TY - JOUR A1 - Grünewald, Benedikt A1 - Lange, Maren D A1 - Werner, Christian A1 - O'Leary, Aet A1 - Weishaupt, Andreas A1 - Popp, Sandy A1 - Pearce, David A A1 - Wiendl, Heinz A1 - Reif, Andreas A1 - Pape, Hans C A1 - Toyka, Klaus V A1 - Sommer, Claudia A1 - Geis, Christian T1 - Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis JF - eLife N2 - Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3\(^{Δex1-6}\)) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition. KW - CLN3 KW - mutation KW - mouse model KW - synaptic transmission KW - amygdala KW - hippocampus Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170004 VL - 6 IS - e28685 ER - TY - JOUR A1 - Osorio, Ana A1 - Milne, Roger L. A1 - Kuchenbaecker, Karoline A1 - Vaclová, Tereza A1 - Pita, Guillermo A1 - Alonso, Rosario A1 - Peterlongo, Paolo A1 - Blanco, Ignacio A1 - de la Hoya, Miguel A1 - Duran, Mercedes A1 - Diez, Orland A1 - Ramón y Cajal, Teresa A1 - Konstantopoulou, Irene A1 - Martínez-Bouzas, Christina A1 - Conejero, Raquel Andrés A1 - Soucy, Penny A1 - McGuffog, Lesley A1 - Barrowdale, Daniel A1 - Lee, Andrew A1 - Arver, Brita A1 - Rantala, Johanna A1 - Loman, Niklas A1 - Ehrencrona, Hans A1 - Olopade, Olufunmilayo I. A1 - Beattie, Mary S. A1 - Domchek, Susan M. A1 - Nathanson, Katherine A1 - Rebbeck, Timothy R. A1 - Arun, Banu K. A1 - Karlan, Beth Y. A1 - Walsh, Christine A1 - Lester, Jenny A1 - John, Esther M. A1 - Whittemore, Alice S. A1 - Daly, Mary B. A1 - Southey, Melissa A1 - Hopper, John A1 - Terry, Mary B. A1 - Buys, Saundra S. A1 - Janavicius, Ramunas A1 - Dorfling, Cecilia M. A1 - van Rensburg, Elizabeth J. A1 - Steele, Linda A1 - Neuhausen, Susan L. A1 - Ding, Yuan Chun A1 - Hansen, Thomas V. O. A1 - Jønson, Lars A1 - Ejlertsen, Bent A1 - Gerdes, Anne-Marie A1 - Infante, Mar A1 - Herráez, Belén A1 - Moreno, Leticia Thais A1 - Weitzel, Jeffrey N. A1 - Herzog, Josef A1 - Weeman, Kisa A1 - Manoukian, Siranoush A1 - Peissel, Bernard A1 - Zaffaroni, Daniela A1 - Scuvera, Guilietta A1 - Bonanni, Bernardo A1 - Mariette, Frederique A1 - Volorio, Sara A1 - Viel, Alessandra A1 - Varesco, Liliana A1 - Papi, Laura A1 - Ottini, Laura A1 - Tibiletti, Maria Grazia A1 - Radice, Paolo A1 - Yannoukakos, Drakoulis A1 - Garber, Judy A1 - Ellis, Steve A1 - Frost, Debra A1 - Platte, Radka A1 - Fineberg, Elena A1 - Evans, Gareth A1 - Lalloo, Fiona A1 - Izatt, Louise A1 - Eeles, Ros A1 - Adlard, Julian A1 - Davidson, Rosemarie A1 - Cole, Trevor A1 - Eccles, Diana A1 - Cook, Jackie A1 - Hodgson, Shirley A1 - Brewer, Carole A1 - Tischkowitz, Marc A1 - Douglas, Fiona A1 - Porteous, Mary A1 - Side, Lucy A1 - Walker, Lisa A1 - Morrison, Patrick A1 - Donaldson, Alan A1 - Kennedy, John A1 - Foo, Claire A1 - Godwin, Andrew K. A1 - Schmutzler, Rita Katharina A1 - Wappenschmidt, Barbara A1 - Rhiem, Kerstin A1 - Engel, Christoph A1 - Meindl, Alftons A1 - Ditsch, Nina A1 - Arnold, Norbert A1 - Plendl, Hans Jörg A1 - Niederacher, Dieter A1 - Sutter, Christian A1 - Wang-Gohrke, Shan A1 - Steinemann, Doris A1 - Preisler-Adams, Sabine A1 - Kast, Karin A1 - Varon-Mateeva, Raymonda A1 - Gehrig, Andrea A1 - Stoppa-Lyonnet, Dominique A1 - Sinilnikova, Olga M. A1 - Mazoyer, Sylvie A1 - Damiola, Francesca A1 - Poppe, Bruce A1 - Claes, Kathleen A1 - Piedmonte, Marion A1 - Tucker, Kathy A1 - Backes, Floor A1 - Rodríguez, Gustavo A1 - Brewster, Wendy A1 - Wakeley, Katie A1 - Rutherford, Thomas A1 - Caldés, Trinidad A1 - Nevanlinna, Heli A1 - Aittomäki, Kristiina A1 - Rookus, Matti A. A1 - van Os, Theo A. M. A1 - van der Kolk, Lizet A1 - de Lange, J. L. A1 - Meijers-Heijboer, Hanne E. J. A1 - van der Hout, A. H. A1 - van Asperen, Christi J. A1 - Goméz Garcia, Encarna B. A1 - Encarna, B. A1 - Hoogerbrugge, Nicoline A1 - Collée, J. Margriet A1 - van Deurzen, Carolien H. M. A1 - van der Luijt, Rob B. A1 - Devilee, Peter A1 - Olah, Edith A1 - Lázaro, Conxi A1 - Teulé, Alex A1 - Menéndez, Mireia A1 - Jakubowska, Anna A1 - Cybulski, Cezary A1 - Gronwald, Jecek A1 - Lubinski, Jan A1 - Durda, Katarzyna A1 - Jaworska-Bieniek, Katarzyna A1 - Johannsson, Oskar Th. A1 - Maugard, Christine A1 - Montagna, Marco A1 - Tognazzo, Silvia A1 - Teixeira, Manuel R. A1 - Healey, Sue A1 - Olswold, Curtis A1 - Guidugli, Lucia A1 - Lindor, Noralane A1 - Slager, Susan A1 - Szabo, Csilla I. A1 - Vijai, Joseph A1 - Robson, Mark A1 - Kauff, Noah A1 - Zhang, Liying A1 - Rau-Murthy, Rohini A1 - Fink-Retter, Anneliese A1 - Singer, Christine F. A1 - Rappaport, Christine A1 - Kaulich, Daphne Geschwantler A1 - Pfeiler, Georg A1 - Tea, Muy-Kheng A1 - Berger, Andreas A1 - Phelan, Catherine M. A1 - Greene, Mark H. A1 - Mai, Phuong L. A1 - Lejbkowicz, Flavio A1 - Andrulis, Irene A1 - Mulligan, Anna Marie A1 - Glendon, Gord A1 - Toland, Amanda Ewart A1 - Bojesen, Anders A1 - Pedersen, Inge Sokilde A1 - Sunde, Lone A1 - Thomassen, Mads A1 - Kruse, Torben A. A1 - Jensen, Uffe Birk A1 - Friedman, Eitan A1 - Laitman, Yeal A1 - Shimon, Shanie Paluch A1 - Simard, Jaques A1 - Easton, Douglas F. A1 - Offit, Kenneth A1 - Couch, Fergus J. A1 - Chenevix-Trench, Georgia A1 - Antoniou, Antonis C. A1 - Benitez, Javier T1 - DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers JF - PLOS Genetics N2 - Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7x10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95% CI: 1.03-1.21, p = 4.8x10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied. KW - single-nucleotide polymorphisms KW - breast cancer KW - ovarian cancer KW - genetic modifiers KW - common variants KW - NEIL2 KW - OGG1 KW - investigators KW - consortium KW - damage Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116820 SN - 1553-7404 VL - 4 IS - e1004256 ER - TY - JOUR A1 - Grammatikos, Georgios A1 - Lange, Christian A1 - Susser, Simon A1 - Schwendy, Susanne A1 - Dikopoulos, Nektarios A1 - Buggisch, Peter A1 - Encke, Jens A1 - Teuber, Gerlinde A1 - Goeser, Tobias A1 - Thimme, Robert A1 - Klinker, Hartwig A1 - Boecher, Wulf O. A1 - Schulte-Frohlinde, Ewert A1 - Penna-Martinez, Marissa A1 - Badenhoop, Klaus A1 - Zeuzem, Stefan A1 - Berg, Thomas A1 - Sarrazin, Christoph T1 - Vitamin D Levels Vary during Antiviral Treatment but Are Unable to Predict Treatment Outcome in HCV Genotype 1 Infected Patients JF - PLOS ONE N2 - Background: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed. Methods: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-alpha and ribavirin for 24-72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome. Results: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002-1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975-0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000-1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073-2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271-4.695, P = 0.007) constituted the strongest predictors of treatment response. Conclusions: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients. KW - chronic Hepatitis C KW - sustained virological response KW - common genetic determinants KW - D serum-levels KW - IL28B polymorphisms KW - interferon alpha KW - viral clearance KW - virus infection KW - severe fibrosis KW - D insufficiency Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117310 SN - 1932-6203 VL - 9 IS - 2 ER - TY - JOUR A1 - Gonzalez‐Escamilla, Gabriel A1 - Muthuraman, Muthuraman A1 - Reich, Martin M. A1 - Koirala, Nabin A1 - Riedel, Christian A1 - Glaser, Martin A1 - Lange, Florian A1 - Deuschl, Günther A1 - Volkmann, Jens A1 - Groppa, Sergiu T1 - Cortical network fingerprints predict deep brain stimulation outcome in dystonia JF - Movement Disorders N2 - Background Deep brain stimulation (DBS) is an effective evidence‐based therapy for dystonia. However, no unequivocal predictors of therapy responses exist. We investigated whether patients optimally responding to DBS present distinct brain network organization and structural patterns. Methods From a German multicenter cohort of 82 dystonia patients with segmental and generalized dystonia who received DBS implantation in the globus pallidus internus, we classified patients based on the clinical response 3 years after DBS. Patients were assigned to the superior‐outcome group or moderate‐outcome group, depending on whether they had above or below 70% motor improvement, respectively. Fifty‐one patients met MRI‐quality and treatment response requirements (mean age, 51.3 ± 13.2 years; 25 female) and were included in further analysis. From preoperative MRI we assessed cortical thickness and structural covariance, which were then fed into network analysis using graph theory. We designed a support vector machine to classify subjects for the clinical response based on individual gray‐matter fingerprints. Results The moderate‐outcome group showed cortical atrophy mainly in the sensorimotor and visuomotor areas and disturbed network topology in these regions. The structural integrity of the cortical mantle explained about 45% of the DBS stimulation amplitude for optimal response in individual subjects. Classification analyses achieved up to 88% of accuracy using individual gray‐matter atrophy patterns to predict DBS outcomes. Conclusions The analysis of cortical integrity, informed by group‐level network properties, could be developed into independent predictors to identify dystonia patients who benefit from DBS. KW - brain networks KW - clinical outcome KW - deep brain stimulation KW - dystonia Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213532 VL - 34 IS - 10 SP - 1536 EP - 1545 ER - TY - JOUR A1 - Leyh, Catherine A1 - Ehmer, Ursula A1 - Roessler, Daniel A1 - Philipp, Alexander B. A1 - Reiter, Florian P. A1 - Jeliazkova, Petia A1 - Jochheim, Leonie S. A1 - Jeschke, Matthias A1 - Hammig, Janina A1 - Ludwig, Johannes M. A1 - Theysohn, Jens M. A1 - Geier, Andreas A1 - Lange, Christian M. T1 - Sorafenib versus lenvatinib-based sequential systemic therapy for advanced hepatocellular carcinoma: a real-world analysis JF - Cancers N2 - The optimal treatment sequence of tyrosine kinase inhibitor (TKI)-based therapy in patients with hepatocellular carcinoma (HCC) remains unclear. Therefore, sequential systemic therapy after first-line therapy with sorafenib or lenvatinib was compared in a retrospective real-world cohort. In total, 164 patients with HCC were included. Child B cirrhosis was present in 26 patients (16.5%), whereas 132 patients (83.5%) had preserved liver function. In total, 72 patients (44%) discontinued systemic therapy after first-line therapy while 51 (31%) and 31 (19%) patients received 2 or more treatment lines. Most notably, median overall survival (mOS) was influenced by liver functional status and patient performance status at the beginning of first-line therapy. Patients receiving a sequential therapy regimen had significantly longer mOS compared to patients that discontinued systemic therapy after omitting first-line treatment. The choice of the initial TKI did not impact mOS. A clear deterioration of liver function could be observed during the course of TKI-based treatment. KW - hepatocellular carcinoma KW - systemic therapy KW - tyrosine-kinase inhibitor Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270765 SN - 2072-6694 VL - 14 IS - 8 ER -