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1. Assessing Regional Variation in Support for the Radical Right-Wing Party ‘Alternative for Germany’ (AfD)—A Novel Application of Institutional Anomie Theory across German Districts

Author: Amelie Nickel and Eva Groß
Subjects: right-wing populism, institutional anomie, electoral geography, Social Sciences
Abstract: The paper at hand aims to address a research gap by examining the spatial impact of economic and non-economic institutions on regional variation in the support for the German populist far-right party ‘Alternative for Germany (AfD)’. Adopting an interdisciplinary approach and drawing on institutional anomie theory, the study explores the relationship between economic dominance—economic inequality and economic strength—and regional AfD vote share, as well as the role of non-economic institutions in shaping support for the party. Using various regional indicators, the study assesses the strength of different institutions and their impact on the AfD’s electoral results in the year 2021 across 401 German districts (NUTS 3-level). The results point to significant differences between eastern and western Germany in the analysis of regional populist voting patterns. Economic dominance emerges as a stronger predictor of the AfD’s vote share in eastern regions. However, the findings on the protective effect of strong non-economic institutions against AfD voting are ambiguous and partly contrary to theoretical expectations. Overall, the study’s findings show that the newly introduced indicators deduced from institutional anomie theory contribute to the existing literature to help better understand regional variances in AfD support. Furthermore, the study contributes to the existing literature on the rise of contemporary radical right movements by employing Karl Polanyi’s framework of ‘disembedded’ markets. In doing so, it sheds light on the complex interplay between social change, anomic tendencies, and the growth of radical right movements in capitalist societies.
Published: 2023
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2. Gene panel testing of 5589 BRCA1/2‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

Author: Jan Hauke, Judit Horvath, Eva Groß, Andrea Gehrig, Ellen Honisch, Karl Hackmann, Gunnar Schmidt, Norbert Arnold, Ulrike Faust, Christian Sutter, Julia Hentschel, Shan Wang‐Gohrke, Mateja Smogavec, Bernhard H. F. Weber, Nana Weber‐Lassalle, Konstantin Weber‐Lassalle, Julika Borde, Corinna Ernst, Janine Altmüller, Alexander E. Volk, Holger Thiele, Verena Hübbel, Peter Nürnberg, Katharina Keupp, Beatrix Versmold, Esther Pohl, Christian Kubisch, Sabine Grill, Victoria Paul, Natalie Herold, Nadine Lichey, Kerstin Rhiem, Nina Ditsch, Christian Ruckert, Barbara Wappenschmidt, Bernd Auber, Andreas Rump, Dieter Niederacher, Thomas Haaf, Juliane Ramser, Bernd Dworniczak, Christoph Engel, Alfons Meindl, Rita K. Schmutzler, and Eric Hahnen
Subjects: Breast cancer predisposition, hereditary breast cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract The prevalence of germ line mutations in non‐BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67–4.94), CDH1 (OR: 17.04, 95%CI: 3.54–82), CHEK2 (OR: 2.93, 95%CI: 2.29–3.75), PALB2 (OR: 9.53, 95%CI: 6.25–14.51), and TP53 (OR: 7.30, 95%CI: 1.22–43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73–2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple‐negative breast cancer (TNBC) and estrogen receptor (ER)‐negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)‐positive tumors.
Published: 2018
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3. BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer

Author: Nana Weber-Lassalle, Jan Hauke, Juliane Ramser, Lisa Richters, Eva Groß, Britta Blümcke, Andrea Gehrig, Anne-Karin Kahlert, Clemens R. Müller, Karl Hackmann, Ellen Honisch, Konstantin Weber-Lassalle, Dieter Niederacher, Julika Borde, Holger Thiele, Corinna Ernst, Janine Altmüller, Guido Neidhardt, Peter Nürnberg, Kristina Klaschik, Christopher Schroeder, Konrad Platzer, Alexander E. Volk, Shan Wang-Gohrke, Walter Just, Bernd Auber, Christian Kubisch, Gunnar Schmidt, Judit Horvath, Barbara Wappenschmidt, Christoph Engel, Norbert Arnold, Bernd Dworniczak, Kerstin Rhiem, Alfons Meindl, Rita K. Schmutzler, and Eric Hahnen
Subjects: Breast cancer, Ovarian cancer, BRIP1 gene, Germline mutations, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial. Methods To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants. Results BRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02–36.57, P
Published: 2018
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4. Placental Galectin-2 Expression in Gestational Diabetes: A Systematic, Histological Analysis

Author: Paula Hepp, Laura Unverdorben, Stefan Hutter, Christina Kuhn, Nina Ditsch, Eva Groß, Sven Mahner, Udo Jeschke, Julia Knabl, and Helene H. Heidegger
Subjects: galectin-2, gestational diabetes (GDM), placenta, insulin resistance, chronic low-grade inflammation, metabolism, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Gestational diabetes mellitus (GDM) is the most common pregnancy-associated metabolic disorder that negatively impacts on the health of both mothers and their offspring in the long-term. The molecular mechanisms involved are not fully understood. As in other states of insulin resistance, a disproportionate immune response in GDM leads to a state of chronic low-grade inflammation. Galectin-2 exerts regulatory effects on different immune cells. This study investigated galectin-2 expression in the placenta of 40 GDM patients and 40 controls, in a sex-specific manner. Immunohistochemistry was used for semi-quantitative analysis of expression strength. The phenotypes of galectin-2 expressing cells were characterized through double immunofluorescence. We found a significant up-regulation of galectin-2 in the fetal syncytiotrophoblast, as well as in the maternal decidua of GDM placentas. Double staining showed a strong galectin-2 expression in extra villous trophoblast cells and fetal endothelial cells in GDM. These findings present the first systematic investigation of galectin-2 in GDM. The findings contribute to the emerging understanding of the role of immunomodulation and inflammation in GDM and of galectin-2 itself. This might also have implications for the long-term cardiovascular health of the offspring.
Published: 2020
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5. Two novel mutations identified in familial cases with Donohue syndrome

Author: Tzipora C. Falik Zaccai, Limor Kalfon, Aharon Klar, Mordechai Ben Elisha, Haggit Hurvitz, Galina Weingarten, Emelia Chechik, Vered Fleisher Sheffer, Raid Haj Yahya, Gal Meidan, Eva Gross‐Kieselstein, Dvora Bauman, Sylvia Hershkovitz, Yuval Yaron, Avi Orr‐Urtreger, and Efrat Wertheimer
Subjects: Cardiomyopathy, Donohue syndrome, genotype–phenotype, insulin receptor., Genetics, QH426-470
Abstract: Abstract Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We report the clinical, molecular, and biochemical characterization of three new patients with DS, and address genotype–phenotype issues playing a role in the pathophysiology of DS. A female infant born to first‐degree cousins Muslim Arab parents and two brothers born to first‐degree cousins Druze parents presented classical features of DS with hypertrophic cardiomyopathy and died in infancy. Each patient was found homozygous for one missense mutation within the extracellular domain of the INSR gene. Western blot analysis identified the proreceptor of INSR, but not its mature subunits alpha and beta. Of 95 healthy Muslims, no heterozygous was found and of 52 healthy Druze from the same village, one was heterozygous. This study presents two novel familial mutations in the alpha subunit of the INSR which appear to impair post‐translational processing of the INSR, resulting loss of its function. Both mutations cause DS with hypertrophic cardiomyopathy and early death. Identification of the causative mutation enables prevention of this devastating disease.
Published: 2014
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6. Downregulation of serine protease HTRA1 is associated with poor survival in breast cancer.

Author: Anna Lehner, Viktor Magdolen, Tibor Schuster, Matthias Kotzsch, Marion Kiechle, Alfons Meindl, Fred C G J Sweep, Paul N Span, and Eva Gross
Subjects: Medicine, Science
Abstract: HTRA1 is a highly conserved serine protease which has been implicated in suppression of epithelial-to-mesenchymal-transition (EMT) and cell motility in breast cancer. Its prognostic relevance for breast cancer is unclear so far. Therefore, we evaluated the impact of HTRA1 mRNA expression on patient outcome using a cohort of 131 breast cancer patients as well as a validation cohort including 2809 publically available data sets. Additionally, we aimed at investigating for the presence of promoter hypermethylation as a mechanism for silencing the HTRA1 gene in breast tumors. HTRA1 downregulation was detected in more than 50% of the breast cancer specimens and was associated with higher tumor stage (p = 0.025). By applying Cox proportional hazard models, we observed favorable overall (OS) and disease-free survival (DFS) related to high HTRA1 expression (HR = 0.45 [CI 0.23-0.90], p = 0.023; HR = 0.55 [CI 0.32-0.94], p = 0.028, respectively), with even more pronounced impact in node-positive patients (HR = 0.21 [CI 0.07-0.63], p = 0.006; HR = 0.29 [CI 0.13-0.65], p = 0.002, respectively). Moreover, HTRA1 remained a statistically significant factor predicting DFS among established clinical parameters in the multivariable analysis. Its impact on patient outcome was independently confirmed in the validation set (for relapse-free survival (n = 2809): HR = 0.79 [CI 0.7-0.9], log-rank p = 0.0003; for OS (n = 971): HR = 0.63 [CI 0.48-0.83], log-rank p = 0.0009). In promoter analyses, we in fact detected methylation of HTRA1 in a small subset of breast cancer specimens (two out of a series of 12), and in MCF-7 breast cancer cells which exhibited 22-fold lower HTRA1 mRNA expression levels compared to unmethylated MDA-MB-231 cells. In conclusion, we show that downregulation of HTRA1 is associated with shorter patient survival, particularly in node-positive breast cancer. Since HTRA1 loss was demonstrated to induce EMT and cancer cell invasion, these patients might benefit from demethylating agents or histone deacetylase inhibitors previously reported to lead to HTRA1 upregulation, or from novel small-molecule inhibitors targeting EMT-related processes.
Published: 2013
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7. Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients.

Author: Eva Gross, Birgit Busse, Matthias Riemenschneider, Steffi Neubauer, Katharina Seck, Hanns-Georg Klein, Marion Kiechle, Florian Lordick, and Alfons Meindl
Subjects: Medicine, Science
Abstract: BACKGROUND: Cancer patients carrying mutations in the dihydropyrimidine dehydrogenase gene (DPYD) have a high risk to experience severe drug-adverse effects following chemotherapy with fluoropyrimidine drugs such as 5-fluorouracil (5-FU) or capecitabine. The pretreatment detection of this impairment of pyrimidine catabolism could prevent serious, potentially lethal side effects. As known deleterious mutations explain only a limited proportion of the drug-adverse events, we systematically searched for additional DPYD variations associated with enhanced drug toxicity. METHODOLOGY/PRINCIPAL FINDINGS: We performed a whole gene approach covering the entire coding region and compared DPYD genotype frequencies between cancer patients with good (n = 89) and with poor (n = 39) tolerance of a fluoropyrimidine-based chemotherapy regimen. Applying logistic regression analysis and sliding window approaches we identified the strongest association with fluoropyrimidine-related grade III and IV toxicity for the non-synonymous polymorphism c.496A>G (p.Met166Val). We then confirmed our initial results using an independent sample of 53 individuals suffering from drug-adverse-effects. The combined odds ratio calculated for 92 toxicity cases was 4.42 [95% CI 2.12-9.23]; p (trend)G with toxicity was particularly present in patients with gastroesophageal and breast cancer, but did not reach significance in patients with colorectal malignancies. CONCLUSION: Our results show compelling evidence that, at least in distinct tumor types, a common DPYD polymorphism strongly contributes to the occurrence of fluoropyrimidine-related drug adverse effects. Carriers of this variant could benefit from individual dose adjustment of the fluoropyrimidine drug or alternate therapies.
Published: 2008
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8. Basislehrbuch Kriminologie

Author: Stefanie Kemme, Eva Groß, Lena Posch, Anabel Taefi, Ulrike Zähringer, Stefanie Kemme, Eva Groß and Stefanie Kemme, Eva Groß, Lena Posch, Anabel Taefi, Ulrike Zähringer, Stefanie Kemme, Eva Groß
Published: 2023

9. Auf steinigen Wegen oder wie das empirische Forschen über die Polizei erschwert wird

Author: Stefanie Kemme, Julia Clasen, Eva Groß, Joachim Häfele, Ilka Kammigan, Anabel Taefi, and Ulrike Zähringer
Subjects: General Engineering
Abstract: Durch den Prozess der Akademisierung und die Reform der Polizeiausbildung zeigt sich die Polizei inzwischen in vielen Bereichen wissenschaftsoffener als noch in den 1990er Jahren. Doch auch wenn sich die Erkenntnis der Nützlichkeit empirischer Forschung bei vielen Akteur:innen in der Polizei durchgesetzt zu haben scheint, sind die Grenzen, nicht anders als schon zu Beginn der empirischen Polizeiforschung, bei gesellschaftlich hoch sensiblen Themen dann erreicht, wenn durch empirische Forschung in der und über die Polizei das Bild bzw. der Ruf der Organisation in Frage gestellt werden könnte. Zugangsschwierigkeiten zum Feld betreffen regelmäßig auch Forscher:innen an polizeilichen Hochschulen. Der nachfolgende Beitrag zeigt auf, inwiefern die Struktur der Polizeihochschulen und Stakeholder wie Polizeiführung, Gewerkschaften, Personalräte, Innenbehörden und Medien sicherheitspolitische empirische Forschung erschweren können. Die Ausführungen werden mit Beispielen aus der Studie „Demokratiebezogene Einstellungen und Werthaltungen in der Polizei Hamburg“ (DeWePol) untermauert.
Published: 2022

10. Echtzeiten des Hasses

Author: Eva Groß and Sighard Neckel
Published: 2023

11. Are women of all age groups equally affected by the shadow of sexual assault? Evidence from Germany

Author: Helmut Hirtenlehner, Stephen Farrall, and Eva Groß
Subjects: Law
Abstract: Ample evidence suggests that women are more fearful of crime than men. The ‘shadow of sexual assault hypothesis’ offers a possible explanation for this gender gap: in patriarchal societies females are more afraid of sexual violence, which, in turn, drives their fear of other types of criminal victimization. Although the shadow hypothesis has received some empirical support, knowledge on the role of age in this context has remained scant. Therefore, the present study examines whether fear of sexual assault translates into fear of other offenses in all age segments of the female population, and whether the magnitude of this shadow effect varies with age. Statistical analyses are based on a large-scale random sample of women living in Germany. The findings suggest that although the proportion of women who are fearful of sexual assault declines with age, a shadow effect of this fear can be observed in all age groups. The ‘radiation effect’ of fear of sexual violence on fear of other crimes increases slightly with age. We interpret this interaction as result of older women's heightened vulnerability to many sorts of harm.
Published: 2023

12. TP53 germline mutations in the context of families with hereditary breast and ovarian cancer: a clinical challenge

Author: Eva Groß, Thomas Meitinger, Christine E Brambs, Nina Ditsch, Alfons Meindl, Nicole Pfarr, Anne S. Quante, Marion Kiechle, Melanie Boxberg, Heide Hellebrand, Juliane Ramser, and Sabine Grill
Subjects: 0301 basic medicine, Oncology, p53, Male, medicine.medical_specialty, Li-fraumeni-syndrome, Context (language use), Breast Neoplasms, Li-Fraumeni Syndrome, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Germline mutation, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, ddc:610, TP53 germline mutation, Germ-Line Mutation, Ovarian Neoplasms, business.industry, Obstetrics and Gynecology, Cancer, General Medicine, Gynecologic Oncology, Middle Aged, medicine.disease, Cancer surveillance, Human genetics, ddc, 030104 developmental biology, Li–Fraumeni syndrome, 030220 oncology & carcinogenesis, Cohort, Female, Tumor Suppressor Protein p53, Ovarian cancer, business
Abstract: Purpose TP53germline (g) mutations, associated with the Li-Fraumeni syndrome (LFS), have rarely been reported in the context of hereditary breast and ovarian cancer (HBOC). The prevalence and cancer risks in this target group are unknown and counseling remains challenging. Notably an extensive high-risk surveillance program is implemented, which evokes substantial psychological discomfort. Emphasizing the lack of consensus about clinical implications, we aim to further characterize TP53g mutations in HBOC families. Methods Next-generation sequencing was conducted on 1876 breast cancer (BC) patients who fulfilled the inclusion criteria for HBOC. Results (Likely) pathogenic variants in TP53 gene were present in 0.6% of the BC cohort with higher occurrence in early onset BC TP53g variant (c.542G > A; c.375G > A) did not comply with classic LFS/Chompret criteria. Albeit located in the DNA-binding domain of the p53-protein and therefore revealing no difference to LFS-related variants, they only displayed a medium transactivity reduction constituting a retainment of wildtype-like anti-proliferative functionality. Conclusion Among our cohort of HBOC families, we were able to describe a clinical subgroup, which is distinct from the classic LFS-families. Strikingly, two families did not adhere to the LFS criteria, and functional analysis revealed a reduced impact on TP53 activity, which may suit to the attenuated phenotype. This is an approach that could be useful in developing individualized screening efforts for TP53g mutation carrier in HBOC families. Due to the low incidence, national/international cooperation is necessary to further explore clinical implications. This might allow providing directions for clinical recommendations in the future.
Published: 2020

13. ‚Merkel-Goldstücke‘, ‚Rapefugees‘, ‚System-Medien‘ und die ‚Volksverräter-Regierung‘. Eine Analyse rechtsgerichteter Online-Diskurse und emotionaler Mobilisierungsprozesse in Social Media

Author: Eva Groß, Sighard Neckel, Markus Pullen, Julia Gundlach, and Melanie Verhovnik-Heinze
Published: 2022

14. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Author: Marco Montagna, Mark E. Robson, Daniel Barrowdale, Mark H. Greene, Adrià López-Fernández, Miquel Angel Pujana, Paul Brennan, Lucy Side, Jackie Cook, Munaza Ahmed, Christi J. van Asperen, Katherine L. Nathanson, Ian G. Campbell, Shan Wang-Gohrke, Gero Kramer, Debra Frost, Noura Mebirouk, Angel Izquierdo, Conxi Lázaro, Douglas F. Easton, Joe Dennis, Kenneth Offit, Esther Darder, Stefania Tommasi, Angela Toss, Brca, Virginia Valentini, Tu Nguyen-Dumont, Charlotte Kvist Lautrup, Manuel R. Teixeira, Mads Thomassen, Xin Yang, Susan M. Domchek, Valentina Silvestri, Paolo Radice, Marta Venturelli, Joseph Vijai, Pedro Pinto, Caroline Pottinger, Karina Rønlund, Lone Kroeldrup, Paul A. James, Alan Donaldson, Rita K. Schmutzler, Muriel Belotti, Kim De Leeneer, Lesley McGuffog, Susan L. Neuhausen, Amanda E. Toland, Siranoush Manoukian, Vishakha Tripathi, Adalgeir Arason, Pascaline Berthet, Linda Steele, Judit Horvath, Gord Glendon, Goska Leslie, Eva Gross, Anna Coppa, D. J. Gallagher, Payal D. Shah, Hebon Investigators, Alfons Meindl, Orland Diez, Irene L. Andrulis, Angela F. Brady, Giuseppe Damante, Paolo Peterlongo, Ana Sánchez de Abajo, Maria A. Caligo, Alison H. Trainer, Sophie Giraud, Saba Sharif, Christian Sutter, Johanna Rantala, Javier Benitez, Mark T. Rogers, kConFab Investigators, Lídia Feliubadaló, Inge Søkilde Pedersen, Annabeth Høgh Petersen, Jesús del Valle, Agostino Bucalo, Andrea Gehrig, Megan N. Frone, Judith Balmaña, Marc Tischkowitz, Thomas Hansen, Joan Brunet, Ines Zanna, Torben A Kruse, Carole Brewer, Bernard Peissel, Helen Gregory, Mary Porteous, Rosa B. Barkardottir, Andreas Rump, Ros Eeles, Anna Whaite, Saundra S. Buys, Fabienne Lesueur, Lisa Walker, Laura Ottini, Louise Izatt, Antonis C. Antoniou, Georgia Chenevix-Trench, Susanne E. Boonen, Hayley Cassingham, Jacques Simard, Christoph Engel, Patrick J. Morrison, Lise Lotte Christensen, Giulia Cini, Alvaro N.A. Monteiro, Kathleen Claes, Jacqueline Eason, Zoltan Matrai, Uffe Birk Jensen, Kristiina Aittomäki, Ramunas Janavicius, Olufunmilayo I. Olopade, Bjarni A. Agnarsson, Kara N. Maxwell, Julian Barwell, Bernd Auber, Julian Adlard, Esther M. John, Alex Teulé, Miguel de la Hoya, Darcy L. Thull, David E. Goldgar, Alessandra Viel, Dominique Stoppa-Lyonnet, Barbara Wappenschmidt, Phuong L. Mai, Taru A. Muranen, Eric Hahnen, Fergus J. Couch, Laura Matricardi, Domenico Palli, Yen Y. Tan, Julia Hentschel, Florentia Fostira, Ute Hamann, Trinidad Caldés, Rosemarie Davidson, Daniel R. Barnes, Åke Borg, Pedro Pérez-Segura, Aniko Bozsik, Yuan Chun Ding, Dieter Niederacher, Heli Nevanlinna, Helen Hanson, Norbert Arnold, Robin de Putter, Juliane Ramser, Alex Murray, Laura Cortesi, Christian F. Singer, Jacopo Azzollini, Zsofia K. Stadler, Oskar T. Johannsson, Andrew K. Godwin, D. Gareth Evans, Edith Olah, Michael T. Parsons, Medicum, Research Programs Unit, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki University Hospital Area, Research Program in Systems Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Clinicum, Institut Català de la Salut, [Barnes DR, Leslie G, McGuffog L, Dennis J, Yang X] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Silvestri V] Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. [Balmaña J] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Oncology, Male, Cancer Research, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Diàtesi, polygenic, male breast cancer, PRS, Medical Oncology, Prostate cancer, Breast cancer, 0302 clinical medicine, Prostate, Risk Factors, Medicine and Health Sciences, 80 and over, genetics, skin and connective tissue diseases, Aged, 80 and over, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], 0303 health sciences, education.field_of_study, BRCA1 Protein, Men, Articles, ASSOCIATION, Single Nucleotide, prostate cancer, OVARIAN, BRCA1, BRCA2, 3. Good health, Mutation carriers, medicine.anatomical_structure, Ovarian, 030220 oncology & carcinogenesis, Male breast cancer, Pròstata - Càncer - Aspectes genètics, BRCA2 Protein, Genetic Predisposition to Disease, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Risk Assessment, Breast Neoplasms, Prostatic Neoplasms, AcademicSubjects/MED00010, medicine.medical_specialty, Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms [DISEASES], Urology, 3122 Cancers, Population, Single-nucleotide polymorphism, MUTATION CARRIERS, Càncer de mama, Association, 03 medical and health sciences, Internal medicine, medicine, Polymorphism, education, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], 030304 developmental biology, Aged, Càncer de pròstata, business.industry, Cancer, Odds ratio, medicine.disease, neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata [ENFERMEDADES], Homes, Mama - Càncer - Aspectes genètics, business
Abstract: Breast and prostate cancer risks; Pathogenic variant Riscos de càncer de mama i pròstata; Variants patogèniques Riesgos de cáncer de mama y próstata; Variantes patogénicas Background Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. Results PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management. The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861 and PPRPGM-Nov20\100002. The research leading to these results has received funding from the Italian Association for Cancer Research (AIRC) under IG 2018 - ID. 21389 and the Italian League for the Fight Against Cancer (LILT) under IG 2019 projects, P.I. Ottini Laura and Italian Ministry of Education, Universities and Research-Dipartimenti di Eccellenza-L. 232/2016. CIMBA: GCT is a National Health and Medical Research Council (NHMRC) Research Fellow. iCOGS and OncoArray data: the European Community’s Seventh Framework Programme under grant agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (NIH) (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Personalized Risk Stratification for Prevention and Early Detection of Breast Cancer (PERSPECTIVE) and PERSPECTIVE I&I projects were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation and the Ontario Research Fund. Breast Cancer Family Registry (BCFR): UM1 CA164920 from the National Cancer Institute (NCI). Baltic Familial Breast Ovarian Cancer Consortium (BFBOCC): Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. Beth Israel Deaconess Medical Center (BIDMC): Breast Cancer Research Foundation. BRCA-gene mutations and breast cancer in South African women (BMBSA): Cancer Association of South Africa (PI Elizabeth J. van Rensburg). Spanish National Cancer Centre (CNIO): Spanish Ministry of Health PI16/00440 supported by Fondo Europeo de Desarrollo Regional (FEDER) funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). City of Hope - Clinical Cancer Genomics Community Research Network (COH-CCGCRN): Research reported in this publication was supported by the NCI of the NIH under grant No. R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the NCI and the Office of the Director, NIH. CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella (CONSIT TEAM): Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 No.15547) to P. Radice. Funds from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5x1000’) to S. Manoukian. Associazione CAOS Varese to M.G. Tibiletti. AIRC (IG2015 No.16732) to P. Peterlongo. National Centre for Scientific Research Demokritos (DEMOKRITOS): European Union (European Social Fund—ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. German Cancer Research Center (DFKZ): German Cancer Research Center. Epidemiological Study of Familial Breast Cancer (EMBRACE): Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an National Institute for Health Research (NIHR) grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden National Health Service (NHS) Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Fox Chase Cancer Center (FCCC): The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. AKG was in part funded by the NCI (R01 CA214545 and R01 CA140323), The Kansas Institute for Precision Medicine (P20 GM130423), and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. is the Chancellors Distinguished Chair in Biomedical Sciences Professor. Fundación Pública Galega de Medicina Xenómica (FPGMX): FISPI05/2275 and Mutua Madrileña Foundation (FMMA). German Familial Breast Group (GC-HBOC): German Cancer Aid (grant No. 110837, Rita K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE—Leipzig Research Centre for Civilization Diseases, project No. 713-241202, No. 713-241202, No. 14505/2470, and No. 14575/2470). Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO): Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award, the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program and the French National Institute of Cancer (INCa grants 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015). Georgetown University (GEORGETOWN): the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. Ghent University Hospital (G-FAST): Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. Hospital Clinico San Carlos (HCSC): Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. Helsinki Breast Cancer Study (HEBCS): Helsinki University Hospital Research Fund, the Finnish Cancer Society and the Sigrid Juselius Foundation. Hereditary Breast and Ovarian cancer study the Netherlands (HEBON): the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for part of the data collection. Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia (HRBCP): Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health1R 03CA130065, and North California Cancer Center. Molecular Genetic Studies of Breast- and Ovarian Cancer in Hungary (HUNBOCS): Hungarian Research Grants KTIA-OTKA CK-80745 and NKFI_OTKA K-112228. Institut Català d’Oncologia (ICO): The authors would like to particularly acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and “FEDER, una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563 and CIBERONC) and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). International Hereditary Cancer Centre (IHCC): PBZ_KBN_122/P05/2004. Iceland Landspitali – University Hospital (ILUH): Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility (INHERIT): Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program—grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade—grant No. PSR-SIIRI-701. Istituto Oncologico Veneto (IOVHBOCS): Ministero della Salute and “5x1000” Istituto Oncologico Veneto grant. Portuguese Oncology Institute-Porto Breast Cancer Study (IPOBCS): Liga Portuguesa Contra o Cancro. Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab): The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Korean Hereditary Breast Cancer Study (KOHBRA): the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 1020350; 1420190). Mayo Clinic (MAYO): NIH grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer Research Foundation. McGill University (MCGILL): Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Marc Tischkowitz is supported by the funded by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). Modifier Study of Quantitative Effects on Disease (MODSQUAD): MH CZ—DRO (MMCI, 00209805), MEYS—NPS I—LO1413 to LF, and by Charles University in Prague project UNCE204024 (MZ). Memorial Sloane Kettering Cancer Center (MSKCC): the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). Women’s College Research Institute Hereditary Breast and Ovarian Cancer Study (NAROD): 1R01 CA149429-01. National Cancer Institute (NCI): the Intramural Research Program of the US NCI, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. National Israeli Cancer Control Center (NICCC): Clalit Health Services in Israel, the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. N.N. Petrov Institute of Oncology (NNPIO): the Russian Foundation for Basic Research (grants 17-54-12007, 17-00-00171 and 18-515-12007). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. The Ohio State University Comprehensive Cancer Center (OSUCCG): Ohio State University Comprehensive Cancer Center. Università di Pisa (PBCS): AIRC [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. South East Asian Breast Cancer Association Study (SEABASS): Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. Sheba Medical Centre (SMC): the Israeli Cancer Association. Swedish Breast Cancer Study (SWE-BRCA): the Swedish Cancer Society. University of Chicago (UCHICAGO): NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women’s Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an American Cancer Society (ACS) Clinical Research Professor. University of California Los Angeles (UCLA): Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. University of California San Francisco (UCSF): UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UK Familial Ovarian Cancer Registry (UKFOCR): Cancer Research UK. University of Pennsylvania (UPENN): NIH (R01-CA102776 and R01-CA083855); Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. Cancer Family Registry University of Pittsburg (UPITT/MWH): Hackers for Hope Pittsburgh. Victorian Familial Cancer Trials Group (VFCTG): Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. Women’s Cancer Program at Cedars-Sinai Medical Center (WCP): Dr Karlan is funded by the ACS Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. TN-D is a recipient of a Career Development Fellow from the National Breast Cancer Foundation (Australia, ECF-17-001).
Published: 2022

15. Dihydropyrimidine Dehydrogenase Deficiency and Fluoropyrimidine-Toxicity

Author: Eva Gross and André B. P. van Kuilenburga
Subjects: Dihydropyrimidine dehydrogenase deficiency, business.industry, Toxicity, Medicine, Pharmacology, business, medicine.disease
Published: 2021

16. Furcht vor Kriminalität im Einfluss von sichtbarer ethnischer Vielfalt und allgemeinen sozialen Ängsten

Author: Eva Groß
Published: 2021

17. High levels of KLK7 protein expression are related to a favorable prognosis in triple-negative breast cancer patients

Author: Xiaocong, Geng, Lamiya, Babayeva, Axel, Walch, Michaela, Aubele, Eva, Groß, Marion, Kiechle, Holger, Bronger, Tobias, Dreyer, Viktor, Magdolen, and Julia, Dorn
Subjects: Original Article
Abstract: In normal physiology, kallikrein-related peptidase 7 (KLK7), together with other members of the kallikrein-related peptidase family, is mainly involved in skin desquamation and keratinization processes. Moreover, expression of KLK7 was shown in various tumor types to be dysregulated and to correlate to patients' survival time. However, there are contradictory reports in breast cancer whether KLK7 represents an unfavorable or favorable prognostic biomarker. In the present study, we examined the prognostic value of KLK7 protein expression in triple-negative breast cancer (TNBC), determined by immunohistochemistry (IHC). A cohort encompassing 133 TNBC specimens, present on tissue microarrays, was analyzed. For quantification of the staining intensity, an automated digital IHC image analysis algorithm was applied. In both Kaplan-Meier and univariate Cox analyses, elevated KLK7 protein levels were significantly linked with prolonged overall survival (OS). In multivariable Cox analysis, addition of KLK7 immunoreactivity scores to the base model (including the clinical parameters age, tumor size, and nodal status) demonstrated that KLK7 protein expression remained as a statistically significant, independent parameter for prolonged OS. These results strongly indicate that KLK7 is a favorable prognostic biomarker in triple-negative breast cancer.
Published: 2020

18. Placental Galectin-2 Expression in Gestational Diabetes: A Systematic, Histological Analysis

Author: Helene Hildegard Heidegger, Stefan Hutter, Christina Kuhn, Julia Knabl, Paula Hepp, Udo Jeschke, Nina Ditsch, Sven Mahner, Eva Groß, and Laura Unverdorben
Subjects: 0301 basic medicine, Male, endocrine system diseases, Galectin 2, 030204 cardiovascular system & hematology, lcsh:Chemistry, 0302 clinical medicine, Pregnancy, insulin resistance, Medicine, lcsh:QH301-705.5, Spectroscopy, Decidua, General Medicine, female genital diseases and pregnancy complications, Computer Science Applications, Trophoblasts, Gestational diabetes, medicine.anatomical_structure, embryonic structures, Female, medicine.symptom, Adult, medicine.medical_specialty, placenta, Offspring, Colon, Inflammation, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, Syncytiotrophoblast, Insulin resistance, Fetus, Placenta, Internal medicine, otorhinolaryngologic diseases, Humans, galectin-2, ddc:610, Physical and Theoretical Chemistry, Molecular Biology, business.industry, chronic low-grade inflammation, Organic Chemistry, Endothelial Cells, nutritional and metabolic diseases, medicine.disease, Pregnancy Complications, Diabetes, Gestational, 030104 developmental biology, Endocrinology, Gene Expression Regulation, lcsh:Biology (General), lcsh:QD1-999, gestational diabetes (GDM), business, metabolism
Abstract: Gestational diabetes mellitus (GDM) is the most common pregnancy-associated metabolic disorder that negatively impacts on the health of both mothers and their offspring in the long-term. The molecular mechanisms involved are not fully understood. As in other states of insulin resistance, a disproportionate immune response in GDM leads to a state of chronic low-grade inflammation. Galectin-2 exerts regulatory effects on different immune cells. This study investigated galectin-2 expression in the placenta of 40 GDM patients and 40 controls, in a sex-specific manner. Immunohistochemistry was used for semi-quantitative analysis of expression strength. The phenotypes of galectin-2 expressing cells were characterized through double immunofluorescence. We found a significant up-regulation of galectin-2 in the fetal syncytiotrophoblast, as well as in the maternal decidua of GDM placentas. Double staining showed a strong galectin-2 expression in extra villous trophoblast cells and fetal endothelial cells in GDM. These findings present the first systematic investigation of galectin-2 in GDM. The findings contribute to the emerging understanding of the role of immunomodulation and inflammation in GDM and of galectin-2 itself. This might also have implications for the long-term cardiovascular health of the offspring.
Published: 2020

19. BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer

Author: Christoph Engel, Ellen Honisch, Walter Just, Eva Groß, Nana Weber-Lassalle, Dieter Niederacher, Juliane Ramser, Lisa Richters, Kristina Klaschik, Konrad Platzer, Peter Nürnberg, Guido Neidhardt, Clemens R. Müller, Norbert Arnold, Britta Blümcke, Christopher Schroeder, Corinna Ernst, Barbara Wappenschmidt, Andrea Gehrig, Gunnar Schmidt, Julika Borde, Bernd Auber, Holger Thiele, Janine Altmüller, Alfons Meindl, Konstantin Weber-Lassalle, Karl Hackmann, Bernd Dworniczak, Christian Kubisch, Anne-Karin Kahlert, Eric Hahnen, Kerstin Rhiem, Judit Horvath, Jan Hauke, Shan Wang-Gohrke, Alexander E Volk, and Rita K. Schmutzler
Subjects: Adult, 0301 basic medicine, Oncology, medicine.medical_specialty, Breast Neoplasms, Gene mutation, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Germline mutation, Loss of Function Mutation, Risk Factors, Ovarian cancer, Internal medicine, Humans, Medicine, Missense mutation, Genetic Predisposition to Disease, ddc:610, Family history, Germline mutations, Genetic Association Studies, Germ-Line Mutation, Aged, Ovarian Neoplasms, business.industry, BRIP1, Odds ratio, Middle Aged, BRIP1 gene, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Fanconi Anemia Complementation Group Proteins, Pedigree, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, business, RNA Helicases, Research Article
Abstract: Background Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial. Methods To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants. Results BRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02–36.57, P
Published: 2018

20. Tissue kallikrein-related peptidase 4 (KLK4), a novel biomarker in triple-negative breast cancer

Author: Manfred Schmitt, Feng Yang, Rudolf Napieralski, Axel Walch, Marion Kiechle, Eva Gross, Shuo Zhao, Michaela Aubele, Nancy Ahmed, Julia Dorn, Fred C.G.J. Sweep, Ute Reuning, and Viktor Magdolen
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Stromal cell, Clinical Biochemistry, Triple Negative Breast Neoplasms, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, stomatognathic system, Antineoplastic Combined Chemotherapy Protocols, medicine, Biomarkers, Tumor, Tumor Cells, Cultured, Humans, Molecular Biology, Triple-negative breast cancer, Tissue microarray, Cancer, KLK4, medicine.disease, Primary tumor, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 030104 developmental biology, 030220 oncology & carcinogenesis, Multivariate Analysis, Cancer research, Immunohistochemistry, Kallikreins
Abstract: Triple-negative breast cancer (TNBC), lacking the steroid hormone receptors ER and PR and the oncoprotein HER2, is characterized by its aggressive pattern and insensitivity to endocrine and HER2-directed therapy. Human kallikrein-related peptidases KLK1-15 provide a rich source of serine protease-type biomarkers associated with tumor growth and cancer progression for a variety of malignant diseases. In this study, recombinant KLK4 protein was generated and affinity-purified KLK4-directed polyclonal antibody pAb587 established to allow localization of KLK4 protein expression in tumor cell lines and archived formalin-fixed, paraffin-embedded TNBC tumor tissue specimens. For this, KLK4 protein expression was assessed by immunohistochemistry in primary tumor tissue sections (tissue microarrays) of 188 TNBC patients, mainly treated with anthracycline- or CMF-based polychemotherapy. KLK4 protein is localized in the cytoplasm of tumor and stroma cells. In this patient cohort, elevated stroma cell KLK4 expression, but not tumor cell KLK4 expression, is predictive for poor disease-free survival by univariate analysis (hazard ratio: 2.26,p=0.001) and multivariable analysis (hazard ratio: 2.12,p
Published: 2017

21. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author: Luigi Mori, Sara González, Elia Grau, Dieter Niederacher, Alexandra C. Kölbl, Ares Solanes, Cassandra B. Nichols, Marine Guillaud-Bataille, Ulrike Schoenwiese, Katherine L. Nathanson, Alfons Meindl, Ellen Honisch, Hans Ehrencrona, Ute Enders, Anke Waha, Trinidad Caldés, Inge Søkilde Pedersen, Ana Blanco, Emma Tudini, Conxi Lázaro, Paolo Radice, Torben A Kruse, María Concepción Alonso-Cerezo, Chantal Farra, Shan Wang-Gohrke, Wilko Weichert, Heli Nevanlinna, Setareh Moghadasi, Bernd Auber, Carla Bruzzone, Aliana Guerrieri-Gonzaga, Sabine Grill, Raymonda Varon, Nicolas Derive, Ana Vega, Nicolai Maass, Åke Borg, Cora M. Aalfs, Nadia Naldi, Silvia Iglesias, Kai Ren Ong, Encarna B. Gomez Garcia, Karl Hackmann, Emma R. Woodward, Norbert Arnold, David E. Goldgar, Bernard Peissel, Karolin Bucksch, Berardino Porfirio, Françoise Révillion, Angel Izquierdo, Isabell Witzel, Sebastian Wagner, Silke Zachariae, Elisa Alducci, Mads Thomassen, Jesús del Valle, Valentina Zampiga, Kerstin Rhiem, Lidia Moserle, Edenir Inêz Palmero, Maaike P.G. Vreeswijk, Christoph Mundhenke, Laura Papi, Alejandro Moles-Fernández, Paula Rofes, Ulrike Faust, Andrea Gehrig, Sandrine M. Caputo, Logan C. Walker, Fiona Lalloo, Ute Felbor, Joan Brunet, Henriette Roed Nielsen, Sean V. Tavtigian, Beatrice Bortesi, Thomas Hansen, Maria Grazia Tibiletti, Estela Carrasco, Lisa Wiesmüller, Viviana Gismondi, Sophie Krieger, Pedro Pérez-Segura, Esther Pohl-Rescigno, Emanuela Lucci-Cordisco, Barbara Wappenschmidt, Rui Manuel Reis, Gabriele Lorenzo Capone, Ileana Carnevali, Christi J. van Asperen, KCon Fab Investigators, Jochen Seggewiß, Rhiannon J. Walters, Irmgard Debatin, Susan M. Domchek, Marco Montagna, Francesca Gensini, Kristiina Aittomäki, Véronique Dutrannoy, Arcangela De Nicolo, Giulia Cagnoli, Elisa J. Cops, Henrique de Campos Reis Galvão, Giulia Cini, Barbara Riboli, Eva Tornero, Paul A. James, Judith Balmaña, Anne-Marie Gerdes, Heide Hellebrand, Miriam Fine, Mathias Stiller, Aldo Germani, Diana Eccles, Britta Blümcke, Dominique Stoppa-Lyonnet, Elena Leinert, Alexandra Lewis, Daniela Rivera, Verena Hübbel, Fergus J. Couch, Gunnar Schmidt, Katharina Keupp, Bernhard H. F. Weber, Tilman Heinrich, Mariarosaria Calvello, Michael Dean, Udo Jeschke, Vanessa Lattimore, Linda A.M. Janssen, Siranoush Manoukian, Eva Gross, Kelly J. Sullivan, Doris Steinemann, Susanne Ledig, Alessandra Viel, Christoph Engel, Ana Sánchez de Abajo, Nina Ditsch, Sandra Bonache, Maria A. Caligo, Katharina Pfeifer, Thomas Haaf, Christian Sutter, Eric Hahnen, Laura Matricardi, Marc Tischkowitz, Alex Teulé, Katherine M. Tucker, Jutta Giesecke, Silvia Tognazzo, Gemma Montalban, Carolina Gómez, Anders Kvist, Joanna Lim, Alison H. Trainer, Rachel Susman, Judit Horvath, Amanda B. Spurdle, Mirjam Larsen, Therese Törngren, Mónica Salinas, Nicholas Pachter, Rachel Austin, Nicola K. Poplawski, C Zeder-Göß, Juliane Ramser, Julia Ritter, Anne Sophie Vesper, Paola Concolino, D. Gareth Evans, Clemens R. Müller, Matilde Navarro, Sara Torres-Esquius, Claus R. Bartram, Laura Cortesi, Jacopo Azzollini, Marion Harris, Edward M. Clarke, Marion Kiechle, Lídia Feliubadaló, Almuth Caliebe, Karen N. Herold, Charlotte Kvist Lautrup, Anne S. Quante, Gardenia Vargas-Parra, Michael T. Parsons, Pietro Cavalli, Hongyan Li, Rodrigo Augusto Depieri Michelli, Irene Feroce, Achim Wöckel, Kerstin Wieland, Silke Kaulfuß, Soo Hwang Teo, Angela Velasco, Capucine Delnatte, Marta Pineda, Marion van Mackelenbergh, Eva Montes, Angela Toss, Rita K. Schmutzler, William D. Foulkes, Alvaro N.A. Monteiro, Jan Hauke, Monica Marabelli, Miguel de la Hoya, Sara Gutiérrez-Enríquez, Esther Darder, Simona Agata, Amanda E. Toland, Bernardo Bonanni, Liliana Varesco, Orland Diez, Andreas Rump, Virginie Caux-Moncoutier, Gaetana Gambino, Markus Loeffler, Claude Houdayer, Elena Barbieri, Adrià López-Fernández, et. al., Universidade do Minho, QIMR Berghofer Medical Research Institute, Chinese Academy of Geological Sciences [Beijing] (CAGS), Ministry of Land and Resources (MLR), Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Programa de Càncer Hereditari, Unitat de Diagnòstic Molecular, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Department of Clinical Genetics, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Helsinki University Central Hospital, University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), Università degli Studi di Milano [Milano] (UNIMI), Medical Oncology Department, Vall d'Hebron University Hospital [Barcelona], Institute of Human Genetics, Universität Heidelberg [Heidelberg], Fundación Pública Galega de Medicina Xenómica-SERGAS & Grupo de Medicina Xenómica-USC, CIBER-ER, Division of Cancer Prevention and Genetics, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Genetic Counseling and Hereditary Cancer Programme, Catalan Institute of Oncology, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Institut Curie [Paris], Programa de Consell Genètic en Càncer, Institut Català d'Oncologia, Girona-IdIBGi, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Centre René Gauducheau, CRLCC René Gauducheau, Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Ludwig-Maximilians-Universität München (LMU), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetics, University of Southampton, Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Department of Genomic Medicine, University of Manchester [Manchester], Department of Medical Genetics, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)-Centre of Familial Breast and Ovarian Cancer, Obstetrics and Gynaecology, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institüt für Humangenetik [Würzburg], Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Institute of Chemistry [Budapest], Faculty of Sciences [Budapest], Eötvös Loránd University (ELTE)-Eötvös Loránd University (ELTE), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), I. Frauenklinik, Klinikum der Ludwig-Maximilians-Universitaet, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Department of Oncology, Lund University [Lund]-Clinical Sciences, Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Institute for Medical Informatics, Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, University Medical Center Kiel, Department of Obstetrics and Gynecology, University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Medical Genetics Unit, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Biochemistry, Section of Molecular Diagnostics, Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Institute of Cell and Molecular Pathology, Medizinische Hochschule Hannover (MHH), University of California [Santa Cruz] (UCSC), University of California, Heidelberg University Hospital [Heidelberg], International Agency for Cancer Research (IACR), Programa de Consejo Genético en Cáncer, Instituto Catalán de Oncología-IDIBELL, L'Hospitalet, Programa de Diagnòstic Molecular de Càncer Hereditari, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Hospital Duran i Reynals, Hospitalet de Llobregat, Unit of Hereditary Cancers, Istituto Nazionale per la Ricerca sul Cancro, CIBER de Enfermedades Raras (CIBERER), Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, University of Otago [Dunedin, Nouvelle-Zélande], Institute of Pathology, Department of Gynecology, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), King‘s College London, Molecular Diagnostic Unit, IDIBELL-Catalan Institute of Oncology, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Medicum, Research Programs Unit, Genome-Scale Biology (GSB) Research Program, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, University Management, University of Helsinki, Università degli Studi di Milano = University of Milan (UNIMI), Universität Heidelberg [Heidelberg] = Heidelberg University, Department of Genetics and Pathology, Uppsala University, Julius-Maximilians-Universität Würzburg (JMU)-Centre of Familial Breast and Ovarian Cancer, Julius-Maximilians-Universität Würzburg (JMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Firenze = University of Florence (UniFI), Université de Lille-UNICANCER-Université de Lille-UNICANCER, University of California [Santa Cruz] (UC Santa Cruz), University of California (UC), Universität Leipzig, University of Cologne, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), and Klinische Genetica
Subjects: Male, Multifactorial Inheritance, BRCA1, BRCA2, classification, clinical, multifactorial, quantitative, uncertain significance, variant, Alternative Splicing, BRCA1 Protein, BRCA2 Protein, Computational Biology, Early Detection of Cancer, Female, Genetic Predisposition to Disease, Humans, Likelihood Functions, Neoplasms, Mutation, Missense, Medicina Básica [Ciências Médicas], Settore MED/03 - GENETICA MEDICA, GUIDELINES, Genetic analysis, CLINGEN, SEQUENCE VARIANTS, Missense mutation, FUNCTIONAL ASSAYS, Genetics (clinical), BRCA1, BRCA2, quantitative, clinical, classification, multifactorial, variant, uncertain significance, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, SPLICING ANALYSIS, OVARIAN, BRCA2 Protein/genetics, 3. Good health, ddc, Mutation (genetic algorithm), Ciências Médicas::Medicina Básica, Medical genetics, Special Articles, medicine.medical_specialty, Posterior probability, Population, Computational biology, Biology, INTEGRATED EVALUATION, 03 medical and health sciences, Special Article, medicine, Genetics, BREAST-CANCER, Genetic variability, ddc:610, education, 030304 developmental biology, Tumors, Science & Technology, Proteins, Computational Biology/methods, RISKS, Mutation, BRCA1 Protein/genetics, 3111 Biomedicine, Missense, Proteïnes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genètica, Neoplasms/diagnosis
Abstract: 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 1,395 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; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with 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 nonpathogenic 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., Ohio State University Comprehensive Cancer Center Barretos Cancer Hospital. Grant Number: FINEP ‐ CT‐INFRA (02/2010) Breast Cancer Foundation of New Zealand Canadian Institutes of Health Research. Grant Number: PSR‐SIIRI‐701 Cancer Research UK. Grant Numbers: C8197/A16565, C5047/A8384, C1281/A12014, C12292/A11174, C1287/A10710, C1287/A10118, C1287/A16563, C5047/A10692, C5047/A15007 Department of Defence, USA. Grant Number: W81XWH‐10‐1‐0341 Helsinki University Hospital Research fund Scientific Foundation Asociación Española Contra el Cáncer Leiden University Medical Centre. Grant Number: Grant 30.925 Generalitat de Catalunya. Grant Numbers: PERIS_MedPerCan, URDCat, 2017SGR1282, 2017SGR496 Royal Society of New Zealand Cancer Council Victoria Netherlands Organization for Scientific Research (NWO). Grant Number: Grant 017.008.022 Breast Cancer Research Foundation Cancer Foundation of Western Australia EU H2020. Grant Number: 634935 Fundación Mutua Madrileña Seventh Framework Programme. Grant Numbers: 634935, 223175, 633784 Cancer Council South Australia Government of Galicia. Grant Number: Consolidation and structuring program: IN607B Cancer Council Tasmania Italian Association of Cancer Research. Grant Number: 15547 Queensland Cancer Fund AstraZeneca National Institute of Health (USA). Grant Numbers: 1U19 CA148065‐01, CA128978, CA192393, 1U19 CA148537, P50 CA1162091, CA116167, 1U19 CA148112 Newcastle University Dutch Cancer Society KWF. Grant Numbers: KWF/Pink Ribbon‐11704, UL2012‐5649 National Institute for Health Research. Grant Number: Manchester Biomedical Research centre (IS‐BRC‐1215 National Council of Technological and Scientific Development (CNPq) Instituto de Salud Carlos III. Grant Numbers: FIS PI15/00355, FIS PI13/01711, CIBERONC, FIS PI16/01218, PI16/00563 French National Institute of Cancer National Breast Cancer Foundation National Health and Medical Research Council. Grant Numbers: ID1061778, ID1104808 Carlos III National Health Centro de Investigación Biomédica en Red de Enferemdades Raras. Grant Number: ACCI 2016: ER17P1AC7112/2018 Cancer Council NSW Deutsche Krebshilfe. Grant Numbers: (#110837, #70111850 Fondazione Pisa. Grant Number: Grant “Clinical characterization of BRCA 1/2 Mis
Published: 2019

22. The Enterprising Self and Prejudices toward Unemployed Persons

Author: Eva Groß
Subjects: 050402 sociology, 0504 sociology, Sociology and Political Science, 05 social sciences, 050401 social sciences methods
Abstract: This research tries to build bridges between sociological and social psychological theoretical ideas for the study of social inequality in neoliberal societies. It adds to research on social inequality by examining amplifiers of prejudices toward unemployed persons. A conceptual model has been developed which draws upon social dominance theory and governmentality studies. The empirical analyses guided by this model assess the mediating effects of the enterprising self – a newly developed attitude measure based on sociological analyses of contemporary self-help literature – and the Protestant Work Ethic in the relationship between social dominance orientation and prejudices toward unemployed persons, both depending on social status. Conditional process models reveal the phenomenon of ideological asymmetry relevant for the enterprising self, indicating that this neoliberal guiding principle serves as a dominant driving force in reproducing social inequality through mechanisms at the intergroup-level.
Published: 2016

23. The International Study of Pregnancy Outcome in Women with Maternal Phenylketonuria: Report of a 12-year study

Author: Platt, Lawrence D., Koch, Richard, Hanley, William B., Levy, Harvey L., Matalon, Reuben, Rouse, Bobbye, Trefz, Fritz, de la Cruz, Felix, Güttler, Flemming, Azen, Colleen, and Friedman, Eva Gross
Published: 2000

24. Intellectual development in 12-year-old children treated for phenylketonuria

Author: Azen, Colleen G., Koch, Richard, Friedman, Eva Gross, Berlow, Stanley, Coldwell, James, Krause, Wilma, Matalon, Reuben, McCabe, Edward, O'Flynn, Margaret, Peterson, Raymond, Rouse, Bobbye, Scott, C. Ronald, Sigman, Bernice, Valle, David, and Warner, Robert
Subjects: Mental retardation -- Prevention, Cognition -- Research, Phenylketonuria -- Complications, Phenylketonuria -- Research, Family and marriage, Health
Abstract: Phenylketonuria (PKU) is an inborn metabolic disorder caused by an absence or deficiency of the enzyme phenylalanine hydroxylase. Deficiency of this enzyme allows the toxic amino acid phenylalanine to accumulate in the brain. Early diagnosis and treatment of phenylketonuria can prevent mental retardation. Treatment consists of limiting dietary intake of phenylalanine beginning as soon as possible after birth. This diet may be discontinued at some time between the age of four and 10; however, several reports have indicated a decrease in IQ (intelligence test) in children who discontinue this diet. A study was undertaken of 95 12-year-old children treated for PKU in an attempt to evaluate their intelligence and achievement test scores. All children had been identified by newborn screening and began dietary therapy before four months of age. There were 23 children who maintained appropriately low blood levels of phenylalanine beyond the age of 10; 72 children had persistently elevated levels at ages ranging from 18 months to 10 years. A negative relationship was found between test scores and the age at the time of dietary restriction. There was a positive correlation between parent IQ scores and the age at which the children discontinued the dietary control. Children who maintained low phenylalanine levels beyond the age of 10 showed a test score deficiency only in arithmetic. The pattern of test scores indicates the best intellectual and academic achievement is obtained with early initiation of treatment and strict control of blood PHE levels. The data obtained from this analysis strongly support maintaining dietary restriction through adolescence. (Consumer Summary produced by Reliance Medical Information, Inc.)
Published: 1991

25. PITX2 DNA-methylation predicts response to anthracycline-based adjuvant chemotherapy in triple-negative breast cancer patients

Author: Julia Dorn, Aurelia Noske, Tibor Schuster, Michaela Aubele, Rudolf Napieralski, Axel Walch, Magdalena Absmaier, Eva Gross, Marion Kiechle, Nadia Harbeck, Manfred Schmitt, and Viktor Magdolen
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_treatment, Pilot Projects, Triple Negative Breast Neoplasms, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Pitx2, Triple-negative Breast Cancer, Anthracycline, Dna-methylation, Therapy Response Prediction, Biomarker, Anthracyclines, Breast, PITX2, Triple-negative breast cancer, Antibiotics, Antineoplastic, Articles, Middle Aged, ddc, Treatment Outcome, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, triple-negative breast cancer, biomarker, Biomarker (medicine), Female, Adult, medicine.medical_specialty, Breast surgery, Biology, anthracycline, Disease-Free Survival, 03 medical and health sciences, Breast cancer, Internal medicine, Biomarkers, Tumor, medicine, Adjuvant therapy, Humans, therapy response prediction, Aged, Retrospective Studies, Homeodomain Proteins, Chemotherapy, Patient Selection, Cancer, DNA Methylation, medicine.disease, 030104 developmental biology, DNA-methylation, Follow-Up Studies, Transcription Factors
Abstract: Triple-negative breast cancer (TNBC) constitutes a heterogeneous breast cancer subgroup with poor prognosis; survival rates are likely to be lower with TNBC compared to other breast cancer subgroups. For this disease, systemic adjuvant chemotherapy regimens often yield suboptimal clinical results. To improve treatment regimens in TNBC, identification of molecular biomarkers may help to select patients for individualized adjuvant therapy. Evidence has accumulated that determination of the methylation status of the PITX2 gene provides a predictive value in various breast cancer subgroups, either treated with endocrine-based therapy or anthracycline-containing chemotherapy. To further explore the validity of this novel predictive candidate biomarker, in the present exploratory retrospective study, determination of the PITX2 DNA-methylation status was assessed for non-metastatic TNBC patients treated with adjuvant anthracycline-based chemotherapy by molecular analysis of breast cancer tissues. The PITX2 DNA-methylation status was determined in fresh-frozen tumor tissue specimens (n=56) by methylation-specific qRT-PCR (qMSP) and the data related to disease-free and overall survival, applying an optimized DNA-methylation score of 6.35%. For non-metastatic TNBC patients treated with adjuvant systemic anthracycline-based chemotherapy, a low PITX2 DNA-methylation status (
Published: 2018

26. Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

Author: Dieter Niederacher, Mateja Smogavec, Konstantin Weber-Lassalle, Ellen Honisch, Judit Horvath, Victoria G. Paul, Christian Ruckert, Thomas Haaf, Norbert Arnold, N Herold, Katharina Keupp, Bernhard H. F. Weber, Julika Borde, Beatrix Versmold, Janine Altmüller, Alfons Meindl, Andreas Rump, Sabine Grill, Verena Hübbel, Christoph Engel, Shan Wang-Gohrke, Juliane Ramser, Holger Thiele, Christian Kubisch, Bernd Dworniczak, Alexander E Volk, Nana Weber-Lassalle, Jan Hauke, Kerstin Rhiem, Corinna Ernst, Gunnar Schmidt, Nadine Lichey, Peter Nürnberg, Christian Sutter, Barbara Wappenschmidt, Julia Hentschel, Nina Ditsch, Rita K. Schmutzler, Andrea Gehrig, Bernd Auber, Karl Hackmann, Eva Groß, Esther Pohl, Eric Hahnen, and Ulrike Faust
Subjects: 0301 basic medicine, Oncology, Cancer Research, Genes, BRCA2, Genes, BRCA1, Estrogen receptor, 0302 clinical medicine, Odds Ratio, Prevalence, Missense mutation, 10. No inequality, skin and connective tissue diseases, Exome, Original Research, Cancer Biology, Aged, 80 and over, medicine.diagnostic_test, hereditary breast cancer, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, Hereditary Breast and Ovarian Cancer Syndrome, Female, Adult, medicine.medical_specialty, PALB2, 03 medical and health sciences, Young Adult, Breast cancer, Internal medicine, medicine, Biomarkers, Tumor, Humans, Radiology, Nuclear Medicine and imaging, Genetic Predisposition to Disease, Genetic Testing, ddc:610, CHEK2, Genetic Association Studies, Genetic testing, Aged, business.industry, Genetic Variation, medicine.disease, 030104 developmental biology, Breast cancer predisposition, Case-Control Studies, business, Ovarian cancer
Abstract: The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95% CI: 2.67-4.94), CDH1 (OR: 17.04, 95% CI: 3.54-82), CHEK2 (OR: 2.93, 95% CI: 2.29-3.75), PALB2 (OR: 9.53, 95% CI: 6.25-14.51), and TP53 (OR: 7.30, 95% CI: 1.22-43.68). NBN germ line mutations were not significantly associated with BC risk (OR: 1.39, 95% CI: 0.73-2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors.
Published: 2018

27. Mehrfachtäterschaft im Jugendalter : Soziale Hintergründe und Verläufe wiederholter Delinquenz

Author: Manuela Freiheit, Eva Groß, Sylja Wandschneider, Wilhelm Heitmeyer, Manuela Freiheit, Eva Groß, Sylja Wandschneider, and Wilhelm Heitmeyer
Subjects: Juvenile delinquents--Germany, Juvenile recidivists--Germany
Abstract: Die Studie befasst sich auf breiter empirischer Basis mit den vielfältigen Lebenswelten und -realitäten junger Menschen und beleuchtet differenziert die möglichen Zusammenhänge wiederholter Jugenddelinquenz.
Published: 2018

28. Empirische Ergebnisse

Author: Manuela Freiheit, Eva Groß, Sylja Wandschneider, and Wilhelm Heitmeyer
Published: 2017

29. Fazit und Ausblick

Author: Manuela Freiheit, Eva Groß, Sylja Wandschneider, and Wilhelm Heitmeyer
Published: 2017

30. Put a Ring in It: Exploring Women's Experiences with the Contraceptive Vaginal Ring in Ontario

Author: Kathryn J. LaRoche, Angel M. Foster, Grace Sheehy, and Eva Gross
Subjects: Adult, medicine.medical_specialty, Health (social science), Intrauterine device, Health Services Accessibility, Interviews as Topic, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Maternity and Midwifery, Health care, medicine, Humans, 030212 general & internal medicine, Qualitative Research, Ontario, 030219 obstetrics & reproductive medicine, Descriptive statistics, business.industry, Contraceptive Devices, Public Health, Environmental and Occupational Health, Obstetrics and Gynecology, Contraceptive Devices, Female, Patient Acceptance of Health Care, Vaginal ring, Contraception, Family medicine, Pill, Health Care Surveys, Survey data collection, Female, business, Psychology, Contraception, Barrier, Qualitative research
Abstract: Background Although the contraceptive vaginal ring (CVR) has been available in Canada since 2001, overall use and availability remain low compared with other combined hormonal contraceptive methods. We aimed to explore women's experiences with the CVR in Ontario as well as factors that influenced their decisions to choose the method and continue/discontinue use. Methods We conducted a multimethod qualitative study that consisted of an anonymous online survey and in-depth telephone interviews with a subset of survey participants. We used descriptive statistics to analyze the survey data and analyzed our interviews for content and themes using both deductive and inductive techniques. Results From May to July 2015, we received 103 survey responses and conducted 29 in-depth interviews. Many participants described positive experiences with the CVR and found it to be an especially convenient method. Women who discontinued use of the CVR cited high costs, access barriers, and negative media reports as important factors in their decision. Our participants primarily relied on their physicians for contraceptive information but did not feel fully informed about potential side effects. Several women identified the CVR as an “in between” method in the transition from oral contraceptive pills to the intrauterine device. Conclusions Our findings suggest that the CVR represents a convenient and desirable contraceptive option for some women. However, participants expressed a desire for health care providers to provide more comprehensive information about a full range of contraceptive methods. Improving access to a full range of low-cost contraceptives in Ontario seems to be warranted.
Published: 2017

31. Differential tumor biological role of the tumor suppressor KAI1 and its splice variant in human breast cancer cells

Author: Anke Benge, Anne Sophie Bächer, Tzenka Miteva, Sarah Preis, Christine Heinrich, Tobias Dreyer, Julia Miller, Ute Reuning, Anthony Roberts, Jan Rother, Eva Gross, Eva-Kathrin Sinner, and Gabriele Nelles
Subjects: 0301 basic medicine, biology, Cell growth, Integrin, integrin avβ3, Cell migration, medicine.disease, cell proliferation/adhesion/migration, ddc, Metastasis, Focal adhesion, 03 medical and health sciences, tumor suppressor KAI1 (CD82), 030104 developmental biology, breast cancer, Oncology, Cell surface receptor, cell motion vector analysis, Cancer cell, Cancer research, biology.protein, medicine, Epidermal growth factor receptor, Research Paper
Abstract: The tetraspanin and tumor suppressor KAI1 is downregulated or lost in many cancers which correlates with poor prognosis. KAI1 acts via physical/functional crosstalk with other membrane receptors. Also, a splice variant of KAI1 (KAI1-SP) has been identified indicative of poor prognosis. We here characterized differential effects of the two KAI1 variants on tumor biological events involving integrin (αvs3) and/or epidermal growth factor receptor (EGF-R). In MDA-MB-231 and -435 breast cancer cells, differential effects were documented on the expression levels of the tumor biologically relevant integrin αvs3 which colocalized with KAI1-WT but not with KAI1-SP. Cellular motility was assessed by video image processing, including motion detection and vector analysis for the quantification and visualization of cell motion parameters. In MDA-MB-231 cells, KAI1-SP provoked a quicker wound gap closure and higher closure rates than KAI1-WT, also reflected by different velocities and average motion amplitudes of singular cells. KAI1-SP induced highest cell motion adjacent to the wound gap borders, whereas in MDA-MB-435 cells a comparable induction of both KAI1 variants was noticed. Moreover, while KAI1-WT reduced cell growth, KAI1-SP significantly increased it going along with a pronounced EGF-R upregulation. KAI1-SP-induced cell migration and proliferation was accompanied by the activation of the focal adhesion and Src kinase. Our findings suggest that splicing of KAI1 does not only abrogate its tumor suppressive functions, but even more, promotes tumor biological effects in favor of cancer progression and metastasis.
Published: 2017

32. Two novel mutations identified in familial cases with Donohue syndrome

Author: Dvora Bauman, Tzipora C. Falik Zaccai, Sylvia Hershkovitz, Raid Haj Yahya, Mordechai Ben Elisha, Haggit Hurvitz, Gal Meidan, Eva Gross-Kieselstein, Avi Orr-Urtreger, Aharon Klar, Vered Fleisher Sheffer, Emelia Chechik, Galina Weingarten, Limor Kalfon, Yuval Yaron, and Efrat Wertheimer
Subjects: Hypertrichosis, lcsh:QH426-470, Cardiomyopathy, medicine.disease_cause, genotype–phenotype, Genetics, Medicine, Missense mutation, Molecular Biology, Genetics (clinical), G alpha subunit, Mutation, biology, business.industry, Hypertrophic cardiomyopathy, Original Articles, medicine.disease, Insulin receptor, lcsh:Genetics, insulin receptor, biology.protein, Donohue syndrome, business
Abstract: Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We report the clinical, molecular, and biochemical characterization of three new patients with DS, and address genotype–phenotype issues playing a role in the pathophysiology of DS. A female infant born to first‐degree cousins Muslim Arab parents and two brothers born to first‐degree cousins Druze parents presented classical features of DS with hypertrophic cardiomyopathy and died in infancy. Each patient was found homozygous for one missense mutation within the extracellular domain of the INSR gene. Western blot analysis identified the proreceptor of INSR, but not its mature subunits alpha and beta. Of 95 healthy Muslims, no heterozygous was found and of 52 healthy Druze from the same village, one was heterozygous. This study presents two novel familial mutations in the alpha subunit of the INSR which appear to impair post‐translational processing of the INSR, resulting loss of its function. Both mutations cause DS with hypertrophic cardiomyopathy and early death. Identification of the causative mutation enables prevention of this devastating disease.
Published: 2014

33. Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer

Author: Alfredo Ramirez, Barbara Wappenschmidt, Peter Nürnberg, Kerstin Rhiem, Rita K. Schmutzler, Wolfgang Lieb, Ellen Honisch, Nina Ditsch, Clemens R. Müller, Alfons Meindl, Frank Jessen, Dieter Niederacher, Andre Franke, Holger Thiele, Kristina Klaschik, Stefanie Heilmann-Heimbach, Karl Hackmann, Corinna Ernst, Christoph Engel, Eva Groß, Anne-Karin Kahlert, Janine Altmüller, Eric Hahnen, Juliane Ramser, Guido Neidhardt, Jan Hauke, and Andrea Gehrig
Subjects: 0301 basic medicine, Oncology, Cancer Research, Mutation rate, endocrine system diseases, FANCM protein, human, DNA Mutational Analysis, Triple Negative Breast Neoplasms, 0302 clinical medicine, Mutation Rate, hemic and lymphatic diseases, FANCM, Mutation frequency, Age of Onset, skin and connective tissue diseases, Genetics, Ovarian Neoplasms, Brief Report, genetics [Breast Neoplasms], Middle Aged, 030220 oncology & carcinogenesis, Female, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Heterozygote, Breast Neoplasms, 03 medical and health sciences, Germline mutation, genetics [DNA Helicases], Internal medicine, medicine, Cancer Family, Humans, Genetic Predisposition to Disease, ddc:610, Germ-Line Mutation, Aged, business.industry, genetics [Triple Negative Breast Neoplasms], Case-control study, DNA Helicases, nutritional and metabolic diseases, Odds ratio, 030104 developmental biology, genetics [Ovarian Neoplasms], Case-Control Studies, Age of onset, business
Abstract: Importance Germline mutations in established moderately or highly penetrant risk genes for breast cancer (BC) and/or ovarian cancer (OC), including BRCA1 and BRCA2 , explain fewer than half of all familial BC and/or OC cases. Based on the genotyping of 2 loss-of-function (LoF) variants c.5101C>T (p.GIn1701Ter [rs147021911]) and c.5791C>T (p.Arg1931Ter [rs144567652]), the FANCM gene has been suggested as a novel BC predisposition gene, while the analysis of the entire coding region of the FANCM gene in familial index cases and geographically matched controls is pending. Objectives To assess the mutational spectrum within the FANCM gene, and to determine a potential association of LoF germline mutations within the FANCM gene with BC and/or OC risk. Design, Setting, and Participants For the purpose of identification and characterization of novel BC and/or OC predisposition genes, a total of 2047 well-characterized familial BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for LoF mutations within the FANCM gene by next-generation sequencing. All patients previously tested negative for pathogenic BRCA1 and BRCA2 mutations. All data collection occurred between June 1, 2013, and April 30, 2016. Data analysis was performed from May 1, 2016, to July 1, 2016. Main Outcomes and Measures FANCM LoF mutation frequencies in patients with BC and/or OC were compared with the FANCM LoF mutation frequencies in geographically matched controls by univariate logistic regression. Positive associations were stratified by age at onset and cancer family history. Results In this case-control study, 2047 well-characterized familial female BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for truncating FANCM alterations. Heterozygous LoF mutations within the FANCM gene were significantly associated with familial BC risk, with an overall odds ratio (OR) of 2.05 (95% CI, 0.94-4.54; P = .049) and a mutation frequency of 1.03% in index cases. In familial patients whose BC onset was before age 51 years, an elevated OR of 2.44 (95% CI, 1.08-5.59; P = .02) was observed. A more pronounced association was identified for patients with a triple-negative BC tumor phenotype (OR, 3.75; 95% CI, 1.00-12.85; P = .02). No significant association was detected for unselected OC cases (OR, 1.74; 95% CI, 0.57-5.08; P = .27). Conclusions and Relevance Based on the significant associations of heterozygous LoF mutations with early-onset or triple-negative BC, FANCM should be included in diagnostic gene panel testing for individual risk assessment. Larger studies are required to determine age-dependent disease risks for BC and to assess a potential role of FANCM mutations in OC pathogenesis.
Published: 2016

34. Brustkrebs: BRCA-Status ohne Einfluss auf das Überleben

Author: Nina Ditsch, Eva Groß, and Beate Schumacher
Subjects: Gynecology, medicine.medical_specialty, Surgical oncology, business.industry, medicine, business
Abstract: Junge Brustkrebspatientinnen mit BRCA1- oder BRCA2-Mutation haben in den ersten 10 Jahren nach der Diagnose dieselben Uberlebenschancen wie Patientinnen ohne BRCA-Mutation.
Published: 2018

35. FUSAFE individual patient data meta-analysis (MA) to assess the performance of dihydropyrimidine dehydrogenase (DPD) gene polymorphisms for predicting grade 4-5 fluoropyrimidine (FP) toxicity

Author: Carlo R. Largiadèr, Fabienne Thomas, Jean-Christophe Boyer, Barbara A. Jennings, Michèle Boisdron-Celle, M.-C. Etienne-Grimaldi, Robert B. Diasio, G. Le Teuff, Julien Taieb, Valérie Boige, Maarten J. Deenen, Eva Gross, Didier Meulendijks, J.P. Pignon, Ulrich M. Zanger, Nathalie Cozic, Claire Palles, Anthony M. Marinaki, and Marie-Anne Loriot
Subjects: 0301 basic medicine, medicine.medical_specialty, business.industry, Advanced stage, Stock options, Hematology, Patient data, Capecitabine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, Dose adjustment, 030220 oncology & carcinogenesis, Internal medicine, Meta-analysis, medicine, Dihydropyrimidine dehydrogenase, DPYD, business, medicine.drug
Abstract: Background Despite decades of research, performance of DPYD genotyping to predict FP toxicity (tox) is poorly documented. GPCO-UNICANCER and RNPGx groups initiated the FUSAFE MA on individual patient data (IPD) to assess the prognostic value of consensual deleterious DPYD variants on grade (G) 4-5 FP tox. Methods Eligibility criteria included unbiased recruitment of Caucasian patients (pts) without FP dose adjustment based on DPD status. Main endpoint was 12 weeks hematological or digestive G4-5 tox. Age, sex, body mass index (BMI), advanced stage (M- vs M+), FP drug (5FU vs capecitabine), FP administration (bolus±continuous vs continuous alone or p.o.) and associated anticancer drugs (AAD) were collected. Multivariable logistic models were applied. Performance was assessed by AUC and diagnostic indices maximizing Youden index. Results From the 18 identified eligible studies (10230 pts), 14 were included (9030 pts), with complete IPD collected for 6403 pts (84% colorectal, 16% M+, 66% 5FU, 80% AAD). G4-5 tox prevalence was 8% (518 events). DPYD variants *2A, D949V, *13 and HapB3 were carried by 0.9%, 1.2%, 0.2% and 3.9% of pts, respectively. The clinical model (M1) retained age, sex, BMI, FP-administration, AAD. Adding variants *2A/D949V/*13 (at least one mutated allele) significantly (p Table . 569P Model AUC (area under the curve) Sensitivity Specificity Positive predictive value Negative predictive value M1 0.725 69.7% 65.4% 15.1% 96.1% M2 0.750 75.5% 62.8% 15.2% 96.7% M3 0.752 76.4% 61.9% 15.0% 96.8% Conclusions This is the largest MA on DPYD genotyping and toxicity. It shows the relevance of clinical variables and of the 3 consensual DPYD variants. Despite its association with tox, HapB3 does not improve the discriminant ability to identify pts at risk of G4-5 toxicity. Legal entity responsible for the study Centre Antoine Lacassagne, Nice, France (Dr Marie-Christine Etienne-Grimaldi, coordinator). Funding French Cancer Institute (INCa) funding (PHRC-K 14-193 FUSAFE) and French Ligue Nationale Contre le Cancer. Disclosure V. Boige: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Travel / Accommodation / Expenses: Roche Genentech; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy: Prestizia; Advisory / Consultancy: Eisai; Travel / Accommodation / Expenses: Sanofi. J. Taieb: Advisory / Consultancy: Amgen; Advisory / Consultancy: Lily; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: Celgene; Advisory / Consultancy: Servier; Advisory / Consultancy: Sirtex; Advisory / Consultancy: Pierre Fabre. D. Meulendijks: Full / Part-time employment: AstraZeneca UK. C. Palles: Advisory / Consultancy: Oxford Cancer Biomarkers. U. Zanger: Licensing / Royalties: Robert Bosch GmbH. M. Boisdron-Celle: Speaker Bureau / Expert testimony, Leadership role, Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: ODPM. A. Marinaki: Full / Part-time employment: Viapath. E. Gross: Licensing / Royalties: Klinikum Rechts der Isar der Technischen Universitat Munchen. All other authors have declared no conflicts of interest.
Published: 2019

36. uPAR enhances malignant potential of triple-negative breast cancer by directly interacting with uPA and IGF1R

Author: Rebecca Mall, Katrin Lindner, Herbert Braselmann, Michaela Aubele, Sara Molatore, Axel Walch, Eva Gross, Manfred Schmitt, Annette Feuchtinger, Michaela C. Huber, and Natalie Falkenberg
Subjects: 0301 basic medicine, Cancer Research, Cell Survival, medicine.medical_treatment, Triple Negative Breast Neoplasms, uPA system, Igf-1r, Prognostic Impact, Tnbc, Upa System, Upar Interactome, Upas, Receptor, IGF Type 1, Receptors, Urokinase Plasminogen Activator, Targeted therapy, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Growth factor receptor, Cell Movement, Cell Line, Tumor, Progesterone receptor, Genetics, medicine, Humans, skin and connective tissue diseases, Triple-negative breast cancer, uPAR interactome, Cell Proliferation, Insulin-like growth factor 1 receptor, business.industry, Receptors, Somatomedin, medicine.disease, Urokinase-Type Plasminogen Activator, ddc, Gene Expression Regulation, Neoplastic, Urokinase receptor, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Immunology, MCF-7 Cells, Cancer research, Prognostic impact, Female, Neoplasm Grading, business, IGF-1R, TNBC, uPAS, Research Article
Abstract: Background Due to lack of a targeted therapy for the triple-negative breast cancer (TNBC) patients, it is important to explore this aggressive breast cancer type in more detail and to establish novel therapeutic approaches. TNBC is defined negative for the protein expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). One prominent feature of this cancer type is the frequent overexpression of major components of the urokinase-type plasminogen activator system (uPAS) including uPA, its receptor uPAR and the inhibitor PAI-1, which may be valuable as therapeutic targets. Methods Direct interactions of uPAR with interactors were demonstrated by immunoprecipitations and proximity ligation assays. For stable knockdowns of target proteins, lentiviral vectors were used and the effects were analysed by immunoblottings and using in vitro cell viability, migration and invasion assays. Immunohistochemical and statistical analyses of biomarkers and clinical parameters were conducted in a TNBC cohort (n = 174). Results Direct tumour-promoting interactions of uPAR with uPA and the insulin-like growth factor receptor 1 (IGF1R) were shown in TNBC cells and these interactions were significantly reduced (p = 0.001) when uPAR was downregulated. The combined knockdown of uPAR and uPA or IGF1R additively and significantly reduced cell viability, migration and invasion of the model cell lines. In TNBC tissue, the complexes formed by uPAR with uPA or with IGF1R significantly correlated with the histological grade (p = 0.0019) as well as with cathepsin B and D (p ≤ 0.0001) that are implicated in cell invasion and metastasis. Conclusions Our outcomes show that not only overexpressed biomarkers promote tumourigenesis, but rather their interactions further potentiate tumour progression. This study emphasises the potential of combined approaches targeting uPAR and its interactors with regard to an improved therapy of TNBC. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2663-9) contains supplementary material, which is available to authorized users.
Published: 2016

37. Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity

Author: Doreen Dobritzsch, Rutger Meinsma, Marion Kiechle, Adri Mul, Veronika Schmid, Veerle A. Derleyn, Ed Maartense, Marie-Christine Etienne-Grimaldi, Marcel M.A.M. Mannens, André B.P. van Kuilenburg, Heinz-Josef Klümpen, Raymon Vijzelaar, J. G. Maring, Raoul C.M. Hennekam, Eva Gross, Gérard Milano, Judith Meijer, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Laboratory Genetic Metabolic Diseases, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatrics, ACS - Amsterdam Cardiovascular Sciences, ARD - Amsterdam Reproduction and Development, Human Genetics, Oncology, and Faculteit der Geneeskunde
Subjects: Adult, Male, Silent mutation, Antimetabolites, Antineoplastic, RNA Splicing, Population, Mutation, Missense, Biology, Polymerase Chain Reaction, Exon, Dihydropyrimidine dehydrogenase, Genetics, Humans, Genetics(clinical), RNA, Messenger, education, Dihydrouracil Dehydrogenase (NADP), Genetics (clinical), Aged, Sequence Deletion, Original Investigation, Gene Rearrangement, Comparative Genomic Hybridization, education.field_of_study, Polymorphism, Genetic, Sequence Analysis, DNA, Gene rearrangement, Middle Aged, Molecular biology, Introns, Mutation (genetic algorithm), RNA splicing, Female, DPYD, Fluorouracil
Abstract: Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme acting in the catabolism of the widely used antineoplastic agent 5-fluorouracil (5FU). DPD deficiency is known to cause a potentially lethal toxicity following administration of 5FU. Here, we report novel genetic mechanisms underlying DPD deficiency in patients presenting with grade III/IV 5FU-associated toxicity. In one patient a genomic DPYD deletion of exons 21–23 was observed. In five patients a deep intronic mutation c.1129–5923C>G was identified creating a cryptic splice donor site. As a consequence, a 44 bp fragment corresponding to nucleotides c.1129–5967 to c.1129–5924 of intron 10 was inserted in the mature DPD mRNA. The deleterious c.1129–5923C>G mutation proved to be in cis with three intronic polymorphisms (c.483 + 18G>A, c.959–51T>G, c.680 + 139G>A) and the synonymous mutation c.1236G>A of a previously identified haplotype. Retrospective analysis of 203 cancer patients showed that the c.1129–5923C>G mutation was significantly enriched in patients with severe 5FU-associated toxicity (9.1%) compared to patients without toxicity (2.2%). In addition, a high prevalence was observed for the c.1129–5923C>G mutation in the normal Dutch (2.6%) and German (3.3%) population. Our study demonstrates that a genomic deletion affecting DPYD and a deep intronic mutation affecting pre-mRNA splicing can cause severe 5FU-associated toxicity. We conclude that screening for DPD deficiency should include a search for genomic rearrangements and aberrant splicing. Electronic supplementary material The online version of this article (doi:10.1007/s00439-010-0879-3) contains supplementary material, which is available to authorized users.
Published: 2010

38. Towards a comprehensive approach? The EU’s contribution to Security Sector Reform (SSR) in Afghanist

Author: Eva Gross
Subjects: Economic growth, Economic policy, Security sector reform, Business
Published: 2010

39. The dihydrouracil/uracil ratio in plasma, clinical and genetic analysis for screening of dihydropyrimidine dehydrogenase deficiency in colorectal cancer patients treated with 5-fluorouracil

Author: R. Ben Fredj, Saâd Saguem, Eva Gross, S. Ben Ahmed, and H. Hassine
Subjects: Adult, Male, Antimetabolites, Antineoplastic, Dihydropyrimidine Dehydrogenase Deficiency, High-performance liquid chromatography, Dihydropyrimidine dehydrogenase deficiency, chemistry.chemical_compound, Blood plasma, medicine, Dihydropyrimidine dehydrogenase, Humans, Genetic Testing, Uracil, Chromatography, High Pressure Liquid, Dihydrouracil Dehydrogenase (NADP), Aged, Chromatography, business.industry, Homozygote, Dihydrouracil, DNA, General Medicine, Middle Aged, medicine.disease, Biochemistry, chemistry, Fluorouracil, Female, Spectrophotometry, Ultraviolet, DPYD, Colorectal Neoplasms, business, Biomarkers, Half-Life, medicine.drug
Abstract: A rapid and cost-effective reversed phase high performance liquid chromatography (HPLC) method for quantification of dihydrouracil to uracil ratio (UH2/U) in plasma has been developed and used to screen for dihydropyrimidine dehydrogenase (DPD) deficiency in nine patients treated with 5-fluorouracil (5-FU). This HPLC method is based on the use of a simultaneous UV detection at 205 and 268nm during the analysis run of the plasma extract and taking into account the particularity that UH2 shows no absorbance response at 268nm. The plasma UH2/U ratio values evaluated by the use of our HPLC assay were found to be highly correlated with the plasma 5-FU-half-life values and were significantly associated with the toxic side effects, whereas, data set provided from genetic analysis of the coding sequences of the DPD gene (DPYD) were found to be insufficient to explain all the cases of the 5-FU-related toxicity pattern. The proposed HPLC assay could be available for routine clinical use for DPD deficiency assessment in patients prior to 5-FU administration.
Published: 2009

40. Reconstructing Afghanistan: Is the ‘West’ eclipsing the ‘International Community’?

Author: Eva Gross, Political Science, and Institute for European Studies
Subjects: reconstruction, Geography, Afghanistan, International community, international community, Ancient history
Abstract: NA
Published: 2009

41. Cardio-facio cutaneous syndrome: neurological manifestations

Author: Varda Gross-Tsur, Eva Gross-Kieselstein, and Naomi Amir
Subjects: Heart Defects, Congenital, Male, medicine.medical_specialty, integumentary system, Heart disease, business.industry, Eeg abnormalities, Cardio facio cutaneous, Syndrome, medicine.disease, Dermatology, Dermatitis, Seborrheic, Facial Bones, Child, Preschool, Intellectual Disability, Microcephaly, Genetics, Abnormal skin, Humans, Medicine, Abnormalities, Multiple, business, Genetics (clinical), Hair
Abstract: Cardio-facio-cutaneous (CFC) syndrome is a not uncommon syndrome with a characteristic face, mental retardation, abnormal skin and hair and congenital heart disease. We report the 16th case of this syndrome and give details of the spectrum of neurological manifestations in the cases so far reported.
Published: 2008

42. Mutational spectrum of dihydropyrimidine dehydrogenase gene (DPYD) in the Tunisian population

Author: Lotfi Chouchen, Radhia Ben Fredj, Fatma B’chir, Steffi Neubauer, Slim Ben Ahmed, Eva Gross, Marion Kiechle, and Saâd Saguem
Subjects: Adult, Male, Tunisia, Dihydropyrimidine Dehydrogenase Deficiency, DNA Mutational Analysis, Biology, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Polymorphism (computer science), Ethnicity, medicine, Dihydropyrimidine dehydrogenase, Humans, Allele, Allele frequency, Dihydrouracil Dehydrogenase (NADP), Aged, Genetics, General Immunology and Microbiology, General Medicine, Middle Aged, Introns, Arabs, Fluorouracil, Mutation, Population study, Female, DPYD, General Agricultural and Biological Sciences, Pharmacogenetics, medicine.drug
Abstract: Dihydropyrimidine dehydrogenase enzyme (DPD) deficiency is a pharmacogenetic syndrome leading to severe side-effects in patients receiving therapies containing the anticancer drug 5-fluorouracil (5-FU). The aim of this population study is to evaluate gene variations in the coding region of the dihydropyrimidine dehydrogenase gene (DPYD) in the Tunisian population. One hundred and six unrelated healthy Tunisian volunteers were genotyped by denaturing HPLC (DHPLC). Twelve variants in the coding region of the DPYD were detected. Allele frequencies of DPYD*5 (A1627G), DPYD*6 (G2194A), DPYD*9A (T85C), A496G, and G1218A were 12.7%, 7.1%, 13.7%, 5.7%, and 0.5%, respectively. The DPYD alleles DPYD*2A (IVS 14+1g>1), DPYD*3 (1897 del C) and DPYD*4 (G1601A) associated with DPD deficiency were absent from the examined subjects. We describe for the first time a new intronic polymorphism IVS 6-29 g>t, found in an allelic frequency of 4.7% in the Tunisian population. Comparing our data with that obtained in Caucasian, Egyptian, Japanese and African-American populations, we found that the Tunisian population resembles Egyptian and Caucasian populations with regard to their allelic frequencies of DPYD polymorphisms. This study describes for the first time the spectrum of DPYD sequence variations in the Tunisian population.
Published: 2007

43. The EU and Asia

Author: Eva Gross
Published: 2015

44. The impact of the uPAR system and its interaction partners as potential therapeutic targets in TNBC

Author: N. Falkenberg, Herbert Braselmann, M. Aubele, M. Schmitt, M. Huber, Eva Gross, and R. Mall
Subjects: Urokinase receptor, Oncology, business.industry, Cancer research, Medicine, Hematology, business, Triple-negative breast cancer
Published: 2015

45. Mutationen im Dihydropyrimidindehydrogenase-Gen als Ursache von 5-Fluororuracil-Intoleranz

Author: Eva Gross, Marion Kiechle, and K. Seck
Subjects: chemistry.chemical_classification, Genetics, business.industry, Obstetrics and Gynecology, Cancer, medicine.disease, Enzyme, chemistry, Dihydropyrimidine dehydrogenase, Cancer research, Medicine, Population study, Coding region, DPYD, business, Gene, Pharmacogenetics
Abstract: Cancer patients developing severe side effects upon chemotherapy with 5-fluorouracil (5-FU) are assumed to display reduced activity of the enzyme dihydropyrimidine dehydrogenase (DPD). Meanwhile over 20 different mutations are known in the dihydropyrimidine dehydrogenase gene (DPYD) which could be associated with a loss of enzyme function. For most of these genetic alterations, however, clear genotype-phenotype relations are still lacking. We are conducting a population study using a German cohort to determine the frequency of DPD defects in the German population and to detect new toxicity-associated mutations. Our aim is to develop a sensitive and efficient screening of tumor patients to identify patients with mutations in the DPYD gene which might be related to 5-FU-toxicity. For this purpose we analysed the whole coding region of DPYD by the technique of denaturing HPLC (DHPLC). The DHPLC analysis turned out to be a reliable method for the investigation of large samples in an acceptable cost and time range. To further elucidate the molecular basis of the DPD deficiency syndrome we will continue to analyse a patient panel receiving 5-FU.
Published: 2002

46. NGS-based multi-gene panel analysis in BRCA1/2-negative breast and ovarian cancer families

Author: Dieter Niederacher, Mateja Smogavec, Kerstin Rhiem, Ulrike Faust, Bernd Dworniczak, Judit Horvath, Gunnar Schmidt, Norbert Arnold, Bernhard H. F. Weber, Jan Hauke, Walter Just, Eva Gross, Rita K. Schmutzler, Christian Sutter, Andrea Gehrig, Juliane Ramser, Julia Hentschel, Karl Hackmann, Eric Hahnen, and Esther Pohl
Subjects: 0301 basic medicine, Genetics, Cancer Research, business.industry, PALB2, medicine.disease, Germline, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Cohort, Medicine, RAD51C, Copy-number variation, business, Ovarian cancer, CHEK2, Illumina dye sequencing
Abstract: 1526 Background: 24% of familial breast cancer (BC) and/or ovarian cancer (OC) cases analyzed within the framework of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) are due to pathogenic mutations in the BRCA1 or BRCA2 genes. The population-specific mutation prevalence of non- BRCA1/2 genes associated with familial BC and/or OC is largely unknown and was determined in a large German cohort. Methods: Here, we present next-generation sequencing (NGS) data established from TruRisk (GC-HBOC-designed) or TruSight cancer gene panels. A cohort of 6,507 BRCA1/2-negative index cases fulfilling the inclusion criteria of the GC-HBOC for germline testing was analyzed. Illumina sequencing platforms were used and data analysis was carried out at each individual center using different analysis pipelines. Analysis of copy number variations (CNV) was not included in the present data evaluation. Results: By focusing on 8 confirmed BC/OC risk genes ( ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, TP53), the 6,507 cancer patients revealed 165 different deleterious variants in 378 unrelated mutation carriers (5.8%). We found a high prevalence of CHEK2 (n = 150, 2.3%), ATM (n = 89, 1.4% ), and PALB2 (n = 72, 1.1%) mutations while RAD51C (n = 21, 0.3%), TP53 (n = 16, 0.2%), NBN (n = 15, 0.2%), CDH1 (n = 10, 0.2%), and RAD51D (n = 5, 0.1%) were less frequently mutated. Conclusions: The high frequency of pathologic mutations in the genes ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53, together accounting for almost 6% of familial BC/OC risk, highlights the importance of these genes to be included in BC/OC routine diagnostics. The relevance of these mutations in a clinical setting for early detection of breast and ovarian cancer needs to be established.
Published: 2017

47. Alternative splicing of KAI1 abrogates its tumor-suppressive effects on integrin αvβ3-mediated ovarian cancer biology

Author: Julia Miller, Alexandra Karle, Ute Reuning, Eva Gross, Sina Upheber, and Stephanie Schlaugk
Subjects: Cell, Integrin, Kangai-1 Protein, Time-Lapse Imaging, Focal adhesion, Cell Movement, Cell Line, Tumor, medicine, Cell Adhesion, Humans, RNA, Messenger, Cell adhesion, Promoter Regions, Genetic, Cell Proliferation, Ovarian Neoplasms, Microscopy, Video, biology, Cadherin, Cell growth, Cell migration, Cell Biology, Cadherins, Integrin alphaVbeta3, Cell biology, ErbB Receptors, Alternative Splicing, medicine.anatomical_structure, Tumor progression, Cancer research, biology.protein, Female
Abstract: Loss or downregulation of the tumor-suppressor KAI1 correlates with poor cancer patient prognosis. KAI1 functions by interacting with other proteins, including integrin cell adhesion and signaling receptors. We previously showed that KAI1 physically and functionally crosstalks with the tumor-biologically relevant integrin αvβ3, thereby suppressing ovarian cancer cell migration and proliferation. Interestingly, in metastases, a KAI1 splice variant had been identified, indicating poor patient prognosis. Thus, we here characterized differential effects of the two KAI1 proteins upon their cellular restoration. Opposite to KAI1, KAI1-splice reduced αvβ3-mediated cell adhesion, thereby inducing cell migration. This was accompanied by elevated αvβ3 levels and drastically elevated focal adhesion kinase activation, however, without any obvious colocalization with αvβ3, as observed for KAI1. Moreover, codistribution of KAI1 with the cell/cell-adhesion molecule E-cadherin was abrogated in KAI1-splice. Whereas KAI1 diminished cell proliferative activity, KAI1-splice prominently enhanced cell proliferation concomitant with elevated transcription and cell-surface expression of the epidermal growth factor receptor. Thus KAI1-splice does not only counteract the tumor-suppressive actions of KAI1, but - beyond that - promotes αvβ3-mediated biological functions in favor of tumor progression and metastasis.
Published: 2014

48. Prognostische Rolle des Metastasierungssuppressors KAI1 (CD82) beim Ovarialkarzinom

Author: Alfons Meindl, M Kotzsch, Marion Kiechle, U Reuning, V Magdolen, Eva Gross, J Rothmeier, and S Schlaugk
Subjects: Maternity and Midwifery, Obstetrics and Gynecology
Published: 2014

49. Identification of specific BRCA1 and BRCA2 variants by DHPLC

Author: Marion Kiechle, Eva Gross, Norbert Arnold, Katrin Bandick, and Katharina Pfeifer
Subjects: Genetics, medicine.medical_specialty, Sequence analysis, Biology, Denaturing high performance liquid chromatography, medicine, Medical genetics, Identification (biology), Primer (molecular biology), skin and connective tissue diseases, Caucasian population, Gene, Genetics (clinical), Sequence (medicine)
Abstract: Denaturing high performance liquid chromatography (DHPLC) is generating increasing interest in clinical genetics as a reliable tool for the analysis of genetic alterations. In the work presented here our intentions were to optimize primer design and DHPLC analysis conditions for a qualitative detection of BRCA1 and BRCA2 variations. The BRCA1 and BRAC2 genes display a high proportion of polymorphisms. Sequencing efforts geared towards the distinction of tumor-related mutations and benign variants still remain time-consuming and expensive. DHPLC elution profiles, however, permit the correlation of a characteristic chromatographic profile with a specific sequence alteration. In this study we evaluate the sensitivity of DHPLC for the identification of unique polymorphisms, which are frequent in the Caucasian population, in lieu of sequence analysis. The complete BRCA1 gene and parts of BRCA2 were examined. In the case of BRCA1, 431 out of 432 heterozygotes were identified correctly. In addition, 18 new profiles were identified which had not been detected previously in our studies and which represented new mutations or rare polymorphisms. For BRCA2, 135 out of 137 simple sequence variants were classified correctly. In addition, six new profiles were identified which represented new mutations or rare polymorphisms.
Published: 2000

50. Maternal Phenylketonuria: An International Study

Author: Harvey L. Levy, Bobbye Rouse, Reuben Matalon, Eva Gross Friedman, Richard Koch, Lawrence D. Platt, Flemming Güttler, F. K. Trefz, F. de la Cruz, Colleen Azen, and William B. Hanley
Subjects: Heart Defects, Congenital, medicine.medical_specialty, Microcephaly, Pediatrics, Heart disease, Offspring, Phenylalanine, Endocrinology, Diabetes and Metabolism, Intelligence, Biochemistry, Endocrinology, Pregnancy, Phenylketonurias, Internal medicine, Genetics, medicine, Humans, Maternal phenylketonuria, Molecular Biology, Socioeconomic status, Fetus, Intelligence quotient, business.industry, Infant, Newborn, Pregnancy Outcome, medicine.disease, Pregnancy Complications, Female, business
Abstract: Maternal phenylketonuria (PKU) syndrome results in multiple congenital anomalies in the offspring, usually consisting of microcephaly, intrauterine growth retardation, dysmorphology, and congenital heart disease. Pregnancies treated preconceptionally with a phenylalanine-restricted diet and control of maternal blood phenylalanine levels within the recommended range result in normal offspring. However, in this 15-year study, several significant factors resulted in microcephaly in 27% of the offspring, and 7% exhibited serious congenital heart disease. These results occurred chiefly in women with mean IQ scores of 83 associated with low socioeconomic status and decreased educational achievement. Another important factor associated with suboptimal control of blood phenylalanine levels during pregnancy was the fact that most pregnancies were not carefully planned and occurred in women off dietary treatment with phenylalanine-restricted products. These results indicate that greater effort must be developed to assist women with PKU in remaining on diet during their reproductive years. It appears that continued adherence to the diet, resulting in normal maternal intelligence, is an important contribution to improved fetal development.
Published: 2000

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