Medicine and Health Sciences Commons^™

Leveraging Large Language Models For Knowledge-Free Weak Supervision In Clinical Natural Language Processing, Enshuo Hsu, Kirk Roberts

Faculty, Staff and Student Publications

The performance of deep learning-based natural language processing systems is based on large amounts of labeled training data which, in the clinical domain, are not easily available or affordable. Weak supervision and in-context learning offer partial solutions to this issue, particularly using large language models (LLMs), but their performance still trails traditional supervised methods with moderate amounts of gold-standard data. In particular, inferencing with LLMs is computationally heavy. We propose an approach leveraging fine-tuning LLMs and weak supervision with virtually no domain knowledge that still achieves consistently dominant performance. Using a prompt-based approach, the LLM is used to generate weakly-labeled …

A Phase I/Ii Trial Of Avelumab Combinations With Ivuxolimab, Utomilumab, And Radiation Therapy In Patients With Advanced Gastrointestinal Malignancies, Jibran Ahmed, Anne Knisely, Carlos Torrado, Bettzy Stephen, Yali Yang, Juhee Song, Anas Alshawa, Abdulrazzak Zarifa, Anuja Jhingran, Eugene J Koay, Van Karlyle Morris, Milind Javle, Robert A Wolff, Funda Meric-Bernstam, Shubham Pant, Jordi Rodon, Aung Naing

Faculty, Staff and Student Publications

Background: Checkpoint agonists utomilumab (4-1BB agonist) and ivuxolimab (OX40 agonist) enhance Teffector cell function. Preclinical studies suggest that combining these drugs with avelumab (anti-PD-L1 antibody) can potentially synergize this effect. In addition, tissue abscopal effects of radiation therapy may improve antigen presentation, complementing PD-L1 blockade. We conducted a single institution, open-label, multi-arm, non-randomized, phase 1/2 clinical trial of avelumab in combination with ivuxolimab, with or without utomilumab, and radiation therapy in patients with advanced solid tumors. Herein, we present a subgroup analysis in patients with gastrointestinal (GI) tumors (pancreatic, colon, gastric, and hepatocellular).

Methods: The primary objectives of this study …

Suppression Of Stress Granule Formation Is A Vulnerability Imposed By Mutant P53., Elizabeth A. Thoenen, Atul Ranjan, Alejandro Parrales, Shigeto Nishikawa, Dan A. Dixon, Sugako Oka, Tomoo Iwakuma

Manuscripts, Articles, Book Chapters and Other Papers

Missense mutations in the TP53 (p53) gene have been linked to malignant progression. However, our in-silico analyses reveal that hepatocellular carcinoma (HCC) patients with mutant p53 (mutp53) have better overall survival compared to those with p53-null (p53^null) HCC, unlike other cancer types. Given the historical use of sorafenib (SOR) monotherapy for advanced HCC, we hypothesize that mutp53 increases sensitivity to SOR, a multikinase inhibitor that induces endoplasmic reticulum (ER) stress. Here we show that mutp53 inhibits stress granule (SG) formation by binding to an ER stress sensor, PKR-like ER kinase (PERK), and a key SG component, GAP SH3 …

Incidence And Correlates Of High-Grade Chemotherapy-Induced Peripheral Neuropathy In Patients With Lung Cancer, Mitchell S Von Itzstein, Sawsan Rashdan, Suzanne E Dahlberg, David E Gerber, Alan B Sandler, Joan H Schiller, David H Johnson, Yating Wang, Zhuoxin Sun, Suresh S Ramalingam

Faculty, Staff and Student Publications

Background: High-grade chemotherapy-induced peripheral neuropathy (CIPN) represents a dreaded toxicity of cancer treatments. In some cases, it may limit activities of daily living and become permanent. Because many prior studies of CIPN were conducted in breast cancer populations, less is known about CIPN in men. We therefore determined the incidence and correlates of high-grade CIPN in a large cohort of patients with lung cancer.

Methods: We collected data from the ECOG-ACRIN E1594 (comparison of 4 chemotherapy regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, carboplatin-paclitaxel) and E4599 (carboplatin-paclitaxel ± concurrent and maintenance bevacizumab) clinical trials. We identified cases with grade ≥3 CIPN. Multivariable logistic …

Prophylaxis, Clinical Management, And Monitoring Of Datopotamab Deruxtecan-Associated Oral Mucositis/Stomatitis, Funda Meric-Bernstam, Aditya Bardia, Paolo Bossi, Giampaolo Bianchini, Frances Gatlin, Rajesh V Lalla, Barbara Melosky, Naoki Niikura, Timothy A Yap, Sophie S Kim, Rachana Rajagopalan, Rick M Fairhurst, Stephanie L Graff, Hope S Rugo

Faculty, Staff and Student Publications

Oral mucositis/stomatitis (hereafter stomatitis) is a common dose-limiting toxicity seen with various classes of cancer treatment. Symptoms associated with stomatitis, primarily oral pain, may impact patient quality of life and may lead to dose delay and reduction or treatment discontinuation. Datopotamab deruxtecan (Dato-DXd) is a novel trophoblast cell surface antigen 2-directed antibody-drug conjugate undergoing clinical investigation in multiple solid tumor types. Stomatitis is among the most reported adverse events associated with Dato-DXd, with most cases being grades 1-2. This article reviews the incidence of stomatitis seen with Dato-DXd, including in the phase III pivotal studies TROPION-Lung01 and TROPION-Breast01 (in patients …

Augmented Expression Of Superoxide Dismutase 2 Mitigates Progression And Rupture Of Experimental Abdominal Aortic Aneurysm, Huimin Yan, Ying Hu, Yang Lyu, Antonina Akk, Angela C Hirbe, Samuel A Wickline, Hua Pan, Elisha D O Roberson, Christine T N Pham

2020-Current year OA Pubs

No abstract provided.

Apobec3a Drives Ovarian Cancer Metastasis By Altering Epithelial-Mesenchymal Transition, Jessica M. Devenport, Thi Tran, Brooke R. Harris, Dylan Fingerman, Rachel A. Deweerd, Lojain H. Elkhidir, Danielle Lavigne, Katherine Fuh, Lulu Sun, Jeffrey J. Bednarski, Ronny Drapkin, Mary M. Mullen, Abby M. Green

2020-Current year OA Pubs

High-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive histological subtype of ovarian cancer and often presents with metastatic disease. The drivers of metastasis in HGSOC remain enigmatic. APOBEC3A (A3A), an enzyme that generates mutations across various cancers, has been proposed as a mediator of tumor heterogeneity and disease progression. However, the role of A3A in HGSOC has not been explored. We observed an association between high levels of APOBEC3-mediated mutagenesis and poor overall survival in primary HGSOC. We experimentally addressed this correlation by modeling A3A expression in HGSOC, and this resulted in increased metastatic behavior of HGSOC …

Multi-Ancestry Transcriptome-Wide Association Studies Of Cognitive Function, White Matter Hyperintensity, And Alzheimer's Disease, Dima L Chaar, Zheng Li, Lulu Shang, Scott M Ratliff, Thomas H Mosley, Sharon L R Kardia, Wei Zhao, Xiang Zhou, Jennifer A Smith

Faculty, Staff and Student Publications

Genetic variants increase the risk of neurocognitive disorders in later life, including vascular dementia (VaD) and Alzheimer's disease (AD), but the precise relationships between genetic risk factors and underlying disease etiologies are not well understood. Transcriptome-wide association studies (TWASs) can be leveraged to better characterize the genes and biological pathways underlying genetic influences on disease. To date, almost all existing TWASs on VaD and AD have been conducted using expression studies from individuals of a single genetic ancestry, primarily European. Using the joint likelihood-based inference framework in Multi-ancEstry TRanscriptOme-wide analysis (METRO), we leveraged gene expression data from European ancestry (EA) …

Meta-Analysis On Sex Differences In Mortality And Neurodevelopment In Congenital Heart Defects, Alyssa K Crain, Zhia N Lim, Chloe J Sarfatis, Magela Arias, Travis Holder, Alvaro G Moreira, Antonio F Corno, Tina O Findley

Faculty, Staff and Student Publications

Given the increasing survival rates among congenital heart disease (CHD) patients and the growing emphasis on their quality of life, there is a need to comprehensively assess the impact of surgical interventions on neurodevelopmental outcomes. With increasing awareness in sex-related disparities in CHD, there is a need to explore potential differences in surgical mortality and neurodevelopmental outcomes between male and female patients. In this systematic review, we adhered to PRISMA guidelines and PROSPERO registration (#CRD42021225610). Articles published from 2015 to 2021 were searched using MeSH descriptors in three major databases (MEDLINE Ovid, Elsevier Embase, and Cochrane Library). Study selection criteria …

Gatad2b O-Glcnacylation Regulates Breast Cancer Stem-Like Potential And Drug Resistance, Giang Le Minh, Jessica Merzy, Emily Esquea, Nusaiba Ahmed, Riley Young, Ryan Sharp, Tejsi Dhameliya, Bernice Agana, Mi-Hye Lee, Jennifer Bethard, Susana Comte-Walters, Lauren Ball, Mauricio Reginato

Kimmel Cancer Center Faculty Papers

The growth of breast tumors is driven and controlled by a subpopulation of cancer cells resembling adult stem cells, which are called cancer stem-like cells (CSCs). In breast cancer, the function and maintenance of CSCs are influenced by protein O-GlcNAcylation and the enzyme responsible for this post-translational modification, O-GlcNAc transferase (OGT). However, the mechanism of CSCs regulation by OGT and O-GlcNAc cycling in breast cancer is still unclear. Analysis of the proteome and O-GlcNAcome, revealed GATAD2B, a component of the Nucleosome Remodeling and Deacetylase (NuRD) complex, as a substrate regulated by OGT. Reducing GATAD2B genetically impairs mammosphere formation, decreases expression …

Condensed Low-Dose Total Skin Electron Beam Therapy For Mycosis Fungoides: An Institutional Retrospective Review And Subgroup Analysis Of Patients With Large Cell Transformation, Louis Cappelli, Megan Cappelli, Nilanjan Haldar, Tiara Paul, Jenna Mandel, Tingting Zhan, Neda Nikbakht, Wenyin Shi

Department of Dermatology and Cutaneous Biology Faculty Papers

Low-dose total skin electron beam therapy (TSEBT) is an effective treatment option for mycosis fungoides (MF) with proven palliative effects and reduced toxicity. Presented is an institutional analysis of survival/response rate and quality of life for MF patients with subgroup analysis of those possessing pathologic large cell transformation (LCT). This is a single institutional retrospective review of patients with mycosis fungicides treated from 2014 to 2023 with low-dose TSEBT. All patients received 12 Gy in 6 fractions every other day with the modified Stanford technique, with boosts to shadowed sites between treatments, completed in 2 weeks. Outcomes evaluated included clinical …

Molecular Model Of Tfiih Recruitment To The Transcription-Coupled Repair Machinery, Tanmoy Paul, Chunli Yan, Jina Yu, Susan E Tsutakawa, John A Tainer, Dong Wang, Ivaylo Ivanov

Faculty, Staff and Student Publications

Transcription-coupled repair (TCR) is a vital nucleotide excision repair sub-pathway that removes DNA lesions from actively transcribed DNA strands. Binding of CSB to lesion-stalled RNA Polymerase II (Pol II) initiates TCR by triggering the recruitment of downstream repair factors. Yet it remains unknown how transcription factor IIH (TFIIH) is recruited to the intact TCR complex. Combining existing structural data with AlphaFold predictions, we build an integrative model of the initial TFIIH-bound TCR complex. We show how TFIIH can be first recruited in an open repair-inhibited conformation, which requires subsequent CAK module removal and conformational closure to process damaged DNA. In …

Kir7.1 Is The Physiological Target For Hormones And Steroids That Regulate Uteroplacental Function, Monika Haoui, Citlalli Vergara, Lina Kenzler, Jerome Schröer, Geraldine Zimmer-Bensch, David Fleck, Christopher Wiesbrock, Marc Spehr, Polina V Lishko

2020-Current year OA Pubs

Preterm birth is detrimental to the well-being of both the mother and the newborn. During normal gestation, the myometrium is maintained in a quiescent state by progesterone. As a steroid hormone, progesterone is thought to modify uterine and placental morphology by altering gene expression, but another direct mode of action has long been suspected. Here, we reveal the nongenomic molecular mechanism of progesterone as the activation of human and murine inwardly rectifying potassium channel Kir7.1, which is expressed in myometrium and placental pericytes during late gestation. Kir7.1 is also activated by selective steroids, including those used to prevent premature labor, …

Predictors Of Perioperative Stroke In Patients With Ischemic-Type Moyamoya Disease Treated With Surgical Revascularization: A Retrospective Multicenter Study, Basel Musmar, Joanna M. Roy, Hammam Abdalrazeq, Elias Atallah, Kareem El Naamani, Ching-Jen Chen, Roland Jabre, Hassan Saad, Jonathan A. Grossberg, Adam A. Dmytriw, Aman B. Patel, Mirhojjat Khorasanizadeh, Christopher S. Ogilvy, Ajith J. Thomas, Andre Monteiro, Adnan Siddiqui, Gustavo M. Cortez, Ricardo A. Hanel, Guilherme Porto, Alejandro M. Spiotta, Anthony J. Piscopo, David M. Hasan, Mohammad Ghorbani, Joshua Weinberg, Shahid M. Nimjee, Kimon Bekelis, Mohamed M. Salem, Jan-Karl Burkhardt, Akli Zetchi, Charles Matouk, Brian M. Howard, Rosalind Lai, Rose Du, Rawad Abbas, Georgios S Sioutas, Abdelaziz Amllay, Alfredo Munoz, Nabeel A Herial, Stavropoula I Tjoumakaris, Michael Reid Gooch, Robert H Rosenwasser, Pascal Jabbour

Department of Neurosurgery Faculty Papers

INTRODUCTION: Moyamoya disease (MMD) is a chronic cerebrovascular disorder characterized by progressive stenosis or occlusion of the internal carotid arteries and the development of collateral moyamoya vessels. Surgical revascularization is commonly used to prevent future ischemic events in ischemic-type MMD, but there remains a high rate of stroke perioperatively. This study aims to analyze the predictive factors for perioperative stroke in patients with ischemic-type MMD undergoing surgical revascularization using a large multicenter database.

METHODS: We conducted a multicenter retrospective study in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. This study included patients with ischemic-type …

Consensus Recommendations For An Integrated Diagnostic Approach To Peripheral Nerve Sheath Tumors Arising In The Setting Of Neurofibromatosis Type 1, Calixto-Hope G Lucas, Andrea M Gross, Carlos G Romo, Carina A Dehner, Alexander J Lazar, Markku Miettinen, Melike Pekmezci, Martha Quezado, Fausto J Rodriguez, Anat Stemmer-Rachamimov, David Viskochil, Arie Perry

Faculty, Staff and Student Publications

Consensus recommendations published in 2017 histologically defining atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) and malignant peripheral nerve sheath tumor (MPNST) were codified in the 2021 WHO Classification of Tumors of the Central Nervous System and the 2022 WHO Classification of Tumors of Soft Tissue and Bone. However, given the shift in diagnostic pathology toward the use of integrated histopathologic and genomic approaches, the incorporation of additional molecular strata in the classification of Neurofibromatosis Type 1 (NF1)-associated peripheral nerve sheath tumors should be formalized to aid in accurate diagnosis and early identification of malignant transformation and enable appropriate intervention …

Immunotherapy-Related Neurotoxicity In The Central Nervous System Of Children With Cancer, Jiasen He, Jeremy Connors, Andrew Meador, Shuo Xu, Heather Meador, Hong Jiang, Juan Fueyo, Candelaria Gomez-Manzano, Gregory K Friedman, Wafik Zaky, Zsila Sadighi, John M Slopis, Ali H Ahmad

Faculty, Staff and Student Publications

Significant gaps remain in our understanding of immunotherapy-related neurotoxicity in pediatric patients, largely because much of our knowledge comes from studies in adults. Accurately identifying the adverse effects of immunotherapy in children is also challenging, owing to variations in terminology and grading systems. Moreover, the manifestation of immunotherapy-related neurotoxicity differs greatly across different diseases, various modalities, dosages, and delivery methods. Combining immunotherapy with other treatments might improve outcomes but introduces new complexities and potential for increased toxicities. Additionally, pediatric patients with intracranial malignancy have unique responses to immunotherapies and distinct neurotoxicity compared to those with extracranial malignancy. Consequently, we must …

Cryptic Kmt2a::Afdn Fusion Due To Afdn Insertion Into Kmt2a In A Patient With Acute Monoblastic Leukemia, Qing Wei, Gokce A Toruner, Beenu Thakral, Keyur P Patel, Naveen Pemmaraju, Sa A Wang, Rashmi Kanagal-Shamanna, Guilin Tang, Ghayas C Issa, Sanam Loghavi, L Jeffrey Medeiros, Courtney Dinardo

Faculty, Staff and Student Publications

Background: KMT2A rearrangements occur in ~10% of acute myeloid leukemia (AML) cases and are critical for classification, risk stratification, and use of targeted therapy. However, insertions involving the KMT2A gene can evade detection using chromosomal analysis and/or fluorescence in situ hybridization (FISH).

Methods: We present a case of a 22-year-old woman with acute monoblastic leukemia harboring a cryptic KMT2A::AFDN fusion identified by RNA sequencing. Initial FISH showed a 3' KMT2A deletion, while conventional karyotyping and the automated bioinformatic pipeline for optical genome mapping (OGM) did not identify the canonical translocation.

Results: To resolve these discrepancies, metaphase KMT2A FISH (break-apart fusion …

Cryptic Kmt2a::Afdn Fusion Due To Afdn Insertion Into Kmt2a In A Patient With Acute Monoblastic Leukemia, Qing Wei, Gokce A Toruner, Beenu Thakral, Keyur P Patel, Naveen Pemmaraju, Sa A Wang, Rashmi Kanagal-Shamanna, Guilin Tang, Ghayas C Issa, Sanam Loghavi, L Jeffrey Medeiros, Courtney Dinardo

Faculty, Staff and Student Publications

Background: KMT2A rearrangements occur in ~10% of acute myeloid leukemia (AML) cases and are critical for classification, risk stratification, and use of targeted therapy. However, insertions involving the KMT2A gene can evade detection using chromosomal analysis and/or fluorescence in situ hybridization (FISH).

Methods: We present a case of a 22-year-old woman with acute monoblastic leukemia harboring a cryptic KMT2A::AFDN fusion identified by RNA sequencing. Initial FISH showed a 3' KMT2A deletion, while conventional karyotyping and the automated bioinformatic pipeline for optical genome mapping (OGM) did not identify the canonical translocation.

Results: To resolve these discrepancies, metaphase KMT2A FISH (break-apart fusion …

Clinical And Genetic Markers Of Vascular Toxicity In Glioblastoma Patients: Insights From Nrg Oncology Rtog-0825, Joshua D Strauss, Mark R Gilbert, Minesh Mehta, Ang Li, Renke Zhou, Melissa L Bondy, Erik P Sulman, Ying Yuan, Yanhong Liu, Elizabeth Vera, Merideth M Wendland, Volker W Stieber, Vinay K Puduvalli, Serah Choi, Nina L Martinez, H Ian Robins, Grant K Hunter, Chi-Fan Lin, Vivian A Guedes, Melissa A Richard, Stephanie L Pugh, Terri S Armstrong, Michael E Scheurer

Faculty, Staff and Students Publications

Background: Glioblastoma (GBM) is an aggressive form of brain cancer in which treatment is associated with toxicities that can result in therapy discontinuation or death. This analysis investigated clinical and genetic markers of vascular toxicities in GBM patients during active treatment.

Methods: In total, 591 non-Hispanic White GBM patients with clinical data were included in the analysis from NRG RTOG-0825. Genome-wide association studies (GWAS) were performed from genotyped blood samples (N = 367) by occurrence of thrombosis or hypertension (grade ≥ 2). A clinical prediction model was produced for each vascular toxicity. Significant GWAS variants were then added to the …

Investigating The Impact Of Electroconvulsive Therapy On Brain Networks And Sleep: An Observational Study Protocol, Mohammadmehdi Kafashan, Lucas Lebovitz, Robby Greenspan, Sijia Zhao, Tae Kim, Masud Husain, Tamara Hershey, Pilar Cristancho, R Edward Hogan, Ben Julian Agustin Palanca, Nuri B Farber, Dns-Ect Study Team

2020-Current year OA Pubs

INTRODUCTION: Electroconvulsive therapy (ECT) is a highly effective treatment for refractory depression, but it may also cause cognitive side effects. Despite decades of use, the mechanisms by which ECT exerts both its antidepressant and cognitive effects are still poorly understood, with the latter substantially limiting referral and adherence to therapy. ECT induces changes in correlated neural activity-functional connectivity-across various brain networks, which may underlie both its clinical efficacy and associated cognitive side effects. Electroencephalography (EEG) could address these knowledge gaps by identifying biomarkers that predict therapeutic outcomes or cognitive side effects. Such developments could ultimately improve patient selection and adherence. …

Orthopedic Frailty Risk Stratification (Ofrs): A Systematic Review Of The Frailty Indices Predicting Adverse Outcomes In Orthopedics., Nithin K Gupta, Forrest Dunivin, Hikmat R Chmait, Chase Smitterberg, Azhaan Buttar, Moiz Fazal-Ur-Rehman, Taylor Manes, Morgan Turnow, Tyler K Williamson, Benjamin C Taylor, Jack W Weick, Christian Bowers

Surgery Articles

BACKGROUND: With a growing number of elderly patients requiring elective and non-elective procedures, frailty-based preoperative risk stratification is an emerging tool in orthopedic surgery to minimize adverse postoperative outcomes. This paper sought to understand the current literature regarding preoperative Orthopedic Frailty Risk Stratification (OFRS) and describe the disparate frailty indices and their capabilities for discrimination in predicting adverse postoperative outcomes.

METHODS: A literature search was conducted in Pubmed, Cochrane, and Scopus for articles published during or prior to February 2024 assessing frailty following surgery for orthopedic pathologies. Qualitative variables including study characteristics and application of frailty were collected and synthesized. …

Emerging Domains For Measuring Health Care Delivery With Electronic Health Record Metadata, Daniel Tawfik, Sunny S Lou, Et Al.

2020-Current year OA Pubs

This article aims to introduce emerging measurement domains made feasible through the electronic health record (EHR) use metadata, to inform the changing landscape of health care delivery. We reviewed emerging domains in which EHR metadata may be used to measure health care delivery, outlining a framework for evaluating measures based on desirability, feasibility, and viability. We argue that EHR use metadata may be leveraged to develop and operationalize novel measures in the domains of team structure and dynamics, workflows, and cognitive environment to provide a clearer understanding of modern health care delivery. Examples of measures feasible using metadata include quantification …

Oncology Provider And Patient Perspectives On A Cardiovascular Health Assessment Tool Used During Posttreatment Survivorship Care In Community Oncology (Results From Wf-1804cd): Mixed Methods Observational Study, Chandylen L Nightingale, Maura Kepper, Randi E Foraker, Et Al.

2020-Current year OA Pubs

BACKGROUND: Most survivors of cancer have multiple cardiovascular risk factors, increasing their risk of poor cardiovascular and cancer outcomes. The Automated Heart-Health Assessment (AH-HA) tool is a novel electronic health record clinical decision support tool based on the American Heart Association's Life's Simple 7 cardiovascular health metrics to promote cardiovascular health assessment and discussion in outpatient oncology. Before proceeding to future implementation trials, it is critical to establish the acceptability of the tool among providers and survivors.

OBJECTIVE: This study aims to assess provider and survivor acceptability of the AH-HA tool and provider training at practices randomized to the AH-HA …

Roles Of Mir-223 In Platelet Function And High On-Treatment Platelet Reactivity: A Brief Report And Review, Shayan Askari, Lawrence E. Goldfinger

Cardeza Foundation for Hematologic Research

BACKGROUND: Platelets are highly enriched in microRNAs (miRNAs), which are genomically encoded 19-25 nucleotide non-coding RNAs that target complementary mRNAs through total or near-total base pairing. MiR-223 is among the most abundant miRNAs in human and murine platelets, but despite ongoing investigations in recent years, miR-223 roles in platelet physiology and its putative roles in high on-treatment platelet reactivity (HTPR) remain controversial, as studies showed varying findings.

OBJECTIVES: In the current hybrid review/report, we aim to compare studies that investigated miR-223 in platelet function and HTPR. Additionally, we briefly report our own findings on murine miR-223-deficient platelets.

METHODS: We have …

Structure-Function Relationship Of Ash1l And Histone H3k36 And H3k4 Methylation, Kendra R Vann, Rajal Sharma, Chih-Chao Hsu, Maeva Devoucoux, Adam H Tencer, Lei Zeng, Kevin Lin, Li Zhu, Qin Li, Catherine Lachance, Ruben Rosas Ospina, Qiong Tong, Ka Lung Cheung, Shuai Yang, Soumi Biswas, Hongwen Xuan, Jovylyn Gatchalian, Lorena Alamillo, Jianlong Wang, Suk Min Jang, Brianna J Klein, Yue Lu, Patricia Ernst, Brian D Strahl, Scott B Rothbart, Martin J Walsh, Michael L Cleary, Jacques Côté, Xiaobing Shi, Ming-Ming Zhou, Tatiana G Kutateladze

Faculty, Staff and Student Publications

The histone H3K36-specific methyltransferase ASH1L plays a critical role in development and is frequently dysregulated in human diseases, particularly cancer. Here, we report on the biological functions of the C-terminal region of ASH1L encompassing a bromodomain (ASH1LBD), a plant homeodomain (ASH1LPHD) finger, and a bromo-adjacent homology (ASH1LBAH) domain, structurally characterize these domains, describe their mechanisms of action, and explore functional crosstalk between them. We find that ASH1LPHD recognizes H3K4me2/3, whereas the neighboring ASH1LBD and ASH1LBAH have DNA binding activities. The DNA binding function of ASH1LBAH is a driving force for the association of ASH1L with the linker DNA in the …

Identification Of Genes Associated With Testicular Germ Cell Tumor Susceptibility Through A Transcriptome-Wide Association Study, Emilio Ugalde-Morales, Rona Wilf, John Pluta, Alexander Ploner, Mengyao Fan, Mohammad Damra, Katja K Aben, Lynn Anson-Cartwright, Chu Chen, Victoria K Cortessis, Siamak Daneshmand, Alberto Ferlin, Marija Gamulin, Jourik A Gietema, Anna Gonzalez-Niera, Tom Grotmol, Robert J Hamilton, Mark Harland, Trine B Haugen, Russ Hauser, Michelle A T Hildebrandt, Robert Karlsson, Lambertus A Kiemeney, Jung Kim, Davor Lessel, Ragnhild A Lothe, Chey Loveday, Stephen J Chanock, Katherine A Mcglynn, Coby Meijer, Kevin T Nead, Jeremie Nsengimana, Maja Popovic, Thorunn Rafnar, Lorenzo Richiardi, Maria S Rocca, Stephen M Schwartz, Rolf I Skotheim, Kari Stefansson, Douglas R Stewart, Clare Turnbull, David J Vaughn, Sofia B Winge, Tongzhang Zheng, Alvaro N Monteiro, Kristian Almstrup, Peter A Kanetsky, Katherine L Nathanson, Fredrik Wiklund, Testicular Cancer Consortium

Faculty, Staff and Student Publications

Transcriptome-wide association studies (TWASs) have the potential to identify susceptibility genes associated with testicular germ cell tumors (TGCTs). We conducted a comprehensive TGCT TWAS by integrating genome-wide association study (GWAS) summary data with predicted expression models from normal testis, TGCT tissues, and a cross-tissue panel that encompasses shared regulatory features across 22 normal tissues, including the testis. Gene associations were evaluated while accounting for variant-level effects from GWASs, followed by fine-mapping analyses in regions exhibiting multiple TWAS signals, and finally supplemented by colocalization analysis. Expression and protein patterns of identified TWAS genes were further examined in relevant tissues. Our analysis …

Pspc1 Exerts An Oncogenic Role In Aml By Regulating A Leukemic Transcription Program In Cooperation With Pu1, Juyeong Hong, Pinpin Sui, Ying Li, Kerryn Y Xu, Ji-Hoon Lee, Juan Wang, Shi Chen, Peng Zhang, Noah Wingate, Asra Noor, Yaxia Yuan, Robert Hromas, Hongwei Zhou, Karina Hamamoto, Rui Su, C Cameron Yin, Fengxi Ye, Andrés E Quesada, Jianjun Chen, Suming Huang, Daohong Zhou, M James You, Feng-Chun Yang, Jianlong Wang, Mingjiang Xu

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy characterized by the blockage of myeloid cell differentiation and uncontrolled proliferation of immature myeloid cells. Here, we show that paraspeckle component 1 (PSPC1) is aberrantly overexpressed and associated with poor survival in AML patients. Using human AML cells and mouse models, we demonstrate that PSPC1 is not required for normal hematopoiesis, but it is critical and essential for AML cells to maintain their leukemic characteristics. PSPC1 loss induces robust differentiation, suppresses proliferation, and abolishes leukemogenesis in diverse AML cells. Mechanistically, PSPC1 exerts a pro-leukemia effect by regulating a unique leukemic transcription …

Lasalocid A Selectively Induces The Degradation Of Myd88 In Lymphomas Harboring The Myd88 L265p Mutation, Wei Li, Ruirui Wang, Junhao Wang, Dafei Chai, Xiaohui Xie, Ken H Young, Ya Cao, Yong Li, Xinfang Yu

Faculty, Staff and Students Publications

Myeloid differentiation primary response protein 88 (MYD88) is a key adaptor molecule in the signaling pathways of toll-like receptor and interleukin-1 receptor. A somatic mutation resulting in a leucine-to-proline change at position 265 of the MYD88 protein (MYD88 L265P) is one of the most prevalent oncogenic mutations found in patients with hematological malignancies. In this study, we used high-throughput screening to identify lasalocid A as a potent small molecule that selectively inhibited the viability of lymphoma cells expressing MYD88 L265P and the associated activation of NF-κB. Further investigations using CRISPR-CRISPR-associated protein 9 genetic screening, proteomics, and biochemical assays revealed that …

2024 Lifetime Achievement Award: Biology Unbalanced: Genes, Gene Dosage, And Disease Susceptibility, James R Lupski

Faculty, Staff and Students Publications

This article is based on the address given by the author at the 2024 meeting of The American Society of Human Genetics (ASHG) in Denver, CO. A video of the original address can be found at the ASHG website.

Sequence Variants In Hectd1 Result In A Variable Neurodevelopmental Disorder, Gazelle Zerafati-Jahromi, Elias Oxman, Hieu D Hoang, Wu-Lin Charng, Tanvitha Kotla, Weimin Yuan, Keito Ishibashi, Sonia Sebaoui, Kathryn Luedtke, Bryce Winrow, Rebecca D Ganetzky, Anna Ruiz, Carmen Manso-Basúz, Nino Spataro, Peter Kannu, Taryn Athey, Christina Peroutka, Caitlin Barnes, Richard Sidlow, George Anadiotis, Kari Magnussen, Irene Valenzuela, Alejandro Moles-Fernandez, Seth Berger, Christina L Grant, Eric Vilain, Gudny A Arnadottir, Patrick Sulem, Telma S Sulem, Kari Stefansson, Shavonne Massey, Natalie Ginn, Annapurna Poduri, Alissa M D'Gama, Rozalia Valentine, Sara K Trowbridge, Chaya N Murali, Rachel Franciskovich, Yen Tran, Bryn D Webb, Kim M Keppler-Noreuil, April L Hall, Bobbi Mcgivern, Kristin G Monaghan, Maria J Guillen Sacoto, Dustin Baldridge, Gary A Silverman, Sonika Dahiya, Tychele N Turner, Tim Schedl, Joshua G Corbin, Stephen C Pak, Irene E Zohn, Christina A Gurnett

Faculty, Staff and Students Publications

Dysregulation of genes encoding the homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases has been linked to cancer and structural birth defects. One member of this family, the HECT-domain-containing protein 1 (HECTD1), mediates developmental pathways, including cell signaling, gene expression, and embryogenesis. Through GeneMatcher, we identified 14 unrelated individuals with 15 different variants in HECTD1 (10 missense, 3 frameshift, 1 nonsense, and 1 splicing variant) with neurodevelopmental disorders (NDDs), including autism, attention-deficit/hyperactivity disorder, and epilepsy. Of these 15 HECTD1 variants, 10 occurred de novo, 3 had unknown inheritance, and 2 were compound heterozygous. While all individuals in this cohort displayed …