Medical Genetics Commons^™

Defining A Quantitative Threshold For Adaptive Re-Planning Using A Percentile-Based Scoring System, Alexandra O Leone, Christine B Peterson, Anna Lee, Adam S Garden, G Brandon Gunn, Lauren L Mayo, Amy C Moreno, Steven J Frank, C David Fuller, Jay P Reddy, Karen Hoffman, Ivan Vazquez, Ming Yang, Joshua S Niedzielski, Laurence E Court, Thomas J Whitaker

Faculty, Staff and Student Publications

Background: Despite the frequent need for adaptive planning in head and neck proton therapy, no quantitative indicators have been identified to determine when a plan should be adapted. Here, we aimed to determine a quantitative threshold for the change in plan quality between the primary treatment plan and verification plans that correlates with the physician's decision to adapt.

Methods: Primary treatment and verification plans were extracted from the clinical treatment planning system for 167 patients who underwent intensity-modulated proton therapy for base of tongue, tonsillar, or oropharyngeal cancers, with and without nodal involvement, between 2016 and 2021. All plans were …

Clemastine Ameliorates Cognitive Deficits In An Experimental Rat Model Of Chronic Cerebral Hypoperfusion, Xuemei Zong, Zhihai Huang, Fanfei Kong, Yu Feng, Yulan Zhang, Peibin Zou, Hung Wen Lin, David C Hess, Quanguang Zhang

Faculty, Staff and Student Publications

Chronic cerebral hypoperfusion (CCH) profoundly affects patient well-being and has been proposed as a risk factor for cognitive impairment and dementia. However, due to the limited understanding of the pathophysiology of CCH, there are currently no effective preventive or therapeutic approaches for CCH-associated cognitive impairment. Therefore, identifying new targets for CCH is essential to bridge this knowledge gap. In this study, we sought to determine whether enhanced myelination could prevent cognitive impairment associated with CCH. Experimental CCH was induced via bilateral common carotid artery occlusion (BCCAO) in rats, and clemastine, a well-established pro-myelinating agent, was administered to boost myelin renewal. …

Shiny-Magec: A Bayesian R Shiny Application For Meta-Analysis Of Censored Adverse Events, Zihan Zhou, Zizhong Tian, Christine Peterson, Le Bao, Shouhao Zhou

Faculty, Staff and Student Publications

Accurate assessment of adverse event (AE) incidence is critical in clinical research for drug safety. While meta-analysis serves as an essential tool to comprehensively synthesize the evidence across multiple studies, incomplete AE reporting in clinical trials remains a persistent challenge. In particular, AEs occurring below study-specific reporting thresholds are often omitted from publications, leading to left-censored data. Failure to account for these censored AE counts can result in biased AE incidence estimates. We present an R Shiny application that implements a Bayesian meta-analysis model specifically designed to incorporate censored AE data into the estimation process. This interactive tool provides a …

Barriers To Occupational And Physical Therapy Utilization For Children With Cancer, Maria C Swartz, Shiming Zhang, Donna Kelly, Clark R Andersen, Keri Schadler, Alakh P Rajan, Eduardo Gonzalez Villarreal, Stephanie J Wells, Amy Heaton, Karen Moody

Faculty, Staff and Student Publications

Introduction: Occupational and physical therapy (OT/PT) referrals and utilization barriers for childhood cancer patients have not been adequately examined. The current study investigated factors influencing referrals to and utilization of OT/PT services among children with cancer at an NIH-designated cancer center.

Methods: This retrospective cohort study included pediatric cancer patients (up to 18.99 years) presenting to the center over a 33.5-month period. Variables that could influence referrals to OT/PT were extracted from the electronic medical record (EMR) including OT and PT referrals (inpatient and outpatient), OT and PT consult completion, age at diagnosis, cancer type, sex, race/ethnicity, insurance, cancer treatment, …

Selective Deletion Of Fgfr1 In Agrp Neurons Impairs Energy Homeostasis Under High-Fat Diet In Mice, Daniel Shookster, Shea O'Connell, Patel Darshan, Taylor Landry, Wyatt Bunner, Zhiying Jiang, Qingchun Tong, Hu Huang

Faculty, Staff and Student Publications

Background: The global obesity crisis and the limited success of current treatments underscore the need to identify novel regulatory pathways. While central administration of α-Klotho exerts anti-obesity effects in rodents through AgRP neurons, the intracellular signaling mechanisms that mediate this process remain undefined.

Methods: To define the role of FGFR1 within the α-Klotho signaling pathway in AgRP neurons, we performed a targeted deletion of the receptor in adult mice using an AAV-mediated CRISPR/Cas9 system alongside transgenic models.

Results: Deletion of FGFR1 in AgRP neurons disrupted energy homeostasis, promoting weight gain induced by a high-fat diet. Electrophysiological recordings revealed that FGFR1 …

Clinicopathologic And Molecular Characteristics Of High-Grade Appendiceal Mucinous Neoplasms, Ashlee N Seldomridge, Michael G White, Christopher Scally, Richard E Royal, Mark Routbort, Jbryan Iorgulescu, Michael J Overman, Sun Mi Lee, Wai Chin Foo, Melissa W Taggart, Yun Song, Paul F Mansfield, Keith F Fournier, John Paul Shen, Beth A Helmink

Faculty, Staff and Student Publications

Background: Although 2016 consensus guidelines defined high-grade appendiceal mucinous neoplasms (HAMNs) as a distinct histologic entity, their clinical course and optimal management remain poorly characterized. Comparative data with low-grade appendiceal mucinous neoplasms (LAMNs) are limited. This study aims to detail the clinical management and outcomes of patients with HAMN and those with LAMN.

Methods: This retrospective cohort study was conducted at a large academic cancer center. An internal database was queried to identify patients with LAMN or HAMN who underwent appendectomy between 2016 and 2024. Kaplan-Meier survival analyses were used to assess the impact of primary tumor type and peritoneal …

Optimizing Feasibility And Acceptability Of An Online Expressive Writing Intervention For Survivors Of Adolescent And Young Adult Cancer: A Pilot Randomized Trial Of Iterative Modifications And Outcomes, Eunju Choi, Yusi Aveva Xu, Celia Cy Wong-Meli, Michael E Roth, Yisheng Li, Qian Lu

Faculty, Staff and Student Publications

Objective: To evaluate the feasibility of an online expressive writing (EW) intervention for survivors of adolescent and young adult (AYA) cancer and determine whether iterative, theory-driven modifications can enhance response, adherence, and completion rates.

Methods: In this randomized pilot trial, survivors of AYA cancer were recruited through a hospital-based AYA oncology clinic and an online community. Forty participants were randomly assigned to the EW intervention or control group. To improve on lower-than-expected adherence and completion rates in a previous cohort, the protocol was iteratively revised using the Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies (FRAME-IS). Modifications included …

A Comprehensive Biomechanical Material Characterization Of The Human Breast Fibro-Structural Support System, Aroj Bhattarai, Gregory P Reece, Kristy K Brock, Krishnaswamy Ravi-Chandar

Faculty, Staff and Student Publications

Breast surgery for aesthetic purposes, such as breast augmentation or breast reduction, and breast reconstruction after cancer treatment require an accurate structural (anatomical) and mechanical (functional) understanding of the breast components, including the fascial-ligamentous support system of the breast, to achieve optimal results. This paper aims to provide a comprehensive description of the mechanical behavior of the ligamentous and fascial connective tissues of the human female breast. Fasciae and ligaments obtained from 17 patients between 35 and 85 years of age who were undergoing mastectomy and three female cadavers were tested. Uniaxial tensile tests were conducted, and three constitutive models …

Fgl2-Knockout Tumor Cells Serve As A Vaccine Inducing Long-Duration Brain-Resident Memory T Cells That Reject Subsequent Intracranial Tumor Cell Challenges, Sheng Zhang, Yining Jin, Zhiliang Jia, Xueqing Xia, Yang Li, Qi Wang, Jing Wang, Jian Wang, Joya Chandra, Gregory K Friedman, Shulin Li

Faculty, Staff and Student Publications

The failure to prevent brain tumors, including both recurrent primary and metastatic brain tumors, is the primary cause of patients' mortality. We developed a novel whole tumor-cell vaccine to rapidly induce long-duration brain-resident memory T (TRM) cells that prevent brain tumor progression. Ten Fgl2-KO primary and metastatic tumor cell lines, generated via CRISPR/Cas9, were used to vaccinate mice and for intracranial challenges with the WT tumor cells. Not only did vaccinated mice reject these tumor cell challenges, but also more than half of these mice became long-duration survivors. Transplanting brain immune cells from vaccinated mice into naïve mice enabled this …

Intraoperative Ultrasound Imaging Features Guiding Surgical Strategy In Spinal Cord Ependymoma Resection, Esteban Ramirez-Ferrer, Ian E Mccutcheon, Gil Kimchi, Behrang Amini, Romulo Andrade Almeida, Francisco Call-Orellana, Juan Pablo Zuluaga-Garcia, Robert Y North, Christopher A Alvarez-Breckenridge, Jeffrey S Weinberg, Laurence D Rhines, Claudio E Tatsui

Faculty, Staff and Student Publications

Background and objectives: Preoperative imaging provides surgeons with an initial estimate of tumor infiltration and the likelihood of achieving an en-bloc resection in spinal cord ependymomas, yet the definitive decision is made intraoperatively. This study characterizes the intraoperative ultrasound (iUS) features that guide real-time surgical strategy and are associated with successful en-bloc removal.

Methods: A retrospective review of iUS images obtained during resection of spinal cord ependymomas was performed. The presence of a peritumoral halo representing the transition zone between the tumor and the spinal cord, the dorsal sagittal area of the spinal cord overlying the tumoral poles, the presence …

Pharmacokinetic Modeling Strategies For Dynamic Hyperpolarized Urea Imaging, Keith A Michel, Collin J Harlan, Christopher M Walker, Matthew E Merritt, Yunyun Chen, Stephen Y Lai, James A Bankson

Faculty, Staff and Student Publications

Purpose: To evaluate pharmacokinetic modeling methods for quantification of tissue perfusion/permeability with hyperpolarized 13C urea.

Methods: Three models for quantitative analysis of dynamic HP urea imaging data were proposed and evaluated in numerical simulations and a thyroid cancer mouse model. A multicompartment model resembling the extended Tofts model for DCE-MRI (Model I) and two simplified models were used. The simplified models each eliminate a volume parameter representing vascular (Model II) or impermeable cellular space (Model III). Signal curves were generated from Model I, and models were fit to these synthetic data to quantify the effects of acquisition settings, bias in …

Post-Dobbs Realities: Ethical Imperatives For Data Transparency And Trust In Maternal Health Care, Faith E Fletcher, Sophie L Schott, Kelley Akhiemokhali, Kari White

Center for Medical Ethics and Health Policy Staff Publications

No abstract provided.

Non-Synaptic Function And Localization Of Syntaxin-Binding Protein 1 In A Mouse Model Of Stxbp1-Related Epileptic Encephalopathy, Tao Yang, Rajat Banerjee, Yamei Deng, Sheetal Jahagirdar, Joo Hyun Kim, Wu Chen, Mingshan Xue, Alexey I Nesvizhskii, Michael D Uhler, Jack M Parent, Yu Wang

Duncan NRI Faculty and Staff Publications

Objective: De novo mutations in the syntaxin-binding protein 1 (STXBP1), encoded by STXBP1, are among the most prevalent causes of variable neurodevelopmental disorders, including epileptic encephalopathy, developmental delay, and movement disorders. Although STXBP1 has been proposed as a critical presynaptic protein controlling synaptic vesicle exocytosis, clinical phenotypes also suggest that its biological function could be more diverse.

Methods: The expression pattern of STXBP1 was studied using immunostaining in vitro and in vivo. Synaptosome isolation was performed to investigate the synaptic and non-synaptic localization of STXBP1 in the brain. STXBP1 immunoprecipitation followed by mass spectrometry (MS) was conducted to identify protein …

Alpha 7 Nicotinic Acetylcholine Receptor Contributes To Long-Term Cognitive Recovery Following Ischemic Stroke, Dustin T Nguyen, Kate Mendoza, Cassandra Hall, Chunfeng Tan, Anjali Chauhan

Faculty, Staff and Student Publications

Stroke is associated with autonomic dysfunction and reduced acetylcholine (ACh), a neurotransmitter critical for cognition. ACh signals in part through the alpha-7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel involved in synaptic plasticity, learning, and memory. Impaired α7nAChR signaling has been linked to heightened neuroinflammation and poor acute stroke recovery. Here, we investigated whether α7nAChR contributes to post-stroke cognitive recovery in young male mice. Wild-type (WT) and α7nAChR knockout (α7n0KO) mice underwent 60-min middle cerebral artery occlusion (MCAO). In a pharmacology cohort, the α7nAChR agonist GTS-21 was administered immediately after reperfusion and then daily for 20 days. Cognitive performance …

Analysis Of Patients With Monocytic And Monocytic-Like Acute Myeloid Leukemia, Including Aml-M4 And Aml-M5, Treated With Venetoclax Plus Azacitidine, Marina Konopleva, Courtney D Dinardo, Yan Sun, Paul Jung, Sanam Loghavi, Jalaja Potluri, Monique Dail, Brenda Chyla, Daniel A Pollyea

Faculty, Staff and Student Publications

No abstract provided.

Impact Of Mutational Landscape And Burden On Rbc Transfusion Response In Patients With Lower-Risk Myelodysplastic Syndromes (Lr-Mds) In The Commands Study, Rami S Komrokji, Sheida Hayati, Manuel Ugidos, Guillermo Garcia-Manero, Matteo Giovanni Della Porta, Amer M Zeidan, Valeria Santini, Uwe Platzbecker, Anita K Gandhi, Rajasekhar N V S Suragani

Faculty, Staff and Student Publications

The COMMANDS trial established luspatercept as a first‐line treatment for anemia in transfusion‐dependent lower‐risk (LR) myelodysplastic syndromes (MDS). Here we report red blood cell (RBC) transfusion response analysis based on somatic mutations profile and disease risk for patients treated with luspatercept or epoetin alfa in the COMMANDS trial. Of 350 evaluable patients, 238 (68.0%) had MDS with multiple lineage dysplasia and ring sideroblasts (RS) according to World Health Organization 2016 criteria, and 320 (91.4%) had somatic mutations in ≥ 1 gene (median, 2) with median variant allele frequencies (VAF) of 2%–59%. Mutation profiles were similar in the treatment groups. Luspatercept …

Prenatal Stress Induces Changes In Behavior, Hpa Axis, Inflammation, And Oxidative Stress In Adult Rats Offspring, Jorge M Aguiar-Geraldo, Jefté Peper-Nascimento, José Henrique Cararo, Taise Possamai-Della, Alexandra I Zugno, Anilkumar Pillai, João Quevedo, Samira S Valvassori

Faculty, Staff and Student Publications

Prenatal stress is related to the development of psychiatric disorders involving inflammation, oxidative stress, and hypothalamic-pituitary-adrenal (HPA) axis. Therefore, the aim of the present study was to evaluate the effects of prenatal stress on behavior, inflammation, oxidative stress, and the HPA-axis in the dams and their offspring treated with lithium. Thirteen pregnant Wistar rats were exposed to a prenatal chronic unpredictable stress protocol from the 14th day of gestation until birth. At the 60th postnatal day (PND), a treatment protocol was carried out in the offspring with lithium (intraperitoneally - 47.5 mg/kg) or saline for seven days (twice a day). …

Profiling The Genomic Landscape And Evolutionary History Of Polyploid Giant Cancer Cells In Undifferentiated Pleomorphic Sarcomas, Amy L Bowes, Sara Waise, Tom Lesluyes, Thomas Butters, Christie English, Haixi Yan, Annelien Verfaillie, Christopher Davies, Jianan Chen, Emma Nye, Richard Stone, Jiten Manji, Adrienne M Flanagan, Jonas Demeulemeester, Maxime Tarabichi, Nischalan Pillay, Peter Van Loo

Faculty, Staff and Student Publications

Polyploid giant cancer cells (PGCCs), characterised by multinucleation and atypical nuclear morphology, are a common feature of undifferentiated pleomorphic sarcomas. While PGCCs may be a critical substrate for cancer evolution, their formation pathways and genomic consequences remain underexplored. In this study, we characterise PGCCs in ten pleomorphic sarcomas and use topographic single-cell DNA sequencing (scDNA-seq) to investigate their genomic landscape. We selected PGCCs based on their nuclear morphology, including mononucleated or multinucleated bizarre, misshapen nuclei, and analysed them at single-cell resolution. Histopathological analysis showed that PGCCs were often randomly distributed throughout the tumour and did not appear in clusters, suggesting …

Profiling The Genomic Landscape And Evolutionary History Of Polyploid Giant Cancer Cells In Undifferentiated Pleomorphic Sarcomas, Amy L Bowes, Sara Waise, Tom Lesluyes, Thomas Butters, Christie English, Haixi Yan, Annelien Verfaillie, Christopher Davies, Jianan Chen, Emma Nye, Richard Stone, Jiten Manji, Adrienne M Flanagan, Jonas Demeulemeester, Maxime Tarabichi, Nischalan Pillay, Peter Van Loo

Faculty, Staff and Student Publications

Polyploid giant cancer cells (PGCCs), characterised by multinucleation and atypical nuclear morphology, are a common feature of undifferentiated pleomorphic sarcomas. While PGCCs may be a critical substrate for cancer evolution, their formation pathways and genomic consequences remain underexplored. In this study, we characterise PGCCs in ten pleomorphic sarcomas and use topographic single-cell DNA sequencing (scDNA-seq) to investigate their genomic landscape. We selected PGCCs based on their nuclear morphology, including mononucleated or multinucleated bizarre, misshapen nuclei, and analysed them at single-cell resolution. Histopathological analysis showed that PGCCs were often randomly distributed throughout the tumour and did not appear in clusters, suggesting …

Phase I Trial Of Binimetinib Plus Hydroxychloroquine In Patients With Previously Treated Metastatic Pancreatic Cancer, S Daniel Haldar, Fen Saj, So Jung Hong, Rishi Surana, Lianchun Xiao, J Jack Lee, Brandon Smaglo, Dan Zhao, Huili Zhu, Ryan Huey, Jason Willis, M Pia Morelli, Michael Overman, Florencia Mcallister, Robert Wolff, Anirban Maitra, David Fogelman, Channing Der, Shubham Pant

Faculty, Staff and Student Publications

Background: Dual mitogen-activated protein kinase (MAPK) pathway and autophagy inhibition shows synergistic antitumor activity in preclinical models of RAS-mutant cancers. We hypothesized that autophagy blockade with hydroxychloroquine (HCQ) could overcome resistance to MEK inhibition with binimetinib (BINI) and provide clinical benefit in previously treated, KRAS-mutated, metastatic pancreatic ductal adenocarcinoma (PDAC).

Methods: This investigator-led, single-arm, open-label, phase I dose escalation/expansion trial evaluated the safety and tolerability of BINI + HCQ in patients with previously treated, metastatic PDAC (NCT04132505). Key eligibility criteria: ECOG 0-1, adequate organ function, ≥ 1 prior line of therapy for metastatic disease, and presence of KRAS …

Bone Marrow Endosteum Houses Hedgehog-Susceptible Dlx5-Expressing Osteoblast Precursor Cells, Keita Kondo, Yuki Matsushita, Shion Orikasa, Yuta Nakai, Aiko Kuroda, Shinsuke Ohba, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

The bone marrow endosteum provides a robust source of bone-making osteoblasts by housing various types of osteoblast precursor cells, including endosteal stem cells expressing fibroblast growth factor receptor 3 (Fgfr3) and their downstream progenitor cell populations. In fetal bone development, Dlx5 marks early perichondrial cells that populate the diaphyseal bone and marrow stroma in the postnatal stages. However, the location of Dlx5-expressing cells in the postnatal bone marrow and how they contribute to osteogenesis remain undefined. Here, we show that Dlx5

Endosteal Stem Cells At The Bone-Blood Interface: A Double-Edged Sword For Rapid Bone Formation: Bone Marrow Endosteal Stem Cells Provide A Robust Source Of Bone-Making Osteoblasts Both In Normal And Abnormal Bone Formation, Keita Kondo, Yuki Matsushita, Shion Orikasa, Yuta Nakai, Aiko Kuroda, Shinsuke Ohba, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

Endosteal stem cells are a subclass of bone marrow skeletal stem cell populations that are particularly important for rapid bone formation occurring in growth and regeneration. These stem cells are strategically located near the bone surface in a specialized microenvironment of the endosteal niche. These stem cells are abundant in young stages but eventually depleted and replaced by other stem cell types residing in a non-endosteal perisinusoidal niche. Single-cell molecular profiling and in vivo cell lineage analyses play key roles in discovering endosteal stem cells. Importantly, endosteal stem cells can transform into bone tumor-making cells when deleterious mutations occur in …

Development And Validation Of A Prognostic Risk Score For Patients With Cancer And Neutropenic Fever Presenting To The Emergency Department, Sandy Nath, Aiham Qdaisat, Andriy Derkach, Afia Babar, Deepti Zalavadia, Patrick Chaftari, Ziyi Li, Monica K Wattana, Joseph Schmeltz, Rocio Perez Johnston, Eduardo Ortiz, Kumar Alagappan, Adam Klotz, Sai-Ching Jim Yeung

Faculty, Staff and Student Publications

Objectives: Neutropenic fever (NF) is a life-threatening oncologic emergency associated with significant morbidity and mortality. Current predictive risk-stratification scores' limitations include outdated criteria, subjectivity, and low usage in the emergency department (ED). We sought to develop and externally validate a pragmatic, objective risk score to predict adverse outcomes in patients presenting to the ED with cancer and NF.

Methods: A retrospective cohort study was performed using data from 2 comprehensive cancer centers. The derivation cohort included adults presenting with NF to Memorial Sloan Kettering Cancer Center. External validation was conducted using data from the MD Anderson Cancer Center. The primary …

Pretreatment Risk Model For Radiation-Induced Lymphopenia Is Associated With Adjuvant Durvalumab Efficacy In Patients With Unresectable Stage Iii Nsclc, Peter S N Van Rossum, Pim J J Damen, Francesco Cortiula, Brian P Hobbs, Lorenzo De Marchi, Radhe Mohan, Max Peters, Famke L Schneiders, Dirk De Ruysscher, Robin Wijsman, Joost J C Verhoeff, Ting Xu, Zhongxing Liao, Steven H Lin

Faculty, Staff and Student Publications

Introduction: Severe radiation-induced lymphopenia (RIL) during concurrent chemoradiotherapy (CCRT) for NSCLC has been associated with poorer outcomes and reduced immunotherapy efficacy. Because RIL often develops late during CCRT, identifying patients at risk before treatment may be clinically relevant. This study aimed to develop and validate a nomogram based on pretreatment predictors for severe RIL, and secondarily to explore associations between predicted RIL risk and adjuvant durvalumab-associated survival.

Methods: A retrospective development cohort of consecutive patients with NSCLC treated with CCRT (2010-2019) was established, along with an independent external validation cohort from other institutions. A multivariable logistic regression model was developed …

Social Roles And Emotional Distress Are Associated With Successful Aging In Adult Childhood Cancer Survivors, Samah Hayek, Kimberly A Miller, Michael E Roth, Michelle A T Hildebrandt, David R Freyer, Joel Milam

Faculty, Staff and Student Publications

Childhood cancer survivors (CCS) face complex long-term health consequences resulting from intensive treatments that may impact their aging trajectory. This study assessed the associations between social role attainment, emotional distress, and indicators of successful aging (SA) among adult CCS, considering treatment intensity. SA, is a multidimensional concept encompassing physical, cognitive, and psychosocial well-being, provides a framework for understanding and optimizing outcomes in this population. This cross-sectional study utilized data from Project Forward, a cohort, of 1,248 adult CCS diagnosed between 1996 and 2010. Participants were identified through the Los Angeles County Cancer Surveillance Program and completed a comprehensive self-report survey …

Winner's Curse Free Robust Mendelian Randomization With Summary Data, Zhongming Xie, Wanheng Zhang, Jingshen Wang, Chong Wu

Faculty, Staff and Student Publications

In the past decade, the increased availability of genome-wide association studies summary data has popularized Mendelian Randomization (MR) for conducting causal inference. MR analyses, incorporating genetic variants as instrumental variables, are known for their robustness against reverse causation bias and unmeasured confounders. Nevertheless, classical MR analyses using summary data may still produce biased causal effect estimates due to the winner’s curse and pleiotropy issues. To address these two issues and establish valid causal conclusions, we propose a unified robust Mendelian Randomization framework with summary data, which systematically removes the winner’s curse and screens out invalid genetic instruments with pleiotropic effects. …

Eepd1 Evolved A Unique Dna Clamping Dimer Protecting Reversed Replication Forks, Runze Shen, Altaf H Sarker, Yue Chen, Min Liu, Sunetra Roy, Andrew S Arvai, Albino Bacolla, Zamal Ahmed, Panagiotis Katsonis, Michal Hammel, Isao Kuraoka, Miaw-Sheue Tsai, Corydon Irie, Lukas Webb, Olivier Lichtarge, Chi-Lin Tsai, Susan E Tsutakawa, Katharina Schlacher, John A Tainer

Faculty, Staff and Student Publications

Exonuclease/endonuclease/phosphatase (EEP)-fold hydrolases are canonically monomeric phosphodiesterases exemplified by APE1, DNase I, and TDP2 nucleases. While EEP family domain containing protein 1 (EEPD1) acts in DNA stress responses, its proposed nuclease activities are enigmatic. Here, we integrate hybrid structural methods, evolution, biochemistry, cancer genomics, plus molecular and cell biology to define EEPD1 structure, assembly, and function at stalled DNA replication forks. Results imply EEPD1 surprisingly requires both unique EEP domain dimer and distinctive tandem Helix-hairpin-Helix [(HhH)2] domains to clamp double-stranded (ds) DNA at reversed DNA replication forks for fork protection. Small-angle X-ray Scattering (SAXS), crystal, and cryo-EM structures unveil an …

Concordance Analysis Of Dna And Rna Profiling: The Md Anderson Impact2 Study In Precision Oncology, Stephanie T Schmidt, Mehmet A Baysal, Siqing Fu, David S Hong, Sarina A Piha-Paul, Aung Naing, Jordi Rodon Ahnert, Timothy A Yap, Ecaterina Elena Dumbrava, Jennifer Beck, Funda Meric-Bernstam, Apostolia Maria Tsimberidou

Faculty, Staff and Student Publications

DNA profiling is an established method for cancer treatment selection, while RNA profiling remains investigational. We explored associations between DNA and RNA alterations and between the number of genes with altered expression and overall survival (OS) using patient data from IMPACT2 (NCT02152254), a randomized study evaluating molecular profiling for guiding cancer therapy across tumor types. Molecular profiling, including DNA next-generation sequencing, was performed on all 829 patients in the IMPACT2 study. RNA profiling was performed by Tempus for 253 of 829 patients. We evaluated the concordance between DNA and RNA profiling, analyzed OS in 217 treated patients with …

Risk Stratification Of Low-Dose Cytarabine And Venetoclax In Patients With Aml Ineligible For Intensive Chemotherapy, Andrew H Wei, Panayiotis Panayiotidis, Pau Montesinos, Kamel Laribi, Vladimir Ivanov, Inho Kim, Jan Novak, Rebecca Champion, Walter Fiedler, Maria Pagoni, Julie Bergeron, Stephen B Ting, Jing-Zhou Hou, Takahiro Yamauchi, Jianxiang Wang, Stephen A Strickland, Michael R Savona, Tara L Lin, Anoop Enjeti, Ing Soo Tiong, Sangmin Lee, Gail J Roboz, Relja Popovic, Qi Jiang, Zihuan Liu, Yan Sun, Wellington Mendes, Brenda Chyla, Courtney D Dinardo

Faculty, Staff and Student Publications

Prognostic risk categorization aids treatment selection for patients with acute myeloid leukemia (AML). Although the European LeukemiaNet (ELN) classifications (2017 and 2022) for AML have been used to stratify outcomes for patients receiving intensive chemotherapy, their application to patients receiving less intensive therapy, such as azacitidine plus venetoclax, has been less satisfactory. In response, a 4-gene classifier that stratifies older patients with AML unfit for intensive chemotherapy into those with higher benefit (wild type), intermediate benefit (FLT3-internal tandem duplication [ITD] or NRAS/KRAS mutation), or lower benefit (TP53 mutation) after azacitidine plus venetoclax treatment was developed. We hypothesized that this 4-gene …

Supt16h-Associated Neurodevelopmental Disorder And Neurocristopathy: Genetic And Phenotypic Spectrum, Eunhye Lee, Seungmin Sim, Hee-Jung Choi, Eugene Y Liang, Carolyn Le, Roya Bina, Ryan Cohen, Elizabeth George, Soo Yeon Kim, Gifty Bhat, Erin Falsey, Richard Sidlow, Kristin Clinard, Shay Ben-Shachar, Eleina England, Beatriz Menendez, Isabella Herman, Shelly Nielsen, Jaya Punetha, Priya Bhola, J Austin Hamm, Megan A Keeney, Nike Sitzman, Sara Berger, Lakshmi Mehta, Alison J Conn, Lilian Downie, Myla Ashfaq, Hope Northrup, Ange-Line Bruel, Sylvie Odent, Justin O Szot, Noelia Nunez Martinez, Sunju Park, Julie Refkin, Jean-Marc Good, Fabienne Maurer, Cédric Le Caignec, David J Coman, Erin Anderson, Linda J Richards, Ryan J Dean, Caleb Yang, Chulwon Choi, Byung Joon Hwang, Jin Sook Lee, William B Dobyns, Murim Choi, Elliott H Sherr, Jong-Hee Chae, Yun Kee, Emanuela Argilli

Faculty, Staff and Student Publications

SUPT16H encodes a subunit of the FACT (FAcilitates Chromatin Transcription) complex, a histone chaperone essential for maintaining chromatin integrity during transcription, replication, and DNA repair. Pathogenic de novo SUPT16H missense variants have previously been linked to neurodevelopmental disorders in eight individuals. Here, we expand the genotypic and phenotypic spectrum by identifying 24 additional individuals harboring ultrarare heterozygous missense or truncating variants, who share overlapping clinical features including intellectual disability, autism spectrum disorder, hypotonia, and characteristic craniofacial dysmorphism. To elucidate the underlying mechanisms, we generated a supt16h knockout zebrafish model using CRISPR/Cas9. The supt16h loss-of-function (LOF) model recapitulated key patient phenotypes …