Biomedical Informatics Commons^™

Late Effects Of Craniospinal Irradiation Using Electron Spinal Fields For Pediatric Patients With Cancer, Brian De, Marcus A Florez, Ethan B Ludmir, Moshe H Maor, Susan L Mcgovern, Mary Frances Mcaleer, David R Grosshans, Eric L Chang, Anita Mahajan, Arnold C Paulino

Faculty, Staff and Student Publications

Purpose: For children, craniospinal irradiation (CSI) with photons is associated with significant toxic effects. The use of electrons for spinal fields is hypothesized to spare anterior structures but the long-term effects remain uncertain. We studied late effects of CSI using electrons for spinal radiation therapy (RT).

Methods and materials: Records of 84 consecutive patients treated with CSI using electrons for the spine at a single institution between 1983 and 2014 were reviewed. Median age at RT was 5 (range, 1-14) years. The most common histologies were medulloblastoma/primitive neuroectodermal tumor (59%) and ependymoma (8%). The median prescribed dose to the entire …

Protective Role Of Colitis In Inflammatory Arthritis Via Propionate-Producing Bacteroides In The Gut, Hoh-Jeong Shon, Yu-Mi Kim, Kyeong Seog Kim, Jin-Ouk Choi, Sang-Hyun Cho, Sujin An, Se-Hyeon Park, Yong-Joon Cho, Joo-Hong Park, Sang-Uk Seo, Joo-Youn Cho, Wan-Uk Kim, Donghyun Kim

Faculty, Staff and Student Publications

OBJECTIVES: To investigate whether and how inflammatory disease in the intestine influences the development of arthritis, considering that organ-to-organ communication is associated with many physiological and pathological events.

METHODS: First, mice were given drinking water containing dextran sodium sulfate (DSS) and then subjected to inflammatory arthritis. We compared the phenotypic symptoms between the cohoused and separately-housed mice. Next, donor mice were divided into DSS-treated and untreated groups and then cohoused with recipient mice. Arthritis was then induced in the recipients. The fecal microbiome was analyzed by 16S rRNA amplicon sequencing. We obtained type strains of the candidate bacteria and generated …

Chronic Kidney Disease Prediction Using Boosting Techniques Based On Clinical Parameters, Shahid Mohammad Ganie, Pijush Kanti Dutta Pramanik, Saurav Mallik, Zhongming Zhao

Faculty, Staff and Student Publications

Chronic kidney disease (CKD) has become a major global health crisis, causing millions of yearly deaths. Predicting the possibility of a person being affected by the disease will allow timely diagnosis and precautionary measures leading to preventive strategies for health. Machine learning techniques have been popularly applied in various disease diagnoses and predictions. Ensemble learning approaches have become useful for predicting many complex diseases. In this paper, we utilise the boosting method, one of the popular ensemble learnings, to achieve a higher prediction accuracy for CKD. Five boosting algorithms are employed: XGBoost, CatBoost, LightGBM, AdaBoost, and gradient boosting. We experimented …

Accurate Prediction Of Functional Effect Of Single Amino Acid Variants With Deep Learning, Houssemeddine Derbel, Zhongming Zhao, Qian Liu

Faculty, Staff and Student Publications

The assessment of functional effect of amino acid variants is a critical biological problem in proteomics for clinical medicine and protein engineering. Although natively occurring variants offer insights into deleterious variants, high-throughput deep mutational experiments enable comprehensive investigation of amino acid variants for a given protein. However, these mutational experiments are too expensive to dissect millions of variants on thousands of proteins. Thus, computational approaches have been proposed, but they heavily rely on hand-crafted evolutionary conservation, limiting their accuracy. Recent advancement in transformers provides a promising solution to precisely estimate the functional effects of protein variants on high-throughput experimental data. …

Optimal Ranking And Directional Signature Classification Using The Integral Strategy Of Multi-Objective Optimization-Based Association Rule Mining Of Multi-Omics Data, Saurav Mallik, Soumita Seth, Amalendu Si, Tapas Bhadra, Zhongming Zhao

Faculty, Staff and Student Publications

No abstract provided.

3pnmf-Mkl: A Non-Negative Matrix Factorization-Based Multiple Kernel Learning Method For Multi-Modal Data Integration And Its Application To Gene Signature Detection\, Saurav Mallik, Anasua Sarkar, Sagnik Nath, Ujjwal Maulik, Supantha Das, Soumen Kumar Pati, Soumadip Ghosh, Zhongming Zhao

Faculty, Staff and Student Publications

In this current era, biomedical big data handling is a challenging task. Interestingly, the integration of multi-modal data, followed by significant feature mining (gene signature detection), becomes a daunting task. Remembering this, here, we proposed a novel framework, namely, three-factor penalized, non-negative matrix factorization-based multiple kernel learning with soft margin hinge loss (3PNMF-MKL) for multi-modal data integration, followed by gene signature detection. In brief, limma, employing the empirical Bayes statistics, was initially applied to each individual molecular profile, and the statistically significant features were extracted, which was followed by the three-factor penalized non-negative matrix factorization method used for data/matrix fusion …

Predictive Modeling Using Shape Statistics For Interpretable And Robust Quality Assurance Of Automated Contours In Radiation Treatment Planning, Zachary T Wooten, Cenji Yu, Laurence E Court, Christine B Peterson

Faculty, Staff and Student Publications

Deep learning methods for image segmentation and contouring are gaining prominence as an automated approach for delineating anatomical structures in medical images during radiation treatment planning. These contours are used to guide radiotherapy treatment planning, so it is important that contouring errors are flagged before they are used for planning. This creates a need for effective quality assurance methods to enable the clinical use of automated contours in radiotherapy. We propose a novel method for contour quality assurance that requires only shape features, making it independent of the platform used to obtain the images. Our method uses a random forest …

Grid Cells, Border Cells, And Discrete Complex Analysis, Yuri Dabaghian

Faculty, Staff and Student Publications

We propose a mechanism enabling the appearance of border cells-neurons firing at the boundaries of the navigated enclosures. The approach is based on the recent discovery of discrete complex analysis on a triangular lattice, which allows constructing discrete epitomes of complex-analytic functions and making use of their inherent ability to attain maximal values at the boundaries of generic lattice domains. As it turns out, certain elements of the discrete-complex framework readily appear in the oscillatory models of grid cells. We demonstrate that these models can extend further, producing cells that increase their activity toward the frontiers of the navigated environments. …

Pediatric Diarrhea Patients Living In Urban Areas Have A Higher Incidence Of Clostridioides Difficile Infection, Ayodele T Adesoji, Osaro Mgbere, Charles Darkoh

Faculty, Staff and Student Publications

Clostridioides difficile infection (CDI) is a major cause of antibiotic-associated diarrhea and an unappreciated contributor to child mortality in low- and middle-income countries where the diagnosis may be difficult. There is little information about the prevalence of CDI among infants, children, and adolescents in Africa. Using a cross-sectional design, seventy-six samples were collected from pediatric patients presenting with diarrhea, including infants (≤ 2 years old), children (2-12 years), and adolescents (13 ≤17 years) from three hospitals between January and December 2019. Demographic data, medical history, and prior antibiotic use were recorded. Toxigenic culture and PCR were used to detect and …

Population-Based Assessment Of The Burden Of Covid-19 Infection In African Countries: A First-Year Report Card And Public Health Implications, Osaro Mgbere, Ogbonna Collins Nwabuko, Olajumoke A Olateju, Omolola E Adepoju, Winston Liaw, Charles Darkoh, Ekere James Essien

Faculty, Staff and Student Publications

BACKGROUND: The COVID-19 pandemic constitutes a global health threat and poses a major burden on the African continent. We assessed the real-world burden of COVID-19 infection in African Union (AU) member states to determine the distributional patterns of epidemiological measures during the first 1 year of the pandemic.

METHODS: This retrospective cross-sectional study utilized COVID-19 data from publicly available data repositories of the African Center for Disease Control and Prevention and

RESULTS: A total of 3.21 million cases were reported during the 1-year period, with 2.6 million recoveries, 536,784 cases remaining active, and 77,486 deaths. Most countries (49.1%,

CONCLUSION: Understanding …

Evolutionary Aspects Of Infections: Inflammation And Sickness Behaviors, Robert Dantzer

Faculty, Staff and Student Publications

Sickness behavior was conceptualized initially as the behavioral counterpart of the fever response to infectious pathogens. It helps to raise body temperature to its higher setpoint and to maintain it at this new level and it has the additional benefit of enabling a weakened organism to protect itself from other dangers. The discovery of the behavioral effects of proinflammatory cytokines produced by activated immune cells provided a cellular and molecular basis to this phenomenon. The administration of cytokines or cytokine inducers like lipopolysaccharide to healthy rodents allowed to reveal the similarities and differences between inflammation-induced sickness behavior and the fever …

Inhibition Of Nox2 Or Nlrp3 Inflammasome Prevents Cardiac Remote Ischemic Preconditioning, Sandra Benavides, Rodrigo Palavecino, Jaime A Riquelme, Luis Montecinos, José Pablo Finkelstein, Paulina Donoso, Gina Sánchez

Faculty, Staff and Student Publications

Introduction: Short episodes of ischemia-reperfusion (IR) in the heart (classical ischemic preconditioning, IPC) or in a limb (remote ischemic preconditioning, RIPC) before a prolonged ischemic episode, reduce the size of the infarct. It is unknown whether IPC and RIPC share common mechanisms of protection. Animals KO for NOX2, a superoxide-producing enzyme, or KO for NLRP3, a protein component of inflammasome, are not protected by IPC. The aim of this study was to investigate if NOX2 or NLRP3 inflammasome are involved in the protection induced by RIPC. Methods: We preconditioned rats using 4 × 5 min periods of IR in the …

Endothelial Activation Impairs The Function Of Small Extracellular Vesicles, Nicolas Herrera-Zelada, Úrsula Zúñiga-Cuevas, Andrés Ramírez-Reyes, Ignacio Norambuena-Soto, Leslye Venegas-Zamora, Mayarling F Troncoso, Alejandra Hernández, Gina Sánchez, Zully Pedrozo, Sergio Lavandero, Jaime A Riquelme

Faculty, Staff and Student Publications

Small extracellular vesicles are nanosized vesicles (30-200 nm) that can ferry proteins, nucleic acids, and lipids between cells and therefore, have significant potential as biomarkers, drug delivery tools or therapeutic agents. SEVs of endothelial origin have been shown to -among other functions-reduce in vitro ischemia/reperfusion (I/R) injury in cardiomyocytes, but whether a pro-inflammatory state of the endothelium impairs the functionality of these SEVs remains to be elucidated. To test this, human umbilical vein endothelial cells cells were treated with TNF-α 10 ng/mL and the expression of the pro-inflammatory parameters VCAM-1, ICAM-1 and eNOS were determined by Western blot. SEVs were …

Targeting Mcl-1 Protein To Treat Cancer: Opportunities And Challenges, Shady I Tantawy, Natalia Timofeeva, Aloke Sarkar, Varsha Gandhi

Faculty, Staff and Student Publications

Evading apoptosis has been linked to tumor development and chemoresistance. One mechanism for this evasion is the overexpression of prosurvival B-cell lymphoma-2 (BCL-2) family proteins, which gives cancer cells a survival advantage. Mcl-1, a member of the BCL-2 family, is among the most frequently amplified genes in cancer. Targeting myeloid cell leukemia-1 (MCL-1) protein is a successful strategy to induce apoptosis and overcome tumor resistance to chemotherapy and targeted therapy. Various strategies to inhibit the antiapoptotic activity of MCL-1 protein, including transcription, translation, and the degradation of MCL-1 protein, have been tested. Neutralizing MCL-1's function by targeting its interactions …

Editorial: Lipid Droplets And Mitochondria In Metabolic Diseases, Wen Su, Yujing Chi, Yu A An

Faculty, Staff and Student Publications

No abstract provided.

Implementing Stroke Care In A Lower-Middle-Income Country: Results And Recommendations Based On An Implementation Study Within The Nepal Stroke Project, Christine Tunkl, Raju Paudel, Sunanjay Bajaj, Lekhjung Thapa, Patrick Tunkl, Avinash Chandra, Bhupendra Shah, Balgopal Karmacharya, Ashim Subedi, Pankaj Jalan, Pradesh Ghimire, Mahesh Raj Ghimire, Gampo Dorje, Nima Haji Begli, Jessica Golenia, Bikram Prasad Gajurel, Shirsho Shreyan, Nooma Sharma, Alexandra Krauss, Jeyaraj Pandian, Thomas Fischer, Jan Van Der Merwe, Wolfgang Wick, Werner Hacke, Christoph Gumbinger

Faculty, Staff and Student Publications

Background: Globally, the majority of strokes affect people residing in lower- and lower-middle-income countries (LMICs), but translating evidence-based knowledge into clinical practice in regions with limited healthcare resources remains challenging. As an LMIC in South Asia, stroke care has remained a healthcare problem previously unaddressed at a national scale in Nepal. The Nepal Stroke Project (NSP) aims to improve acute stroke care in the tertiary healthcare sector of Nepal. We hereby describe the methods applied and analyze the barriers and facilitators of the NSP after 18 months.

Methods: The NSP follows a four-tier strategy: (1) quality improvement by training healthcare …

Editorial: Metabolic Regulation Under Oxidative Stress In Cancer, Elavarasan Subramani, Abishai Dominic, Pratip K Bhattacharya, Daniel E Frigo, Ilya Bederman, Ali Vaziri-Gohar

Faculty, Staff and Student Publications

Oxidative stress has emerged as a key component of cancer metabolism that impacts multiple facets of tumor biology (1). Recent studies have shed light on the complex interplay of cellular redox and its impact on molecular mechanisms that govern metabolic reprogramming under oxidative stress (2, 3). It is well established that altered glucose metabolism exhibited by tumor cells leads to an enormous oxidative burden through various metabolic routes (4, 5). What is less known but remains a great interest to the field is whether elevated oxidative stress has a causal role in …

Imaging Peripheral Lymphatic Dysfunction In Chronic Conditions, Eva M Sevick-Muraca, Caroline E Fife, John C Rasmussen

Faculty, Staff and Student Publications

The lymphatics play important roles in chronic diseases/conditions that comprise the bulk of healthcare worldwide. Yet the ability to routinely image and diagnose lymphatic dysfunction, using commonly available clinical imaging modalities, has been lacking and as a result, the development of effective treatment strategies suffers. Nearly two decades ago, investigational near-infrared fluorescence lymphatic imaging and ICG lymphography were developed as routine diagnostic for clinically evaluating, quantifying, and treating lymphatic dysfunction in cancer-related and primary lymphedema, chronic venous disease, and more recently, autoimmune and neurodegenerative disorders. In this review, we provide an overview of what these non-invasive technologies have taught us …

Editorial: In Celebration Of Women In Science: Lipids, Membranes, And Membranous Organelles, Isabel M López-Lara, Elena G Govorunova

Faculty, Staff and Student Publications

No abstract provided.

Automated Type 2 Diabetes Case And Control Identification From The Mimic-Iv Database, Wanheng Zhang, Tru Cao

Faculty, Staff and Student Publications

Phenotyping for Type 2 Diabetes (T2DM) is needed due to the increasing demand for T2DM research on electronic health records (EHRs). eMERGE is a reliable and interpretable rule-based algorithm for the identification of T2DM cases and controls in EHRs. MIMIC-IV, an extension of MIMIC-III, contains more than 520,000 hospital admissions and has become a valuable EHR database for secondary medical research. However, there was no prior work to extract T2DM cases and controls from MIMIC-IV, which requires a comprehensive knowledge of the database. Our work provided insight into the structure and data elements in MIMIC-IV and adapted eMERGE to accomplish …

Segmentation Stability Of Human Head And Neck Cancer Medical Images For Radiotherapy Applications Under De-Identification Conditions: Benchmarking Data Sharing And Artificial Intelligence Use-Cases, Jaakko Sahlsten, Kareem A Wahid, Enrico Glerean, Joel Jaskari, Mohamed A Naser, Renjie He, Benjamin H Kann, Antti Mäkitie, Clifton D Fuller, Kimmo Kaski

Faculty, Staff and Student Publications

BACKGROUND: Demand for head and neck cancer (HNC) radiotherapy data in algorithmic development has prompted increased image dataset sharing. Medical images must comply with data protection requirements so that re-use is enabled without disclosing patient identifiers. Defacing, i.e., the removal of facial features from images, is often considered a reasonable compromise between data protection and re-usability for neuroimaging data. While defacing tools have been developed by the neuroimaging community, their acceptability for radiotherapy applications have not been explored. Therefore, this study systematically investigated the impact of available defacing algorithms on HNC organs at risk (OARs).

METHODS: A publicly available dataset …

Autologous T Cell Therapy For Mage-A4+ Solid Cancers In Hla-A*02+ Patients: A Phase 1 Trial, David S Hong, Brian A Van Tine, Swethajit Biswas, Cheryl Mcalpine, Melissa L Johnson, Anthony J Olszanski, Jeffrey M Clarke, Dejka Araujo, George R Blumenschein, Partow Kebriaei, Quan Lin, Alex J Tipping, Joseph P Sanderson, Ruoxi Wang, Trupti Trivedi, Thejo Annareddy, Jane Bai, Stavros Rafail, Amy Sun, Lilliam Fernandes, Jean-Marc Navenot, Frederic D Bushman, John K Everett, Derin Karadeniz, Robyn Broad, Martin Isabelle, Revashnee Naidoo, Natalie Bath, Gareth Betts, Zohar Wolchinsky, Dzmitry G Batrakou, Erin Van Winkle, Erica Elefant, Armin Ghobadi, Amanda Cashen, Anne Grand'maison, Philip Mccarthy, Paula M Fracasso, Elliot Norry, Dennis Williams, Mihaela Druta, David A Liebner, Kunle Odunsi, Marcus O Butler

Faculty, Staff and Student Publications

Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced …

Keeping Employees Safe During Health Crises: The Effects Of Media Exposure, Hr Practices, And Age, Shuqi Li, Henry R Young, Majid Ghorbani, Byron Y Lee, Daan Van Knippenberg, Russell E Johnson

Faculty, Staff and Student Publications

Occupational health and safety are critical in promoting the wellness of organizations and employees. The COVID-19 pandemic is one of the most life-threatening viruses encountered in recent history, providing a unique opportunity for research to examine factors that drive employee safety behavior. Drawing from terror management theory, we propose and test a moderated mediation model using data collected from employees working during a peak of the pandemic. We identify two sources of influence - one external (i.e., media exposure), and one internal (i.e., HR practices) to the organization - that shape employees' mortality salience and safety behaviors. We find that …

Self-Administered Meditation Application Intervention For Cancer Patients With Psychosocial Distress: A Pilot Study, Gabriel Lopez, Alejandro Chaoul, Carla L Warneke, Aimee J Christie, Catherine Powers-James, Wenli Liu, Santhosshi Narayanan, Marvin Delgado-Guay, Yisheng Li, Eduardo Bruera, Lorenzo Cohen

Faculty, Staff and Student Publications

BACKGROUND: We explored the use of a novel smart phone-based application (APP) for delivery and monitoring of meditation to treat mood symptoms experienced by cancer patients.

METHODS: We assessed the feasibility of using a meditation delivery and tracking APP over 2-weeks and its impact on cancer patients' self-reported anxiety and depression. Outpatients reporting depression and/or anxiety were recruited and randomized to the APP or waitlist control group. Assessments included an expectancy scale, exit survey, mood rating before and after each meditation, and the Edmonton Symptom Assessment Scale (ESAS-FS), Hospital Anxiety and Depression Scale (HADS), and Pittsburgh Sleep Quality Index (PSQI) …

Resveratrol Rescues Cutaneous Radiation-Induced Dna Damage Via A Novel Ampk/Sirt7/Hmgb1 Regulatory Axis, Yi Jin, Xingyuan Liu, Xiaoting Liang, Jiabin Liu, Jieyu Liu, Zonglin Han, Qianxin Lu, Ke Wang, Bingyao Meng, Chunting Zhang, Minna Xu, Jian Guan, Li Ma, Liang Zhou

Faculty, Staff and Student Publications

Cutaneous radiation injury (CRI) interrupts the scheduled process of radiotherapy and even compromises the life quality of patients. However, the current clinical options for alleviating CRI are relatively limited. Resveratrol (RSV) has been shown to be a promising protective agent against CRI; yet the mechanisms of RSV enhancing radioresistance were not fully elucidated and limited its clinical application. In this study, we demonstrate RSV promotes cutaneous radioresistance mainly through SIRT7. During ionizing radiation (IR) treatment, RSV indirectly phosphorylates and activates SIRT7 through AMPK, which is critical for maintaining the genome stability of keratinocytes. Immunoprecipitation and mass spectrometry identified HMGB1 to …

Easy Nanostring Ncounter Data Analysis With The Nanotube, Caleb A Class, Caiden J Lukan, Christopher A Bristow, Kim-Anh Do

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Summary: The NanoTube is an open-source pipeline that simplifies the processing, quality control, normalization and analysis of NanoString nCounter gene expression data. It is implemented in an extensible R library, which performs a variety of gene expression analysis techniques and contains additional functions for integration with other R libraries performing advanced NanoString analysis techniques. Additionally, the NanoTube web application is available as a simple tool for researchers without programming expertise.

Availability and implementation: The NanoTube R package is available on Bioconductor under the GPL-3 license (https://www.bioconductor.org/packages/NanoTube/). The R-Shiny application can be downloaded at https://github.com/calebclass/Shiny-NanoTube, or a simplified …

Clinical Outcomes: Endoscopic Resection Of Duodenal Ampullary Lesions, Stephanie M Woo, Mark J Real, Brett M Will, Eric J Kim, Jiling Chou, Ahmed A Alsaiari, Ahmad Nakshabandi, Walid M Chalhoub, Nadim G Haddad

Faculty, Staff and Student Publications

Background: Ampullary adenomas are lesions at the duodenum's major papilla commonly associated with familial adenomatous polyposis (FAP) but may also occur sporadically. Historically, ampullary adenomas were removed surgically, however endoscopic resection has become the preferred method of resection. Most of the literature on management of ampullary adenomas are small single-center retrospective reviews. The objective of this study is to describe endoscopic papillectomy outcomes to further refine management guidelines.

Methods: This is a retrospective study of patients who underwent endoscopic papillectomy. Demographic data were included. Details regarding lesions and procedures were also collected, including endoscopic impression, size, resection method and adjunctive …

Assessing The Most Vulnerable Subgroup To Type Ii Diabetes Associated With Statin Usage: Evidence From Electronic Health Record Data, Xinzhou Guo, Waverly Wei, Molei Liu, Tianxi Cai, Chong Wu, Jingshen Wang

Faculty, Staff and Student Publications

There have been increased concerns that the use of statins, one of the most commonly prescribed drugs for treating coronary artery disease, is potentially associated with the increased risk of new-onset Type II diabetes (T2D). Nevertheless, to date, there is no robust evidence supporting as to whether and what kind of populations are indeed vulnerable for developing T2D after taking statins. In this case study, leveraging the biobank and electronic health record data in the Partner Health System, we introduce a new data analysis pipeline and a novel statistical methodology that address existing limitations by (i) designing a rigorous causal …

Self-Assembling Peptides As Immunomodulatory Biomaterials, Andrea Hernandez, Jeffrey D Hartgerink, Simon Young

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Self-assembling peptides are a type of biomaterial rapidly emerging in the fields of biomedicine and material sciences due to their promise in biocompatibility and effectiveness at controlled release. These self-assembling peptides can form diverse nanostructures in response to molecular interactions, making them versatile materials. Once assembled, the peptides can mimic biological functions and provide a combinatorial delivery of therapeutics such as cytokines and drugs. These self-assembling peptides are showing success in biomedical settings yet face unique challenges that must be addressed to be widely applied in the clinic. Herein, we describe self-assembling peptides' characteristics and current applications in immunomodulatory therapeutics.

Evolutionary History Of Transformation From Chronic Lymphocytic Leukemia To Richter Syndrome, Erin M Parry, Ignaty Leshchiner, Romain Guièze, Connor Johnson, Eugen Tausch, Sameer A Parikh, Camilla Lemvigh, Julien Broséus, Sébastien Hergalant, Conor Messer, Filippo Utro, Chaya Levovitz, Kahn Rhrissorrakrai, Liang Li, Daniel Rosebrock, Shanye Yin, Stephanie Deng, Kara Slowik, Raquel Jacobs, Teddy Huang, Shuqiang Li, Geoff Fell, Robert Redd, Ziao Lin, Binyamin A Knisbacher, Dimitri Livitz, Christof Schneider, Neil Ruthen, Liudmila Elagina, Amaro Taylor-Weiner, Bria Persaud, Aina Martinez, Stacey M Fernandes, Noelia Purroy, Annabelle J Anandappa, Jialin Ma, Julian Hess, Laura Z Rassenti, Thomas J Kipps, Nitin Jain, William Wierda, Florence Cymbalista, Pierre Feugier, Neil E Kay, Kenneth J Livak, Brian P Danysh, Chip Stewart, Donna Neuberg, Matthew S Davids, Jennifer R Brown, Laxmi Parida, Stephan Stilgenbauer, Gad Getz, Catherine J Wu

Faculty, Staff and Student Publications

Richter syndrome (RS) arising from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that develops from an indolent neoplasm. To decipher the genetics underlying this transformation, we computationally deconvoluted admixtures of CLL and RS cells from 52 patients with RS, evaluating paired CLL-RS whole-exome sequencing data. We discovered RS-specific somatic driver mutations (including IRF2BP2, SRSF1, B2M, DNMT3A and CCND3), recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which were confirmed in 45 independent RS cases and in an external set of RS whole genomes. Through unsupervised clustering, clonally related RS was largely distinct from diffuse large B cell lymphoma. …