Medical Genetics Commons^™

Structural Basis Of The Human Transcriptional Mediator Regulated By Its Dissociable Kinase Module, Ti-Chun Chao, Shin-Fu Chen, Hee Jong Kim, Hui-Chi Tang, Hsiang-Ching Tseng, An Xu, Leon Palao, Subash Khadka, Tao Li, Mo-Fan Huang, Dung-Fang Lee, Kenji Murakami, Thomas G Boyer, Kuang-Lei Tsai

Faculty, Staff and Student Publications

The eukaryotic transcriptional Mediator comprises a large core (cMED) and a dissociable CDK8 kinase module (CKM). cMED recruits RNA polymerase II (RNA Pol II) and promotes pre-initiation complex formation in a manner repressed by the CKM through mechanisms presently unknown. Herein, we report cryoelectron microscopy structures of the complete human Mediator and its CKM. The CKM binds to multiple regions on cMED through both MED12 and MED13, including a large intrinsically disordered region (IDR) in the latter. MED12 and MED13 together anchor the CKM to the cMED hook, positioning CDK8 downstream and proximal to the transcription start site. Notably, the …

Safety Of Kidney Transplantation From Donors With Hiv, Christine M Durand, Allan Massie, Sander Florman, Tao Liang, Meenakshi M Rana, Rachel Friedman-Moraco, Alexander Gilbert, Peter Stock, Sapna A Mehta, Shikha Mehta, Valentina Stosor, Marcus R Pereira, Michele I Morris, Jonathan Hand, Saima Aslam, Maricar Malinis, Ghady Haidar, Catherine B Small, Carlos A Q Santos, Joanna Schaenman, John Baddley, David Wojciechowski, Emily A Blumberg, Karthik Ranganna, Oluwafisayo Adebiyi, Nahel Elias, Jose A Castillo-Lugo, Emmanouil Giorgakis, Senu Apewokin, Diane Brown, Darin Ostrander, Yolanda Eby, Niraj Desai, Fizza Naqvi, Serena Bagnasco, Natasha Watson, Erica Brittain, Jonah Odim, Andrew D Redd, Aaron A R Tobian, Dorry L Segev

Faculty, Staff and Student Publications

Background: Kidney transplantation from donors with human immunodeficiency virus (HIV) to recipients with HIV is an emerging practice. It has been performed since 2016 under the U.S. congressional HIV Organ Policy Equity Act and is currently approved for research only. The Department of Health and Human Services is considering expanding the procedure to clinical practice, but data are limited to small case series that did not include donors without HIV as controls.

Methods: In an observational study conducted at 26 U.S. centers, we compared transplantation of kidneys from deceased donors with HIV and donors without HIV to recipients with HIV. …

Yap1 Status Defines Two Intrinsic Subtypes Of Lcnec With Distinct Molecular Features And Therapeutic Vulnerabilities, C Allison Stewart, Lixia Diao, Yuanxin Xi, Runsheng Wang, Kavya Ramkumar, Alejandra G Serrano, Azusa Tanimoto, B Leticia Rodriguez, Benjamin B Morris, Li Shen, Bingnan Zhang, Yan Yang, Samera H Hamad, Robert J Cardnell, Alberto Duarte, Moushumi Sahu, Veronica Y Novegil, Bernard E Weissman, Michael Frumovitz, Neda Kalhor, Luisa Solis Soto, Pedro Da Rocha, Natalie Vokes, Don L Gibbons, Jing Wang, John V Heymach, Bonnie Glisson, Lauren Averett Byers, Carl M Gay

Faculty, Staff and Student Publications

Purpose: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with the absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies, which are often adapted from SCLC and non-small cell lung cancer approaches.

Experimental design: To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed IHC and single-cell RNA sequencing of core needle biopsies from patients with LCNEC and preclinical models.

Results: In this study, we demonstrate that the presence …

Accurate Identification Of Locally Aneuploid Cells By Incorporating Cytogenetic Information In Single Cell Data Analysis, Ziyi Li, Ruoxing Li, Irene Ganan-Gomez, Hussein A Abbas, Guillermo Garcia-Manero, Wei Sun

Faculty, Staff and Student Publications

Single-cell RNA sequencing is a powerful tool to investigate the cellular makeup of tumor samples. However, due to the sparse data and the complex tumor microenvironment, it can be challenging to identify neoplastic cells that play important roles in tumor growth and disease progression. This is especially relevant for blood cancers, where neoplastic cells may be highly similar to normal cells. To address this challenge, we have developed partCNV and partCNVH, two methods for rapid and accurate detection of aneuploid cells with local copy number deletion or amplification. PartCNV uses an expectation-maximization (EM) algorithm with mixtures of Poisson distributions and …

Npm1-Mutated Myeloid Neoplasms Are A Unique Entity Not Defined By Bone Marrow Blast Percentage, Georgina Gener-Ricos, Alex Bataller, Juan Jose Rodriguez-Sevilla, Kelly S Chien, Andres E Quesada, Emmanuel Almanza-Huante, Danielle Hammond, Koji Sasaki, Courtney Dinardo, Tapan Kadia, Naval Daver, Gautam Borthakur, Ghayas C Issa, Nicholas J Short, Rashmi Kanagal-Shamanna, Hagop M Kantarjian, Guillermo Garcia-Manero, Guillermo Montalban-Bravo

Faculty, Staff and Student Publications

Introduction: NPM1-mutated (NPM1mut) myeloid neoplasms (MNs) with < 20% bone marrow (BM) blasts (NPM1mut MNs< 20) are uncommon, and their classification remains inconsistent.

Methods: The clinicopathologic features of 54 patients with NPM1mut MNs < 20 were evaluated and compared with wild-type NPM1 MNs < 20 and NPM1mut MNs≥20, respectively.

Results: NPM1mut MNs had similar features regardless of blast percentage, except for higher IDH2 (29% vs 7%, p = .023) and FLT3 (70% vs 11%, p < .001) frequency in patients with ≥20% BM blasts. Thirty-three (61%) patients with NPM1mut MNs < 20 received low-intensity chemotherapy (LIC) and 12 (22%) received intensive chemotherapy (IC). Higher complete remission rates (75% vs 27%, p = .006) and median overall survival (mOS) (not reached vs 30.4 months, p = .06) were observed with IC compared to LIC. Young patients (age < 60 years) did not reach mOS either when treated with LIC or IC. Stem cell transplant was associated with increased survival only in patients treated with LIC (HR, 0.24; p = .025). No differences in mOS were observed by BM blast strata (32.2 months, not reached and 46.9 months for < 10%, 10%-19%, and ≥20% blasts, p = .700) regardless of treatment modality (LIC: p = .900; IC: p = .360). Twenty-three patients (43%) with NPM1mut MNs < 20 had marrow blast progression to ≥20%.

Conclusions: Overall, NPM1mut MNs define a unique entity independent of BM blast percentage.

Biochemical And Structural Insights Into A 5′ To 3′ Rna Ligase Reveal A Potential Role In Trna Ligation, Yingjie Hu, Victor A Lopez, Hengyi Xu, James P Pfister, Bing Song, Kelly A Servage, Masahiro Sakurai, Benjamin T Jones, Joshua T Mendell, Tao Wang, Jun Wu, Alan M Lambowitz, Diana R Tomchick, Krzysztof Pawłowski, Vincent S Tagliabracci

Faculty, Staff and Student Publications

ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here, we identify C12orf29 (RLIG1) as an atypical ATP-grasp enzyme that ligates RNA. Human RLIG1 and its homologs autoadenylate on an active site Lys residue as part of a reaction intermediate that specifically ligates RNA halves containing a 5’-phosphate and a 3’-hydroxyl. RLIG1 binds tRNA in cells and can ligate tRNA within the anticodon loop in vitro. Transcriptomic …

Proportional Hazards Violations In Phase Iii Cancer Clinical Trials: A Potential Source Of Trial Misinterpretation, Timothy A Lin, Zachary R Mccaw, Alex Koong, Christine Lin, Joseph Abi Jaoude, Roshal Patel, Ramez Kouzy, Molly B El Alam, Alexander D Sherry, Sonal S Noticewala, Clifton D Fuller, Charles R Thomas, Ryan Sun, J Jack Lee, Ruitao Lin, Ying Yuan, Yu Shyr, Tomer Meirson, Ethan B Ludmir

Faculty, Staff and Student Publications

Purpose: Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHV) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase III oncology trials and assess the utility of restricted mean survival time and maximum combination test as additional analyses.

Experimental design: Clinicaltrials.gov and PubMed were searched to identify two-arm, randomized, phase III superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published …

Evaluating Debio 1347 In Patients With Fgfr Fusion-Positive Advanced Solid Tumors From The Fuze Multicenter, Open-Label, Phase Ii Basket Trial, Petros Grivas, Elena Garralda, Funda Meric-Bernstam, Ingo K Mellinghoff, Lipika Goyal, James J Harding, E Claire Dees, Rastislav Bahleda, Nilofer S Azad, Asha Karippot, Razelle Kurzrock, Josep Tabernero, Juha Kononen, Matthew C H Ng, Rutika Mehta, Nataliya V Uboha, Frédéric Bigot, Valentina Boni, Samantha E Bowyer, Valeriy Breder, Andrés Cervantes, Nancy Chan, James M Cleary, Mallika Dhawan, Rikke L Eefsen, James Ewing, Donna M Graham, Tormod K Guren, Jin Won Kim, Krassimir Koynov, Do-Youn Oh, Rebecca Redman, Chia-Jui Yen, David Spetzler, Marie-Claude Roubaudi-Fraschini, Valerie Nicolas-Metral, Rafik Ait-Sarkouh, Claudio Zanna, Abdallah Ennaji, Anna Pokorska-Bocci, Keith T Flaherty

Faculty, Staff and Student Publications

Purpose: This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion.

Patients and methods: Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of …

First-In-Human Clinical Outcomes With Ng-350a, An Anti-Cd40 Expressing Tumor-Selective Vector Designed To Remodel Immunosuppressive Tumor Microenvironments, Aung Naing, Danny Khalil, Oliver Rosen, D Ross Camidge, Tom Lillie, Rui-Ru Ji, Andrea Stacey, Matthew Thomas, Lee Rosen

Faculty, Staff and Student Publications

Background: Tumor-selective oncolytic viral vectors are promising anticancer therapeutics; however, challenges with dosing and potency in advanced/metastatic cancers have limited efficacy and usage. NG-350A is a next-generation blood-stable adenoviral vector engineered to express an agonist anti-cluster of differentiation (CD)40 antibody without affecting tumor-selectivity and oncolytic potency.

Methods: Intravenous and intratumoral (IT) administration of NG-350A was assessed in a phase Ia/Ib study in patients with metastatic/advanced epithelial tumors (NCT03852511). Dose-escalation was performed separately for intravenous (four dose levels available, each with infusions on Days 1, 3 and 5 of a 57-day treatment period) and IT (single injection on D1 …

Cdk12 Loss Drives Prostate Cancer Progression, Transcription-Replication Conflicts, And Synthetic Lethality With Paralog Cdk13, Jean Ching-Yi Tien, Jie Luo, Yu Chang, Yuping Zhang, Yunhui Cheng, Xiaoju Wang, Jianzhang Yang, Rahul Mannan, Somnath Mahapatra, Palak Shah, Xiao-Ming Wang, Abigail J Todd, Sanjana Eyunni, Caleb Cheng, Ryan J Rebernick, Lanbo Xiao, Yi Bao, James Neiswender, Rachel Brough, Stephen J Pettitt, Xuhong Cao, Stephanie J Miner, Licheng Zhou, Yi-Mi Wu, Estefania Labanca, Yuzhuo Wang, Abhijit Parolia, Marcin Cieslik, Dan R Robinson, Zhen Wang, Felix Y Feng, Jonathan Chou, Christopher J Lord, Ke Ding, Arul M Chinnaiyan

Faculty, Staff and Student Publications

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a metastatic castration-resistant prostate cancer (mCRPC) subtype. It remains unclear, however, whether CDK12 loss drives prostate cancer (PCa) development or uncovers pharmacologic vulnerabilities. Here, we show Cdk12 ablation in murine prostate epithelium is sufficient to induce preneoplastic lesions with lymphocytic infiltration. In allograft-based CRISPR screening, Cdk12 loss associates positively with Trp53 inactivation but negatively with Pten inactivation. Moreover, concurrent Cdk12/Trp53 ablation promotes proliferation of prostate-derived organoids, while Cdk12 knockout in Pten-null mice abrogates prostate tumor growth. In syngeneic systems, Cdk12/Trp53-null allografts exhibit luminal morphology and immune checkpoint blockade sensitivity. Mechanistically, Cdk12 inactivation …

A Phase Ib/Ii Randomized Clinical Trial Of Oleclumab With Or Without Durvalumab Plus Chemotherapy In Patients With Metastatic Pancreatic Ductal Adenocarcinoma, Andrew L Coveler, Matthew J Reilley, Mark Zalupski, Teresa Macarulla, Christos Fountzilas, Mariano Ponz-Sarvisé, Adnan Nagrial, Nataliya V Uboha, Sophia Frentzas, Michael Overman, Anne Noonan, Wells A Messersmith, Nick Pavlakis, Niharika B Mettu, Ina Bisha, Ying Wang, Paul Smith, Elina Murtomaki, Agata A Bielska, Veronique Bragulat, Zachary A Cooper, Rakesh Kumar, David R Spigel

Faculty, Staff and Student Publications

Purpose: Pancreatic ductal adenocarcinoma upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option.

Patients and methods: We describe a multicenter phase Ib/II randomized clinical trial in patients with metastatic pancreatic ductal adenocarcinoma, untreated (cohort A) or previously received gemcitabine-based chemotherapy (cohort B; NCT03611556). During escalation, patients received oleclumab 1,500 or 3,000 mg, durvalumab 1,500 mg, and gemcitabine plus nab-paclitaxel (GnP; cohort A; n = 14) or modified FOLFOX (cohort B; n = 11). During expansion, cohort A patients (n = 170) were randomized to GnP (arm …

Development And Validation Of A Machine Learning Model To Predict Myocardial Blood Flow And Clinical Outcomes From Patients’ Electrocardiogram, Fares Alahdab, Maliazurina Binti Saad, Ahmed Ibrahim Ahmed, Qasem Al Tashi, Muhammad Aminu, Yushui Han, Jonathan B Moody, Venkatesh L Murthy, Jia Wu, Mouaz H Al-Mallah

Faculty, Staff and Student Publications

We develop a machine learning (ML) model using electrocardiography (ECG) to predict myocardial blood flow reserve (MFR) and assess its prognostic value for major adverse cardiovascular events (MACEs). Using 3,639 ECG-positron emission tomography (PET) and 17,649 ECG-single-photon emission computed tomography (SPECT) data pairs, the ML model is trained with a swarm intelligence approach and support vector regression (SVR). The model achieves a receiver-operator curve (ROC) area under the curve (AUC) of 0.83, with a sensitivity and specificity of 0.75. An ECG-MFR value below 2 is significantly associated with MACE, with hazard ratios (HRs) of 3.85 and 3.70 in the discovery …

Exposure To Per- And Polyfluoroalkyl Substances And Alterations In Plasma Microrna Profiles In Children, Yijie Li, Brittney O Baumert, Nikos Stratakis, Jesse A Goodrich, Haotian Wu, Shelley H Liu, Hongxu Wang, Emily Beglarian, Scott M Bartell, Sandrah Proctor Eckel, Douglas Walker, Damaskini Valvi, Michele Andrea La Merrill, Thomas H Inge, Todd Jenkins, Justin R Ryder, Stephanie Sisley, Rohit Kohli, Stavra A Xanthakos, Marina Vafeiadi, Aikaterini Margetaki, Theano Roumeliotaki, Max Aung, Rob Mcconnell, Andrea Baccarelli, David Conti, Lida Chatzi

Faculty, Staff and Students Publications

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment and can accumulate in humans, leading to adverse health effects. MicroRNAs (miRNAs) are emerging biomarkers that can advance the understanding of the mechanisms of PFAS effects on human health. However, little is known about the associations between PFAS exposures and miRNA alterations in humans.

OBJECTIVE: To investigate associations between PFAS concentrations and miRNA levels in children.

METHODS: Data from two distinct cohorts were utilized: 176 participants (average age 17.1 years; 75.6% female) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort in the United States, and …

Ovarian Cancer Metastasis: Looking Beyond The Surface, Emine Bayraktar, Sisy Chen, Sara Corvigno, Jinsong Liu, Anil K Sood

Faculty, Staff and Student Publications

Historically, ovarian cancer (OC) was thought to metastasize by surface-to-surface spread, but recent developments have yielded a new understanding of the paths of metastatic spread. Given the histologic and molecular heterogeneity of OC, we will focus on high-grade serous carcinoma (HGSC). Here, we provide a critical and more holistic view of the evidence supporting various routes of metastasis, including peritoneal, hematogenous, lymphatic, and nerve-related. Understanding the underlying mechanisms is necessary to improve treatment strategies for this challenging disease.

Left Ventricular Diastolic Dysfunction With Elevated Filling Pressures Is Associated With Embolic Stroke Of Undetermined Source And Atrial Fibrillation, Zubair Bashir, Liqi Shu, Yuqian Guo, Edward W Chen, Shuyuan Wang, Eric D Goldstein, Maheen Rana, Narendra Kala, Xing Dai, Daniel Mandel, Shadi Yaghi, Phinnara Has, Mingxing Xie, Tao Wang, James Simmons, Christopher Song, Philip Haines

Faculty, Staff and Student Publications

Background/Objectives: Left ventricular diastolic dysfunction (LVDD) and elevated left ventricular filling pressure (LVFP) are strong predictors of clinical outcomes across various populations. However, their diagnostic utility in embolic stroke of undetermined source (ESUS) remains unclear. We hypothesized that LVDD with elevated LVFP (based on echocardiography) was more likely to be prevalent in ESUS compared to non-cardioembolic stroke (NCE) and to be associated with atrial fibrillation (AF) on follow-up monitoring.

Methods: This is a single-center retrospective study that included adult patients with a diagnosis of acute ischemic stroke between January 2016 and June 2017. LV function was assessed by …

When Less Is More: Sketching With Minimizers In Genomics, Malick Ndiaye, Silvia Prieto-Baños, Lucy M Fitzgerald, Ali Yazdizadeh Kharrazi, Sergey Oreshkov, Christophe Dessimoz, Fritz J Sedlazeck, Natasha Glover, Sina Majidian

Faculty, Staff and Students Publications

The exponential increase in sequencing data calls for conceptual and computational advances to extract useful biological insights. One such advance, minimizers, allows for reducing the quantity of data handled while maintaining some of its key properties. We provide a basic introduction to minimizers, cover recent methodological developments, and review the diverse applications of minimizers to analyze genomic data, including de novo genome assembly, metagenomics, read alignment, read correction, and pangenomes. We also touch on alternative data sketching techniques including universal hitting sets, syncmers, or strobemers. Minimizers and their alternatives have rapidly become indispensable tools for handling vast amounts of data.

Bi-Directional Allosteric Pathway In Nmda Receptor Activation And Modulation, Paula A Bender, Subhajit Chakraborty, Ryan J Durham, Vladimir Berka, Elisa Carrillo, Vasanthi Jayaraman

Faculty, Staff and Student Publications

N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors involved in learning and memory. NMDA receptors primarily comprise two GluN1 and two GluN2 subunits. The GluN2 subunit dictates biophysical receptor properties, including the extent of receptor activation and desensitization. GluN2A- and GluN2D-containing receptors represent two functional extremes. To uncover the conformational basis of their functional divergence, we utilize single-molecule fluorescence resonance energy transfer to probe the extracellular domains of these receptor subtypes under resting and ligand-bound conditions. We find that the conformational profile of the GluN2 amino-terminal domain correlates with the disparate functions of GluN2A- and GluN2D-containing receptors. Changes at the pre-transmembrane …

Stratomod: Predicting Sequencing And Variant Calling Errors With Interpretable Machine Learning, Nathan Dwarshuis, Peter Tonner, Nathan D Olson, Fritz J Sedlazeck, Justin Wagner, Justin M Zook

Faculty, Staff and Students Publications

Despite the variety in sequencing platforms, mappers, and variant callers, no single pipeline is optimal across the entire human genome. Therefore, developers, clinicians, and researchers need to make tradeoffs when designing pipelines for their application. Currently, assessing such tradeoffs relies on intuition about how a certain pipeline will perform in a given genomic context. We present StratoMod, which addresses this problem using an interpretable machine-learning classifier to predict germline variant calling errors in a data-driven manner. We show StratoMod can precisely predict recall using Hifi or Illumina and leverage StratoMod's interpretability to measure contributions from difficult-to-map and homopolymer regions for …

Sex Hormones And Risk Of Lung And Colorectal Cancers In Women: A Mendelian Randomization Study, Marion Denos, Yi-Qian Sun, Ben Michael Brumpton, Yafang Li, Demetrius Albanes, Andrea Burnett-Hartman, Peter T Campbell, Sébastien Küry, Christopher I Li, Emily White, Jewel N Samadder, Mark A Jenkins, Xiao-Mei Mai

Faculty, Staff and Students Publications

The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies on sex hormones and from the Trøndelag Health Study (HUNT) and large consortia on cancers. There was suggestive evidence of 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio 0.60, 95% confidence interval …

Genetic Knock-In Of Eif2ak3 Variants Reveals Differences In Perk Activity In Mouse Liver And Pancreas Under Endoplasmic Reticulum Stress, Shivesh Ghura, Noah R. Beratan, Xinglong Shi, Elena Alvarez-Periel, Sarah E. Bond Newton, Cagla Akay-Espinoza, Kelly L. Jordan-Sciutto

Farber Institute for Neuroscience Staff Papers and Presentations

Common single-nucleotide variants (SNVs) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) slightly increase the risk of disorders in the periphery and the central nervous system. EIF2AK3 encodes protein kinase RNA-like endoplasmic reticulum kinase (PERK), a key regulator of ER stress. Three exonic EIF2AK3 SNVs form the PERK-B haplotype, which is present in 28% of the global population. Importantly, the precise impact of these SNVs on PERK activity remains elusive. In this study, we demonstrate that PERK-B SNVs do not alter PERK expression or basal activity in vitro and in the novel triple knock-in mice expressing the exonic …

Mates: A Deep Learning-Based Model For Locus-Specific Quantification Of Transposable Elements In Single Cell, Ruohan Wang, Yumin Zheng, Zijian Zhang, Kailu Song, Erxi Wu, Xiaopeng Zhu, Tao P Wu, Jun Ding

Faculty, Staff and Students Publications

Transposable elements (TEs) are crucial for genetic diversity and gene regulation. Current single-cell quantification methods often align multi-mapping reads to either 'best-mapped' or 'random-mapped' locations and categorize them at the subfamily levels, overlooking the biological necessity for accurate, locus-specific TE quantification. Moreover, these existing methods are primarily designed for and focused on transcriptomics data, which restricts their adaptability to single-cell data of other modalities. To address these challenges, here we introduce MATES, a deep-learning approach that accurately allocates multi-mapping reads to specific loci of TEs, utilizing context from adjacent read alignments flanking the TE locus. When applied to diverse single-cell …

Multivariable Mendelian Randomization With Incomplete Measurements On The Exposure Variables In The Hispanic Community Health Study/Study Of Latinos, Yilun Li, Kin Yau Wong, Annie Green Howard, Penny Gordon-Larsen, Heather M Highland, Mariaelisa Graff, Kari E North, Carolina G Downie, Christy L Avery, Bing Yu, Kristin L Young, Victoria L Buchanan, Robert Kaplan, Lifang Hou, Brian Thomas Joyce, Qibin Qi, Tamar Sofer, Jee-Young Moon, Dan-Yu Lin

Faculty, Staff and Student Publications

Multivariable Mendelian randomization allows simultaneous estimation of direct causal effects of multiple exposure variables on an outcome. When the exposure variables of interest are quantitative omic features, obtaining complete data can be economically and technically challenging: the measurement cost is high, and the measurement devices may have inherent detection limits. In this paper, we propose a valid and efficient method to handle unmeasured and undetectable values of the exposure variables in a one-sample multivariable Mendelian randomization analysis with individual-level data. We estimate the direct causal effects with maximum likelihood estimation and develop an expectation-maximization algorithm to compute the estimators. We …

Impact Of Age On Pharmacogenomics And Treatment Outcomes Of B-Cell Acute Lymphoblastic Leukemia, Satoshi Yoshimura, Zhenhua Li, Yoshihiro Gocho, Wenjian Yang, Kristine R Crews, Shawn H R Lee, Kathryn G Roberts, Charles G Mullighan, Mary V Relling, Jiyang Yu, Allen E J Yeoh, Mignon L Loh, Caner Saygin, Mark R Litzow, Sima Jeha, Seth E Karol, Hiroto Inaba, Ching-Hon Pui, Marina Konopleva, Nitin Jain, Wendy Stock, Elisabeth Paietta, Elias Jabbour, Steven M Kornblau, William E Evans, Jun J Yang

Faculty, Staff and Student Publications

Purpose: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear.

Methods: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations …

Larp1 Haploinsufficiency Is Associated With An Autosomal Dominant Neurodevelopmental Disorder, James Chettle, Raymond J Louie, Olivia Larner, Robert Best, Kevin Chen, Josephine Morris, Zinaida Dedeic, Anna Childers, R Curtis Rogers, Barbara R Dupont, Cindy Skinner, Sébastien Küry, Kevin Uguen, Marc Planes, Danielle Monteil, Megan Li, Aviva Eliyahu, Lior Greenbaum, Nofar Mor, Thomas Besnard, Bertrand Isidor, Benjamin Cogné, Alyssa Blesson, Anne Comi, Ingrid M Wentzensen, Blake Vuocolo, Seema R Lalani, Roberta Sierra, Lori Berry, Kent Carter, Stephan J Sanders, Sarah P Blagden

Faculty, Staff and Students Publications

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and …

Phase I/Ii Study Of Bms-986156 With Ipilimumab Or Nivolumab With Or Without Stereotactic Ablative Radiotherapy In Patients With Advanced Solid Malignancies, Joe Y Chang, Xinyan Xu, Girish S Shroff, Nathan I Comeaux, Wei Li, Jordi Rodon Ahnert, Daniel D Karp, Ecaterina E Dumbrava, Vivek Verma, Aileen Chen, James Welsh, David S Hong

Faculty, Staff and Student Publications

Background: BMS-986156 is an agonist of the glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) and promotes increased effector T-cell activation. Combined anti-GITR, anti-programmed death-1, anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and radiotherapy improve tumor control in preclinical studies. Herein we describe the results of the safety and efficacy of BMS-986156+ipilimumab or nivolumab with/without stereotactic ablative radiotherapy (SABR) in patients with advanced solid cancers (NCT04021043).

Methods: This open-label, multigroup, single-center phase I/II study enrolled patients with histologically-confirmed stage IV solid cancers resistant to standard treatments. Group 1 (G1, n=20) received four cycles of ipilimumab (3 mg/kg) plus BMS-986156 (30 …

Single-Cell Somatic Copy Number Variants In Brain Using Different Amplification Methods And Reference Genomes, Ester Kalef-Ezra, Zeliha Gozde Turan, Diego Perez-Rodriguez, Ida Bomann, Sairam Behera, Caoimhe Morley, Sonja W Scholz, Zane Jaunmuktane, Jonas Demeulemeester, Fritz J Sedlazeck, Christos Proukakis

Faculty, Staff and Students Publications

The presence of somatic mutations, including copy number variants (CNVs), in the brain is well recognized. Comprehensive study requires single-cell whole genome amplification, with several methods available, prior to sequencing. Here we compare PicoPLEX with two recent adaptations of multiple displacement amplification (MDA): primary template-directed amplification (PTA) and droplet MDA, across 93 human brain cortical nuclei. We demonstrate different properties for each, with PTA providing the broadest amplification, PicoPLEX the most even, and distinct chimeric profiles. Furthermore, we perform CNV calling on two brains with multiple system atrophy and one control brain using different reference genomes. We find that 20.6% …

Development And Assessment Of A Point-Of-Care Application (Genomic Medicine Guidance) For Heritable Thoracic Aortic Disease, Rohan Patil, Fatima Ashraf, Samer Abu Dayeh, Siddharth K Prakash

Faculty, Staff and Student Publications

Background: Genetic testing can determine familial and personal risks for heritable thoracic aortic aneurysms and dissections (TAD). The 2022 American College of Cardiology/American Heart Association guidelines for TAD recommend management decisions based on the specific gene mutation. However, many clinicians lack sufficient comfort or insight to integrate genetic information into clinical practice.

Objective: We therefore developed the Genomic Medicine Guidance (GMG) application, an interactive point-of-care tool to inform clinicians and patients about TAD diagnosis, treatment, and surveillance. GMG is a REDCap-based application that combines publicly available genetic data and clinical recommendations based on the TAD guidelines into one translational education …

Flagellar Motility Is Mutagenic, Souvik Bhattacharyya, Shelby Lopez, Abhyudai Singh, Rasika M Harshey

Faculty, Staff and Student Publications

Flagella are highly complex rotary molecular machines that enable bacteria to not only migrate to optimal environments but also to promote range expansion, competitiveness, virulence, and antibiotic survival. Flagellar motility is an energy-demanding process, where the sum of its production (biosynthesis) and operation (rotation) costs has been estimated to total ~10% of the entire energy budget of an

Rapid Hyperspectral Photothermal Mid-Infrared Spectroscopic Imaging From Sparse Data For Gynecologic Cancer Tissue Subtyping, Reza Reihanisaransari, Chalapathi Charan Gajjela, Xinyu Wu, Ragib Ishrak, Sara Corvigno, Yanping Zhong, Jinsong Liu, Anil K Sood, David Mayerich, Sebastian Berisha, Rohith Reddy

Faculty, Staff and Student Publications

Ovarian cancer detection has traditionally relied on a multistep process that includes biopsy, tissue staining, and morphological analysis by experienced pathologists. While widely practiced, this conventional approach suffers from several drawbacks: it is qualitative, time-intensive, and heavily dependent on the quality of staining. Mid-infrared (MIR) hyperspectral photothermal imaging is a label-free, biochemically quantitative technology that, when combined with machine learning algorithms, can eliminate the need for staining and provide quantitative results comparable to traditional histology. However, this technology is slow. This work presents a novel approach to MIR photothermal imaging that enhances its speed by an order of magnitude. This …

Fast, Variable Stiffness-Induced Braided Coiled Artificial Muscles, Xinghao Hu, Xiangyu Wang, Jian Wang, Guorong Zhang, Shaoli Fang, Fengrui Zhang, Ye Xiao, Guanggui Cheng, Ray H Baughman, Jianning Ding

Faculty, Staff and Student Publications

Biomimetic actuation technologies with high muscle strokes, cycle rates, and work capacities are necessary for robotic systems. We present a muscle type that operates based on changes in muscle stiffness caused by volume expansion. This muscle is created by coiling a mechanically strong braid, in which an elastomer hollow tube is adhesively attached inside. We show that the muscle reversibly contracts by 47.3% when driven by an oscillating input air pressure of 120 kilopascals at 10 Hz. It generates a maximum power density of 3.0 W/g and demonstrates a mechanical contractile efficiency of 74%. The muscle's low-pressure operation allowed for …