Life Sciences Commons^™

Mass Cytometry Defines Virus-Specific Cd4 + T Cells In Influenza Vaccination, Priyanka B Subrahmanyam, Tyson H Holmes, Dongxia Lin, Laura F Su, Gerlinde Obermoser, Jacques Banchereau, Virginia Pascual, Adolfo García-Sastre, Randy A Albrecht, Karolina Palucka, Mark M Davis, Holden T Maecker

Faculty Research 2020

The antiviral response to influenza virus is complex and multifaceted, involving many immune cell subsets. There is an urgent need to understand the role of CD4+ T cells, which orchestrate an effective antiviral response, to improve vaccine design strategies. In this study, we analyzed PBMCs from human participants immunized with influenza vaccine, using high-dimensional single-cell proteomic immune profiling by mass cytometry. Data were analyzed using a novel clustering algorithm, denoised ragged pruning, to define possible influenza virus-specific clusters of CD4+ T cells. Denoised ragged pruning identified six clusters of cells. Among these, one cluster (Cluster 3) was found to increase …

Deep Learning-Based Cross-Classifications Reveal Conserved Spatial Behaviors Within Tumor Histological Images., Javad Noorbakhsh, Saman Farahmand, Ali Foroughi Pour, Sandeep Namburi, Dennis Caruana, David Rimm, Mohammad Soltanieh-Ha, Kourosh Zarringhalam, Jeffrey Chuang

Faculty Research 2020

Histopathological images are a rich but incompletely explored data type for studying cancer. Manual inspection is time consuming, making it challenging to use for image data mining. Here we show that convolutional neural networks (CNNs) can be systematically applied across cancer types, enabling comparisons to reveal shared spatial behaviors. We develop CNN architectures to analyze 27,815 hematoxylin and eosin scanned images from The Cancer Genome Atlas for tumor/normal, cancer subtype, and mutation classification. Our CNNs are able to classify TCGA pathologist-annotated tumor/normal status of whole slide images (WSIs) in 19 cancer types with consistently high AUCs (0.995 ± 0.008), as …

Deciphering Functional Redundancy In The Human Microbiome., Liang Tian, Xu-Wen Wang, Ang-Kun Wu, Yuhang Fan, Jonathan Friedman, Amber Dahlin, Matthew K Waldor, George M. Weinstock, Scott T Weiss, Yang-Yu Liu

Faculty Research 2020

Although the taxonomic composition of the human microbiome varies tremendously across individuals, its gene composition or functional capacity is highly conserved - implying an ecological property known as functional redundancy. Such functional redundancy has been hypothesized to underlie the stability and resilience of the human microbiome, but this hypothesis has never been quantitatively tested. The origin of functional redundancy is still elusive. Here, we investigate the basis for functional redundancy in the human microbiome by analyzing its genomic content network - a bipartite graph that links microbes to the genes in their genomes. We find that this network exhibits several …

C11orf95-Rela Reprograms 3d Epigenome In Supratentorial Ependymoma., Jacqueline Jufen Zhu, Nathaniel L. Jillette, Xiao-Nan Li, Albert Cheng, Ching C Lau

Faculty Research 2020

Supratentorial ependymoma (ST-EPN) is a type of malignant brain tumor mainly seen in children. Since 2014, it has been known that an intrachromosomal fusion C11orf95-RELA is an oncogenic driver in ST-EPN [Parker et al. Nature 506:451-455 (2014); Pietsch et al. Acta Neuropathol 127:609-611 (2014)] but the molecular mechanisms of oncogenesis are unclear. Here we show that the C11orf95 component of the fusion protein dictates DNA binding activity while the RELA component is required for driving the expression of ependymoma-associated genes. Epigenomic characterizations using ChIP-seq and HiChIP approaches reveal that C11orf95-RELA modulates chromatin states and mediates chromatin interactions, leading to transcriptional …

New Hints Towards A Precision Medicine Strategy For Idh Wild-Type Glioblastoma., K White, K Connor, J Clerkin, B M Murphy, M Salvucci, A C O'Farrell, M Rehm, D O'Brien, J H M Prehn, S P Niclou, M L M Lamfers, M Verreault, A Idbaih, Roel G W Verhaak, A Golebiewska, A T Byrne

Faculty Research 2020

Glioblastoma represents the most common primary malignancy of the central nervous system in adults and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wild-type setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wild-type glioblastoma setting, and …

Petri Net Modelling Approach For Analysing The Behaviour Of Wnt/[Inline-Formula Removed] -Catenin And Wnt/Ca 2+ Signalling Pathways In Arrhythmogenic Right Ventricular Cardiomyopathy., Nazia Azim, Jamil Ahmad, Nadeem Iqbal, Amnah Siddiqa, Abdul Majid, Javaria Ashraf, Fazal Jalil

Faculty Research 2020

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that may result in arrhythmia, heart failure and sudden death. The hallmark pathological findings are progressive myocyte loss and fibro fatty replacement, with a predilection for the right ventricle. This study focuses on the adipose tissue formation in cardiomyocyte by considering the signal transduction pathways including Wnt/[inline-formula removed]-catenin and Wnt/Ca2+ regulation system. These pathways are modelled and analysed using stochastic petri nets (SPN) in order to increase our comprehension of ARVC and in turn its treatment regimen. The Wnt/[inline-formula removed]-catenin model predicts that the dysregulation …

Gtpbp1 Resolves Paused Ribosomes To Maintain Neuronal Homeostasis., Markus Terrey, Scott I Adamson, Alana L Gibson, Tianda Deng, Ryuta Ishimura, Jeffrey Chuang, Susan L Ackerman

Faculty Research 2020

Ribosome-associated quality control pathways respond to defects in translational elongation to recycle arrested ribosomes and degrade aberrant polypeptides and mRNAs. Loss of a tRNA gene leads to ribosomal pausing that is resolved by the translational GTPase GTPBP2, and in its absence causes neuron death. Here, we show that loss of the homologous protein GTPBP1 during tRNA deficiency in the mouse brain also leads to codon-specific ribosome pausing and neurodegeneration, suggesting that these non-redundant GTPases function in the same pathway to mitigate ribosome pausing. As observed in

Differences In Gut Microbiome In Hospitalized Immunocompetent Vs. Immunocompromised Children, Including Those With Sickle Cell Disease., Sindhu Mohandas, Vijaya L Soma, Thi Dong Binh Tran, Erica Sodergren, Tresa Ambooken, David L Goldman, George M. Weinstock, Betsy C Herold

Faculty Research 2020

Background: Gut microbial diversity and composition play important roles in health. This cross-sectional study was designed to test the hypothesis that hospitalized children who may be relatively immunocompromised (IC), defined as those with cancer, sickle cell disease (SCD), transplantation, or receiving immunosuppressive therapy) would have decreased microbial diversity, increased Clostridioides difficile colonization and different species composition compared to non-immunocompromised (Non-IC) children admitted to the same pediatric unit. Methods: A stool sample was obtained within 72 h of admission to a single unit at The Children's Hospital at Montefiore, Bronx, NY from March 2016 to February 2017 and the microbiome assessed …

Predicting The Early Risk Of Ophthalmopathy In Graves' Disease Patients Using Tcr Repertoire., Yue Wang, Yufeng Liu, Xiaofei Yang, Hui Guo, Jiadong Lin, Jinkui Yang, Mingqian He, Jingya Wang, Xiaomei Liu, Tingting Shi, Liping Wu, Chengsheng Zhang, Kai Ye, Bingyin Shi

Faculty Research 2020

No abstract provided.

Depletion Of Clk2 Sensitizes Glioma Stem-Like Cells To Pi3k/Mtor And Fgfr Inhibitors., Soon Young Park, Sandeep Mittal, Jianwen Dong, Kangjin Jeong, Emmanuel Martinez-Ledesma, Yuji Piao, Sabbir Khan, Verlene Henry, Roel G W Verhaak, Nazanin Majd, Veerakumar Balasubramaniyan, John F De Groot

Faculty Research 2020

The Cdc2-like kinases (CLKs) regulate RNA splicing and have been shown to suppress cell growth. Knockdown of CLK2 was found to block glioma stem-like cell (GSC) growth in vivo through the AKT/FOXO3a/p27 pathway without activating mTOR and MAPK signaling, suggesting that these pathways mediate resistance to CLK2 inhibition. We identified CLK2 binding partners using immunoprecipitation assays and confirmed their interactions in vitro in GSCs. We then tested the cellular viability of several signaling inhibitors in parental and CLK2 knockdown GSCs. Our results demonstrate that CLK2 binds to 14-3-3τ isoform and prevents its ubiquitination in GSCs. Stable CLK2 knockdown increased PP2A …

Gene Selection For Optimal Prediction Of Cell Position In Tissues From Single-Cell Transcriptomics Data., Jovan Tanevski, Thin Nguyen, Buu Truong, Nikos Karaiskos, Mehmet Eren Ahsen, Xinyu Zhang, Chang Shu, Ke Xu, Xiaoyu Liang, Ying Hu, Hoang Vv Pham, Li Xiaomei, Thuc D Le, Adi L Tarca, Gaurav Bhatti, Roberto Romero, Nestoras Karathanasis, Phillipe Loher, Yang Chen, Zhengqing Ouyang, Disheng Mao, Yuping Zhang, Maryam Zand, Jianhua Ruan, Christoph Hafemeister, Peng Qiu, Duc Tran, Tin Nguyen, Attila Gabor, Thomas Yu, Justin Guinney, Enrico Glaab, Roland Krause, Peter Banda, Dream Sctc Consortium, Gustavo Stolovitzky, Nikolaus Rajewsky, Julio Saez-Rodriguez, Pablo Meyer

Faculty Research 2020

Single-cell RNA-sequencing (scRNAseq) technologies are rapidly evolving. Although very informative, in standard scRNAseq experiments, the spatial organization of the cells in the tissue of origin is lost. Conversely, spatial RNA-seq technologies designed to maintain cell localization have limited throughput and gene coverage. Mapping scRNAseq to genes with spatial information increases coverage while providing spatial location. However, methods to perform such mapping have not yet been benchmarked. To fill this gap, we organized the DREAM Single-Cell Transcriptomics challenge focused on the spatial reconstruction of cells from the Drosophila embryo from scRNAseq data, leveraging as silver standard, genes with in situ hybridization …

Cellular Taxonomy And Spatial Organization Of The Murine Ventral Posterior Hypothalamus., Laura E Mickelsen, William F Flynn, Kristen Springer, Lydia Wilson, Eric J Beltrami, Mohan Bolisetty, Paul Robson, Alexander C Jackson

Faculty Research 2020

The ventral posterior hypothalamus (VPH) is an anatomically complex brain region implicated in arousal, reproduction, energy balance, and memory processing. However, neuronal cell type diversity within the VPH is poorly understood, an impediment to deconstructing the roles of distinct VPH circuits in physiology and behavior. To address this question, we employed a droplet-based single-cell RNA sequencing (scRNA-seq) approach to systematically classify molecularly distinct cell populations in the mouse VPH. Analysis of >16,000 single cells revealed 20 neuronal and 18 non-neuronal cell populations, defined by suites of discriminatory markers. We validated differentially expressed genes in selected neuronal populations through fluorescence in …

Enhancer Reprogramming Confers Dependence On Glycolysis And Igf Signaling In Kmt2d Mutant Melanoma., Mayinuer Maitituoheti, Emily Z Keung, Ming Tang, Liang Yan, Hunain Alam, Guangchun Han, Anand K Singh, Ayush T Raman, Christopher Terranova, Sharmistha Sarkar, Elias Orouji, Samir B Amin, Sneha Sharma, Maura Williams, Neha S Samant, Mayura Dhamdhere, Norman Zheng, Tara Shah, Amiksha Shah, Jacob B Axelrad, Nazanin E Anvar, Yu-Hsi Lin, Shan Jiang, Edward Q Chang, Davis R Ingram, Wei-Lien Wang, Alexander Lazar, Min Gyu Lee, Florian Muller, Linghua Wang, Haoqiang Ying, Kunal Rai

Faculty Research 2020

Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific deletion of KMT2D. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways, including glycolysis. KMT2D deficiency aberrantly upregulates glycolysis enzymes, intermediate metabolites, and glucose consumption rates. Mechanistically, KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states. Enhancer loss and subsequent repression of IGFBP5 activates IGF1R-AKT to increase …

Genetic Variant Effects On Gene Expression In Human Pancreatic Islets And Their Implications For T2d., Ana Viñuela, Arushi Varshney, Martijn Van De Bunt, Rashmi B Prasad, Olof Asplund, Amanda Bennett, Michael Boehnke, Andrew A Brown, Michael R Erdos, João Fadista, Ola Hansson, Gad Hatem, Cédric Howald, Apoorva K Iyengar, Paul Johnson, Ulrika Krus, Patrick E Macdonald, Anubha Mahajan, Jocelyn E Manning Fox, Narisu Narisu, Vibe Nylander, Peter Orchard, Nikolay Oskolkov, Nikolaos I Panousis, Anthony Payne, Michael L. Stitzel, Swarooparani Vadlamudi, Ryan Welch, Francis S Collins, Karen L Mohlke, Anna L Gloyn, Laura J Scott, Emmanouil T Dermitzakis, Leif Groop, Stephen C J Parker, Mark I Mccarthy

Faculty Research 2020

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in …

Association Of Cnvs With Methylation Variation., Xinghua Shi, Saranya Radhakrishnan, Jia Wen, Jin Yun Chen, Junjie Chen, Brianna Ashlyn Lam, Ryan E Mills, Barbara E Stranger, Charles Lee, Sunita R Setlur

Faculty Research 2020

Germline copy number variants (CNVs) and single-nucleotide polymorphisms (SNPs) form the basis of inter-individual genetic variation. Although the phenotypic effects of SNPs have been extensively investigated, the effects of CNVs is relatively less understood. To better characterize mechanisms by which CNVs affect cellular phenotype, we tested their association with variable CpG methylation in a genome-wide manner. Using paired CNV and methylation data from the 1000 genomes and HapMap projects, we identified genome-wide associations by methylation quantitative trait locus (mQTL) analysis. We found individual CNVs being associated with methylation of multiple CpGs and vice versa. CNV-associated methylation changes were correlated with …

The Case For Open Science: Rare Diseases., Yaffa R Rubinstein, Peter N Robinson, William A Gahl, Paul Avillach, Gareth Baynam, Helene Cederroth, Rebecca M Goodwin, Stephen C Groft, Mats G Hansson, Nomi L Harris, Vojtech Huser, Deborah Mascalzoni, Julie A Mcmurry, Matthew Might, Christoffer Nellaker, Barend Mons, Dina N Paltoo, Jonathan Pevsner, Manuel Posada, Alison P Rockett-Frase, Marco Roos, Tamar B Rubinstein, Domenica Taruscio, Esther Van Enckevort, Melissa A Haendel

Faculty Research 2020

The premise of Open Science is that research and medical management will progress faster if data and knowledge are openly shared. The value of Open Science is nowhere more important and appreciated than in the rare disease (RD) community. Research into RDs has been limited by insufficient patient data and resources, a paucity of trained disease experts, and lack of therapeutics, leading to long delays in diagnosis and treatment. These issues can be ameliorated by following the principles and practices of sharing that are intrinsic to Open Science. Here, we describe how the RD community has adopted the core pillars …

Prognostic Gene Expression Signature For High-Grade Serous Ovarian Cancer., J Millstein, T Budden, E L Goode, M S Anglesio, A Talhouk, M P Intermaggio, H S Leong, S Chen, W Elatre, B Gilks, T Nazeran, M Volchek, R C Bentley, C Wang, D S Chiu, S Kommoss, S C Y Leung, J Senz, A Lum, V Chow, H Sudderuddin, R Mackenzie, Joshy George, Aocs Group, S Fereday, J Hendley, N Traficante, H Steed, J M Koziak, M Köbel, I A Mcneish, T Goranova, D Ennis, G Macintyre, D Silva De Silva, T Ramón Y Cajal, J García-Donas, S Hernando Polo, G C Rodriguez, K L Cushing-Haugen, H R Harris, C S Greene, R A Zelaya, S Behrens, R T Fortner, P Sinn, E Herpel, J Lester, J Lubiński, O Oszurek, A Tołoczko, C Cybulski, J Menkiszak, C L Pearce, M C Pike, C Tseng, J Alsop, V Rhenius, H Song, M Jimenez-Linan, A M Piskorz, A Gentry-Maharaj, C Karpinskyj, M Widschwendter, N Singh, C J Kennedy, R Sharma, P R Harnett, B Gao, S E Johnatty, R Sayer, J Boros, S J Winham, G L Keeney, S H Kaufmann, M C Larson, H Luk, B Y Hernandez, P J Thompson, L R Wilkens, M E Carney, B Trabert, J Lissowska, L Brinton, M E Sherman, C Bodelon, S Hinsley, L A Lewsley, R Glasspool, S N Banerjee, E A Stronach, P Haluska, I Ray-Coquard, S Mahner, B Winterhoff, D Slamon, D A Levine, L E Kelemen, J Benitez, J Chang-Claude, J Gronwald, A H Wu, U Menon, M T Goodman, J M Schildkraut, N Wentzensen, R Brown, A Berchuck, G Chenevix-Trench, A Defazio, S A Gayther, M J García, M J Henderson, M A Rossing, A Beeghly-Fadiel, P A Fasching, S Orsulic, B Y Karlan, G E Konecny, D G Huntsman, D D Bowtell, J D Brenton, J A Doherty, P D P Pharoah, S J Ramus

Faculty Research 2020

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.

PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for …

Genetic Identification And Drug-Resistance Characterization Of, Jorge Cervantes, Noemí Yokobori, Bo-Young Hong

Faculty Research 2020

Clinical management of tuberculosis (TB) in endemic areas is often challenged by a lack of resources including laboratories for Mycobacterium tuberculosis (Mtb) culture. Traditional phenotypic drug susceptibility testing for Mtb is costly and time consuming, while PCR-based methods are limited to selected target loci. We herein utilized a portable, USB-powered, long-read sequencing instrument (MinION), to investigate Mtb genomic DNA from clinical isolates to determine the presence of anti-TB drug-resistance conferring mutations. Data analysis platform EPI2ME and antibiotic-resistance analysis using the real time ARMA workflow, identified Mtb species as well as extensive resistance gene profiles. The approach was highly sensitive, being …

Transcriptional Regulatory Networks Of Tumor-Associated Macrophages That Drive Malignancy In Mesenchymal Glioblastoma., Jason K Sa, Nakho Chang, Hye Won Lee, Hee Jin Cho, Michele Ceccarelli, Luigi Cerulo, Jinlong Yin, Sung Soo Kim, Francesca P Caruso, Mijeong Lee, Donggeon Kim, Young Taek Oh, Yeri Lee, Nam-Gu Her, Byeongkwi Min, Hye-Jin Kim, Da Eun Jeong, Hye-Mi Kim, Hyunho Kim, Seok Chung, Hyun Goo Woo, Jeongwu Lee, Doo-Sik Kong, Ho Jun Seol, Jung-Il Lee, Jinho Kim, Woong-Yang Park, Qianghu Wang, Erik P Sulman, Amy B Heimberger, Michael Lim, Jong Bae Park, Antonio Iavarone, Roel G W Verhaak, Do-Hyun Nam

Faculty Research 2020

BACKGROUND: Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages.

RESULTS: We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCO

CONCLUSIONS: Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for …

Addressing The Batch Effect Issue For Lc/Ms Metabolomics Data In Data Preprocessing., Qin Liu, Douglas Walker, Karan Uppal, Zihe Liu, Chunyu Ma, Vilinh Tran, Shuzhao Li, Dean P Jones, Tianwei Yu

Faculty Research 2020

With the growth of metabolomics research, more and more studies are conducted on large numbers of samples. Due to technical limitations of the Liquid Chromatography-Mass Spectrometry (LC/MS) platform, samples often need to be processed in multiple batches. Across different batches, we often observe differences in data characteristics. In this work, we specifically focus on data generated in multiple batches on the same LC/MS machinery. Traditional preprocessing methods treat all samples as a single group. Such practice can result in errors in the alignment of peaks, which cannot be corrected by post hoc application of batch effect correction methods. In this …

Hemodynamics During The 10-Minute Nasa Lean Test: Evidence Of Circulatory Decompensation In A Subset Of Me/Cfs Patients., Jihyun Lee, Suzanne D Vernon, Patricia Jeys, Weam Ali, Andrea Campos, Derya Unutmaz, Brayden Yellman, Lucinda Bateman

Faculty Research 2020

BACKGROUND: Lightheadedness, fatigue, weakness, heart palpitations, cognitive dysfunction, muscle pain, and exercise intolerance are some of the symptoms of orthostatic intolerance (OI). There is substantial comorbidity of OI in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome). The 10-minute NASA Lean Test (NLT) is a simple, point-of-care method that can aid ME/CFS diagnosis and guide management and treatment of OI. The objective of this study was to understand the hemodynamic changes that occur in ME/CFS patients during the 10-minute NLT.

METHODS: A total of 150 ME/CFS patients and 75 age, gender and race matched healthy controls (HCs) were enrolled. We recruited 75 ME/CFS …

Mechanisms Of T-Cell Exhaustion In Pancreatic Cancer., Didem Saka, Muazzez Gökalp, Betül Piyade, Nedim Can Cevik, Elif Arik Sever, Derya Unutmaz, Güralp O Ceyhan, Ihsan Ekin Demir, Hande Asimgil

Faculty Research 2020

T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to …

A Guide To Writing Systematic Reviews Of Rare Disease Treatments To Generate Fair-Compliant Datasets: Building A Treatabolome., Antonio Atalaia, Rachel Thompson, Alberto Corvo, Leigh Carmody, Davide Piscia, Leslie Matalonga, Alfons Macaya, Angela Lochmuller, Bertrand Fontaine, Birte Zurek, Carles Hernandez-Ferrer, Carola Rheinard, David Gómez-Andrés, Jean-François Desaphy, Katherine Schon, Katja Lohmann, Matthew J Jennings, Matthis Synofzik, Olaf Riess, Rabah Ben Yaou, Teresinha Evangelista, Thiloka Ratnaike, Virginie Bros-Facer, Gulcin Gumus, Rita Horvath, Patrick Chinnery, Steven Laurie, Holm Graessner, Peter N Robinson, Hanns Lochmuller, Sergi Beltran, Gisèle Bonne

Faculty Research 2020

BACKGROUND: Rare diseases are individually rare but globally affect around 6% of the population, and in over 70% of cases are genetically determined. Their rarity translates into a delayed diagnosis, with 25% of patients waiting 5 to 30 years for one. It is essential to raise awareness of patients and clinicians of existing gene and variant-specific therapeutics at the time of diagnosis to avoid that treatment delays add up to the diagnostic odyssey of rare diseases' patients and their families.

AIMS: This paper aims to provide guidance and give detailed instructions on how to write homogeneous systematic reviews of rare …

Mgmt Genomic Rearrangements Contribute To Chemotherapy Resistance In Gliomas., Barbara Oldrini, Nuria Vaquero-Siguero, Quanhua Mu, Paula Kroon, Ying Zhang, Marcos Galán-Ganga, Zhaoshi Bao, Zheng Wang, Hanjie Liu, Jason K Sa, Junfei Zhao, Hoon Kim, Sandra Rodriguez-Perales, Do-Hyun Nam, Roel G W Verhaak, Raul Rabadan, Tao Jiang, Jiguang Wang, Massimo Squatrito

Faculty Research 2020

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in …

Ontologies, Knowledge Representation, And Machine Learning For Translational Research: Recent Contributions, Peter N Robinson, Melissa A. Haendel

Faculty Research 2020

No abstract provided.

Role Of Lncrna Morrbid In Ptpn11(Shp2)E76k-Driven Juvenile Myelomonocytic Leukemia., Zhigang Cai, Chi Zhang, Jonathan J Kotzin, Adam Williams, Jorge Henao-Mejia, Reuben Kapur

Faculty Research 2020

Mutations in PTPN11, which encodes the protein tyrosine phosphatase SHP2, contribute to ∼35% of cases of juvenile myelomonocytic leukemia (JMML). A common clinical picture in children with JMML is that it presents as a constitutive hyperinflammatory syndrome, partially reminiscent of chronic myelomonocytic leukemia in adults. Thus, a component of JMML is associated with a hyperinflammatory state and abundant innate immune cells such as neutrophils and monocytes. Recently, we showed that the evolutionarily conserved mouse lncRNA Morrbid is specifically expressed in myeloid cells and uniquely represses the expression of the proapoptotic gene Bim to regulate the lifespan of myeloid cells. However, …

3d Bioprinting For Reconstituting The Cancer Microenvironment., Pallab Datta, Madhuri Dey, Zaman Ataie, Derya Unutmaz, Ibrahim T Ozbolat

Faculty Research 2020

The cancer microenvironment is known for its complexity, both in its content as well as its dynamic nature, which is difficult to study using two-dimensional (2D) cell culture models. Several advances in tissue engineering have allowed more physiologically relevant three-dimensional (3D) in vitro cancer models, such as spheroid cultures, biopolymer scaffolds, and cancer-on-a-chip devices. Although these models serve as powerful tools for dissecting the roles of various biochemical and biophysical cues in carcinoma initiation and progression, they lack the ability to control the organization of multiple cell types in a complex dynamic 3D architecture. By virtue of its ability to …

Inter-Strain Epigenomic Profiling Reveals A Candidate Iap Master Copy In C3h Mice., Rita Rebollo, Mariana Galvão-Ferrarini, Liane Gagnier, Ying Zhang, Ardian Ferraj, Christine R Beck, Matthew C Lorincz, Dixie L Mager

Faculty Research 2020

Insertions of endogenous retroviruses cause a significant fraction of mutations in inbred mice but not all strains are equally susceptible. Notably, most new Intracisternal A particle (IAP) ERV mutagenic insertions have occurred in C3H mice. We show here that strain-specific insertional polymorphic IAPs accumulate faster in C3H/HeJ mice, relative to other sequenced strains, and that IAP transcript levels are higher in C3H/HeJ embryonic stem (ES) cells compared to other ES cells. To investigate the mechanism for high IAP activity in C3H mice, we identified 61 IAP copies in C3H/HeJ ES cells enriched with H3K4me3 (a mark of active promoters) and, …

Abgri4, A Novel Antibiotic Resistance Island In Multiply Antibiotic-Resistant Acinetobacter Baumannii Clinical Isolates., Agnes P Chan, Yongwook Choi, Thomas H Clarke, Lauren M Brinkac, Richard C White, Michael R Jacobs, Robert A Bonomo, Mark D Adams, Derrick E Fouts

Faculty Research 2020

OBJECTIVES: To investigate the genomic context of a novel resistance island (RI) in multiply antibiotic-resistant Acinetobacter baumannii clinical isolates and global isolates.

METHODS: Using a combination of long and short reads generated from the Oxford Nanopore and Illumina platforms, contiguous chromosomes and plasmid sequences were determined. BLAST-based analysis was used to identify the RI insertion target.

RESULTS: Genomes of four multiply antibiotic-resistant A. baumannii clinical strains, from a US hospital system, belonging to prevalent MLST ST2 (Pasteur scheme) and ST281 (Oxford scheme) clade F isolates were sequenced to completion. A class 1 integron carrying aadB (tobramycin resistance) and aadA2 (streptomycin/spectinomycin …

Hba-Deals: Accurate And Simultaneous Identification Of Differential Expression And Splicing Using Hierarchical Bayesian Analysis., Guy Karlebach, Peter Hansen, Diogo Ft Veiga, Robin Steinhaus, Daniel Danis, Sheng Li, Olga Anczuków, Peter N Robinson

Faculty Research 2020

We present Hierarchical Bayesian Analysis of Differential Expression and ALternative Splicing (HBA-DEALS), which simultaneously characterizes differential expression and splicing in cohorts. HBA-DEALS attains state of the art or better performance for both expression and splicing and allows genes to be characterized as having differential gene expression, differential alternative splicing, both, or neither. HBA-DEALS analysis of GTEx data demonstrated sets of genes that show predominant DGE or DAST across multiple tissue types. These sets have pervasive differences with respect to gene structure, function, membership in protein complexes, and promoter architecture.