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1. Microhabitat of Myotis leibii summer roosts at the southwestern periphery of their range

Author

Kearny, Valerie M., Perry, Roger W., Risch, Thomas S., and Rolland, Virginie

Subjects
Home range -- Research, Zoological research, Niche (Ecology) -- Research, Zoology and wildlife conservation
Abstract

Understanding microhabitat use is needed to make sound conservation decisions for at-risk, patchy-habitat specialists, such as rock-habitat specialists. Rock habitats offer unique microclimatic refugia for reptiles and mammals. Eastern small-footed bats (Myotis leibii (Audubon and Bachman, 1842)) use rock roosts during the summer, but data on these summer roosts are lacking for this species classified as (critically) imperiled in several US states and Canadian provinces and globally endangered. Our goal was to characterize the structure and microclimate of Myotis leibii roosts at the southwestern periphery of their range. We predicted that Myotis leibii roost temperatures would be warmer and less variable than ambient temperatures and that solitary bats would use horizontal roosts cooler at night, whereas maternity group roosts would be vertical and warmer at night. During summers of 2019 and 2020, we recorded physical (e.g., width) and temperature attributes of 58 Myotis leibii roosts at 16 sites in the Ouachita Mountains. Crevice roosts of Myotis leibii had narrow dimensions like elsewhere in their range and roost temperatures (measured with iButtons) were warmer and more variable than ambient temperatures. Group roosts were larger and had more stable temperatures than solitary roosts. These findings may be useful for assessing population threats, monitoring roost suitability, identifying roost-rich areas that need protection, and even planning artificial roost structures where natural roosts are limited. Key words: Eastern small-footed bat, microhabitat, Myotis leibii, rock roosts, summer roost, temperature, Introduction Species that specialize in habitats with patchy distributions (i.e., habitats that are spatially disjunct on the landscape, such as high elevations, ephemeral pools, rock outcrops) are particularly at risk [...]

Published
2023
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4. Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories.

Author

Gerhauser, Clarissa, Favero, Francesco, Risch, Thomas, Simon, Ronald, Feuerbach, Lars, Assenov, Yassen, Heckmann, Doreen, Sidiropoulos, Nikos, Waszak, Sebastian M, Hübschmann, Daniel, Urbanucci, Alfonso, Girma, Etsehiwot G, Kuryshev, Vladimir, Klimczak, Leszek J, Saini, Natalie, Stütz, Adrian M, Weichenhan, Dieter, Böttcher, Lisa-Marie, Toth, Reka, Hendriksen, Josephine D, Koop, Christina, Lutsik, Pavlo, Matzk, Sören, Warnatz, Hans-Jörg, Amstislavskiy, Vyacheslav, Feuerstein, Clarissa, Raeder, Benjamin, Bogatyrova, Olga, Schmitz, Eva-Maria, Hube-Magg, Claudia, Kluth, Martina, Huland, Hartwig, Graefen, Markus, Lawerenz, Chris, Henry, Gervaise H, Yamaguchi, Takafumi N, Malewska, Alicia, Meiners, Jan, Schilling, Daniela, Reisinger, Eva, Eils, Roland, Schlesner, Matthias, Strand, Douglas W, Bristow, Robert G, Boutros, Paul C, von Kalle, Christof, Gordenin, Dmitry, Sültmann, Holger, Brors, Benedikt, Sauter, Guido, Plass, Christoph, Yaspo, Marie-Laure, Korbel, Jan O, Schlomm, Thorsten, and Weischenfeldt, Joachim

Subjects
Humans, Prostatic Neoplasms, RNA-Binding Proteins, Risk Factors, Evolution, Molecular, DNA Methylation, Gene Expression Regulation, Neoplastic, Mutation, Adult, Middle Aged, Male, Transcriptome, Biomarkers, Tumor, Whole Genome Sequencing, APOBEC, cancer genomics, early-onset cancer, epigenetic risk-score, mutational processes, prostate cancer, structural variants, tumor evolution, tumor evolution prediction, Human Genome, Aging, Prevention, Cancer, Urologic Diseases, Prostate Cancer, Genetics, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples.

Published
2018

5. The whole-genome landscape of medulloblastoma subtypes

Author

Northcott, Paul A, Buchhalter, Ivo, Morrissy, A Sorana, Hovestadt, Volker, Weischenfeldt, Joachim, Ehrenberger, Tobias, Gröbner, Susanne, Segura-Wang, Maia, Zichner, Thomas, Rudneva, Vasilisa A, Warnatz, Hans-Jörg, Sidiropoulos, Nikos, Phillips, Aaron H, Schumacher, Steven, Kleinheinz, Kortine, Waszak, Sebastian M, Erkek, Serap, Jones, David TW, Worst, Barbara C, Kool, Marcel, Zapatka, Marc, Jäger, Natalie, Chavez, Lukas, Hutter, Barbara, Bieg, Matthias, Paramasivam, Nagarajan, Heinold, Michael, Gu, Zuguang, Ishaque, Naveed, Jäger-Schmidt, Christina, Imbusch, Charles D, Jugold, Alke, Hübschmann, Daniel, Risch, Thomas, Amstislavskiy, Vyacheslav, Gonzalez, Francisco German Rodriguez, Weber, Ursula D, Wolf, Stephan, Robinson, Giles W, Zhou, Xin, Wu, Gang, Finkelstein, David, Liu, Yanling, Cavalli, Florence MG, Luu, Betty, Ramaswamy, Vijay, Wu, Xiaochong, Koster, Jan, Ryzhova, Marina, Cho, Yoon-Jae, Pomeroy, Scott L, Herold-Mende, Christel, Schuhmann, Martin, Ebinger, Martin, Liau, Linda M, Mora, Jaume, McLendon, Roger E, Jabado, Nada, Kumabe, Toshihiro, Chuah, Eric, Ma, Yussanne, Moore, Richard A, Mungall, Andrew J, Mungall, Karen L, Thiessen, Nina, Tse, Kane, Wong, Tina, Jones, Steven JM, Witt, Olaf, Milde, Till, Von Deimling, Andreas, Capper, David, Korshunov, Andrey, Yaspo, Marie-Laure, Kriwacki, Richard, Gajjar, Amar, Zhang, Jinghui, Beroukhim, Rameen, Fraenkel, Ernest, Korbel, Jan O, Brors, Benedikt, Schlesner, Matthias, Eils, Roland, Marra, Marco A, Pfister, Stefan M, Taylor, Michael D, and Lichter, Peter

Subjects
Cancer, Human Genome, Brain Disorders, Pediatric Cancer, Brain Cancer, Genetics, Biotechnology, Rare Diseases, Neurosciences, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Good Health and Well Being, Carcinogenesis, Carrier Proteins, Cohort Studies, DNA Methylation, DNA Mutational Analysis, Datasets as Topic, Epistasis, Genetic, Genome, Human, Genomics, Humans, Medulloblastoma, Molecular Targeted Therapy, Muscle Proteins, Mutation, Oncogenes, Transcription Factors, Whole Genome Sequencing, Wnt Proteins, General Science & Technology
Abstract

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

Published
2017

6. The hematopoietic stem cell marker VNN2 is associated with chemoresistance in pediatric B-cell precursor ALL

Author

Bornhauser, Beat, Cario, Gunnar, Rinaldi, Anna, Risch, Thomas, Rodriguez Martinez, Virginia, Schütte, Moritz, Warnatz, Hans-Jörg, Scheidegger, Nastassja, Mirkowska, Paulina, Temperli, Martina, Möller, Claudia, Schumich, Angela, Dworzak, Michael, Attarbaschi, Andishe, Brüggemann, Monika, Ritgen, Mathias, Mejstrikova, Ester, Hofmann, Andreas, Buldini, Barbara, Scarparo, Pamela, Basso, Giuseppe, Maglia, Oscar, Gaipa, Giuseppe, Skroblyn, Tessa Lara, Ngo, Quy A., te Kronnie, Geertruij, Vendramini, Elena, Panzer-Grümayer, Renate, Barz, Malwine Jeanette, Marovca, Blerim, Hauri-Hohl, Mathias, Niggli, Felix, Eckert, Cornelia, Schrappe, Martin, Stanulla, Martin, Zimmermann, Martin, Wollscheid, Bernd, Yaspo, Marie-Laure, and Bourquin, Jean-Pierre

Published
2020
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8. Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress

Author

Oh, Sekyung, Flynn, Ryan A, Floor, Stephen N, Purzner, James, Martin, Lance, T., Brian, Schubert, Simone, Vaka, Dedeepya, Morrissy, Sorana, Li, Yisu, Kool, Marcel, Hovestadt, Volker, Jones, David TW, Northcott, Paul A, Risch, Thomas, Warnatz, Hans-Jörg, Yaspo, Marie-Laure, Adams, Christopher M, Leib, Ryan D, Breese, Marcus, Marra, Marco A, Malkin, David, Lichter, Peter, Doudna, Jennifer A, Pfister, Stefan M, Taylor, Michael D, Chang, Howard Y, and Cho, Yoon-Jae

Subjects
Pediatric, Genetics, Brain Disorders, Cancer, Rare Diseases, Brain Cancer, Cerebellar Neoplasms, DEAD-box RNA Helicases, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Medulloblastoma, Protein Biosynthesis, Stress, Physiological, Transcriptome, medulloblastoma, DDX3X, DDX3, RNA helicase, CLIP-seq, Oncology and Carcinogenesis
Abstract

DDX3X encodes a DEAD-box family RNA helicase (DDX3) commonly mutated in medulloblastoma, a highly aggressive cerebellar tumor affecting both children and adults. Despite being implicated in several facets of RNA metabolism, the nature and scope of DDX3's interactions with RNA remain unclear. Here, we show DDX3 collaborates extensively with the translation initiation machinery through direct binding to 5'UTRs of nearly all coding RNAs, specific sites on the 18S rRNA, and multiple components of the translation initiation complex. Impairment of translation initiation is also evident in primary medulloblastomas harboring mutations in DDX3X, further highlighting DDX3's role in this process. Arsenite-induced stress shifts DDX3 binding from the 5'UTR into the coding region of mRNAs concomitant with a general reduction of translation, and both the shift of DDX3 on mRNA and decreased translation are blunted by expression of a catalytically-impaired, medulloblastoma-associated DDX3R534H variant. Furthermore, despite the global repression of translation induced by arsenite, translation is preserved on select genes involved in chromatin organization in DDX3R534H-expressing cells. Thus, DDX3 interacts extensively with RNA and ribosomal machinery to help remodel the translation landscape in response to stress, while cancer-related DDX3 variants adapt this response to selectively preserve translation.

Published
2016

10. Grundlagenuntersuchungen zur Faserdeformation an Vibrationsflächenförderern

Author

Technische Universität Chemnitz, Müller, Elisabeth, Strube, Simon, Risch, Thomas, Golder, Markus, Technische Universität Chemnitz, Müller, Elisabeth, Strube, Simon, Risch, Thomas, and Golder, Markus

Abstract

Vibrationsflächenförderer bieten höhere Flexibilität bei der Teilehandhabung durch elastische Fasern auf der Förderfläche. Der Materialtransport wird dabei entscheidend durch die Faserverformung beeinflusst. Dieser Beitrag untersucht das Deformationsverhalten von Einzelfasern und Faserbündeln mittels Simulation und Experiment. Die Erkenntnisse ermöglichen die analytische Berechnung der Verformungen in guter Näherung und die Ableitung einer Kalibriermethode zur Charakterisierung unterschiedlicher Faseroberflächen., Vibratory brush conveyors offer higher flexibility for part handling using elastic fibers on conveyor surfaces. Material transport is hereby decisively affected by fiber deformation. This paper studies the deformation behavior of single fibers as well as bundles with simulation and experiment. The findings enable analytical prediction of deflections in close approximation and deduction of a calibration method to characterize given fiber surfaces.

Published
2024

21. Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells

Author

Chen, Lu, Ge, Bing, Casale, Francesco Paolo, Vasquez, Louella, Kwan, Tony, Garrido-Martín, Diego, Watt, Stephen, Yan, Ying, Kundu, Kousik, Ecker, Simone, Datta, Avik, Richardson, David, Burden, Frances, Mead, Daniel, Mann, Alice L., Fernandez, Jose Maria, Rowlston, Sophia, Wilder, Steven P., Farrow, Samantha, Shao, Xiaojian, Lambourne, John J., Redensek, Adriana, Albers, Cornelis A., Amstislavskiy, Vyacheslav, Ashford, Sofie, Berentsen, Kim, Bomba, Lorenzo, Bourque, Guillaume, Bujold, David, Busche, Stephan, Caron, Maxime, Chen, Shu-Huang, Cheung, Warren, Delaneau, Oliver, Dermitzakis, Emmanouil T., Elding, Heather, Colgiu, Irina, Bagger, Frederik O., Flicek, Paul, Habibi, Ehsan, Iotchkova, Valentina, Janssen-Megens, Eva, Kim, Bowon, Lehrach, Hans, Lowy, Ernesto, Mandoli, Amit, Matarese, Filomena, Maurano, Matthew T., Morris, John A., Pancaldi, Vera, Pourfarzad, Farzin, Rehnstrom, Karola, Rendon, Augusto, Risch, Thomas, Sharifi, Nilofar, Simon, Marie-Michelle, Sultan, Marc, Valencia, Alfonso, Walter, Klaudia, Wang, Shuang-Yin, Frontini, Mattia, Antonarakis, Stylianos E., Clarke, Laura, Yaspo, Marie-Laure, Beck, Stephan, Guigo, Roderic, Rico, Daniel, Martens, Joost H.A., Ouwehand, Willem H., Kuijpers, Taco W., Paul, Dirk S., Stunnenberg, Hendrik G., Stegle, Oliver, Downes, Kate, Pastinen, Tomi, and Soranzo, Nicole

Published
2016
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30. Active medulloblastoma enhancers reveal subgroup-specific cellular origins

Author

Lin, Charles Y., Erkek, Serap, Tong, Yiai, Yin, Linlin, Federation, Alexander J., Zapatka, Marc, Haldipur, Parthiv, Kawauchi, Daisuke, Risch, Thomas, Warnatz, Hans-Jörg, Worst, Barbara C., Ju, Bensheng, Orr, Brent A., Zeid, Rhamy, Polaski, Donald R., Segura-Wang, Maia, Waszak, Sebastian M., Jones, David T. W., Kool, Marcel, Hovestadt, Volker, Buchhalter, Ivo, Sieber, Laura, Johann, Pascal, Chavez, Lukas, Gröschel, Stefan, Ryzhova, Marina, Korshunov, Andrey, Chen, Wenbiao, Chizhikov, Victor V., Millen, Kathleen J., Amstislavskiy, Vyacheslav, Lehrach, Hans, Yaspo, Marie-Laure, Eils, Roland, Lichter, Peter, Korbel, Jan O., Pfister, Stefan M., Bradner, James E., and Northcott, Paul A.

Published
2016
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31. Genomics and drug profiling of fatal TCF3-HLF−positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options

Author

Fischer, Ute, Forster, Michael, Rinaldi, Anna, Risch, Thomas, Sungalee, Stéphanie, Warnatz, Hans-Jörg, Bornhauser, Beat, Gombert, Michael, Kratsch, Christina, Stütz, Adrian M, Sultan, Marc, Tchinda, Joelle, Worth, Catherine L, Amstislavskiy, Vyacheslav, Badarinarayan, Nandini, Baruchel, André, Bartram, Thies, Basso, Giuseppe, Canpolat, Cengiz, Cario, Gunnar, Cavé, Hélène, Dakaj, Dardane, Delorenzi, Mauro, Dobay, Maria Pamela, Eckert, Cornelia, Ellinghaus, Eva, Eugster, Sabrina, Frismantas, Viktoras, Ginzel, Sebastian, Haas, Oskar A, Heidenreich, Olaf, Hemmrich-Stanisak, Georg, Hezaveh, Kebria, Höll, Jessica I, Hornhardt, Sabine, Husemann, Peter, Kachroo, Priyadarshini, Kratz, Christian P, Kronnie, Geertruy te, Marovca, Blerim, Niggli, Felix, McHardy, Alice C, Moorman, Anthony V, Panzer-Grümayer, Renate, Petersen, Britt S, Raeder, Benjamin, Ralser, Meryem, Rosenstiel, Philip, Schäfer, Daniel, Schrappe, Martin, Schreiber, Stefan, Schütte, Moritz, Stade, Björn, Thiele, Ralf, Weid, Nicolas von der, Vora, Ajay, Zaliova, Marketa, Zhang, Langhui, Zichner, Thomas, Zimmermann, Martin, Lehrach, Hans, Borkhardt, Arndt, Bourquin, Jean-Pierre, Franke, Andre, Korbel, Jan O, Stanulla, Martin, and Yaspo, Marie-Laure

Published
2015
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37. Experimentelle Untersuchung vibrationsbasierter Ausrichtkonzepte für Rohblechtafeln

Author

Technische Universität Chemnitz, Müller, Elisabeth, Risch, Thomas, Golder, Markus, Technische Universität Chemnitz, Müller, Elisabeth, Risch, Thomas, and Golder, Markus

Abstract

Effizienz, Prozesssicherheit und Teilequalität in der Blechtafelbearbeitung erfordern die exakte Positionierung der Rohblechtafel zur Bearbeitungsmaschine. Dieser Beitrag beschreibt die experimentelle Erprobung vibrationsbasierter Ausrichtkonzepte an einer eigens entwickelten Versuchsanlage. Die Versuchsergebnisse führen zur Identifikation einer Vorzugslösung sowie möglicher Stellgrößen des Ausrichtprozesses., Efficiency, process reliability and part quality in sheet metal processing require the precise positioning of the raw sheet metal to the processing machine. This paper presents the experimental investigation of vibration-based alignment concepts in a dedicated test facility. The test results enable identification of a preferential solution as well as possible control parameters of the alignment process.

Published
2022

38. Analyse des Materialtransports auf Vibrationsflächenförderern für das vibrationsbasierte Blechhandling

Author

Wissenschaftliche Gesellschaft für Technische Logistik e. V., Müller, Elisabeth, Risch, Thomas, Golder, Markus, Wissenschaftliche Gesellschaft für Technische Logistik e. V., Müller, Elisabeth, Risch, Thomas, and Golder, Markus

Abstract

Vibrationsflächenförderer sind eine effiziente Alternative für automatisiertes Blechhandling mit geringem materiellen und technischen Aufwand. Geneigte, vertikal vibrierende Faseroberflächen ermöglichen flexible Transportwege bei gleichzeitiger Funktionsintegration. Die Wirkzusammenhänge sind für den Praxiseinsatz jedoch nicht hinreichend bekannt. In diesem Beitrag wird der Förderprozess auf einem Vibrationsflächenförderer analysiert. Die Ergebnisse erlauben die Charakterisierung der Bewegungsphasen und Abhängigkeiten der Fördergeschwindigkeit. Darüber hinaus wird die Effizienz der Förderbewegung betrachtet.

Published
2022

39. Analyse des Materialtransports auf Vibrationsflächenförderern für das vibrationsbasierte Blechhandling

Author

Müller, Elisabeth, Risch, Thomas, Golder, Markus, Müller, Elisabeth, Risch, Thomas, and Golder, Markus

Abstract

Vibrationsflächenförderer sind eine effiziente Alternative für automatisiertes Blechhandling mit geringem materiellen und technischen Aufwand. Geneigte, vertikal vibrierende Faseroberflächen ermöglichen flexible Transportwege bei gleichzeitiger Funktionsintegration. Die Wirkzusammenhänge sind für den Praxiseinsatz jedoch nicht hinreichend bekannt. In diesem Beitrag wird der Förderprozess auf einem Vibrationsflächenförderer analysiert. Die Ergebnisse erlauben die Charakterisierung der Bewegungsphasen und Abhängigkeiten der Fördergeschwindigkeit. Darüber hinaus wird die Effizienz der Förderbewegung betrachtet., Vibratory brush conveyors are an efficient alternative for automated sheet handling with low material and technical expenditure. Inclined, vertically vibrating fibre surfaces enable flexible transport routes with integrated functionality. However, the interrelationships are not sufficiently known for practical use. In this paper, the conveying process on a vibratory brush conveyor is analysed. The results enable characterisation of motion sequences and dependencies of the conveying speed. Furthermore, the conveying efficiency is considered.

Published
2022

44. Elevated MACC1 Expression in Colorectal Cancer Is Driven by Chromosomal Instability and Is Associated with Molecular Subtype and Worse Patient Survival

Author

Vuaroqueaux, Vincent, primary, Musch, Alexandra, additional, Kobelt, Dennis, additional, Risch, Thomas, additional, Herrmann, Pia, additional, Burock, Susen, additional, Peille, Anne-Lise, additional, Yaspo, Marie-Laure, additional, Fiebig, Heinz-Herbert, additional, and Stein, Ulrike, additional

Published
2022
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45. Computational analysis of cancer transcriptomes: drug response prediction in colorectal cancer and gene regulatory networks and long non-coding genes in medulloblastoma

Author

Risch, Thomas

Subjects
000 Informatik, Informationswissenschaft, allgemeine Werke::000 Informatik, Wissen, Systeme::000 Informatik, Informationswissenschaft, allgemeine Werke, machine learning, long non-coding RNA, colorectal cancer, 500 Naturwissenschaften und Mathematik::570 Biowissenschaften, Biologie::570 Biowissenschaften, Biologie, bioinformatics, medulloblastoma, transcriptome, gene regulatory networks, drug response classification
Abstract

During cancer development, malignant tumours accumulate genetic and epigenetic alterations that cause dysregulation of gene expression and cellular processes. Since the regulation of gene expression controls many cellular processes, understanding the transcriptome of malignant tumours provides insights into the biology of cancer. Key technology for the molecular analysis of whole cancer transcriptomes is next- generation sequencing (NGS) of RNA (RNA-seq) from bulk tumours. However, to derive information about cancer transcriptomes from RNA-seq data, a variety of computational tools and analyses are needed. The following work presents two cancer transcriptome studies addressing the computational analysis of RNA-seq data from colorectal carcinomas (CRC) and medulloblastomas (MB) by applying statistical and machine learning (ML) methods. CRC is a clinically challenging disease because only a fraction of tumours responds to available chemo- and targeted therapies. Functional loss of the tumour suppressor APC has been suggested to represent the initial mutation, activating Wnt signalling. Additional events include mutually exclusive mutations in the RAS/RAF proto-oncogenes as well as in the TGFβ, PI3K, and TP53 pathways. Routinely used biomarkers of resistance to the EGFR inhibitor cetuximab are RAS/RAF mutations that activate signalling downstream of EGFR. Still, a fraction of wild-type CRCs is resistant to cetuximab treatment. Addressing the need for a better molecular understanding of CRC in precision oncology, the OncoTrack consortium (Innovative Medicine Initiative) designed a multi-omics strategy integrating the establishment of a pre-clinical platform for CRC organoid and animal models. In the study presented below, we focused on the integrative analysis of gene expression and drug response data obtained from patient-derived xenografts (PDXs) treated with cetuximab. Applying statistical methods, we identified a signature of 241 genes associated with response to cetuximab, which allowed us to dissect the expression profiles of responding and non-responding CRC. We used a support vector machine (SVM), a supervised ML algorithm, to obtain a gene-expression-based classifier predictive of response to cetuximab. Here, we selected 16 highly predictive genes using multiple SVM recursive feature elimination. The built classifier outperformed RAS/RAF mutations as a predictor of cetuximab response and performed well in RAS/RAF-wild-type CRC that currently lacks biomarkers of cetuximab treatment outcome in clinical practice. The second study addressed the molecular analysis of MB. MB, a tumour of the cerebellum, is the most common malignant brain tumour in children. Transcriptome profiling of MB using microarrays had revealed four tumour subgroups, namely WNT, SHH, Group 3 and Group 4, each related to distinct genetic alterations, molecular profiles, and clinical features. Recurrent mutations mainly cause pathway activation in WNT and SHH MB, respectively, whereas in Group 3 and Group 4 MB, gross chromosomal alterations are more prevalent and tumours express a specific cell-type- rather than a pathway-related gene signature. Additional molecular complexity has been identified within these four main subgroups, which could be dissected further into subtypes. However, the gene regulatory networks that contribute to the molecular heterogeneity in MB are only partially known, and the role of long non-coding (lnc) genes remains poorly addressed in this disease. To gain further insights into the molecular biology of MB, the PedBrain project was founded within the ICGC framework. As a contribution to this project, we sequenced and computationally analysed 164 MB RNA-seq samples. Addressing the heterogeneity of MB, we identified and validated molecular subclusters within the four main subgroups. Subgroup- and subcluster-specific gene expression profiles were analysed by functional enrichments and gene regulatory networks (GRNs) inferred from gene expression data. These GRNs revealed communalities and differences in gene regulation among subclusters and subgroups. By estimating the impact of TFs, we could unravel master regulators of subcluster-specific gene expression in a systematic fashion for the first time and highlight unknown regulators of Group 4 MB. Furthermore, we characterised lnc genes that were differentially expressed in MB. Among these genes, we identified 20 lnc genes that show brain- development-associated expression patterns, which is of interest due to the embryonic origin of MB. We identified a co-expression cluster that accumulates known cancer-related lnc genes and associates these genes with cancer-promoting protein biogenesis. Survival analyses revealed the lnc gene MEG3 as a prognostic marker in SHH and Group 4 subcluster, potentially acting as a tumour suppressor that negatively regulates cell cycle and TGFβ receptor expression.

Published
2022

50. The Relationship Between Entering Students' Expectations for the College Environment and the Level of Formal Education Completed by Their Parents.

Author

American Coll. Personnel Association, Washington, DC. and Risch, Thomas J.

Abstract

In this study, the relationship between students' expectations for the environment of the college they are about to enter and the level of formal education completed by their parents was investigated. It was hypothesized that entering freshmen students whose parents both had only a high school education differed from entering freshmen whose parents were both college graduates in their expectations for the universities' environment. Students' expectations were measured by using the College and University Environment Scale (CUES). On the basis of students' responses to a question asking the occupational level of their fathers, students were placed into one of eight categories. A total of 82 students were then given the CUES. Findings include: (1) it may not be useful to categorize students only on the basis of parents' level of education; and (2) significant differences between sexes in their expectations were found. However, this may vary from campus to campus. (SJ)

Published
1970

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