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2. Determining physical properties of the cell cortex

Author

Saha, A., Nishikawa, M., Behrndt, M., Heisenberg, C. -P., Jülicher, F., and Grill, S. W.

Subjects
Physics - Biological Physics, Condensed Matter - Soft Condensed Matter, Quantitative Biology - Cell Behavior
Abstract

Actin and myosin assemble into a thin layer of a highly dynamic network underneath the membrane of eukaryotic cells. This network generates the forces that drive cell and tissue-scale morphogenetic processes. The effective material properties of this active network determine large-scale deformations and other morphogenetic events. For example,the characteristic time of stress relaxation (the Maxwell time)in the actomyosin sets the time scale of large-scale deformation of the cortex. Similarly, the characteristic length of stress propagation (the hydrodynamic length) sets the length scale of slow deformations, and a large hydrodynamic length is a prerequisite for long-ranged cortical flows. Here we introduce a method to determine physical parameters of the actomyosin cortical layer (in vivo). For this we investigate the relaxation dynamics of the cortex in response to laser ablation in the one-cell-stage {\it C. elegans} embryo and in the gastrulating zebrafish embryo. These responses can be interpreted using a coarse grained physical description of the cortex in terms of a two dimensional thin film of an active viscoelastic gel. To determine the Maxwell time, the hydrodynamic length and the ratio of active stress and per-area friction, we evaluated the response to laser ablation in two different ways: by quantifying flow and density fields as a function of space and time, and by determining the time evolution of the shape of the ablated region. Importantly, both methods provide best fit physical parameters that are in close agreement with each other and that are similar to previous estimates in the two systems. We provide an accurate and robust means for measuring physical parameters of the actomyosin cortical layer.It can be useful for investigations of actomyosin mechanics at the cellular-scale, but also for providing insights in the active mechanics processes that govern tissue-scale morphogenesis., Comment: 17 pages, 4 figures

Published
2015
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4. Präzisionsonkologie im Praxisalltag der Uro-Onkologie

Author

Ulmer, K, Retz, M, Lange, S, Illert, L, Pfarr, N, Schwamborn, K, Weichert, W, Lörsch, A, Jung, J, Kirchhoff, F, Jahnen, M, Meissner, V, Schatz, U, Grill, S, Herkommer, K, Gschwend, JE, Lunger, L, Ulmer, K, Retz, M, Lange, S, Illert, L, Pfarr, N, Schwamborn, K, Weichert, W, Lörsch, A, Jung, J, Kirchhoff, F, Jahnen, M, Meissner, V, Schatz, U, Grill, S, Herkommer, K, Gschwend, JE, and Lunger, L

Published
2024

5. Glycolic acid and D-lactate—putative products of DJ-1— restore neurodegeneration in FUS - and SOD1-ALS

Author

Pal, A., Grossmann, D., Glaß, H., Zimyanin, V., Günther, R., Catinozzi, M., Boeckers, T. M., Sterneckert, J., Storkebaum, E., Petri, S., Wegner, F., Grill, S. W., Pan-Montojo, F., Hermann, A., Pal, A., Grossmann, D., Glaß, H., Zimyanin, V., Günther, R., Catinozzi, M., Boeckers, T. M., Sterneckert, J., Storkebaum, E., Petri, S., Wegner, F., Grill, S. W., Pan-Montojo, F., and Hermann, A.

Abstract

Amyotrophic lateral sclerosis (ALS) leads to death within 2–5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)— both putative products of the Parkinson’s disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes ofmitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.

Published
2024

6. The significance of tree height as a predictor of tree mortality during bark beetle outbreaks in a small catchment

Author

Schmidt, Susanne Isabel, Fluksová, H., Grill, S., Kopáček, J., Schmidt, Susanne Isabel, Fluksová, H., Grill, S., and Kopáček, J.

Abstract

Bark beetle outbreaks damage forests and kill trees worldwide, but many aspects of their dynamics remain unexplained. Our aim was to identify predictors for individual tree deaths within the small (0.7 km2) Plešné Lake catchment in the Šumava National Park in southwestern Czechia. Within this area, >60,000 trees were geo-referenced and categorized from ten aerial images (20 cm spatial resolution) between 2000 and 2015. For each year for which aerial images were available, we calculated tree densities of different categories and diameters. Tree height was evaluated by means of LiDAR in two terrestrial campaigns (2010 and 2011). A machine learning technique was then used to evaluate the most important variables. The resulting relationships were largely nonlinear and differed among years; however, individual trait tree height proved to be the most influential variable in each year. Higher trees were more likely to have died during either the undisturbed phase (2000 and 2003), the disturbed phase (2005–2011), or the recovery phase (2013). Our results indicate that salvage logging may not be the most effective measure for protecting trees in small catchments.

Published
2024

7. Equivalence Tests in Subgroup Analyses

Author

Ring, A., Scharpenberg, M., Grill, S., Schall, R., Brannath, W., Chen, Jiahua, Series Editor, Chen, Ding-Geng (Din), Series Editor, Zhao, Yichuan, editor, and Chen, Ding-Geng, editor

Published
2018
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14. INTEREST IN CD2, a global patient-centred study of long-term cervical dystonia treatment with botulinum toxin

Author

Misra, Vijay P., Colosimo, Carlo, Charles, David, Chung, Tae Mo, Maisonobe, Pascal, Om, Savary, Abdulnayef, A., Adatepe, N. U., Araujo Leite, M. A., Badarny, S., Bajenaru, O., Bares, M., Bejjani, P., Bergmans, B., Bhidayasiri, R., Bozic, H., Cardoso Costa, F. E., Carlstrom, C., Castelnovo, G., Chang, M. H., Chang, Y. Y., Coletti-Moja, M., Delvaux, V., Dioszhegy, P., Dogu, O., Duzynski, W., Ehler, E., Espinosa Sierra, L., Fabbrini, G., Ferreira, J., Ferreira Valadas, A., Foresti, C., Girlanda, P., Goh, K. J., Graca Velon, A., Grill, S., Gurevitch, T., Hadidi, M., Hamimed, M. A., Hamri, A., Harrower, T., Hassin, S., Hedera, P., Hernandez, J. F. J. G., Hernandez Franco, J., Ho, B., Ho, S. L., Hughes, A., Ilic, T., Inshasi, J. S., Ip, C. W., Jamieson, S., Jamora, R. D. G., Jech, R., Jeon, B. S., Kaminska, A., Karpova, M., Khasanova, D., Kim, J. M., Kim, J. W., Kok, C. Y., Korenko, A., Korv, J., Koussa, S., Kovacs, T., Kreisler, A., Krystkowiak, P., Kumthornthip, W., Lin, C. H., Lundin, F., Lus, G., Magalhaes, M., Masmoudi, A. N., Mercelis, R., Misbahuddin, A., Moebius, C., Mohammadi, B., Nazem, B., Ng, K., Nurlu, G., Nyberg, J., Nyholm, D., Ochudlo, S., Otruba, P., Pfister, R., Pirtosek, Z., Pokhabov, D., Quinones Aguilar, S., Quinones Canales, G., Raghev, S., Rickmann, H., Romano, M., Rosales, R. L., Rubanovits, I., Santilli, V., Schoels, L., Simonetta-Moreau, M., Simu, M. A., Sohn, Y. H., Soulayrol, S., Supe, I., Svetel, M., Sycha, T., Tan, E. K., Timerbaeva, S., Tokcaer, A. B., Trosch, R., Tugnoli, V., Tumas, V., van der Linden, C., Vetra, A., Vial, C., Vidry, E., Williams, D., Wimalaratna, S., Yiannikas, C., Misra, Vijay P., Colosimo, Carlo, Charles, David, Chung, Tae Mo, Maisonobe, Pascal, Om, Savary, Abdulnayef, A., Adatepe, N. U., Araujo Leite, M. A., Badarny, S., Bajenaru, O., Bares, M., Bejjani, P., Bergmans, B., Bhidayasiri, R., Bozic, H., Cardoso Costa, F. E., Carlstrom, C., Castelnovo, G., Chang, M. H., Chang, Y. Y., Coletti-Moja, M., Delvaux, V., Dioszhegy, P., Dogu, O., Duzynski, W., Ehler, E., Espinosa Sierra, L., Fabbrini, G., Ferreira, J., Ferreira Valadas, A., Foresti, C., Girlanda, P., Goh, K. J., Graca Velon, A., Grill, S., Gurevitch, T., Hadidi, M., Hamimed, M. A., Hamri, A., Harrower, T., Hassin, S., Hedera, P., Hernandez, J. F. J. G., Hernandez Franco, J., Ho, B., Ho, S. L., Hughes, A., Ilic, T., Inshasi, J. S., Ip, C. W., Jamieson, S., Jamora, R. D. G., Jech, R., Jeon, B. S., Kaminska, A., Karpova, M., Khasanova, D., Kim, J. M., Kim, J. W., Kok, C. Y., Korenko, A., Korv, J., Koussa, S., Kovacs, T., Kreisler, A., Krystkowiak, P., Kumthornthip, W., Lin, C. H., Lundin, F., Lus, G., Magalhaes, M., Masmoudi, A. N., Mercelis, R., Misbahuddin, A., Moebius, C., Mohammadi, B., Nazem, B., Ng, K., Nurlu, G., Nyberg, J., Nyholm, D., Ochudlo, S., Otruba, P., Pfister, R., Pirtosek, Z., Pokhabov, D., Quinones Aguilar, S., Quinones Canales, G., Raghev, S., Rickmann, H., Romano, M., Rosales, R. L., Rubanovits, I., Santilli, V., Schoels, L., Simonetta-Moreau, M., Simu, M. A., Sohn, Y. H., Soulayrol, S., Supe, I., Svetel, M., Sycha, T., Tan, E. K., Timerbaeva, S., Tokcaer, A. B., Trosch, R., Tugnoli, V., Tumas, V., van der Linden, C., Vetra, A., Vial, C., Vidry, E., Williams, D., Wimalaratna, S., and Yiannikas, C.

Subjects
Male, Neurology, SATISFACTION, International Cooperation, Cohort Studies, 0302 clinical medicine, QUALITY-OF-LIFE, Botulinum toxin, Observational study, Tremor, Epidemiology, 030212 general & internal medicine, Cervical dystonia, Botulinum Toxins, Type A, Torticollis, Neuroradiology, BLEPHAROSPASM, education.field_of_study, Original Communication, INTEREST IN CD2 study group, Middle Aged, Treatment Outcome, Neuromuscular Agents, Female, Life Sciences & Biomedicine, medicine.drug, Adult, medicine.medical_specialty, Population, Clinical Neurology, DIAGNOSIS, 03 medical and health sciences, Patient satisfaction, Neurology (clinical), Internal medicine, medicine, Humans, education, Aged, Science & Technology, Neurology & Neurosurgery, Electromyography, GUIDANCE, business.industry, 1103 Clinical Sciences, medicine.disease, NEUROTOXIN, REGISTRY, UPDATE, Neurosciences & Neurology, 1109 Neurosciences, business, 030217 neurology & neurosurgery
Abstract

Background Longitudinal cohort studies provide important information about the clinical effectiveness of an intervention in the routine clinical setting, and are an opportunity to understand how a population presents for treatment and is managed. Methods INTEREST IN CD2 (NCT01753349) is a prospective, international, 3-year, longitudinal, observational study following the course of adult idiopathic cervical dystonia (CD) treated with botulinum neurotoxin type A (BoNT-A). The primary objective is to document long-term patient satisfaction with BoNT-A treatment. Here we report baseline data. Results This analysis includes 1036 subjects (67.4% of subjects were female; mean age was 54.7 years old; mean TWSTRS Total score was 31.7). BoNT-A injections were usually given in line with BoNT-A prescribing information. The most commonly injected muscles were splenius capitis (87.3%), sternocleidomastoid (82.6%), trapezius (64.3%), levator scapulae (40.9%) and semispinalis capitis (26.9%); 35.5% of subjects were injected using a guidance technique. Most subjects (87.8%) had been previously treated with BoNT-A (median interval between last pre-study injection and study baseline was 4 months); of these 84.8% reported satisfaction with BoNT-A treatment at peak effect during their previous treatment cycle and 51.5% remained satisfied at the end of the treatment. Analyses by geographical region revealed heterogeneity in the clinical characteristics and BoNT-A injection practice of CD subjects presenting for routine treatment. Conclusions These baseline analyses provide sizeable data regarding the epidemiology and clinical presentation of CD, and demonstrate an international heterogeneity of clinical practice. Future longitudinal analyses of the full 3-year study will explore how these factors impact treatment satisfaction. Electronic supplementary material The online version of this article (10.1007/s00415-017-8698-2) contains supplementary material, which is available to authorized users.

Published
2017
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17. Nonlinear machine learning pattern recognition and bacteria-metabolite multilayer network analysis of perturbed gastric microbiome

Author

Duran, C., Ciucci, S., Palladini, A., Ijaz, U. Z., Zippo, A. G., Sterbini, F. P., Masucci, Luca, Cammarota, Giovanni, Ianiro, Gianluca, Spuul, P., Schroeder, M., Grill, S. W., Parsons, B. N., Pritchard, D. M., Posteraro, Brunella, Sanguinetti, Maurizio, Gasbarrini, Giovanni Battista, Gasbarrini, Antonio, Cannistraci, C. V., Masucci L. (ORCID:0000-0002-8358-6726), Cammarota G. (ORCID:0000-0002-3626-6148), Ianiro G. (ORCID:0000-0002-8318-0515), Posteraro B. (ORCID:0000-0002-1663-7546), Sanguinetti M. (ORCID:0000-0002-9780-7059), Gasbarrini G., Gasbarrini A. (ORCID:0000-0002-7278-4823), Duran, C., Ciucci, S., Palladini, A., Ijaz, U. Z., Zippo, A. G., Sterbini, F. P., Masucci, Luca, Cammarota, Giovanni, Ianiro, Gianluca, Spuul, P., Schroeder, M., Grill, S. W., Parsons, B. N., Pritchard, D. M., Posteraro, Brunella, Sanguinetti, Maurizio, Gasbarrini, Giovanni Battista, Gasbarrini, Antonio, Cannistraci, C. V., Masucci L. (ORCID:0000-0002-8358-6726), Cammarota G. (ORCID:0000-0002-3626-6148), Ianiro G. (ORCID:0000-0002-8318-0515), Posteraro B. (ORCID:0000-0002-1663-7546), Sanguinetti M. (ORCID:0000-0002-9780-7059), Gasbarrini G., and Gasbarrini A. (ORCID:0000-0002-7278-4823)

Abstract

The stomach is inhabited by diverse microbial communities, co-existing in a dynamic balance. Long-term use of drugs such as proton pump inhibitors (PPIs), or bacterial infection such as Helicobacter pylori, cause significant microbial alterations. Yet, studies revealing how the commensal bacteria re-organize, due to these perturbations of the gastric environment, are in early phase and rely principally on linear techniques for multivariate analysis. Here we disclose the importance of complementing linear dimensionality reduction techniques with nonlinear ones to unveil hidden patterns that remain unseen by linear embedding. Then, we prove the advantages to complete multivariate pattern analysis with differential network analysis, to reveal mechanisms of bacterial network re-organizations which emerge from perturbations induced by a medical treatment (PPIs) or an infectious state (H. pylori). Finally, we show how to build bacteria-metabolite multilayer networks that can deepen our understanding of the metabolite pathways significantly associated to the perturbed microbial communities.

Published
2021

20. Creating Coordination in the Cerebellum Catania, 2–4 October 2003

Author

Andjus, P. R., Zhu, L., Strata, P., Arata, A., Ito, M., Bearzatto, B., Servais, L., Baba-Aïssa, F., de Kerchove d’Exaerde, A., Schurmans, S., Cheron, G., Schiffmann, S. N., Bower, J. M., Devor, A., Burguière, E., Rutteman, M., De Zeeuw, C. I., Berthoz, A., Wiener, S., Rondi-Reig, L., Campana, A., Dusart, I., Wherlé, R., Weitzman, J., Yaniv, M., Sotelo, C., Mariani, J., Cavallari, P., Esposti, R., Cerri, G., Cerminara, N. L., Apps, R., Marple-Horvat, D. E., Wagstaff, J., Dan, B., Chorev, E., Manor, Y., Sohl, G., Willecke, K., Yarom, Y., Philipona, D., Dognin, E., Coenen, O. J., Sola, E., Prestori, F., Rossi, P., Taglietti, V., D’Angelo, E., De Filippi, G., Baldwinson, T., Sher, E., Ekerot, C., Jorntell, H., Fernández, G., Martínez, S., Gall, D., Roussel, C., Forti, L., Schiffmann, S., Gruol, D. L., Netzeband, J. G., Quina, L. A., Blakely Gonzalez, P. K., Hoebeek, F. E., Van Alphen, A. M., Schonewille, M., Frens, M. A., Goossens, H. H. L. M., Stahl, J., Ango, F., di Cristo, G., Hagashiyama, H., Bennett, V., Huang, Z. J., Jörntell, H., Ekerot, C.- F., Launey, T., Endo, S., Sakai, R., Harano, J., Lohof, A. M., Sherrard, R. M., Lu, H., Huang, C., Hartmann, M. J., Marshall, S. P., Lang, E. J., Michikawa, T., Mikoshiba, K., Nitschke, M. F., Erdmann, C., Melchert, U., Arp, T., Sprenger, A., Petersen, D., Kömpf, D., Binkofski, F., Heide, W., Pedroarena, C., Schwarz, C., Parsons, L. M., Schmahmann, J. D., Grill, S. E., Walker, M. S., Petacchi, A., Rokni, D., Saito, S., Kato, K., Sajdel-Sulkowska, E. M., Nguon, K., Selimi, F., Wang, Q., Cristea, I., Chait, B., Heintz, N., Serapide, M. F., Cicirata, F., De Saedeleer, C., Schwaller, B., Swinny, J. D., Ijkema-Paassen, J., Metzger, F., Kalicharan, D., Gramsbergen, A., van der Want, J. J. L., Slemmer, J. E., Weber, J. T., Winkelman, B. H. J., Chédotal, A., De Schutter, E., Maex, R., Koekkoek, S. K. E., Bouslama, L., Ghoumari, A., Ebner, T., Häusser, M., Hawkes, R., Herrup, K., Lisberger, S. G., Mugnaini, E., Nunzi, M. -G., Russo, M., Ptak, K., Orr, H. T., Zoghbi, H. Y., Rossi, F., Ruigrok, T. J. H., Sabel-Goedknegt, E., Simpson, J. I., Morando, L., Cesa, R., Dumoulin, A., Dieudonné, S., Dugué, G., Triller, A., Louvi, A., Alexandre, P., Wurst, W., and Wassef, M.

Published
2004
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24. How satisfied are cervical dystonia patients after 3 years of botulinum toxin type A treatment? Results from a prospective, long-term observational study

Author

Colosimo, C, Charles, D, Misra, VP, Maisonobe, P, Om, S, Abdulnayef, A, Adatepe, NU, Leite, AMA, Badarny, S, Bajenaru, O, Bares, M, Bejjani, P, Bergmans, B, Bhidayasiri, R, Bozic, H, Costa, CFE, Carlstrom, C, Castelnovo, G, Chang, MH, Chang, YY, Chung, TM, Coletti-Moja, M, Delvaux, V, Dioszhegy, P, Dogu, O, Duzynski, W, Ehler, E, Sierra, EL, Fabbrini, G, Ferreira, J, Valadas, FA, Foresti, C, Girlanda, P, Goh, KJ, Velon, GA, Grill, S, Gurevitch, T, Hadidi, M, Hamimed, MA, Hamri, A, Harrower, T, Hassin, S, Hedera, P, Hernandez, JFJG, Franco, HJ, Ho, B, Ho, SL, Hughes, A, Ilic, T, Inshasi, JS, Ip, CW, Jamieson, S, Jamora, RDG, Jech, R, Jeon, BS, Kaminska, A, Karpova, M, Khasanova, D, Kim, JM, Kim, JW, Kok, CY, Korenko, A, Korv, J, Koussa, S, Kovacs, T, Kreisler, A, Krystkowiak, P, Kumthornthip, W, Lin, CH, Lundin, F, Lus, G, Magalhaes, M, Masmoudi, AN, Mercelis, R, Misbahuddin, A, Moebius, C, Mohammadi, B, Nazem, B, Ng, K, Nurlu, G, Nyberg, J, Nyholm, D, Ochudlo, S, Otruba, P, Pfister, R, Pirtosek, Z, Pokhabov, D, Aguilar, QS, Canales, QG, Raghev, S, Rickmann, H, Romano, M, Rosales, RL, Rubanovits, I, Santilli, V, Schoels, L, Simonetta-Moreau, M, Ma, S, Sohn, YH, Soulayrol, S, Supe, I, Svetel, M, Sycha, T, Tan, EK, Timerbaeva, S, Tokcaer, AB, Trosch, R, Tugnoli, V, Tumas, V, Van der Linden, C, Vetra, A, Vial, C, Vidry, E, Williams, D, Wimalaratna, S, and Yiannikas, C

Subjects
0301 basic medicine, Male, Pediatrics, Neurology, SATISFACTION, Botulinum toxin, Cervical dystonia, Observational study, Satisfaction, Treatment, 0302 clinical medicine, QUALITY-OF-LIFE, Outcome Assessment, Health Care, Prospective Studies, Botulinum Toxins, Type A, Torticollis, Neuroradiology, BLEPHAROSPASM, INTEREST IN CD2 study group, Middle Aged, Neuromuscular Agents, Patient Satisfaction, SAFETY, Female, Life Sciences & Biomedicine, medicine.drug, Adult, medicine.medical_specialty, Adolescent, MEDLINE, Clinical Neurology, Treatment results, DIAGNOSIS, 03 medical and health sciences, Young Adult, medicine, Humans, Aged, Science & Technology, Neurology & Neurosurgery, business.industry, Correction, 1103 Clinical Sciences, medicine.disease, EFFICACY, 030104 developmental biology, Neurology (clinical), Neurosciences & Neurology, business, FOLLOW-UP, 1109 Neurosciences, 030217 neurology & neurosurgery, Botulinum toxin type
Abstract

Background Patients with cervical dystonia (CD) typically require regular injections of botulinum toxin to maintain symptomatic control. We aimed to document long-term patient satisfaction with CD symptom control in a large cohort of patients treated in routine practice. Methods This was a prospective, international, observational study (NCT01753349) following the course of adult CD treated with botulinum neurotoxin type A (BoNT-A) over 3 years. A comprehensive clinical assessment status was performed at each injection visit and subjects reported satisfaction in two ways: satisfaction with symptom control at peak effect and at the end of treatment cycle. Results Subject satisfaction remained relatively stable from the first to the last injection visit. At 3 years, 89.9% of subjects reported satisfaction with symptom control at peak effect and 55.6% reported satisfaction with symptom control at end of treatment cycle. By contrast, objective ratings of CD severity showed an overall reduction over 3 years. Mean ± SD Toronto Western Spasmodic Rating Scale (TWSTRS) Total scores (clinician assessed at end of treatment cycle) decreased from 31.59 ± 13.04 at baseline to 24.49 ± 12.43 at 3 years (mean ± SD reduction from baseline of − 6.97 ± 11.56 points). Tsui scale scores also showed gradual improvement; the percent of subjects with a tremor component score of 4 reduced from 12.4% at baseline to 8.1% at 3 years. Conclusions Despite objective clinical improvements over 3 years, subject satisfaction with symptom control remained relatively constant, indicating that factors other than symptom control also play a role in patient satisfaction.

Published
2019

27. Soluble fms-like tyrosine kinase-1 to placental growth factor ratio: ruling out pre-eclampsia for up to 4 weeks and value of retesting

Author

Zeisler, H, Llurba, E, Chantraine, F, Vatish, M, Staff, A, Sennström, M, Olovsson, M, Brennecke, S, Stepan, H, Allegranza, D, Schoedl, M, Grill, S, Hund, M, and Verlohren, S

Subjects
Adult, sFlt‐1, PROGNOSIS, angiogenic factors, Gestational Age, Fetus, Pre-Eclampsia, Predictive Value of Tests, Pregnancy, Prenatal Diagnosis, Humans, Prospective Studies, reproductive and urinary physiology, Placenta Growth Factor, Retrospective Studies, Original Paper, Vascular Endothelial Growth Factor Receptor-1, rule out, Original Papers, pre‐eclampsia, retesting, sFlt‐1/PlGF, PlGF, embryonic structures, Female, Biomarkers
Abstract

Objectives: The soluble fms‐like tyrosine kinase‐1 (sFlt‐1) to placental growth factor (PlGF) ratio is generally elevated some time before and at the clinical onset of pre‐eclampsia. The PROGNOSIS study validated a sFlt‐1/PlGF ratio cut‐off of ≤ 38 to rule out the onset of pre‐eclampsia within 1 week of testing in women with suspected disease. The aim of this study was to assess the predictive value of the sFlt‐1/PlGF ratio to rule out the onset of pre‐eclampsia for up to 4 weeks, and to assess the value of repeat measurements.Methods: This was an exploratory post‐hoc analysis of data from the PROGNOSIS study performed in pregnant women aged ≥ 18 years with suspected pre‐eclampsia, who were at 24 + 0 to 36 + 6 weeks' gestation at their first clinic visit. Serum samples were collected at the first visit and weekly thereafter. sFlt‐1 and PlGF levels were measured using Elecsys® sFlt‐1 and PlGF immunoassays. Whether the sFlt‐1/PlGF ratio cut‐off of ≤ 38 used to rule out the onset of pre‐eclampsia within 1 week could predict the absence of pre‐eclampsia 2, 3, and 4 weeks post‐baseline was assessed. The value of repeat sFlt‐1/PlGF testing was assessed by examining the difference in sFlt‐1/PlGF ratio 2 and 3 weeks after the first measurement in women with, and those without, pre‐eclampsia or adverse fetal outcome.Results: On analysis of 550 women, sFlt‐1/PlGF ratio ≤ 38 ruled out the onset of pre‐eclampsia 2 and 3 weeks post‐baseline with high negative predictive values (NPV) of 97.9% and 95.7%, respectively. The onset of pre‐eclampsia within 4 weeks was ruled out with a high NPV (94.3%) and high sensitivity and specificity (66.2% and 83.1%, respectively). Compared with women who did not develop pre‐eclampsia, those who developed pre‐eclampsia had significantly larger median increases in sFlt‐1/PlGF ratio at 2 weeks (∆, 31.22 vs 1.45; P < 0.001) and at 3 weeks (∆, 48.97 vs 2.39; P < 0.001) after their initial visit. Women who developed pre‐eclampsia and/or adverse fetal outcome compared with those who did not had a significantly greater median increase in sFlt‐1/PlGF ratio over the same period (∆, 21.22 vs 1.40; P < 0.001 at 2 weeks; ∆, 34.95 vs 2.30; P < 0.001 at 3 weeks).Conclusion: The Elecsys® immunoassay sFlt‐1/PlGF ratio can help to rule out the onset of pre‐eclampsia for 4 weeks in women with suspected pre‐eclampsia. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Published
2019

28. Soluble fms-like tyrosine kinase-1 to placental growth factor ratio : ruling out pre-eclampsia for up to 4 weeks and value of retesting

Author

Zeisler, H., Llurba, E., Chantraine, F.J., Vatish, M., Staff, A.C., Sennström, M., Olovsson, M., Brennecke, S.P., Stepan, H., Allegranza, D., Schoedl, M., Grill, S., Hund, M., Verlohren, S., and Universitat Autònoma de Barcelona

Subjects
embryonic structures
Abstract

Objectives: The soluble fm--s-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio is generally elevated some time before and at the clinical onset of pre-eclampsia. The PROGNOSIS study validated a sFlt-1/PlGF ratio cut-off of ≤ 38 to rule out the onset of pre-eclampsia within 1 week of testing in women with suspected disease. The aim of this study was to assess the predictive value of the sFlt-1/PlGF ratio to rule out the onset of pre-eclampsia for up to 4 weeks, and to assess the value of repeat measurements. Methods: This was an exploratory post-hoc analysis of data from the PROGNOSIS study performed in pregnant women aged ≥ 18 years with suspected pre-eclampsia, who were at 24 + 0 to 36 + 6 weeks' gestation at their first clinic visit. Serum samples were collected at the first visit and weekly thereafter. sFlt-1 and PlGF levels were measured using Elecsys® sFlt-1 and PlGF immunoassays. Whether the sFlt-1/PlGF ratio cut-off of ≤ 38 used to rule out the onset of pre-eclampsia within 1 week could predict the absence of pre-eclampsia 2, 3, and 4 weeks post-baseline was assessed. The value of repeat sFlt-1/PlGF testing was assessed by examining the difference in sFlt-1/PlGF ratio 2 and 3 weeks after the first measurement in women with, and those without, pre-eclampsia or adverse fetal outcome. Results: On analysis of 550 women, sFlt-1/PlGF ratio ≤ 38 ruled out the onset of pre-eclampsia 2 and 3 weeks post-baseline with high negative predictive values (NPV) of 97.9% and 95.7%, respectively. The onset of pre-eclampsia within 4 weeks was ruled out with a high NPV (94.3%) and high sensitivity and specificity (66.2% and 83.1%, respectively). Compared with women who did not develop pre-eclampsia, those who developed pre-eclampsia had significantly larger median increases in sFlt-1/PlGF ratio at 2 weeks (∆, 31.22 vs 1.45; P < 0.001) and at 3 weeks (∆, 48.97 vs 2.39; P < 0.001) after their initial visit. Women who developed pre-eclampsia and/or adverse fetal outcome compared with those who did not had a significantly greater median increase in sFlt-1/PlGF ratio over the same period (∆, 21.22 vs 1.40; P < 0.001 at 2 weeks; ∆, 34.95 vs 2.30; P < 0.001 at 3 weeks). Conclusion: The Elecsys® immunoassay sFlt-1/PlGF ratio can help to rule out the onset of pre-eclampsia for 4 weeks in women with suspected pre-eclampsia. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Published
2019

30. Soluble fms-like tyrosine kinase-1 to placental growth factor ratio : ruling out pre-eclampsia for up to 4weeks and value of retesting

Author

Zeisler, H., Llurba, E., Chantraine, F. J., Vatish, M., Staff, A. C., Sennstrom, M., Olovsson, Matts, Brennecke, S. P., Stepan, H., Allegranza, D., Schoedl, M., Grill, S., Hund, M., Verlohren, S., Zeisler, H., Llurba, E., Chantraine, F. J., Vatish, M., Staff, A. C., Sennstrom, M., Olovsson, Matts, Brennecke, S. P., Stepan, H., Allegranza, D., Schoedl, M., Grill, S., Hund, M., and Verlohren, S.

Abstract

Objectives The soluble fms-like tyrosine kinase-1 ( sFlt-1) to placental growth factor ( PlGF) ratio is generally elevated some time before and at the clinical onset of pre-eclampsia. The PROGNOSIS study validated a sFlt-1/PlGF ratio cut-off of = 38 to rule out the onset of pre-eclampsia within 1week of testing in women with suspected disease. The aim of this study was to assess the predictive value of the sFlt-1/PlGF ratio to rule out the onset of pre-eclampsia for up to 4 weeks, and to assess the value of repeat measurements. Methods This was an exploratory post-hoc analysis of data from the PROGNOSIS study performed in pregnant women aged = 18 years with suspected pre-eclampsia, who were at 24+ 0 to 36+ 6weeks' gestation at their first clinic visit. Serum samples were collected at the first visit and weekly thereafter. sFlt-1 and PlGF levels were measured using Elecsys (R) sFlt-1 and PlGF immunoassays. Whether the sFlt-1/PlGF ratio cut-off of = 38 used to rule out the onset of pre-eclampsia within 1week could predict the absence of pre-eclampsia 2, 3, and 4 weeks post-baseline was assessed. The value of repeat sFlt-1/PlGF testing was assessed by examining the difference in sFlt-1/PlGF ratio 2 and 3 weeks after the first measurement in women with, and those without, pre-eclampsia or adverse fetal outcome. Results On analysis of 550 women, sFlt-1/PlGF ratio = 38 ruled out the onset of pre-eclampsia 2 and 3weeks post-baseline with high negative predictive values (NPV) of 97.9% and 95.7%, respectively. The onset of pre-eclampsia within 4weeks was ruled out with a high NPV (94.3%) and high sensitivity and specificity (66.2% and 83.1%, respectively). Compared with women who did not develop pre-eclampsia, those who developed pre-eclampsia had significantly larger median increases in sFlt-1/PlGF ratio at 2 weeks (., 31.22 vs 1.45; P< 0.001) and at 3 weeks (., 48.97 vs 2.39; P< 0.001) after their initial visit. Women who developed pre-eclampsia and/or adverse fetal

Published
2019
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31. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Author

Feroce I., Schoenwiese U., Seggewiss J., Solanes A., Steinemann D., Stiller M., Stoppa-Lyonnet D., Sullivan K.J., Susman R., Sutter C., Tavtigian S.V., Teo S.H., Teule A., Thomassen M., Tibiletti M.G., Tischkowitz M., Tognazzo S., Toland A.E., Tornero E., Torngren T., Torres-Esquius S., Toss A., Trainer A.H., Tucker K.M., van Asperen C.J., van Mackelenbergh M.T., Varesco L., Vargas-Parra G., Varon R., Vega A., Velasco A., Vesper A.-S., Viel A., Vreeswijk M.P.G., Wagner S.A., Waha A., Walker L.C., Walters R.J., Wang-Gohrke S., Weber B.H.F., Weichert W., Wieland K., Wiesmuller L., Witzel I., Wockel A., Woodward E.R., Zachariae S., Zampiga V., Zeder-Goss C., Investigators K., Lazaro C., De Nicolo A., Radice P., Engel C., Schmutzler R.K., Goldgar D.E., Spurdle A.B., Harris M., Parsons M.T., Tudini E., Li H., Hahnen E., Wappenschmidt B., Feliubadalo L., Aalfs C.M., Agata S., Aittomaki K., Alducci E., Alonso-Cerezo M.C., Arnold N., Auber B., Austin R., Azzollini J., Balmana J., Barbieri E., Bartram C.R., Blanco A., Blumcke B., Bonache S., Bonanni B., Borg A., Bortesi B., Brunet J., Bruzzone C., Bucksch K., Cagnoli G., Caldes T., Caliebe A., Caligo M.A., Calvello M., Capone G.L., Caputo S.M., Carnevali I., Carrasco E., Caux-Moncoutier V., Cavalli P., Cini G., Clarke E.M., Concolino P., Cops E.J., Cortesi L., Couch F.J., Darder E., de la Hoya M., Dean M., Debatin I., Del Valle J., Delnatte C., Derive N., Diez O., Ditsch N., Domchek S.M., Dutrannoy V., Eccles D.M., Ehrencrona H., Enders U., Evans D.G., Farra C., Faust U., Felbor U., Fine M., Foulkes W.D., Galvao H.C.R., Gambino G., Gehrig A., Gensini F., Gerdes A.-M., Germani A., Giesecke J., Gismondi V., Gomez C., Gomez Garcia E.B., Gonzalez S., Grau E., Grill S., Gross E., Guerrieri-Gonzaga A., Guillaud-Bataille M., Gutierrez-Enriquez S., Haaf T., Hackmann K., Hansen T.V.O., Hauke J., Heinrich T., Hellebrand H., Herold K.N., Honisch E., Horvath J., Houdayer C., Hubbel V., Iglesias S., Izquierdo A., James P.A., Janssen L.A.M., Jeschke U., Kaulfuss S., Keupp K., Kiechle M., Kolbl A., Krieger S., Kruse T.A., Kvist A., Lalloo F., Larsen M., Lattimore V.L., Lautrup C., Ledig S., Leinert E., Lewis A.L., Lim J., Loeffler M., Lopez-Fernandez A., Lucci-Cordisco E., Maass N., Manoukian S., Marabelli M., Matricardi L., Meindl A., Michelli R.D., Moghadasi S., Moles-Fernandez A., Montagna M., Montalban G., Monteiro A.N., Montes E., Mori L., Moserle L., Muller C.R., Mundhenke C., Naldi N., Nathanson K.L., Navarro M., Nevanlinna H., Nichols C.B., Niederacher D., Nielsen H.R., Ong K.-R., Pachter N., Palmero E.I., Papi L., Pedersen I.S., Peissel B., Perez-Segura P., Pfeifer K., Pineda M., Pohl-Rescigno E., Poplawski N.K., Porfirio B., Quante A.S., Ramser J., Reis R.M., Revillion F., Rhiem K., Riboli B., Ritter J., Rivera D., Rofes P., Rump A., Salinas M., Sanchez de Abajo A.M., Schmidt G., Feroce I., Schoenwiese U., Seggewiss J., Solanes A., Steinemann D., Stiller M., Stoppa-Lyonnet D., Sullivan K.J., Susman R., Sutter C., Tavtigian S.V., Teo S.H., Teule A., Thomassen M., Tibiletti M.G., Tischkowitz M., Tognazzo S., Toland A.E., Tornero E., Torngren T., Torres-Esquius S., Toss A., Trainer A.H., Tucker K.M., van Asperen C.J., van Mackelenbergh M.T., Varesco L., Vargas-Parra G., Varon R., Vega A., Velasco A., Vesper A.-S., Viel A., Vreeswijk M.P.G., Wagner S.A., Waha A., Walker L.C., Walters R.J., Wang-Gohrke S., Weber B.H.F., Weichert W., Wieland K., Wiesmuller L., Witzel I., Wockel A., Woodward E.R., Zachariae S., Zampiga V., Zeder-Goss C., Investigators K., Lazaro C., De Nicolo A., Radice P., Engel C., Schmutzler R.K., Goldgar D.E., Spurdle A.B., Harris M., Parsons M.T., Tudini E., Li H., Hahnen E., Wappenschmidt B., Feliubadalo L., Aalfs C.M., Agata S., Aittomaki K., Alducci E., Alonso-Cerezo M.C., Arnold N., Auber B., Austin R., Azzollini J., Balmana J., Barbieri E., Bartram C.R., Blanco A., Blumcke B., Bonache S., Bonanni B., Borg A., Bortesi B., Brunet J., Bruzzone C., Bucksch K., Cagnoli G., Caldes T., Caliebe A., Caligo M.A., Calvello M., Capone G.L., Caputo S.M., Carnevali I., Carrasco E., Caux-Moncoutier V., Cavalli P., Cini G., Clarke E.M., Concolino P., Cops E.J., Cortesi L., Couch F.J., Darder E., de la Hoya M., Dean M., Debatin I., Del Valle J., Delnatte C., Derive N., Diez O., Ditsch N., Domchek S.M., Dutrannoy V., Eccles D.M., Ehrencrona H., Enders U., Evans D.G., Farra C., Faust U., Felbor U., Fine M., Foulkes W.D., Galvao H.C.R., Gambino G., Gehrig A., Gensini F., Gerdes A.-M., Germani A., Giesecke J., Gismondi V., Gomez C., Gomez Garcia E.B., Gonzalez S., Grau E., Grill S., Gross E., Guerrieri-Gonzaga A., Guillaud-Bataille M., Gutierrez-Enriquez S., Haaf T., Hackmann K., Hansen T.V.O., Hauke J., Heinrich T., Hellebrand H., Herold K.N., Honisch E., Horvath J., Houdayer C., Hubbel V., Iglesias S., Izquierdo A., James P.A., Janssen L.A.M., Jeschke U., Kaulfuss S., Keupp K., Kiechle M., Kolbl A., Krieger S., Kruse T.A., Kvist A., Lalloo F., Larsen M., Lattimore V.L., Lautrup C., Ledig S., Leinert E., Lewis A.L., Lim J., Loeffler M., Lopez-Fernandez A., Lucci-Cordisco E., Maass N., Manoukian S., Marabelli M., Matricardi L., Meindl A., Michelli R.D., Moghadasi S., Moles-Fernandez A., Montagna M., Montalban G., Monteiro A.N., Montes E., Mori L., Moserle L., Muller C.R., Mundhenke C., Naldi N., Nathanson K.L., Navarro M., Nevanlinna H., Nichols C.B., Niederacher D., Nielsen H.R., Ong K.-R., Pachter N., Palmero E.I., Papi L., Pedersen I.S., Peissel B., Perez-Segura P., Pfeifer K., Pineda M., Pohl-Rescigno E., Poplawski N.K., Porfirio B., Quante A.S., Ramser J., Reis R.M., Revillion F., Rhiem K., Riboli B., Ritter J., Rivera D., Rofes P., Rump A., Salinas M., Sanchez de Abajo A.M., and Schmidt G.

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.Copyright © 2019 Wiley Periodicals, Inc.

Published
2019

32. Soluble fms-like tyrosine kinase-1 to placental growth factor ratio: ruling out pre-eclampsia for up to 4weeks and value of retesting

Author

Zeisler, H, Llurba, E, Chantraine, FJ, Vatish, M, Staff, AC, Sennstrom, M, Olovsson, M, Brennecke, SP, Stepan, H, Allegranza, D, Schoedl, M, Grill, S, Hund, M, Verlohren, S, Zeisler, H, Llurba, E, Chantraine, FJ, Vatish, M, Staff, AC, Sennstrom, M, Olovsson, M, Brennecke, SP, Stepan, H, Allegranza, D, Schoedl, M, Grill, S, Hund, M, and Verlohren, S

Published
2019

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

Author

Parsons, MT, Tudini, E, Li, H, Hahnen, E, Wappenschmidt, B, Feliubadalo, L, Aalfs, CM, Agata, S, Aittomaki, K, Alducci, E, Concepcion Alonso-Cerezo, M, Arnold, N, Auber, B, Austin, R, Azzollini, J, Balmana, J, Barbieri, E, Bartram, CR, Blanco, A, Bluemcke, B, Bonache, S, Bonanni, B, Borg, A, Bortesi, B, Brunet, J, Bruzzone, C, Bucksch, K, Cagnoli, G, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Capone, GL, Caputo, SM, Carnevali, I, Carrasco, E, Caux-Moncoutier, V, Cavalli, P, Cini, G, Clarke, EM, Concolino, P, Cops, EJ, Cortesi, L, Couch, FJ, Darder, E, de la Hoya, M, Dean, M, Debatin, I, Del Valle, J, Delnatte, C, Derive, N, Diez, O, Ditsch, N, Domchek, SM, Dutrannoy, V, Eccles, DM, Ehrencrona, H, Enders, U, Evans, DG, Farra, C, Faust, U, Felbor, U, Feroce, I, Fine, M, Foulkes, WD, Galvao, HC, Gambino, G, Gehrig, A, Gensini, F, Gerdes, A-M, Germani, A, Giesecke, J, Gismondi, V, Gomez, C, Garcia, EBG, Gonzalez, S, Grau, E, Grill, S, Gross, E, Guerrieri-Gonzaga, A, Guillaud-Bataille, M, Gutierrez-Enriquez, S, Haaf, T, Hackmann, K, Hansen, TV, Harris, M, Hauke, J, Heinrich, T, Hellebrand, H, Herold, KN, Honisch, E, Horvath, J, Houdayer, C, Huebbel, V, Iglesias, S, Izquierdo, A, James, PA, Janssen, LA, Jeschke, U, Kaulfuss, S, Keupp, K, Kiechle, M, Koelbl, A, Krieger, S, Kruse, TA, Kvist, A, Lalloo, F, Larsen, M, Lattimore, VL, Lautrup, C, Ledig, S, Leinert, E, Lewis, AL, Lim, J, Loeffler, M, Lopez-Fernandez, A, Lucci-Cordisco, E, Maass, N, Manoukian, S, Marabelli, M, Matricardi, L, Meindl, A, Michelli, RD, Moghadasi, S, Moles-Fernandez, A, Montagna, M, Montalban, G, Monteiro, AN, Montes, E, Mori, L, Moserle, L, Mueller, CR, Mundhenke, C, Naldi, N, Nathanson, KL, Navarro, M, Nevanlinna, H, Nichols, CB, Niederacher, D, Nielsen, HR, Ong, K-R, Pachter, N, Palmero, E, Papi, L, Pedersen, IS, Peissel, B, Perez-Segura, P, Pfeifer, K, Pineda, M, Pohl-Rescigno, E, Poplawski, NK, Porfirio, B, Quante, AS, Ramser, J, Reis, RM, Revillion, F, Rhiem, K, Riboli, B, Ritter, J, Rivera, D, Rofes, P, Rump, A, Salinas, M, Sanchez de Abajo, AM, Schmidt, G, Schoenwiese, U, Seggewiss, J, Solanes, A, Steinemann, D, Stiller, M, Stoppa-Lyonnet, D, Sullivan, KJ, Susman, R, Sutter, C, Tavtigian, S, Teo, SH, Teule, A, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tornero, E, Torngren, T, Torres-Esquius, S, Toss, A, Trainer, AH, Tucker, KM, van Asperen, CJ, van Mackelenbergh, MT, Varesco, L, Vargas-Parra, G, Varon, R, Vega, A, Velasco, A, Vesper, A-S, Viel, A, Vreeswijk, MPG, Wagner, SA, Waha, A, Walker, LC, Walters, RJ, Wang-Gohrke, S, Weber, BHF, Weichert, W, Wieland, K, Wiesmueller, L, Witzel, I, Woeckel, A, Woodward, ER, Zachariae, S, Zampiga, V, Zeder-Goss, C, Lazaro, C, De Nicolo, A, Radice, P, Engel, C, Schmutzler, RK, Goldgar, DE, Spurdle, AB, Parsons, MT, Tudini, E, Li, H, Hahnen, E, Wappenschmidt, B, Feliubadalo, L, Aalfs, CM, Agata, S, Aittomaki, K, Alducci, E, Concepcion Alonso-Cerezo, M, Arnold, N, Auber, B, Austin, R, Azzollini, J, Balmana, J, Barbieri, E, Bartram, CR, Blanco, A, Bluemcke, B, Bonache, S, Bonanni, B, Borg, A, Bortesi, B, Brunet, J, Bruzzone, C, Bucksch, K, Cagnoli, G, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Capone, GL, Caputo, SM, Carnevali, I, Carrasco, E, Caux-Moncoutier, V, Cavalli, P, Cini, G, Clarke, EM, Concolino, P, Cops, EJ, Cortesi, L, Couch, FJ, Darder, E, de la Hoya, M, Dean, M, Debatin, I, Del Valle, J, Delnatte, C, Derive, N, Diez, O, Ditsch, N, Domchek, SM, Dutrannoy, V, Eccles, DM, Ehrencrona, H, Enders, U, Evans, DG, Farra, C, Faust, U, Felbor, U, Feroce, I, Fine, M, Foulkes, WD, Galvao, HC, Gambino, G, Gehrig, A, Gensini, F, Gerdes, A-M, Germani, A, Giesecke, J, Gismondi, V, Gomez, C, Garcia, EBG, Gonzalez, S, Grau, E, Grill, S, Gross, E, Guerrieri-Gonzaga, A, Guillaud-Bataille, M, Gutierrez-Enriquez, S, Haaf, T, Hackmann, K, Hansen, TV, Harris, M, Hauke, J, Heinrich, T, Hellebrand, H, Herold, KN, Honisch, E, Horvath, J, Houdayer, C, Huebbel, V, Iglesias, S, Izquierdo, A, James, PA, Janssen, LA, Jeschke, U, Kaulfuss, S, Keupp, K, Kiechle, M, Koelbl, A, Krieger, S, Kruse, TA, Kvist, A, Lalloo, F, Larsen, M, Lattimore, VL, Lautrup, C, Ledig, S, Leinert, E, Lewis, AL, Lim, J, Loeffler, M, Lopez-Fernandez, A, Lucci-Cordisco, E, Maass, N, Manoukian, S, Marabelli, M, Matricardi, L, Meindl, A, Michelli, RD, Moghadasi, S, Moles-Fernandez, A, Montagna, M, Montalban, G, Monteiro, AN, Montes, E, Mori, L, Moserle, L, Mueller, CR, Mundhenke, C, Naldi, N, Nathanson, KL, Navarro, M, Nevanlinna, H, Nichols, CB, Niederacher, D, Nielsen, HR, Ong, K-R, Pachter, N, Palmero, E, Papi, L, Pedersen, IS, Peissel, B, Perez-Segura, P, Pfeifer, K, Pineda, M, Pohl-Rescigno, E, Poplawski, NK, Porfirio, B, Quante, AS, Ramser, J, Reis, RM, Revillion, F, Rhiem, K, Riboli, B, Ritter, J, Rivera, D, Rofes, P, Rump, A, Salinas, M, Sanchez de Abajo, AM, Schmidt, G, Schoenwiese, U, Seggewiss, J, Solanes, A, Steinemann, D, Stiller, M, Stoppa-Lyonnet, D, Sullivan, KJ, Susman, R, Sutter, C, Tavtigian, S, Teo, SH, Teule, A, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tornero, E, Torngren, T, Torres-Esquius, S, Toss, A, Trainer, AH, Tucker, KM, van Asperen, CJ, van Mackelenbergh, MT, Varesco, L, Vargas-Parra, G, Varon, R, Vega, A, Velasco, A, Vesper, A-S, Viel, A, Vreeswijk, MPG, Wagner, SA, Waha, A, Walker, LC, Walters, RJ, Wang-Gohrke, S, Weber, BHF, Weichert, W, Wieland, K, Wiesmueller, L, Witzel, I, Woeckel, A, Woodward, ER, Zachariae, S, Zampiga, V, Zeder-Goss, C, Lazaro, C, De Nicolo, A, Radice, P, Engel, C, Schmutzler, RK, Goldgar, DE, and Spurdle, AB

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.

Published
2019

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

Author

Parsons, M. T., Tudini, E., Li, H., Hahnen, E., Wappenschmidt, B., Feliubadalo, L., Aalfs, C. M., Agata, S., Aittomaki, K., Alducci, E., Alonso-Cerezo, M. C., Arnold, N., Auber, B., Austin, R., Azzollini, J., Balmana, J., Barbieri, E., Bartram, C. R., Blanco, A., Blumcke, B., Bonache, S., Bonanni, B., Borg, A., Bortesi, B., Brunet, J., Bruzzone, C., Bucksch, K., Cagnoli, G., Caldes, T., Caliebe, A., Caligo, M. A., Calvello, M., Capone, G. L., Caputo, S. M., Carnevali, I., Carrasco, E., Caux-Moncoutier, V., Cavalli, P., Cini, G., Clarke, E. M., Concolino, Paola, Cops, E. J., Cortesi, L., Couch, F. J., Darder, E., de la Hoya, M., Dean, M., Debatin, I., Del Valle, J., Delnatte, C., Derive, N., Diez, O., Ditsch, N., Domchek, S. M., Dutrannoy, V., Eccles, D. M., Ehrencrona, H., Enders, U., Evans, D. G., Farra, C., Faust, U., Felbor, U., Feroce, I., Fine, M., Foulkes, W. D., Galvao, H. C. R., Gambino, G., Gehrig, A., Gensini, F., Gerdes, A. -M., Germani, A., Giesecke, J., Gismondi, V., Gomez, C., Gomez Garcia, E. B., Gonzalez, S., Grau, E., Grill, S., Gross, E., Guerrieri-Gonzaga, A., Guillaud-Bataille, M., Gutierrez-Enriquez, S., Haaf, T., Hackmann, K., Hansen, T. V. O., Harris, M., Hauke, J., Heinrich, T., Hellebrand, H., Herold, K. N., Honisch, E., Horvath, J., Houdayer, C., Hubbel, V., Iglesias, S., Izquierdo, A., James, P. A., Janssen, L. A. M., Jeschke, U., Kaulfuss, S., Keupp, K., Kiechle, M., Kolbl, A., Krieger, S., Kruse, T. A., Kvist, A., Lalloo, F., Larsen, M., Lattimore, V. L., Lautrup, C., Ledig, S., Leinert, E., Lewis, A. L., Lim, J., Loeffler, M., Lopez-Fernandez, A., Lucci Cordisco, Emanuela, Maass, N., Manoukian, S., Marabelli, M., Matricardi, L., Meindl, A., Michelli, R. D., Moghadasi, S., Moles-Fernandez, A., Montagna, M., Montalban, G., Monteiro, A. N., Montes, E., Mori, L., Moserle, L., Muller, C. R., Mundhenke, C., Naldi, N., Nathanson, K. L., Navarro, M., Nevanlinna, H., Nichols, C. B., Niederacher, D., Nielsen, H. R., Ong, K. -R., Pachter, N., Palmero, E. I., Papi, L., Pedersen, I. S., Peissel, B., Perez-Segura, P., Pfeifer, K., Pineda, M., Pohl-Rescigno, E., Poplawski, N. K., Porfirio, B., Quante, A. S., Ramser, J., Reis, R. M., Revillion, F., Rhiem, K., Riboli, B., Ritter, J., Rivera, D., Rofes, P., Rump, A., Salinas, M., Sanchez de Abajo, A. M., Schmidt, G., Schoenwiese, U., Seggewiss, J., Solanes, A., Steinemann, D., Stiller, M., Stoppa-Lyonnet, D., Sullivan, K. J., Susman, R., Sutter, C., Tavtigian, S. V., Teo, S. H., Teule, A., Thomassen, M., Tibiletti, M. G., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tornero, E., Torngren, T., Torres-Esquius, S., Toss, A., Trainer, A. H., Tucker, K. M., van Asperen, C. J., van Mackelenbergh, M. T., Varesco, L., Vargas-Parra, G., Varon, R., Vega, A., Velasco, A., Vesper, A. -S., Viel, A., Vreeswijk, M. P. G., Wagner, S. A., Waha, A., Walker, L. C., Walters, R. J., Wang-Gohrke, S., Weber, B. H. F., Weichert, W., Wieland, K., Wiesmuller, L., Witzel, I., Wockel, A., Woodward, E. R., Zachariae, S., Zampiga, V., Zeder-Goss, C., Investigators, K., Lazaro, C., De Nicolo, A., Radice, P., Engel, C., Schmutzler, R. K., Goldgar, D. E., Spurdle, A. B., Concolino P., Lucci Cordisco E. (ORCID:0000-0002-6279-7604), Parsons, M. T., Tudini, E., Li, H., Hahnen, E., Wappenschmidt, B., Feliubadalo, L., Aalfs, C. M., Agata, S., Aittomaki, K., Alducci, E., Alonso-Cerezo, M. C., Arnold, N., Auber, B., Austin, R., Azzollini, J., Balmana, J., Barbieri, E., Bartram, C. R., Blanco, A., Blumcke, B., Bonache, S., Bonanni, B., Borg, A., Bortesi, B., Brunet, J., Bruzzone, C., Bucksch, K., Cagnoli, G., Caldes, T., Caliebe, A., Caligo, M. A., Calvello, M., Capone, G. L., Caputo, S. M., Carnevali, I., Carrasco, E., Caux-Moncoutier, V., Cavalli, P., Cini, G., Clarke, E. M., Concolino, Paola, Cops, E. J., Cortesi, L., Couch, F. J., Darder, E., de la Hoya, M., Dean, M., Debatin, I., Del Valle, J., Delnatte, C., Derive, N., Diez, O., Ditsch, N., Domchek, S. M., Dutrannoy, V., Eccles, D. M., Ehrencrona, H., Enders, U., Evans, D. G., Farra, C., Faust, U., Felbor, U., Feroce, I., Fine, M., Foulkes, W. D., Galvao, H. C. R., Gambino, G., Gehrig, A., Gensini, F., Gerdes, A. -M., Germani, A., Giesecke, J., Gismondi, V., Gomez, C., Gomez Garcia, E. B., Gonzalez, S., Grau, E., Grill, S., Gross, E., Guerrieri-Gonzaga, A., Guillaud-Bataille, M., Gutierrez-Enriquez, S., Haaf, T., Hackmann, K., Hansen, T. V. O., Harris, M., Hauke, J., Heinrich, T., Hellebrand, H., Herold, K. N., Honisch, E., Horvath, J., Houdayer, C., Hubbel, V., Iglesias, S., Izquierdo, A., James, P. A., Janssen, L. A. M., Jeschke, U., Kaulfuss, S., Keupp, K., Kiechle, M., Kolbl, A., Krieger, S., Kruse, T. A., Kvist, A., Lalloo, F., Larsen, M., Lattimore, V. L., Lautrup, C., Ledig, S., Leinert, E., Lewis, A. L., Lim, J., Loeffler, M., Lopez-Fernandez, A., Lucci Cordisco, Emanuela, Maass, N., Manoukian, S., Marabelli, M., Matricardi, L., Meindl, A., Michelli, R. D., Moghadasi, S., Moles-Fernandez, A., Montagna, M., Montalban, G., Monteiro, A. N., Montes, E., Mori, L., Moserle, L., Muller, C. R., Mundhenke, C., Naldi, N., Nathanson, K. L., Navarro, M., Nevanlinna, H., Nichols, C. B., Niederacher, D., Nielsen, H. R., Ong, K. -R., Pachter, N., Palmero, E. I., Papi, L., Pedersen, I. S., Peissel, B., Perez-Segura, P., Pfeifer, K., Pineda, M., Pohl-Rescigno, E., Poplawski, N. K., Porfirio, B., Quante, A. S., Ramser, J., Reis, R. M., Revillion, F., Rhiem, K., Riboli, B., Ritter, J., Rivera, D., Rofes, P., Rump, A., Salinas, M., Sanchez de Abajo, A. M., Schmidt, G., Schoenwiese, U., Seggewiss, J., Solanes, A., Steinemann, D., Stiller, M., Stoppa-Lyonnet, D., Sullivan, K. J., Susman, R., Sutter, C., Tavtigian, S. V., Teo, S. H., Teule, A., Thomassen, M., Tibiletti, M. G., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tornero, E., Torngren, T., Torres-Esquius, S., Toss, A., Trainer, A. H., Tucker, K. M., van Asperen, C. J., van Mackelenbergh, M. T., Varesco, L., Vargas-Parra, G., Varon, R., Vega, A., Velasco, A., Vesper, A. -S., Viel, A., Vreeswijk, M. P. G., Wagner, S. A., Waha, A., Walker, L. C., Walters, R. J., Wang-Gohrke, S., Weber, B. H. F., Weichert, W., Wieland, K., Wiesmuller, L., Witzel, I., Wockel, A., Woodward, E. R., Zachariae, S., Zampiga, V., Zeder-Goss, C., Investigators, K., Lazaro, C., De Nicolo, A., Radice, P., Engel, C., Schmutzler, R. K., Goldgar, D. E., Spurdle, A. B., Concolino P., and Lucci Cordisco E. (ORCID:0000-0002-6279-7604)

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.

Published
2019

37. Prophylactic surgery among germline TP53 mutation carriers in Germany – a multicentric observational study

Author

Rippinger, N, additional, Haun, MW, additional, Fischer, C, additional, Rhiem, K, additional, Hübbel, A, additional, Grill, S, additional, Kiechle, M, additional, Cremer, FW, additional, Kast, K, additional, Nguyen, HP, additional, Ditsch, N, additional, Kratz, P, additional, Pfister, S, additional, Pajtler, KW, additional, Speiser, D, additional, Seitz, S, additional, Glimm, H, additional, Maatouk, I, additional, Hahne, A, additional, Sutter, C, additional, Schmutzler, RK, additional, Dikow, N, additional, Sohn, C, additional, and Schott, S, additional

Published
2018
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40. Evaluation of cancer prevention habits in germline TP53 mutation carriers in Germany – a multicentric observational study about acceptance, adherence of surveillance modalities in adulthood

Author

Rippinger, N, additional, Haun, MW, additional, Fischer, C, additional, Rhiem, K, additional, Hübbel, A, additional, Grill, S, additional, Kiechle, M, additional, Cremer, FW, additional, Kast, K, additional, Nguyen, HP, additional, Ditsch, N, additional, Kratz, CP, additional, Pfister, S, additional, Pajtler, KW, additional, Speiser, D, additional, Seitz, S, additional, Glimm, H, additional, Matouk, I, additional, Golas, M, additional, Lemke, J, additional, Hahne, A, additional, Sutter, C, additional, Schmutzler, RK, additional, Dikow, N, additional, Sohn, C, additional, and Schott, S, additional

Published
2018
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41. Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation

Author

Naumann, M., Pal, A., Goswami, A., Lojewski, X., Japtok, J., Vehlow, A., Naujock, M., Günther, R., Jin, M., Stanslowsky, N., Reinhardt, P., Sterneckert, J., Frickenhaus, M., Pan-Montojo, F., Storkebaum, E., Poser, I., Freischmidt, A., Weishaupt, J. H., Holzmann, K., Troost, D., Ludolph, A. C., Boeckers, T. M., Liebau, S., Petri, S., Cordes, N., Hyman, A. A., Wegner, F., Grill, S. W., Weis, J., Storch, A., Hermann, A., Naumann, M., Pal, A., Goswami, A., Lojewski, X., Japtok, J., Vehlow, A., Naujock, M., Günther, R., Jin, M., Stanslowsky, N., Reinhardt, P., Sterneckert, J., Frickenhaus, M., Pan-Montojo, F., Storkebaum, E., Poser, I., Freischmidt, A., Weishaupt, J. H., Holzmann, K., Troost, D., Ludolph, A. C., Boeckers, T. M., Liebau, S., Petri, S., Cordes, N., Hyman, A. A., Wegner, F., Grill, S. W., Weis, J., Storch, A., and Hermann, A.

Abstract

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Cytoplasmic fused in sarcoma (FUS) aggregates are pathological hallmarks of FUS-ALS. Proper shuttling between the nucleus and cytoplasm is essential for physiological cell function. However, the initial event in the pathophysiology of FUS-ALS remains enigmatic. Using human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs), we show that impairment of poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response (DDR) signaling due to mutations in the FUS nuclear localization sequence (NLS) induces additional cytoplasmic FUS mislocalization which in turn results in neurodegeneration and FUS aggregate formation. Our work suggests that a key pathophysiologic event in ALS is upstream of aggregate formation. Targeting DDR signaling could lead to novel therapeutic routes for ameliorating ALS.

Published
2018

42. Enzymes as antiviral targets

Author

Cheng, Y., Bastow, K., Frank, K., Nutter, L., Chiou, J. -F., Grill, S., Paton, William, editor, Mitchell, James, editor, and Turner, Paul, editor

Published
1984
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43. Assoziation zwischen PSA-Wert und Familienanamnese im 45-jährigen Kollektiv der deutschen Prostatakarzinom Screening Studie (PROBASE)

Author

Baade, N., Länger, N., Klorek, T., Grill, S., Schulwitz, H., Albers, P., Arsov, C., Hadaschik, B., Hohenfellner, M., Imkamp, F., Kuczyk, M., Gschwend, J., and Herkommer, K.

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Fragestellung: Studien zeigten, dass der Diagnose-PSA-Wert bei Patienten mit positiver Prostatakarzinom-Familienanamnese (PC-FA) tendenziell niedriger ist. In einem einzigartigen 45-jährigen deutschen Screening-Kollektiv mit mehr als 5.000 Probanden wurde der Zusammenhang zwischen PC-FA und der[zum vollständigen Text gelangen Sie über die oben angegebene URL], 42. Gemeinsame Tagung der Bayerischen Urologenvereinigung und der Österreichischen Gesellschaft für Urologie und Andrologie

Published
2016

45. Smoking and physical inactivity increase cancer prevalence in BRCA-1 and BRCA-2 mutation carriers: results from a retrospective observational study (LIBRE 1 Study)

Author

Grill, S, additional, Yahiaoui-Doktor, M, additional, Dukatz, R, additional, Lammert, J, additional, Ullrich, M, additional, Engel, C, additional, Pfeifer, K, additional, Basrai, M, additional, Siniatchkin, M, additional, Rhiem, K, additional, Ditsch, N, additional, Schmutzler, R, additional, Bischoff, SC, additional, Halle, M, additional, and Kiechle, M, additional

Published
2017
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47. Einfluss der Familienanamnese auf das karzinomspezifische Überleben nach radikaler Prostatovesikulektomie bei jungen Prostatakarzinompatienten

Author

Brath, JMS, Grill, S, Ankerst, DP, Gschwend, JE, and Herkommer, K

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Fragestellung: Jeder 5. Patient mit diagnostiziertem Prostatakarzinom (PC) hat eine positive Familienanamnese (FA). Bei jungen Patienten (, 41. Gemeinsame Tagung der Österreichischen Gesellschaft für Urologie und Andrologie und der Bayerischen Urologenvereinigung

Published
2015
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48. Mechanochemical feedback regulates the dynamics of the PAR system in C. elegans zygotes

Author

Gross, P., Kumar, V. K., Goehring, N. W., Bois, J. S., Jülicher, F., Grill, S. W., Lippincott-Schwartz, Jennifer, Marshall, Wallace, and Marks, Michael

Abstract

The interplay between regulatory biochemistry and cell mechanics is critical for a broad range of morphogenetic changes. Cell mechanics can induce transport via growth and flow-fields, which in turn affect concentration-fields of regulators. Such systems exhibit an intrinsic feedback-architecture between regulators of cell mechanics and mechanical deformation. While we anticipate that this feedback between biochemistry and cell mechanics is widespread in Morphogenesis, there are few examples that are studied with respect to their potential for generating spatiotemporal patterns. Here we establish at a quantitative level that PAR polarization of C. elegans zygotes represents a coupled mechanochemical system. Using Fluorescence Recovery After Photobleaching (FRAP) and RNA interference (RNAi), we first demonstrate that the biochemistry in form of the PAR domains feeds back on the mechanics by establishing and maintaining a non-muscle myosin II (nmy-2) gradient. Additionally, we characterize the effect of the polarity cue associated with the centrosome of the male pronucleus on the local myosin concentration at the posterior pole. We show that it induces a reduction in myosin concentration and thereby triggers the onset of cortical flows. Furthermore we measure the spatiotemporal profile of the anterior and posterior PAR concentration, the myosin II concentration and the induced flow-field. Finally, we capture the feedback-architecture of the coupled actomyosin – PAR system in a quantitative model, based on coupling a thin film active fluid description of cortical mechanics [1] to a reaction-diffusion PAR patterning system [2]. We show that this mathematical model can quantitatively recapitulate the spatiotemporal profile of PAR polarity establishment. Furthermore, we demonstrate that the model predicts the existence of a threshold in cortical flow velocity, which separates the nonpolarizing and the polarizing regime and confirm the existence of this threshold velocity in the living C. elegans zygote.

Published
2014

49. Feasibility assessment on a lifestyle intervention in healthy and diseased BRCA 1/2 mutation carriers

Author

Dukatz, R., Halle, M., Engel, C., Berling, A., Hebestreit, K., Bischoff, S., Pfeifer, K., Grill, S., Yahiaoui-Doktor, M., Enders, U., Siniatchkin, M., Gerber, D., Bridstrup, J., Erickson, N., Loeffler, M., Meindl, A., Rhiem, K., Schmutzler, R., Kiechle, M., Dukatz, R., Halle, M., Engel, C., Berling, A., Hebestreit, K., Bischoff, S., Pfeifer, K., Grill, S., Yahiaoui-Doktor, M., Enders, U., Siniatchkin, M., Gerber, D., Bridstrup, J., Erickson, N., Loeffler, M., Meindl, A., Rhiem, K., Schmutzler, R., and Kiechle, M.

Published
2016

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