Medical Genetics Commons^™

Prediction Of Survival With Lower Intensity Therapy Among Older Patients With Acute Myeloid Leukemia, Koji Sasaki, Farhad Ravandi, Tapan M Kadia, Gautam Borthakur, Nicholas J Short, Nitin Jain, Naval G Daver, Elias J Jabbour, Guillermo Garcia-Manero, Sanam Loghavi, Keyur P Patel, Guillermo Montalban-Bravo, Lucia Masarova, Courtney D Dinardo, Hagop M Kantarjian

Faculty, Staff and Student Publications

BACKGROUND: The aim of this study was to develop a prognostic model for survival in older/unfit patients with newly diagnosed acute myeloid leukemia (AML) who were treated with lower-intensity chemotherapy regimens.

METHODS: The authors reviewed all older/unfit patients with newly diagnosed AML who received lower-intensity chemotherapy from 2000 until 2020 at their institution. A total of 1462 patients were included. They were divided (3:1 basis) into a training (n = 1088) and a validation group (n = 374).

RESULTS: In the training cohort of 1088 patients (median age, 72 years), the multivariate analysis identified 11 consistent independent adverse factors associated …

The Outcomes Of Patients With Chronic Myeloid Leukemia Treated With Third-Line Bcr::Abl1 Tyrosine Kinase Inhibitors, Elias J Jabbour, Koji Sasaki, Fadi G Haddad, Ghayas C Issa, Guillermo Garcia-Manero, Tapan M Kadia, Nitin Jain, Musa Yilmaz, Courtney D Dinardo, Keyur P Patel, Rashmi Kanagal-Shamanna, Richard Champlin, Issa F Khouri, Sara Dellasala, Sherry A Pierce, Hagop Kantarjian

Faculty, Staff and Student Publications

The BCR::ABL1 tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with chronic myeloid leukemia (CML). After failing second-generation TKI (2G-TKI), the optimal third-line therapy in chronic phase CML (CML-CP) is not well established. We analyzed 354 patients with CML-CP treated with a third-line BCR::ABL1 TKI at our institution, and in the PACE and OPTIC trials, and evaluated the outcome after alternate 2G-TKIs or ponatinib. We performed a propensity score matching analysis to compare outcomes and multivariate analysis to identify variables associated with survival. One hundred seventy-three (49%) patients received 2G-TKIs and 181 (51%) ponatinib. Patients in the ponatinib …

Advancing Car T Cell Therapy Through The Use Of Multidimensional Omics Data, Jingwen Yang, Yamei Chen, Ying Jing, Michael R Green, Leng Han

Faculty, Staff and Student Publications

Despite the notable success of chimeric antigen receptor (CAR) T cell therapies in the treatment of certain haematological malignancies, challenges remain in optimizing CAR designs and cell products, improving response rates, extending the durability of remissions, reducing toxicity and broadening the utility of this therapeutic modality to other cancer types. Data from multidimensional omics analyses, including genomics, epigenomics, transcriptomics, T cell receptor-repertoire profiling, proteomics, metabolomics and/or microbiomics, provide unique opportunities to dissect the complex and dynamic multifactorial phenotypes, processes and responses of CAR T cells as well as to discover novel tumour targets and pathways of resistance. In this Review, …

Axicabtagene Ciloleucel In Relapsed Or Refractory Large B-Cell Lymphoma Patients In Complete Metabolic Response, Andrew P Jallouk, Sushanth Gouni, Jason Westin, Lei Feng, Haleigh Mistry, Raphael E Steiner, Jinsu James, Mansoor Noorani, Sandra Horowitz, Nahum Puebla-Osorio, Luis E Fayad, Swaminathan P Iyer, Misha Hawkins, Christopher R Flowers, Sairah Ahmed, Loretta J Nastoupil, Partow Kebriaei, Elizabeth J Shpall, Sattva S Neelapu, Yago Nieto, Paolo Strati

Faculty, Staff and Student Publications

No abstract provided.

Inconsistent Partitioning And Unproductive Feature Associations Yield Idealized Radiomic Models, Mishka Gidwani, Ken Chang, Jay Biren Patel, Katharina Viktoria Hoebel, Syed Rakin Ahmed, Praveer Singh, Clifton David Fuller, Jayashree Kalpathy-Cramer

Faculty, Staff and Student Publications

Background Radiomics is the extraction of predefined mathematic features from medical images for the prediction of variables of clinical interest. While some studies report superlative accuracy of radiomic machine learning (ML) models, the published methodology is often incomplete, and the results are rarely validated in external testing data sets. Purpose To characterize the type, prevalence, and statistical impact of methodologic errors present in radiomic ML studies. Materials and Methods Radiomic ML publications were reviewed for the presence of performance-inflating methodologic flaws. Common flaws were subsequently reproduced with randomly generated features interpolated from publicly available radiomic data sets to demonstrate the …

Molecular Function And Contribution Of Tbx4 In Development And Disease, Justyna A Karolak, Carrie L Welch, Christian Mosimann, Katarzyna Bzdęga, James D West, David Montani, Mélanie Eyries, Mary P Mullen, Steven H Abman, Matina Prapa, Stefan Gräf, Nicholas W Morrell, Anna R Hemnes, Frédéric Perros, Rizwan Hamid, Malcolm P O Logan, Jeffrey Whitsett, Csaba Galambos, Paweł Stankiewicz, Wendy K Chung, Eric D Austin

Faculty, Staff and Students Publications

Over the past decade, recognition of the profound impact of the TBX4 (T-box 4) gene, which encodes a member of the evolutionarily conserved family of T-box–containing transcription factors, on respiratory diseases has emerged. The developmental importance of TBX4 is emphasized by the association of TBX4 variants with congenital disorders involving respiratory and skeletal structures; however, the exact role of TBX4 in human development remains incompletely understood. Here, we discuss the developmental, tissue-specific, and pathological TBX4 functions identified through human and animal studies and review the published TBX4 variants resulting in variable disease phenotypes. We also outline future research …

Familial Hypercholesterolemia In The Electronic Medical Records And Genomics Network: Prevalence, Penetrance, Cardiovascular Risk, And Outcomes After Return Of Results, Ozan Dikilitas, Alborz Sherafati, Seyedmohammad Saadatagah, Benjamin A Satterfield, David C Kochan, Katherine C Anderson, Wendy K Chung, Scott J Hebbring, Zachary M Salvati, Richard R Sharp, Amy C Sturm, Richard A Gibbs, Robb Rowley, Eric Venner, Jodell E Linder, Laney K Jones, Emma F Perez, Josh F Peterson, Gail P Jarvik, Heidi L Rehm, Hana Zouk, Dan M Roden, Marc S Williams, Teri A Manolio, Iftikhar J Kullo

Faculty, Staff and Students Publications

BACKGROUND: The implications of secondary findings detected in large-scale sequencing projects remain uncertain. We assessed prevalence and penetrance of pathogenic familial hypercholesterolemia (FH) variants, their association with coronary heart disease (CHD), and 1-year outcomes following return of results in phase III of the electronic medical records and genomics network.

METHODS: Adult participants (n=18 544) at 7 sites were enrolled in a prospective cohort study to assess the clinical impact of returning results from targeted sequencing of 68 actionable genes, including

RESULTS: The prevalence of FH-associated pathogenic variants was 1 in 188 (69 of 13,019 unselected participants). Penetrance was 87.5%. The …

Machine Learning And Health Care: Potential Benefits And Issues, J Graham Atkinson, Elizabeth G Atkinson

Faculty, Staff and Students Publications

We discuss the potential for machine learning (ML) and artificial intelligence (AI) to improve health care, while detailing caveats and important considerations to ensure unbiased and equitable implementation. If disparities exist in the data used to train ML algorithms, they must be recognized and accounted for, so they do not bias performance accuracy or are not interpreted by the algorithm as simply a lack of need. We pay particular attention to an area in which bias in data composition is particularly striking, that is in large-scale genetics databases, as people of European descent are vastly overrepresented in the existing resources.

Loss Of Neuron Navigator 2 Impairs Brain And Cerebellar Development, Andrea Accogli, Shenzhao Lu, Ilaria Musante, Paolo Scudieri, Jill A Rosenfeld, Mariasavina Severino, Simona Baldassari, Michele Iacomino, Antonella Riva, Ganna Balagura, Gianluca Piccolo, Carlo Minetti, Denis Roberto, Fan Xia, Razaali Razak, Emily Lawrence, Mohamed Hussein, Emmanuel Yih-Herng Chang, Michelle Holick, Elisa Calì, Emanuela Aliberto, Rosalba De-Sarro, Antonio Gambardella, Undiagnosed Diseases Network, Synaps Study Group, Lisa Emrick, Peter J A Mccaffery, Margaret Clagett-Dame, Paul C Marcogliese, Hugo J Bellen, Seema R Lalani, Federico Zara, Pasquale Striano, Vincenzo Salpietro

Faculty, Staff and Students Publications

Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (NAV2) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the central nervous system (CNS), and particularly abundant in the developing cerebellum. Evidence across different species supports a pivotal function of NAV2 in cytoskeletal dynamics and neurite outgrowth. Specifically, deficiency of Nav2 in mice leads to cerebellar hypoplasia with abnormal foliation due to impaired axonal outgrowth. However, little is known about the involvement of the NAV2 gene in human disease phenotypes. In …

Natural History Of Tango2 Deficiency Disorder: Baseline Assessment Of 73 Patients, Christina Y Miyake, Erica J Lay, Claudia Soler-Alfonso, Kevin E Glinton, Kimberly M Houck, Mustafa Tosur, Nancy E Moran, Sara B Stephens, Fernando Scaglia, Taylor S Howard, Jeffrey J Kim, Tam Dam Pham, Santiago O Valdes, Na Li, Chaya N Murali, Lilei Zhang, Maina Kava, Deane Yim, Cheyenne Beach, Gregory Webster, Leonardo Liberman, Christopher M Janson, Prince J Kannankeril, Samantha Baxter, Moriel Singer-Berk, Jordan Wood, Samuel J Mackenzie, Michael Sacher, Lina Ghaloul-Gonzalez, Claudia Pedroza, Shaine A Morris, Saad A Ehsan, Mahshid S Azamian, Seema R Lalani

Faculty, Staff and Students Publications

PURPOSE: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD.

METHODS: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review.

RESULTS: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at …

Kcna1 Gain-Of-Function Epileptic Encephalopathy Treated With 4-Aminopyridine, Peter Müller, Danielle S Takacs, Ulrike B S Hedrich, Rohini Coorg, Laura Masters, Kevin E Glinton, Hongzheng Dai, Jon A Cokley, James J Riviello, Holger Lerche, Edward C Cooper

Faculty, Staff and Students Publications

Precision medicine for Mendelian epilepsy is rapidly developing. We describe an early infant with severely pharmacoresistant multifocal epilepsy. Exome sequencing revealed the de novo variant p.(Leu296Phe) in the gene KCNA1, encoding the voltage‐gated K+ channel subunit KV1.1. So far, loss‐of‐function variants in KCNA1 have been associated with episodic ataxia type 1 or epilepsy. Functional studies of the mutated subunit in oocytes revealed a gain‐of‐function caused by a hyperpolarizing shift of voltage dependence. Leu296Phe channels are sensitive to block by 4‐aminopyridine. Clinical use of 4‐aminopyridine was associated with reduced seizure burden, enabled simplification of co‐medication and prevented rehospitalization.

Genetic Correlations Between Alzheimer’S Disease And Gut Microbiome Genera, Davis Cammann, Yimei Lu, Melika J Cummings, Mark L Zhang, Joan Manuel Cue, Jenifer Do, Jeffrey Ebersole, Xiangning Chen, Edwin C Oh, Jeffrey L Cummings, Jingchun Chen

Faculty, Staff and Student Publications

A growing body of evidence suggests that dysbiosis of the human gut microbiota is associated with neurodegenerative diseases like Alzheimer's disease (AD) via neuroinflammatory processes across the microbiota-gut-brain axis. The gut microbiota affects brain health through the secretion of toxins and short-chain fatty acids, which modulates gut permeability and numerous immune functions. Observational studies indicate that AD patients have reduced microbiome diversity, which could contribute to the pathogenesis of the disease. Uncovering the genetic basis of microbial abundance and its effect on AD could suggest lifestyle changes that may reduce an individual's risk for the disease. Using the largest genome-wide …

Interaction Analysis Of Ancestry-Enriched Variants With Apoe-Ɛ4 On Mci In The Study Of Latinos-Investigation Of Neurocognitive Aging, Einat Granot-Hershkovitz, Rui Xia, Yunju Yang, Brian Spitzer, Wassim Tarraf, Priscilla M Vásquez, Richard B Lipton, Martha Daviglus, Maria Argos, Jianwen Cai, Robert Kaplan, Myriam Fornage, Charles Decarli, Hector M Gonzalez, Tamar Sofer

Faculty, Staff and Student Publications

APOE-ɛ4 risk on Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) differs between race/ethnic groups, presumably due to ancestral genomic background surrounding the APOE locus. We studied whether African and Amerindian ancestry-enriched genetic variants in the APOE region modify the effect of the APOE-ɛ4 alleles on Mild Cognitive Impairment (MCI) in Hispanics/Latinos. We defined African and Amerindian ancestry-enriched variants as those common in one Hispanic/Latino parental ancestry and rare in the other two. We identified such variants in the APOE region with a predicted moderate impact based on the SnpEff tool. We tested their interaction with APOE-ɛ4 on MCI in …

Rare Variant Enrichment Analysis Supports Greb1l As A Contributory Driver Gene In The Etiology Of Mayer-Rokitansky-Küster-Hauser Syndrome, Angad Jolly, Haowei Du, Christelle Borel, Na Chen, Sen Zhao, Christopher M Grochowski, Ruizhi Duan, Jawid M Fatih, Moez Dawood, Sejal Salvi, Shalini N Jhangiani, Donna M Muzny, André Koch, Konstantinos Rouskas, Stavros Glentis, Efthymios Deligeoroglou, Flora Bacopoulou, Carol A Wise, Jennifer E Dietrich, Ignatia B Van Den Veyver, Antigone S Dimas, Sara Brucker, V Reid Sutton, Richard A Gibbs, Stylianos E Antonarakis, Nan Wu, Zeynep H Coban-Akdemir, Lan Zhu, Jennifer E Posey, James R Lupski

Faculty, Staff and Student Publications

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by aplasia of the female reproductive tract; the syndrome can include renal anomalies, absence or dysgenesis, and skeletal anomalies. While functional models have elucidated several candidate genes, only WNT4 (MIM: 603490) variants have been definitively associated with a subtype of MRKH with hyperandrogenism (MIM: 158330). DNA from 148 clinically diagnosed MRKH probands across 144 unrelated families and available family members from North America, Europe, and South America were exome sequenced (ES) and by family-based genomics analyzed for rare likely deleterious variants. A replication cohort consisting of 442 Han Chinese individuals with MRKH was …

Health-Related Quality Of Life In Adolescents And Young Adults With Cancer Who Received Radiation Therapy: A Scoping Review, Kelsey L Corrigan, Bryce B Reeve, John M Salsman, Elizabeth J Siembida, Lauren M Andring, Yimin Geng, Ramez Kouzy, J Andrew Livingston, Susan K Peterson, Andrew J Bishop, Grace L Smith, Jillian R Gunther, Susan K Parsons, Michael Roth

Faculty, Staff and Student Publications

Purpose: Radiation therapy (RT) is a critical component of treatment for adolescents and young adults (AYAs, age 15-39 years old) diagnosed with cancer. Limited prior studies have focused on AYAs receiving RT despite the potentially burdensome effects of RT. We reviewed the literature to assess health-related quality of life (HRQOL) in AYAs with cancer who received RT.

Methods: The MEDLINE, EMBASE, and Web of Science databases were searched in January 2022 to identify studies that analyzed HRQOL measured by patient-reported outcomes in AYAs who received RT. After title (n = 286) and abstract (n = 58) screening and full-text review …

Defects In Lipid Homeostasis Reflect The Function Of Tango2 In Phospholipid And Neutral Lipid Metabolism, Agustin Leonardo Lujan, Ombretta Foresti, Conor Sugden, Nathalie Brouwers, Alex Mateo Farre, Alessio Vignoli, Mahshid Azamian, Alicia Turner, Jose Wojnacki, Vivek Malhotra

Faculty, Staff and Students Publications

We show that TANGO2 in mammalian cells localizes predominantly to mitochondria and partially at mitochondria sites juxtaposed to lipid droplets (LDs) and the endoplasmic reticulum. HepG2 cells and fibroblasts of patients lacking TANGO2 exhibit enlarged LDs. Quantitative lipidomics revealed a marked increase in lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes were exacerbated in nutrient-starved cells. Based on our data, we suggest that TANGO2 function is linked to acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. The defect in acyl-CoA availability impacts the metabolism of many other …

A Phase 2 Study Of Interleukin-22 And Systemic Corticosteroids As Initial Treatment For Acute Gvhd Of The Lower Gi Tract, Doris M Ponce, Amin M Alousi, Ryotaro Nakamura, John Slingerland, Marco Calafiore, Karamjeet S Sandhu, Juliet N Barker, Sean Devlin, Jinru Shia, Sergio Giralt, Miguel-Angel Perales, Gillian Moore, Samira Fatmi, Cristina Soto, Antonio Gomes, Paul Giardina, Leeann Marcello, Xiaoqiang Yan, Tom Tang, Kevin Dreyer, Jianmin Chen, William L Daley, Jonathan U Peled, Marcel R M Van Den Brink, Alan M Hanash

Faculty, Staff and Student Publications

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic transplantation. In experimental models, interleukin-22 promotes epithelial regeneration and induces innate antimicrobial molecules. We conducted a multicenter single-arm phase 2 study evaluating the safety and efficacy of a novel recombinant human interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD. The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. Out of 27 patients, 19 (70%; 80% confidence interval, 56%-79%) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders …

Large Scale Crowdsourced Radiotherapy Segmentations Across A Variety Of Cancer Anatomic Sites, Kareem A Wahid, Diana Lin, Onur Sahin, Michael Cislo, Benjamin E Nelms, Renjie He, Mohammed A Naser, Simon Duke, Michael V Sherer, John P Christodouleas, Abdallah S R Mohamed, James D Murphy, Clifton D Fuller, Erin F Gillespie

Faculty, Staff and Student Publications

Clinician generated segmentation of tumor and healthy tissue regions of interest (ROIs) on medical images is crucial for radiotherapy. However, interobserver segmentation variability has long been considered a significant detriment to the implementation of high-quality and consistent radiotherapy dose delivery. This has prompted the increasing development of automated segmentation approaches. However, extant segmentation datasets typically only provide segmentations generated by a limited number of annotators with varying, and often unspecified, levels of expertise. In this data descriptor, numerous clinician annotators manually generated segmentations for ROIs on computed tomography images across a variety of cancer sites (breast, sarcoma, head and neck, …

Stellettin B Renders Glioblastoma Vulnerable To Poly (Adp-Ribose) Polymerase Inhibitors Via Suppressing Homology-Directed Repair, Xin Peng, Yingying Wang, Shaolu Zhang, Zhennan Tao, Yuxiang Dai, Francois X Claret, Moshe Elkabets, Hou-Wen Lin, Zhe-Sheng Chen, Dexin Kong

Faculty, Staff and Student Publications

No abstract provided.

A First-In-Human Phase I Study Of Milademetan, An Mdm2 Inhibitor, In Patients With Advanced Liposarcoma, Solid Tumors, Or Lymphomas, Mrinal M Gounder, Todd M Bauer, Gary K Schwartz, Amy M Weise, Patricia Lorusso, Prasanna Kumar, Ben Tao, Ying Hong, Parul Patel, Yasong Lu, Arnaud Lesegretain, Vijaya G Tirunagaru, Feng Xu, Robert C Doebele, David S Hong

Faculty, Staff and Student Publications

Purpose: This study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of milademetan, a small-molecule murine double minute-2 (MDM2) inhibitor, in patients with advanced cancers.

Patients and methods: In this first-in-human phase I study, patients with advanced solid tumors or lymphomas received milademetan orally once daily as extended/continuous (days 1-21 or 1-28 every 28 days) or intermittent (days 1-7, or days 1-3 and 15-17 every 28 days) schedules. The primary objective was to determine the recommended phase II dose and schedule. Secondary objectives included tumor response according to standard evaluation criteria. Predefined analyses by tumor type were performed. Safety and …

Genetic Control Of Rna Editing In Neurodegenerative Disease, Sijia Wu, Qiuping Xue, Mengyuan Yang, Yanfei Wang, Pora Kim, Xiaobo Zhou, Liyu Huang

Faculty, Staff and Student Publications

A-to-I RNA editing diversifies human transcriptome to confer its functional effects on the downstream genes or regulations, potentially involving in neurodegenerative pathogenesis. Its variabilities are attributed to multiple regulators, including the key factor of genetic variants. To comprehensively investigate the potentials of neurodegenerative disease-susceptibility variants from the view of A-to-I RNA editing, we analyzed matched genetic and transcriptomic data of 1596 samples across nine brain tissues and whole blood from two large consortiums, Accelerating Medicines Partnership-Alzheimer's Disease and Parkinson's Progression Markers Initiative. The large-scale and genome-wide identification of 95 198 RNA editing quantitative trait loci revealed the preferred genetic effects …

A Mast Cell-Thermoregulatory Neuron Circuit Axis Regulates Hypothermia In Anaphylaxis, Chunjing Bao, Ouyang Chen, Huaxin Sheng, Jeffrey Zhang, Yikai Luo, Byron W Hayes, Han Liang, Wolfgang Liedtke, Ru-Rong Ji, Soman N Abraham

Faculty, Staff and Student Publications

IgE-mediated anaphylaxis is an acute life-threatening systemic reaction to allergens, including certain foods and venoms. Anaphylaxis is triggered when blood-borne allergens activate IgE-bound perivascular mast cells (MCs) throughout the body, causing an extensive systemic release of MC mediators. Through precipitating vasodilatation and vascular leakage, these mediators are believed to trigger a sharp drop in blood pressure in humans and in core body temperature in animals. We report that the IgE/MC-mediated drop in body temperature in mice associated with anaphylaxis also requires the body's thermoregulatory neural circuit. This circuit is activated when granule-borne chymase from MCs is deposited on proximal TRPV1+ …

Comparison Of Four Clinical Prognostic Scores In Patients With Advanced Gastric And Esophageal Cancer, Lucy X Ma, Osvaldo Espin-Garcia, Yvonne Bach, Hiroko Aoyama, Michael J Allen, Xin Wang, Gail E Darling, Jonathan Yeung, Carol J Swallow, Savtaj Brar, Patrick Veit-Haibach, Sangeetha Kalimuthu, Rebecca Wong, Eric X Chen, Grainne M O'Kane, Raymond W Jang, Elena Elimova

Faculty, Staff and Student Publications

Background: Prognostic scores that can identify patients at risk for early death are needed to aid treatment decision-making and patient selection for clinical trials. We compared the accuracy of four scores to predict early death (within 90 days) and overall survival (OS) in patients with metastatic gastric and esophageal (GE) cancer.

Methods: Advanced GE cancer patients receiving first-line systemic therapy were included. Prognostic risks were calculated using: Royal Marsden Hospital (RMH), MD Anderson Cancer Centre (MDACC), Gustave Roussy Immune (GRIm-Score), and MD Anderson Immune Checkpoint Inhibitor (MDA-ICI) scores. Overall survival (OS) was estimated using the Kaplan-Meier method. Cox proportional hazards …

Factors Associated With Open Access Publishing Costs In Oncology Journals: Cross-Sectional Observational Study, Alex Koong, Ulysses Grant Gardner, Jason Burton, Caleb Stewart, Petria Thompson, Clifton David Fuller, Ethan Bernard Ludmir, Michael Kevin Rooney

Faculty, Staff and Student Publications

Background: Open access (OA) publishing represents an exciting opportunity to facilitate the dissemination of scientific information to global audiences. However, OA publishing is often associated with significant article processing charges (APCs) for authors, which may thus serve as a barrier to publication.

Objective: In this observational cohort study, we aimed to characterize the landscape of OA publishing in oncology and, further, identify characteristics of oncology journals that are predictive of APCs.

Methods: We identified oncology journals using the SCImago Journal & Country Rank database. All journals with an OA publication option and APC data openly available were included. We searched …

The Evolution Of Acute Lymphoblastic Leukemia Research And Therapy At Md Anderson Over Four Decades, Elias Jabbour, Nicholas J Short, Nitin Jain, Fadi G Haddad, Mary Alma Welch, Farhad Ravandi, Hagop Kantarjian

Faculty, Staff and Student Publications

Progress in the research and therapy of adult acute lymphoblastic leukemia (ALL) is accelerating. This analysis summarizes the data derived from the clinical trials conducted at MD Anderson between 1985 and 2022 across ALL subtypes. In Philadelphia chromosome-positive ALL, the addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy since 2000, improved outcomes. More recently, a chemotherapy-free regimen with blinatumomab and ponatinib resulted in a complete molecular remission rate of 85% and an estimated 3-year survival rate of 90%, potentially reducing the role of, and need for allogeneic stem cell transplantation (SCT) in remission. In younger patients with pre-B …

Evolutionarily Conserved Regulators Of Tau Identify Targets For New Therapies, Jiyoen Kim, Maria De Haro, Ismael Al-Ramahi, Lorena Laura Garaicoechea, Hyun-Hwan Jeong, Jun Young Sonn, Bakhos Tadros, Zhandong Liu, Juan Botas, Huda Yahya Zoghbi

Duncan NRI Faculty and Staff Publications

Tauopathies are neurodegenerative diseases that involve the pathological accumulation of tau proteins; in this family are Alzheimer disease, corticobasal degeneration, and chronic traumatic encephalopathy, among others. Hypothesizing that reducing this accumulation could mitigate pathogenesis, we performed a cross-species genetic screen targeting 6,600 potentially druggable genes in human cells and Drosophila. We found and validated 83 hits in cells and further validated 11 hits in the mouse brain. Three of these hits (USP7, RNF130, and RNF149) converge on the C terminus of Hsc70-interacting protein (CHIP) to regulate tau levels, highlighting the role of CHIP in maintaining tau proteostasis in the brain. …

Sequential Targeting Of Retinoblastoma And Dna Synthesis Pathways Is A Therapeutic Strategy For Sarcomas That Can Be Monitored In Real Time, Tuyen Duong Thanh Nguyen, Yan Wang, Tuyen N Bui, Rossana Lazcano, Davis R Ingram, Min Yi, Varshini Vakulabharanam, Linjie Luo, Marc A Pina, Cansu Karakas, Mi Li, Nicole M Kettner, Neeta Somaiah, Peter J Hougton, Osama Mawlawi, Alexander J Lazar, Kelly K Hunt, Khandan Keyomarsi

Faculty, Staff and Student Publications

Treatment strategies with a strong scientific rationale based on specific biomarkers are needed to improve outcomes in patients with advanced sarcomas. Suppression of cell cycle progression through reactivation of the tumor suppressor retinoblastoma (Rb) using CDK4/6 inhibitors is a potential avenue for novel targeted therapies in sarcomas that harbor intact Rb signaling. Here, we evaluated combination treatment strategies (sequential and concomitant) with the CDK4/6 inhibitor abemacicib to identify optimal combination strategies. Expression of Rb was examined in 1043 sarcoma tumor specimens, and 50% were found to be Rb-positive. Using in vitro and in vivo models, an effective 2-step sequential combination …

Etnk1 Mutation Occurs In A Wide Spectrum Of Myeloid Neoplasms And Is Not Specific For Atypical Chronic Myeloid Leukemia, Wen Shuai, Zhuang Zuo, Nianyi Li, Sofia Garces, Fatima Zahra Jelloul, Chi Young Ok, Shaoying Li, Jie Xu, M James You, Wei Wang, Catherine Rehder, Elias J Jabbour, Keyur P Patel, L Jeffrey Medeiros, C Cameron Yin

Faculty, Staff and Student Publications

Background: ETNK1 mutation has been suggested as a useful tool to support the diagnosis of atypical chronic myeloid leukemia. ETNK1 mutations, however, occur in other myeloid neoplasms.

Methods: The authors assessed the clinicopathologic and molecular genetic features of 80 ETNK1-mutated myeloid neoplasms.

Results: Thirty-seven neoplasms (46%) were classified as myelodysplastic syndrome, 17 (21%) were classified as myelodysplastic/myeloproliferative neoplasm, 14 (18%) were classified as acute myeloid leukemia, and 12 (15%) were classified as myeloproliferative neoplasm. ETNK1 mutations were detected at the first test in 96% of patients, suggesting that ETNK1 mutation is an early event in pathogenesis. ETNK1 mutations represented the …

Validation Of The Alfa-1200 Model In Older Patients With Aml Treated With Intensive Chemotherapy, Hussein A Abbas, Hanxiao Sun, Sherry Pierce, Rashmi Kanagal-Shamanna, Ziyi Li, Musa Yilmaz, Gautam Borthakur, Adam J Dipippo, Elias Jabbour, Marina Konopleva, Nicholas J Short, Courtney Dinardo, Naval Daver, Farhad Ravandi, Tapan M Kadia

Faculty, Staff and Student Publications

No abstract provided.

The P323l Substitution In The Sars-Cov-2 Polymerase (Nsp12) Confers A Selective Advantage During Infection, Hannah Goldswain, Xiaofeng Dong, Rebekah Penrice-Randal, Muhannad Alruwaili, Ghada T Shawli, Tessa Prince, Maia Kavanagh Williamson, Jayna Raghwani, Nadine Randle, Benjamin Jones, I'Ah Donovan-Banfield, Francisco J Salguero, Julia A Tree, Yper Hall, Catherine Hartley, Maximilian Erdmann, James Bazire, Tuksin Jearanaiwitayakul, Malcolm G Semple, Peter J M Openshaw, J Kenneth Baillie, Isaric4c Investigators, Stevan R Emmett, Paul Digard, David A Matthews, Lance Turtle, Alistair C Darby, Andrew D Davidson, Miles W Carroll, Julian A Hiscox

Faculty, Staff and Student Publications

BACKGROUND: The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure.

RESULTS: Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant …