. Wu, Chiu-Chen Tseng, David van den Berg, Daniel O. Stram, Diether Lambrechts, Bernard Thienpont, Marie-Rose Christiaens, Ann Smeets, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Loris Bernard, Fergus J. Couch, Janet E. Olson, Xianshu Wang, Kristen Purrington, Graham G. Giles, Gianluca Severi, Laura Baglietto, Catriona McLean, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Soo-Hwang Teo, Cheng-Har Yip, Sze-Yee Phuah, Vessela Kristensen, Grethe Grenaker Alnæs, Anne-Lise Børresen-Dale, Wei Zheng, Sandra Deming-Halverson, Martha Shrubsole, Jirong Long, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Sandrine Tchatchou, Peter Devilee, Robert A. E. M. Tollenaar, Caroline M. Seynaeve, Montserrat García-Closas, Jonine Figueroa, Stephen J. Chanock, Jolanta Lissowska, Kamila Czene, Hartef Darabi, Kimael Eriksson, Maartje J. Hooning, John W. M. Martens, Ans M. W. van den Ouweland, Carolien H. M. van Deurzen, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Angela Cox, Malcolm W. R. Reed, William Blot, Lisa B. Signorello, Qiuyin Cai, Paul D. P. Pharoah, Maya Ghoussaini, Patricia Harrington, Jonathan Tyrer, Daehee Kang, Ji-Yeob Choi, Sue K. Park, Dong-Young Noh, Mikael Hartman, Miao Hui, Wei-Yen Lim, Shaik A. Buhari, Ute Hamann, Asta Försti, Thomas Rüdiger, Hans-Ulrich Ulmer, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Celine Vachon, Susan Slager, Florentia Fostira, Robert Pilarski, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Ming-Feng Hou, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Bruce A. J. Ponder, Alison M. Dunning, Douglas F. Easton

Date Published: 1st Dec 2013

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

First evidence for glial pathology in late life minor depression: S100B is increased in males with minor depression.
LIFE Adult

Abstract (Expand)

Minor depression is diagnosed when a patient suffers from 2 to 4 depressive symptoms for at least 2 weeks. Though minor depression is a widespread phenomenon, its pathophysiology has hardly been studied. … To get a first insight into the pathophysiological mechanisms underlying this disorder we assessed serum levels of biomarkers for plasticity, glial and neuronal function: brain-derived neurotrophic factor (BDNF), S100B and neuron specific enolase (NSE). 27 subjects with minor depressive episode and 82 healthy subjects over 60 years of age were selected from the database of the Leipzig population-based study of civilization diseases (LIFE). Serum levels of BDNF, S100B and NSE were compared between groups, and correlated with age, body-mass index (BMI), and degree of white matter hyperintensities (score on Fazekas scale). S100B was significantly increased in males with minor depression in comparison to healthy males, whereas other biomarkers did not differ between groups (p = 0.10-0.66). NSE correlated with Fazekas score in patients with minor depression (rs = 0.436, p = 0.048) and in the whole sample (rs = 0.252, p = 0.019). S100B correlated with BMI (rs = 0.246, p = 0.031) and with age in healthy subjects (rs = 0.345, p = 0.002). Increased S100B in males with minor depression, without alterations in BDNF and NSE, supports the glial hypothesis of depression. Correlation between white matter hyperintensities and NSE underscores the vascular hypothesis of late life depression.

Authors: M. Polyakova, C. Sander, K. Arelin, L. Lampe, T. Luck, M. Luppa, J. Kratzsch, K. T. Hoffmann, S. Riedel-Heller, A. Villringer, P. Schoenknecht, M. L. Schroeter

Date Published: 27th Oct 2015

Publication Type: Not specified

Human Diseases: mental depression

Footprints of Sepsis Framed Within Community Acquired Pneumonia in the Blood Transcriptome.
CAPSys - Footprints of Sepsis Framed Within Community Acquired Pneumonia in the Blood Transcriptome, oBIG - omics Bioinformatics for Health

Abstract (Expand)

We analyzed the blood transcriptome of sepsis framed within community-acquired pneumonia (CAP) and characterized its molecular and cellular heterogeneity in terms of functional modules of co-regulated … genes with impact for the underlying pathophysiological mechanisms. Our results showed that CAP severity is associated with immune suppression owing to T-cell exhaustion and HLA and chemokine receptor deactivation, endotoxin tolerance, macrophage polarization, and metabolic conversion from oxidative phosphorylation to glycolysis. We also found footprints of host's response to viruses and bacteria, altered levels of mRNA from erythrocytes and platelets indicating coagulopathy that parallel severity of sepsis and survival. Finally, our data demonstrated chromatin re-modeling associated with extensive transcriptional deregulation of chromatin modifying enzymes, which suggests the extensive changes of DNA methylation with potential impact for marker selection and functional characterization. Based on the molecular footprints identified, we propose a novel stratification of CAP cases into six groups differing in the transcriptomic scores of CAP severity, interferon response, and erythrocyte mRNA expression with impact for prognosis. Our analysis increases the resolution of transcriptomic footprints of CAP and reveals opportunities for selecting sets of transcriptomic markers with impact for translation of omics research in terms of patient stratification schemes and sets of signature genes.

Authors: L. Hopp, H. Loeffler-Wirth, L. Nersisyan, A. Arakelyan, H. Binder

Date Published: 2nd Aug 2018

Publication Type: Not specified

Human Diseases: disease by infectious agent, pneumonia

Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial.
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, … we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis. METHODS: This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7.5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m(2)), doxorubicin (50 mg/m(2)), and vincristine (1.4 mg/m(2), with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m(2) of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5.5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421. FINDINGS: Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy. INTERPRETATION: In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population. FUNDING: Deutsche Krebshilfe.

Authors: V. Poeschel, G. Held, M. Ziepert, M. Witzens-Harig, H. Holte, L. Thurner, P. Borchmann, A. Viardot, M. Soekler, U. Keller, C. Schmidt, L. Truemper, R. Mahlberg, R. Marks, H. G. Hoeffkes, B. Metzner, J. Dierlamm, N. Frickhofen, M. Haenel, A. Neubauer, M. Kneba, F. Merli, A. Tucci, P. de Nully Brown, M. Federico, E. Lengfelder, A. di Rocco, R. Trappe, A. Rosenwald, C. Berdel, M. Maisenhoelder, O. Shpilberg, J. Amam, K. Christofyllakis, F. Hartmann, N. Murawski, S. Stilgenbauer, M. Nickelsen, G. Wulf, B. Glass, N. Schmitz, B. Altmann, M. Loeffler, M. Pfreundschuh

Date Published: 21st Dec 2019

Publication Type: Journal article

Human Diseases: lymphoma, diffuse large B-cell lymphoma

Frequency of somatic symptoms in the general population: Normative values for the Patient Health Questionnaire-15 (PHQ-15).
LIFE Adult

Abstract (Expand)

BACKGROUND: The PHQ-15 is widely used as an open access screening instrument for somatic symptoms in different health care settings. The objectives of the study were to contribute to the construct … validity and to generate normative data for the PHQ-15. METHODS: The survey was conducted in the general population in Germany from August 2011 to November 2014 (n=9250). All participants underwent an extensive core assessment including a set of questionnaires. RESULTS: Men reported significantly less (p<0.001) physical symptoms than women (4.6 [SD=3.6] vs. 6.3 [SD=4.1]). The PHQ-15 total score was strongly correlated with the physical component of quality of life (r=-0.58), fatigue (r=0.56), anxiety (r=0.54) and sleep problems (r=0.54). While high socioeconomic status was associated with low prevalences of all complaints, obesity was associated with some of the complaints, especially shortness of breath and pain in arms, legs, and joints. Normative data for the PHQ-15 were generated for men and women. CONCLUSIONS: This investigation confirms the burden caused by somatic symptoms in terms of impaired physical quality of life. In association with psychosocial consequences such as anxiety as well as sleep problems, future studies should also focus on the disease burden of somatic symptoms. In addition, the normative data provide a framework for the interpretation and comparison with other populations.

Authors: A. Hinz, J. Ernst, H. Glaesmer, E. Brahler, F. G. Rauscher, K. Petrowski, R. D. Kocalevent

Date Published: 27th May 2017

Publication Type: Journal article

Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

We recently reported a truncating deletion in the NFKBIE gene, which encodes IkappaBepsilon, a negative feedback regulator of NF-kappaB, in clinically aggressive chronic lymphocytic leukemia (CLL). … Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n = 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary central nervous system lymphoma (3% to 4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases [22.7%]) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases [27.3%]). NFKBIE-deleted PMBL patients were more often therapy refractory (P = .022) and displayed inferior outcome compared with wild-type patients (5-year survival, 59% vs 78%; P = .034); however, they appeared to benefit from radiotherapy (P =022) and rituximab-containing regimens (P = .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P = .003) and when restricting the analysis to immunochemotherapy-treated patients (P = .008). Whole-exome sequencing and gene expression profiling verified the importance of NF-kappaB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.

Authors: L. Mansouri, D. Noerenberg, E. Young, E. Mylonas, M. Abdulla, M. Frick, F. Asmar, V. Ljungstrom, M. Schneider, K. Yoshida, A. Skaftason, T. Pandzic, B. Gonzalez, A. Tasidou, N. Waldhueter, A. Rivas-Delgado, M. Angelopoulou, M. Ziepert, C. M. Arends, L. Couronne, D. Lenze, C. D. Baldus, C. Bastard, J. Okosun, J. Fitzgibbon, B. Dorken, H. G. Drexler, D. Roos-Weil, C. A. Schmitt, H. D. Munch-Petersen, T. Zenz, M. L. Hansmann, J. C. Strefford, G. Enblad, O. A. Bernard, E. Ralfkiaer, M. Erlanson, P. Korkolopoulou, M. Hultdin, T. Papadaki, K. Gronbaek, A. Lopez-Guillermo, S. Ogawa, R. Kuppers, K. Stamatopoulos, N. Stavroyianni, G. Kanellis, A. Rosenwald, E. Campo, R. M. Amini, G. Ott, T. P. Vassilakopoulos, M. Hummel, R. Rosenquist, F. Damm

Date Published: 8th Dec 2016

Publication Type: Not specified

Human Diseases: B-cell lymphoma

Frontomedian cortex is central for moral deficits in behavioural variant frontotemporal dementia.
LIFE Adult

Abstract

Not specified

Authors: M. L. Schroeter, D. Bzdok, S. B. Eickhoff, J. Neumann

Date Published: 25th Sep 2014

Publication Type: Not specified

Human Diseases: frontotemporal dementia

FTO Obesity Risk Variants Are Linked to Adipocyte IRX3 Expression and BMI of Children - Relevance of FTO Variants to Defend Body Weight in Lean Children?
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Genome-wide association studies have identified variants within the FTO (fat mass and obesity associated) locus as the strongest predictors of obesity amongst all obesity-associated gene …e loci. Recent evidence suggests that variants in FTO directly affect human adipocyte function through targeting IRX3 and IRX5 and thermogenesis regulation. AIM We addressed the relevance of this proposed FTO-IRX pathway in adipose tissue (AT) of children. RESULTS Expression of IRX3 was higher in adipocytes compared to SVF. We found increased adipocyte-specific expression of IRX3 and IRX5 with the presence of the FTO risk haplotype in lean children, whereas it was unaffected by risk variants in obese peers. We further show that IRX3 expression was elevated in isolated adipocytes and AT of lean compared to obese children, particularly in UCP1-negative adipocytes, and inversely correlated with BMI SDS. Independent of BMI, IRX3 expression in adipocytes was significantly related to adipocyte hypertrophy, and subsequent associations with AT inflammation and HOMA-IR in the children. CONCLUSION One interpretation of our observation of FTO risk variants linked to IRX3 expression and adipocyte size restricted to lean children, along with the decreased IRX3 expression in obese compared to lean peers, may reflect a defense mechanism for protecting body-weight, which is pertinent for lean children.

Authors: Kathrin Landgraf, Markus Scholz, Peter Kovacs, Wieland Kiess, Antje Körner

Date Published: 25th Aug 2016

Publication Type: Journal article

Functional connectivity in major depression: increased phase synchronization between frontal cortical EEG-source estimates.
LIFE Adult

Abstract (Expand)

Structural and metabolic alterations in prefrontal brain areas, including the subgenual (SGPFC), medial (MPFC) and dorsolateral prefrontal cortex (DLPFC), have been shown in major depressive disorder … (MDD). Still it remains largely unknown how brain connectivity within these regions is altered at the level of neuronal oscillations. Therefore, the goal was to analyze prefrontal electroencephalographic phase synchronization in MDD and its changes after antidepressant treatment. In 60 unmedicated patients and 60 healthy controls (HC), a 15-min resting electroencephalogram (EEG) was recorded in subjects at baseline and in a subgroup of patients after 2 weeks of antidepressant medication. EEG functional connectivity between the SGPFC and the MPFC/DLPFC was assessed with eLORETA (low resolution brain electromagnetic tomography) by means of lagged phase synchronization. At baseline, patients revealed increased prefrontal connectivity at the alpha frequency between the SGPFC and the left DLPFC/MPFC. After treatment, an increased connectivity between the SGPFC and the right DLPFC/MPFC at the beta frequency was found for MDD. A positive correlation was found for baseline beta connectivity and reduction in scores on the Hamilton depression rating scale. MDD is characterized by increased EEG functional connectivity within frontal brain areas. These EEG markers of disturbed neuronal communication might have potential value as biomarkers.

Authors: S. Olbrich, A. Trankner, T. Chittka, U. Hegerl, P. Schonknecht

Date Published: 30th Apr 2014

Publication Type: Not specified

Human Diseases: major depressive disorder

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 … controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 \times 10(-20)), ER-negative BC (P=1.1 \times 10(-13)), BRCA1-associated BC (P=7.7 \times 10(-16)) and triple negative BC (P-diff=2 \times 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 \times 10(-3)) and ABHD8 (P\textless2 \times 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3’-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

Authors: Kate Lawrenson, Siddhartha Kar, Karen McCue, Karoline Kuchenbaeker, Kyriaki Michailidou, Jonathan Tyrer, Jonathan Beesley, Susan J. Ramus, Qiyuan Li, Melissa K. Delgado, Janet M. Lee, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Banu K. Arun, Brita Arver, Elisa V. Bandera, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Matthias W. Beckmann, Javier Benitez, Andrew Berchuck, Maria Bisogna, Line Bjorge, Carl Blomqvist, William Blot, Natalia Bogdanova, Anders Bojesen, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Fiona Bruinsma, Joan Brunet, Shaik Ahmad Buhari, Barbara Burwinkel, Ralf Butzow, Saundra S. Buys, Qiuyin Cai, Trinidad Caldes, Ian Campbell, Rikki Canniotto, Jenny Chang-Claude, Jocelyne Chiquette, Ji-Yeob Choi, Kathleen B. M. Claes, Linda S. Cook, Angela Cox, Daniel W. Cramer, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Francesca Damiola, Agnieszka Dansonka-Mieszkowska, Hatef Darabi, Joe Dennis, Peter Devilee, Orland Diez, Jennifer A. Doherty, Susan M. Domchek, Cecilia M. Dorfling, Thilo Dörk, Martine Dumont, Hans Ehrencrona, Bent Ejlertsen, Steve Ellis, Christoph Engel, Eunjung Lee, D. Gareth Evans, Peter A. Fasching, Lidia Feliubadalo, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lenka Foretova, Florentia Fostira, William D. Foulkes, Brooke L. Fridley, Eitan Friedman, Debra Frost, Gaetana Gambino, Patricia A. Ganz, Judy Garber, Montserrat García-Closas, Aleksandra Gentry-Maharaj, Maya Ghoussaini, Graham G. Giles, Rosalind Glasspool, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Ellen L. Goode, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Emily Hallberg, Ute Hamann, Thomas v. O. Hansen, Patricia A. Harrington, Mikael Hartman, Norhashimah Hassan, Sue Healey, Florian Heitz, Josef Herzog, Estrid Høgdall, Claus K. Høgdall, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Peter J. Hulick, Tomasz Huzarski, Evgeny N. Imyanitov, Claudine Isaacs, Hidemi Ito, Anna Jakubowska, Ramunas Janavicius, Allan Jensen, Esther M. John, Nichola Johnson, Maria Kabisch, Daehee Kang, Miroslav Kapuscinski, Beth Y. Karlan, Sofia Khan, Lambertus A. Kiemeney, Susanne Kruger Kjaer, Julia A. Knight, Irene Konstantopoulou, Veli-Matti Kosma, Vessela Kristensen, Jolanta Kupryjanczyk, Ava Kwong, Miguel de La Hoya, Yael Laitman, Diether Lambrechts, Nhu Le, Kim de Leeneer, Jenny Lester, Douglas A. Levine, Jingmei Li, Annika Lindblom, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Karen Lu, Jan Lubinski, Arto Mannermaa, Siranoush Manoukian, Loic Le Marchand, Sara Margolin, Frederik Marme, Leon F. A. G. Massuger, Keitaro Matsuo, Sylvie Mazoyer, Lesley McGuffog, Catriona McLean, Iain McNeish, Alfons Meindl, Usha Menon, Arjen R. Mensenkamp, Roger L. Milne, Marco Montagna, Kirsten B. Moysich, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, Roberta B. Ness, Susan L. Neuhausen, Heli Nevanlinna, Silje Nord, Robert L. Nussbaum, Kunle Odunsi, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Curtis Olswold, David O’Malley, Irene Orlow, Nick Orr, Ana Osorio, Sue Kyung Park, Celeste L. Pearce, Tanja Pejovic, Paolo Peterlongo, Georg Pfeiler, Catherine M. Phelan, Elizabeth M. Poole, Katri Pylkäs, Paolo Radice, Johanna Rantala, Muhammad Usman Rashid, Gad Rennert, Valerie Rhenius, Kerstin Rhiem, Harvey A. Risch, Gus Rodriguez, Mary Anne Rossing, Anja Rudolph, Helga B. Salvesen, Suleeporn Sangrajrang, Elinor J. Sawyer, Joellen M. Schildkraut, Marjanka K. Schmidt, Rita K. Schmutzler, Thomas A. Sellers, Caroline Seynaeve, Mitul Shah, Chen-Yang Shen, Xiao-Ou Shu, Weiva Sieh, Christian F. Singer, Olga M. Sinilnikova, Susan Slager, Honglin Song, Penny Soucy, Melissa C. Southey, Marie Stenmark-Askmalm, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony Swerdlow, Sandrine Tchatchou, Manuel R. Teixeira, Soo H. Teo, Kathryn L. Terry, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Amanda Ewart Toland, Ian Tomlinson, Diana Torres, Thérèse Truong, Chiu-Chen Tseng, Nadine Tung, Shelley S. Tworoger, Celine Vachon, Ans M. W. van den Ouweland, Helena C. van Doorn, Elizabeth J. van Rensburg, Laura J. van’t Veer, Adriaan Vanderstichele, Ignace Vergote, Joseph Vijai, Qin Wang, Shan Wang-Gohrke, Jeffrey N. Weitzel, Nicolas Wentzensen, Alice S. Whittemore, Hans Wildiers, Robert Winqvist, Anna H. Wu, Drakoulis Yannoukakos, Sook-Yee Yoon, Jyh-Cherng Yu, Wei Zheng, Ying Zheng, Kum Kum Khanna, Jacques Simard, Alvaro N. Monteiro, Juliet D. French, Fergus J. Couch, Matthew L. Freedman, Douglas F. Easton, Alison M. Dunning, Paul D. Pharoah, Stacey L. Edwards, Georgia Chenevix-Trench, Antonis C. Antoniou, Simon A. Gayther

Date Published: 1st Nov 2016

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal … maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.

Authors: Juliet D. French, Maya Ghoussaini, Stacey L. Edwards, Kerstin B. Meyer, Kyriaki Michailidou, Shahana Ahmed, Sofia Khan, Mel J. Maranian, Martin O’Reilly, Kristine M. Hillman, Joshua A. Betts, Thomas Carroll, Peter J. Bailey, Ed Dicks, Jonathan Beesley, Jonathan Tyrer, Ana-Teresa Maia, Andrew Beck, Nicholas W. Knoblauch, Constance Chen, Peter Kraft, Daniel Barnes, Anna González-Neira, M. Rosario Alonso, Daniel Herrero, Daniel C. Tessier, Daniel Vincent, Francois Bacot, Craig Luccarini, Caroline Baynes, Don Conroy, Joe Dennis, Manjeet K. Bolla, Qin Wang, John L. Hopper, Melissa C. Southey, Marjanka K. Schmidt, Annegien Broeks, Senno Verhoef, Sten Cornelissen, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A. Fasching, Christian R. Loehberg, Arif B. Ekici, Matthias W. Beckmann, Julian Peto, Isabel Dos Santos Silva, Nichola Johnson, Zoe Aitken, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Florence Menegaux, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Roger L. Milne, M. Pilar Zamora, Jose Ignacio Arias Perez, Javier Benitez, Hoda Anton-Culver, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K. Schmutzler, Christoph Engel, Hiltrud Brauch, Ute Hamann, Christina Justenhoven, Kirsimari Aaltonen, Päivi Heikkilä, Kristiina Aittomäki, Carl Blomqvist, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Aiko Sueta, Natalia V. Bogdanova, Natalia N. Antonenkova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Anna H. Wu, Chiu-Chen Tseng, David van den Berg, Daniel O. Stram, Diether Lambrechts, Stephanie Peeters, Ann Smeets, Giuseppe Floris, Jenny Chang-Claude, Anja Rudolph, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Domenico Sardella, Fergus J. Couch, Xianshu Wang, Vernon S. Pankratz, Adam Lee, Graham G. Giles, Gianluca Severi, Laura Baglietto, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Soo Hwang Teo, Cheng Har Yip, Char-Hong Ng, Eranga Nishanthie Vithana, Vessela Kristensen, Wei Zheng, Sandra Deming-Halverson, Martha Shrubsole, Jirong Long, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Peter Devilee, Caroline Seynaeve, Montserrat García-Closas, Jonine Figueroa, Stephen J. Chanock, Jolanta Lissowska, Kamila Czene, Daniel Klevebring, Nils Schoof, Maartje J. Hooning, John W. M. Martens, J. Margriet Collée, Madeleine Tilanus-Linthorst, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Angela Cox, Sabapathy P. Balasubramanian, William Blot, Lisa B. Signorello, Qiuyin Cai, Paul D. P. Pharoah, Catherine S. Healey, Mitul Shah, Karen A. Pooley, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Mikael Hartman, Hui Miao, Jen-Hwei Sng, Xueling Sim, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, James McKay, Amanda E. Toland, Christine B. Ambrosone, Drakoulis Yannoukakos, Andrew K. Godwin, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Shou-Tung Chen, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Bruce A. J. Ponder, Heli Nevanlinna, Melissa A. Brown, Georgia Chenevix-Trench, Douglas F. Easton, Alison M. Dunning

Date Published: 1st Apr 2013

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Function Shapes Content: DNA-Methylation Marker Genes and their Impact for Molecular Mechanisms of Glioma
GGN - German Glioma Network

Abstract (Expand)

Glioma is a clinically and biologically diverse disease. It challenges diagnosis and prognosis due to its molecular heterogeneity and diverse regimes of biological dysfunctions which are driven by … genetic and epigenetic mechanisms. We discover the functional impact of sets of DNA methylation marker genes in the context of brain cancer subtypes as an exemplary approach how bioinformatics and particularly machine learning using self organizing maps (SOM) complements modern high-throughput genomic technologies. DNA methylation changes in gliomas comprise both, hyper- and hypomethylation in a subtype specific fashion. We compared pediatric (2 subtypes) and adult (4) glioblastoma and non-neoplastic brain. The functional impact of differential methylation marker sets is discovered in terms of gene set analysis which comprises a large collection of markers related to biological processes, literature data on gliomas and also chromatin states of the healthy brain. DNA methylation signature genes from alternative studies well agree with our signatures. SOM mapping of gene sets robustly identifies similarities between different marker sets even under conditions of noisy compositions. Mapping of previous sets of glioma markers reveals high redundancy and mixtures of subtypes in the reference cohorts. Consideration of the regulatory level of DNA methylation is inevitable for understanding cancer genesis and progression. It provides suited markers for diagnosis of glioma subtypes and disentangles tumor heterogeneity.

Authors: E. Willscher, H. Loffler-Wirth, H. Binder, Lydia Hopp

Date Published: 2015

Publication Type: Not specified

Human Diseases: brain glioma

Further evidence for a role of S100B in mood disorders: a human gene expression mega-analysis.
LIFE Adult

Abstract

Not specified

Authors: M. L. Schroeter, J. Steiner, P. Schonknecht, K. Mueller

Date Published: 18th Mar 2014

Publication Type: Not specified

Human Diseases: mood disorder, neurotic disorder

Future medical artificial intelligence application requirements and expectations of physicians in German university hospitals: Web-based survey
SMITH - Smart Medical Information Technology for Healthcare

Abstract (Expand)

BACKGROUND: The increasing development of artificial intelligence (AI) systems in medicine driven by researchers and entrepreneurs goes along with enormous expectations for medical care advancement. … AI might change the clinical practice of physicians from almost all medical disciplines and in most areas of health care. While expectations for AI in medicine are high, practical implementations of AI for clinical practice are still scarce in Germany. Moreover, physicians’ requirements and expectations of AI in medicine and their opinion on the usage of anonymized patient data for clinical and biomedical research have not been investigated widely in German university hospitals. OBJECTIVE: This study aimed to evaluate physicians’ requirements and expectations of AI in medicine and their opinion on the secondary usage of patient data for (bio)medical research (eg, for the development of machine learning algorithms) in university hospitals in Germany. METHODS: A web-based survey was conducted addressing physicians of all medical disciplines in 8 German university hospitals. Answers were given using Likert scales and general demographic responses. Physicians were asked to participate locally via email in the respective hospitals. RESULTS: The online survey was completed by 303 physicians (female: 121/303, 39.9%; male: 173/303, 57.1%; no response: 9/303, 3.0%) from a wide range of medical disciplines and work experience levels. Most respondents either had a positive (130/303, 42.9%) or a very positive attitude (82/303, 27.1%) towards AI in medicine. There was a significant association between the personal rating of AI in medicine and the self-reported technical affinity level (H4=48.3, P<.001). A vast majority of physicians expected the future of medicine to be a mix of human and artificial intelligence (273/303, 90.1%) but also requested a scientific evaluation before the routine implementation of AI-based systems (276/303, 91.1%). Physicians were most optimistic that AI applications would identify drug interactions (280/303, 92.4%) to improve patient care substantially but were quite reserved regarding AI-supported diagnosis of psychiatric diseases (62/303, 20.5%). Of the respondents, 82.5% (250/303) agreed that there should be open access to anonymized patient databases for medical and biomedical research. CONCLUSIONS: Physicians in stationary patient care in German university hospitals show a generally positive attitude towards using most AI applications in medicine. Along with this optimism comes several expectations and hopes that AI will assist physicians in clinical decision making. Especially in fields of medicine where huge amounts of data are processed (eg, imaging procedures in radiology and pathology) or data are collected continuously (eg, cardiology and intensive care medicine), physicians’ expectations of AI to substantially improve future patient care are high. In the study, the greatest potential was seen in the application of AI for the identification of drug interactions, assumedly due to the rising complexity of drug administration to polymorbid, polypharmacy patients. However, for the practical usage of AI in health care, regulatory and organizational challenges still have to be mastered.

Authors: Oliver Maassen, Sebastian Fritsch, Julia Palm, Saskia Deffge, Julian Kunze, Gernot Marx, Morris Riedel, Andreas Schuppert, Johannes Bickenbach

Date Published: 1st Mar 2021

Publication Type: Journal article

Future mobile device usage, requirements, and expectations of physicians in German university hospitals: Web-based survey
SMITH - Smart Medical Information Technology for Healthcare

Abstract (Expand)

Background The use of mobile devices in hospital care constantly increases. However, smartphones and tablets have not yet widely become official working equipment in medical care. Meanwhile, the parallel … use of private and official devices in hospitals is common. Medical staff use smartphones and tablets in a growing number of ways. This mixture of devices and how they can be used is a challenge to persons in charge of defining strategies and rules for the usage of mobile devices in hospital care. Objective Therefore, we aimed to examine the status quo of physicians’ mobile device usage and concrete requirements and their future expectations of how mobile devices can be used. Methods We performed a web-based survey among physicians in 8 German university hospitals from June to October 2019. The online survey was forwarded by hospital management personnel to physicians from all departments involved in patient care at the local sites. Results A total of 303 physicians from almost all medical fields and work experience levels completed the web-based survey. The majority regarded a tablet (211/303, 69.6%) and a smartphone (177/303, 58.4%) as the ideal devices for their operational area. In practice, physicians are still predominantly using desktop computers during their worktime (mean percentage of worktime spent on a desktop computer: 56.8%; smartphone: 12.8%; tablet: 3.6%). Today, physicians use mobile devices for basic tasks such as oral (171/303, 56.4%) and written (118/303, 38.9%) communication and to look up dosages, diagnoses, and guidelines (194/303, 64.0%). Respondents are also willing to use mobile devices for more advanced applications such as an early warning system (224/303, 73.9%) and mobile electronic health records (211/303, 69.6%). We found a significant association between the technical affinity and the preference of device in medical care (\chis2=53.84, P Conclusions Physicians in German university hospitals have a high technical affinity and positive attitude toward the widespread implementation of mobile devices in clinical care. They are willing to use official mobile devices in clinical practice for basic and advanced mobile health uses. Thus, the reason for the low usage is not a lack of willingness of the potential users. Challenges that hinder the wider adoption of mobile devices might be regulatory, financial and organizational issues, and missing interoperability standards of clinical information systems, but also a shortage of areas of application in which workflows are adapted for (small) mobile devices.

Authors: Oliver Maassen, Sebastian Fritsch, Julia Gantner, Saskia Deffge, Julian Kunze, Gernot Marx, Johannes Bickenbach

Date Published: 1st Dec 2020

Publication Type: Journal article

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