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1005 Publications visible to you, out of a total of 1005
MEK inhibitor cobimetinib rescues a dRaf mutant lethal phenotype in Drosophila melanogaster
Genetical Statistics and Systems Biology

Abstract (Expand)

Since Drosophila melanogaster has proven to be a useful model system to study phenotypes of oncogenic mutations and to identify new anti-cancer drugs, we generated human BRAFV600E homologous dRaf mutant … (dRaf A572E ) Drosophila melanogaster strains to use these for characterization of mutant phenotypes and exploit these phenotypes for drug testing. For mutant gene expression, the GAL4/UAS expression system was used. dRaf A572E was expressed tissue-specific in the eye, epidermis, heart, wings, secretory glands and in the whole animal. Expression of dRaf A572E under the control of an eye-specific driver led to semi-lethality and a rough eye phenotype. tumor, genetics, molecular biology, BRAF, small molecule inhibitors The vast majority of other tissue-specific and ubiquitous drivers led to a lethal phenotype only. The rough eye phenotype was used to test BRAF inhibitor vemurafenib and MEK1/2 inhibitor cobimetinib. There was no phenotype rescue by this treatment. However, a significant rescue of the lethal phenotype was observed under a gut-specific driver. Here, MEK1/2 inhibitor cobimetinib rescued Drosophila larvae to reach pupal stage in 37% of cases as compared to 1% in control experiments. Taken together, the BRAFV600E homolog dRaf A572E exerts mostly lethal effects in Drosophila. Gut-specific dRaf A572E expression might in future be developed further for drug testing. This article is protected by copyright. All rights reserved.

Authors: Isabelle Pfeifle, Jens Bohnekamp, Anna Volkhardt, Holger Kirsten, Astrid Rohwedder, Andreas Thum, Thomas M. Magin, Manfred Kunz

Date Published: 1st Aug 2019

Publication Type: Journal article

Integrating heterogeneous data sources for cross-institutional data sharing: Requirements elicitation and management in SMITH
SMITH - Smart Medical Information Technology for Healthcare

Abstract (Expand)

The digitization of health records and cross-institutional data sharing is a necessary precondition to improve clinical research and patient care. The SMITH project unites several university hospitals … and medical faculties in order to provide medical informatics solutions for health data integration and cross-institutional communication. In this paper, we focus on requirements elicitation and management for extracting clinical data from heterogeneous subsystems and data integration based on eHealth standards such as HL7 FHIR and IHE profiles.

Authors: Kais Tahar, Christoph Müller, Andreas Dürschmid, Silke Haferkamp, Kutaiba Saleh, Patrick Jürs, Sebastian Stäubert, Jan Erik Gewehr, Sven Zenker, Danny Ammon, Thomas Wendt

Date Published: 1st Aug 2019

Publication Type: Journal article

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. …. METHODS We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction \textless 0.05). CONCLUSION Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

Authors: Frank Qian, Matti A. Rookus, Goska Leslie, Harvey A. Risch, Mark H. Greene, Cora M. Aalfs, Muriel A. Adank, Julian Adlard, Bjarni A. Agnarsson, Munaza Ahmed, Kristiina Aittomäki, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Margreet G. E. M. Ausems, Jacopo Azzollini, Daniel Barrowdale, Julian Barwell, Javier Benitez, Katarzyna Białkowska, Valérie Bonadona, Julika Borde, Ake Borg, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Jonathan Carter, Jocelyne Chiquette, Wendy K. Chung, Kathleen B. M. Claes, J. Margriet Collée, Marie-Agnès Collonge-Rame, Fergus J. Couch, Mary B. Daly, Capucine Delnatte, Orland Diez, Susan M. Domchek, Cecilia M. Dorfling, Jacqueline Eason, Douglas F. Easton, Ros Eeles, Christoph Engel, D. Gareth Evans, Laurence Faivre, Lidia Feliubadaló, Lenka Foretova, Eitan Friedman, Debra Frost, Patricia A. Ganz, Judy Garber, Vanesa Garcia-Barberan, Andrea Gehrig, Gord Glendon, Andrew K. Godwin, Encarna B. Gómez Garcia, Ute Hamann, Jan Hauke, John L. Hopper, Peter J. Hulick, Evgeny N. Imyanitov, Claudine Isaacs, Louise Izatt, Anna Jakubowska, Ramunas Janavicius, Esther M. John, Beth Y. Karlan, Carolien M. Kets, Yael Laitman, Conxi Lázaro, Dominique Leroux, Jenny Lester, Fabienne Lesueur, Jennifer T. Loud, Jan Lubiński, Alicja Łukomska, Lesley McGuffog, Noura Mebirouk, Hanne E. J. Meijers-Heijboer, Alfons Meindl, Austin Miller, Marco Montagna, Thea M. Mooij, Emmanuelle Mouret-Fourme, Katherine L. Nathanson, Bita Nehoray, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Kenneth Offit, Edith Olah, Kai-Ren Ong, Jan C. Oosterwijk, Laura Ottini, Michael T. Parsons, Paolo Peterlongo, Georg Pfeiler, Nisha Pradhan, Paolo Radice, Susan J. Ramus, Johanna Rantala, Gad Rennert, Mark Robson, Gustavo C. Rodriguez, Ritu Salani, Maren T. Scheuner, Rita K. Schmutzler, Payal D. Shah, Lucy E. Side, Jacques Simard, Christian F. Singer, Doris Steinemann, Dominique Stoppa-Lyonnet, Yen Yen Tan, Manuel R. Teixeira, Mary Beth Terry, Mads Thomassen, Marc Tischkowitz, Silvia Tognazzo, Amanda E. Toland, Nadine Tung, Christi J. van Asperen, Klaartje van Engelen, Elizabeth J. van Rensburg, Laurence Venat-Bouvet, Jeroen Vierstraete, Gabriel Wagner, Lisa Walker, Jeffrey N. Weitzel, Drakoulis Yannoukakos, Antonis C. Antoniou, David E. Goldgar, Olufunmilayo I. Olopade, Georgia Chenevix-Trench, Timothy R. Rebbeck, Dezheng Huo

Date Published: 1st Jul 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Economic modeling of risk-adapted screen-and-treat strategies in women at high risk for breast or ovarian cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND The ’German Consortium for Hereditary Breast and Ovarian Cancer’ (GC-HBOC) offers women with a family history of breast and ovarian cancer genetic counseling. The aim of this modeling study …y was to evaluate the cost-effectiveness of genetic testing for BRCA 1/2 in women with a high familial risk followed by different preventive interventions (intensified surveillance, risk-reducing bilateral mastectomy, risk-reducing bilateral salpingo-oophorectomy, or both mastectomy and salpingo-oophorectomy) compared to no genetic test. METHODS A Markov model with a lifelong time horizon was developed for a cohort of 35-year-old women with a BRCA 1/2 mutation probability of ≥ 10%. The perspective of the German statutory health insurance (SHI) was adopted. The model included the health states ’well’ (women with increased risk), ’breast cancer without metastases’, ’breast cancer with metastases’, ’ovarian cancer’, ’death’, and two post (non-metastatic) breast or ovarian cancer states. Outcomes were costs, quality of life years gained (QALYs) and life years gained (LYG). Important data used for the model were obtained from 4380 women enrolled in the GC-HBOC. RESULTS Compared with the no test strategy, genetic testing with subsequent surgical and non-surgical treatment options provided to women with deleterious BRCA 1 or 2 mutations resulted in additional costs of \text€7256 and additional QALYs of 0,43 (incremental cost-effectiveness ratio of \text€17,027 per QALY; cost per LYG: \text€22,318). The results were robust in deterministic and probabilistic sensitivity analyses. CONCLUSION The provision of genetic testing to high-risk women with a BRCA1 and two mutation probability of ≥ 10% based on the individual family cancer history appears to be a cost-effective option for the SHI.

Authors: Dirk Müller, Marion Danner, Rita Schmutzler, Christoph Engel, Kirsten Wassermann, Björn Stollenwerk, Stephanie Stock, Kerstin Rhiem

Date Published: 1st Jul 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Central neurocytoma: SNP array analyses, subtel FISH, and review of the literature
Genetical Statistics and Systems Biology

Abstract (Expand)

The central neurocytoma (CN) is a rare brain tumor with a frequency of 0.1-0.5% of all brain tumors. According to the World Health Organization classification, it is a benign grade II tumor with good … prognosis. However, some CN occur as histologically \textquotedblatypical\textquotedbl variant, combined with increasing proliferation and poor clinical outcome. Detailed genetic knowledge could be helpful to characterize a potential atypical behavior in CN. Only few publications on genetics of CN exist in the literature. Therefore, we performed cytogenetic analysis of an intraventricular neurocytoma WHO grade II in a 39-year-old male patient by use of genome-wide high-density single nucleotide polymorphism array (SNP array) and subtelomere FISH. Applying these techniques, we could detect known chromosomal aberrations and identified six not previously described chromosomal aberrations, gains of 1p36.33-p36.31, 2q37.1-q37.3, 6q27, 12p13.33-p13.31, 20q13.31-q13.33, and loss of 19p13.3-p12. Our case report contributes to the genetic knowledge about CN and to increased understanding of \textquotedbltypical\textquotedbl and \textquotedblatypical\textquotedbl variants.

Authors: Caroline Sander, Marco Wallenborn, Vivian Pascal Brandt, Peter Ahnert, Vera Reuschel, Christan Eisenlöffel, Wolfgang Krupp, Jürgen Meixensberger, Heidrun Holland

Date Published: 1st Jul 2019

Publication Type: Journal article

Genetic association study of eight steroid hormones and implications for sexual dimorphism of coronary artery disease
LIFE Adult, Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

CONTEXT: Steroid hormones are important regulators of physiological processes in humans and are under genetic control. A link to coronary artery disease (CAD) is supposed. OBJECTIVE: Our main objective …e was to identify genetic loci influencing steroid hormone levels. As secondary aim, we searched for causal effects of steroid hormones on CAD. DESIGN: We conducted genome-wide meta-association studies for eight steroid hormones: cortisol, DHEA-S, estradiol and testosterone in two independent cohorts (LIFE-Adult, LIFE-Heart, max. n=7667), and progesterone, 17-hydroxyprogesterone, androstenedione and aldosterone in LIFE-Heart only (max. n=2070). All genome-wide significant loci were tested for sex interactions. Further, we tested if previously reported CAD SNPs were associated with our steroid hormone panel and investigated causal links between hormone levels and CAD status using Mendelian Randomization (MR) approaches. RESULTS: We discovered 15 novel associated loci for 17-hydroxyprogesterone, progesterone, DHEA-S, cortisol, androstenedione, and estradiol. Five of these loci relate to genes directly involved in steroid metabolism: CYP21A1, CYP11B1, CYP17A1, STS, and HSD17B12, almost completing the set of steroidogenic enzymes with genetic associations. Sexual dimorphisms were found for seven of the novel loci. Other loci correspond, e.g., to the WNT4/β-catenin pathway. MR revealed that cortisol, androstenedione, 17-hydroxyprogesterone and DHEA-S had causal effects on CAD. We also observed enrichment of cortisol and testosterone associations among known CAD hits. CONCLUSION: Our study greatly improves insight into genetic regulation of steroid hormones and their dependency on sex. These results could serve as a basis for analyzing sex-dimorphisms in other complex diseases.

Authors: J. Pott, YJ. Bae, K. Horn, A. Teren, Andreas Kühnapfel, H. Kirsten, U. Ceglarek, Markus Löffler, J. Thiery, J. Kratzsch, Markus Scholz

Date Published: 6th Jun 2019

Publication Type: Not specified

Human Diseases: coronary artery disease

Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129
Genetical Statistics and Systems Biology

Abstract (Expand)

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, … which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field.COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).

Authors: Clarissa Pedrosa da C. Gomes, Bence Ágg, Andrejaana Andova, Serdal Arslan, Andrew Baker, Monika Barteková, Dimitris Beis, Fay Betsou, Stephanie Bezzina Wettinger, Branko Bugarski, Gianluigi Condorelli, Gustavo José Justo da Silva, Sabrina Danilin, David de Gonzalo-Calvo, Alfonso Buil, Maria Carmo-Fonseca, Francisco J. Enguita, Kyriacos Felekkis, Peter Ferdinandy, Mariann Gyöngyösi, Matthias Hackl, Kanita Karaduzovic-Hadziabdic, Jan Hellemans, Stephane Heymans, Markéta Hlavackova, Morten Andre Hoydal, Aleksandra Jankovic, Amela Jusic, Dimitris Kardassis, Risto Kerkelä, Gabriela M. Kuster, Päivi Lakkisto, Przemyslaw Leszek, Mitja Lustrek, Lars Maegdefessel, Fabio Martelli, Susana Novella, Timothy O’Brien, Christos Papaneophytou, Thierry Pedrazzini, Florence Pinet, Octavian Popescu, Ines Potočnjak, Emma Robinson, Shlomo Sasson, Markus Scholz, Maya Simionescu, Monika Stoll, Zoltan V. Varga, Manlio Vinciguerra, Angela Xuereb, Mehmet Birhan Yilmaz, Costanza Emanueli, Yvan Devaux, behalf of the EU-CardioRNA COST Action on

Date Published: 1st Jun 2019

Publication Type: Journal article

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