@article{GruenewaldLangeWerneretal.2017, author = {Gr{\"u}newald, Benedikt and Lange, Maren D and Werner, Christian and O'Leary, Aet and Weishaupt, Andreas and Popp, Sandy and Pearce, David A and Wiendl, Heinz and Reif, Andreas and Pape, Hans C and Toyka, Klaus V and Sommer, Claudia and Geis, Christian}, title = {Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis}, series = {eLife}, volume = {6}, journal = {eLife}, number = {e28685}, doi = {10.7554/eLife.28685}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170004}, year = {2017}, abstract = {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.}, language = {en} } @article{OsorioMilneKuchenbaeckeretal.2014, author = {Osorio, Ana and Milne, Roger L. and Kuchenbaecker, Karoline and Vaclov{\´a}, Tereza and Pita, Guillermo and Alonso, Rosario and Peterlongo, Paolo and Blanco, Ignacio and de la Hoya, Miguel and Duran, Mercedes and Diez, Orland and Ram{\´o}n y Cajal, Teresa and Konstantopoulou, Irene and Mart{\´i}nez-Bouzas, Christina and Conejero, Raquel Andr{\´e}s and Soucy, Penny and McGuffog, Lesley and Barrowdale, Daniel and Lee, Andrew and Arver, Brita and Rantala, Johanna and Loman, Niklas and Ehrencrona, Hans and Olopade, Olufunmilayo I. and Beattie, Mary S. and Domchek, Susan M. and Nathanson, Katherine and Rebbeck, Timothy R. and Arun, Banu K. and Karlan, Beth Y. and Walsh, Christine and Lester, Jenny and John, Esther M. and Whittemore, Alice S. and Daly, Mary B. and Southey, Melissa and Hopper, John and Terry, Mary B. and Buys, Saundra S. and Janavicius, Ramunas and Dorfling, Cecilia M. and van Rensburg, Elizabeth J. and Steele, Linda and Neuhausen, Susan L. and Ding, Yuan Chun and Hansen, Thomas V. O. and J{\o}nson, Lars and Ejlertsen, Bent and Gerdes, Anne-Marie and Infante, Mar and Herr{\´a}ez, Bel{\´e}n and Moreno, Leticia Thais and Weitzel, Jeffrey N. and Herzog, Josef and Weeman, Kisa and Manoukian, Siranoush and Peissel, Bernard and Zaffaroni, Daniela and Scuvera, Guilietta and Bonanni, Bernardo and Mariette, Frederique and Volorio, Sara and Viel, Alessandra and Varesco, Liliana and Papi, Laura and Ottini, Laura and Tibiletti, Maria Grazia and Radice, Paolo and Yannoukakos, Drakoulis and Garber, Judy and Ellis, Steve and Frost, Debra and Platte, Radka and Fineberg, Elena and Evans, Gareth and Lalloo, Fiona and Izatt, Louise and Eeles, Ros and Adlard, Julian and Davidson, Rosemarie and Cole, Trevor and Eccles, Diana and Cook, Jackie and Hodgson, Shirley and Brewer, Carole and Tischkowitz, Marc and Douglas, Fiona and Porteous, Mary and Side, Lucy and Walker, Lisa and Morrison, Patrick and Donaldson, Alan and Kennedy, John and Foo, Claire and Godwin, Andrew K. and Schmutzler, Rita Katharina and Wappenschmidt, Barbara and Rhiem, Kerstin and Engel, Christoph and Meindl, Alftons and Ditsch, Nina and Arnold, Norbert and Plendl, Hans J{\"o}rg and Niederacher, Dieter and Sutter, Christian and Wang-Gohrke, Shan and Steinemann, Doris and Preisler-Adams, Sabine and Kast, Karin and Varon-Mateeva, Raymonda and Gehrig, Andrea and Stoppa-Lyonnet, Dominique and Sinilnikova, Olga M. and Mazoyer, Sylvie and Damiola, Francesca and Poppe, Bruce and Claes, Kathleen and Piedmonte, Marion and Tucker, Kathy and Backes, Floor and Rodr{\´i}guez, Gustavo and Brewster, Wendy and Wakeley, Katie and Rutherford, Thomas and Cald{\´e}s, Trinidad and Nevanlinna, Heli and Aittom{\"a}ki, Kristiina and Rookus, Matti A. and van Os, Theo A. M. and van der Kolk, Lizet and de Lange, J. L. and Meijers-Heijboer, Hanne E. J. and van der Hout, A. H. and van Asperen, Christi J. and Gom{\´e}z Garcia, Encarna B. and Encarna, B. and Hoogerbrugge, Nicoline and Coll{\´e}e, J. Margriet and van Deurzen, Carolien H. M. and van der Luijt, Rob B. and Devilee, Peter and Olah, Edith and L{\´a}zaro, Conxi and Teul{\´e}, Alex and Men{\´e}ndez, Mireia and Jakubowska, Anna and Cybulski, Cezary and Gronwald, Jecek and Lubinski, Jan and Durda, Katarzyna and Jaworska-Bieniek, Katarzyna and Johannsson, Oskar Th. and Maugard, Christine and Montagna, Marco and Tognazzo, Silvia and Teixeira, Manuel R. and Healey, Sue and Olswold, Curtis and Guidugli, Lucia and Lindor, Noralane and Slager, Susan and Szabo, Csilla I. and Vijai, Joseph and Robson, Mark and Kauff, Noah and Zhang, Liying and Rau-Murthy, Rohini and Fink-Retter, Anneliese and Singer, Christine F. and Rappaport, Christine and Kaulich, Daphne Geschwantler and Pfeiler, Georg and Tea, Muy-Kheng and Berger, Andreas and Phelan, Catherine M. and Greene, Mark H. and Mai, Phuong L. and Lejbkowicz, Flavio and Andrulis, Irene and Mulligan, Anna Marie and Glendon, Gord and Toland, Amanda Ewart and Bojesen, Anders and Pedersen, Inge Sokilde and Sunde, Lone and Thomassen, Mads and Kruse, Torben A. and Jensen, Uffe Birk and Friedman, Eitan and Laitman, Yeal and Shimon, Shanie Paluch and Simard, Jaques and Easton, Douglas F. and Offit, Kenneth and Couch, Fergus J. and Chenevix-Trench, Georgia and Antoniou, Antonis C. and Benitez, Javier}, title = {DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers}, series = {PLOS Genetics}, volume = {4}, journal = {PLOS Genetics}, number = {e1004256}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004256}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116820}, year = {2014}, abstract = {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.}, language = {en} } @article{GrammatikosLangeSusseretal.2014, author = {Grammatikos, Georgios and Lange, Christian and Susser, Simon and Schwendy, Susanne and Dikopoulos, Nektarios and Buggisch, Peter and Encke, Jens and Teuber, Gerlinde and Goeser, Tobias and Thimme, Robert and Klinker, Hartwig and Boecher, Wulf O. and Schulte-Frohlinde, Ewert and Penna-Martinez, Marissa and Badenhoop, Klaus and Zeuzem, Stefan and Berg, Thomas and Sarrazin, Christoph}, title = {Vitamin D Levels Vary during Antiviral Treatment but Are Unable to Predict Treatment Outcome in HCV Genotype 1 Infected Patients}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {2}, issn = {1932-6203}, doi = {10.1371/journal.pone.0087974}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117310}, pages = {e87974}, year = {2014}, abstract = {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.}, language = {en} } @article{Gonzalez‐EscamillaMuthuramanReichetal.2019, author = {Gonzalez-Escamilla, Gabriel and Muthuraman, Muthuraman and Reich, Martin M. and Koirala, Nabin and Riedel, Christian and Glaser, Martin and Lange, Florian and Deuschl, G{\"u}nther and Volkmann, Jens and Groppa, Sergiu}, title = {Cortical network fingerprints predict deep brain stimulation outcome in dystonia}, series = {Movement Disorders}, volume = {34}, journal = {Movement Disorders}, number = {10}, doi = {10.1002/mds.27808}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213532}, pages = {1536 -- 1545}, year = {2019}, abstract = {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.}, language = {en} } @article{LeyhEhmerRoessleretal.2022, author = {Leyh, Catherine and Ehmer, Ursula and Roessler, Daniel and Philipp, Alexander B. and Reiter, Florian P. and Jeliazkova, Petia and Jochheim, Leonie S. and Jeschke, Matthias and Hammig, Janina and Ludwig, Johannes M. and Theysohn, Jens M. and Geier, Andreas and Lange, Christian M.}, title = {Sorafenib versus lenvatinib-based sequential systemic therapy for advanced hepatocellular carcinoma: a real-world analysis}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {8}, issn = {2072-6694}, doi = {10.3390/cancers14081975}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270765}, year = {2022}, abstract = {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.}, language = {en} }