Medical Genetics Commons^™

International Consensus-Driven Recommendations For Patient-Reported Outcome Research Objectives In Early Phase Dose-Finding Oncology Trials: Optimise-Ror, Emily Alger, Olalekan Lee Aiyegbusi, Amylou C Dueck, Anna Minchom, Madeline Pe, John D Peipert, Claire Snyder, Stefan N Symeonides, Roger Wilson, Ethan Basch, Yu Qiao, Susan E Bates, Helen Bulbeck, Lizzie Dean, Massimo Di Maio, Aaron R Hansen, Olga Kholmanskikh, Ken Kobayashi, Dónal Landers, Christophe Le Tourneau, J Jack Lee, Brigette B Y Ma, Lynley V Marshall, Sheetal Patel, Joan Petrie, Gregory R Pond, Kieran Prior, Khadija R Rantell, John F Reeve, Olga Solovyeva, Nolan A Wages, Harald A Weber, Melanie J Calvert, Christina Yap

Faculty, Staff and Student Publications

Purpose: There is growing scientific interest in incorporating patient-reported outcomes (PROs) in early phase dose-finding oncology trials (DFOTs) to assess tolerability, inform dose selection, and guide later stage trial design. However, research indicates that PRO objectives in DFOTs are often unclear. The Incorporating Patient-Reported Outcomes in Dose-Finding Trials-Research Objectives Recommendations (OPTIMISE-ROR) project was established to support trialists to effectively incorporate PROs into DFOTs.

Methods: Using the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework, guideline development included the following: (1) a methodological review of published DFOTs incorporating PROs; (2) candidate item generation, refined through expert consultation; (3) …

Bi-Allelic Variants In Nrdc Cause A Neurodevelopmental Disorder Characterized By Neonatal Lethality, Microcephaly, And Brain Abnormalities, Davut Pehlivan, Abigail Sandoval, Reza Maroofian, François Lecoquierre, Aisha M Al Shamsi, Gyu S Lee, Osman Yesilbas, Preston Taylor, Matthew B Mcdougal, Vahid Bahrambeigi, Omid Aryani, Juan Felipe Ramirez, Khalid Hama Salih, Chadi Al Alam, Heba Morsy, Haytham Hussien, Tarek Omar, Ibrahim M Abdelrazek, Anne Claire Brehin, Dana Marafi, Tugba Kalayci, Jubran Abu Rahma, Jawabreh Kassem Talbeya, Husein Dabbah, Eric Verspyck, Toktam Moosavian, Jawid M Fatih, Tadahiro Mitani, Gulsen Akay, Daniel G Calame, Anne-Marie Guerrot, Wendy K Chung, Henry Houlden, James R Lupski, Adel Shalata, Wan Hee Yoon

Faculty, Staff and Students Publications

Nardilysin (NRDC) plays a role in multiple cellular functions in diverse cellular compartments, including ectodomain shedding in the plasma membrane, as well as chaperoning a key Krebs cycle enzyme in mitochondria. We had previously reported limited clinical information from two individuals with homozygous frameshift variants in NRDC. With inclusion of previously published individuals, here we report 14 individuals (10 females, four males) from nine unrelated families carrying homozygous NRDC pathogenic variants. Common clinical features include severe to profound developmental delay/intellectual disability (12/12), microcephaly (13/13), prematurity (5/13), lethality in the first 3 years of life (9/14), seizures (7/11), joint contractures (4/8), …

Medial Pulvinar Nucleus As A Causal Hub For Heteromodal Naming, Oscar Woolnough, Tessy Thomas, Kathryn M Snyder, Ellery Wheeler, Jay Gavvala, Nitin Tandon

Faculty, Staff and Student Publications

Our ability to retrieve the names of objects in our environment is a fundamental aspect of everyday life. This process requires a complex, dynamic network of cortical and subcortical interactions. While the cortical constituents of this network have been extensively studied with intracranial recordings, the subcortical nodes of the naming network are unclear. We probed the role of the left medial pulvinar nucleus in naming with direct intracranial recordings and stimulation in eight humans (three male, five female) as they named objects using pictures and auditory and written descriptions. We found a spectrotemporal signature of naming in the left medial …

Proteomic Profiling Of Pulmonary Function And Cardiovascular Disease Risk In The Atherosclerosis Risk In Communities Study, Yura Lee, Astrid M Manuel, Ngoc Quynh H Nguyen, Christine Ladd-Acosta, Alanna C Morrison, Kari E North, Eric Boerwinkle, Amil M Shah, Zhongming Zhao, Stephanie J London, Bing Yu

Faculty, Staff and Student Publications

Background: Pulmonary function is linked to cardiovascular disease risk; however, the underlying mechanisms remain unclear. We aimed to identify protein biomarkers associated with pulmonary function and examine their impact on incident chronic obstructive pulmonary disease, coronary heart disease, heart failure, and all-cause mortality.

Methods: Data from White and Black Americans in the Atherosclerosis Risk in Communities study (visit 2: N=11 354, mean age=57 years; visit 5: N=3517, mean age=75 years), a prospective cohort, were analyzed. Linear regression assessed associations between protein levels and pulmonary function measures, including forced expiratory volume in 1 second and forced vital capacity. The impact of …

Pd-L1 Positivity Predicts A Unique Hyperaggressive Tumor Group Within Meng C Meningiomas, Vijay Nitturi, Shervin Hosseingholi Nouri, Collin English, Hsiang-Chih Lu, Elizabeth Ledbetter, Diego Rojas, Sean Lau, Malcolm Mcdonald, Jacob J Mandel, Abdul Basit Khan, Arif O Harmanci, Akdes S Harmanci, Tiemo Klisch, Akash J Patel

Duncan NRI Faculty and Staff Publications

Molecular profiling has identified 3 groups of meningiomas, with MenG C tumors exhibiting the vast majority of recurrences. Efforts to find effective treatments for recurrent meningiomas have remained elusive. Higher WHO-grade meningiomas have exhibited greater Programmed Death Ligand 1 (PD-L1) expression through various methods, but the prognostic value of PD-L1 expression has not been described in the context of molecular profiling. Additionally, trials investigating PD-1/PD-L1-targeted immunotherapies have produced disappointing results. Here, we find that PD-L1 positivity, while prevalent in MenG C tumors, does not predict recurrence in the benign MenG A and B tumors. PD-L1 positivity also occurs independently of …

Influence Of Body Composition On The Efficacy Of Nivolumab Plus Ipilimumab For Metastatic Clear Cell Renal Cell Carcinoma, Kabir Grewal, Maria Julia Moura Nascimento Santos, Pankaj Kumar Chauhan, Kai Yu, Nizar M Tannir, Sagar S Mukhida, Neha Venkatesh, Amishi Y Shah, Amado J Zurita, Andrew C Johns, Matthew T Campbell, Sangeeta Goswami, Jianjun Gao, Eric Jonasch, Jennifer L Mcquade, Omar Alhalabi, Pavlos Msaouel, Andrew W Hahn

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitor therapy (ICI) with nivolumab+ipilimumab is a first-line (1L) standard for metastatic clear cell renal cell carcinoma (ccRCC), yet outcomes remain heterogeneous. Increasing evidence suggests that host factors influence the tumor microenvironment and response to ICI. Although higher body mass index (BMI) has been associated with improved outcomes in several malignancies, BMI is an imprecise surrogate for underlying adipose and muscle compartments. We evaluated the association between body composition and outcomes with 1L nivolumab+ipilimumab in metastatic ccRCC.

Methods: We retrospectively analyzed patients with mccRCC treated with 1L nivolumab+ipilimumab at MD Anderson Cancer Center between June 2015 and …

Ectopic B Lymphocyte Follicles Exacerbate Ischemic Brain Damage Via Mif-Cd74/Cxcr4 And Interferon Signaling, Sheng Yang, Hang Zhang, Lu-Lu Xu, Luo-Qi Zhou, Yun-Hui Chu, Lian Chen, Xiao-Wei Pang, Lu-Yang Zhang, Li-Fang Zhu, Ming-Hao Dong, Ke Shang, Jun Xiao, Long-Jun Wu, Wei Wang, Dai-Shi Tian, Chuan Qin

Faculty, Staff and Student Publications

Neuroinflammation, encompassing both innate and adaptive immune responses, plays a crucial role in ischemic stroke. Although B lymphocytes are central to adaptive immunity, their contributions to ischemic stroke remain poorly understood. Here, we demonstrated that B lymphocytes accumulate in ischemic lesions, forming germinal center-like structures at the later stage after stroke, which mainly depended on in situ proliferation. This accumulation correlated with worsened neuroinflammation and ischemic injury, whereas B cell depletion reduced chronic brain damage during stroke. Mechanistically, microglia recruited B cells into ischemic lesions through MIF-CD74/CXCR4 signaling during the early phase of stroke, while IFN-related pathways in B cells …

Poly(Adp-Ribose) Glycohydrolase Enforces P21 Degradation Via Deparylation To Promote Gastric Cancer Progression, Yangchan Hu, Qimei Bao, Yixing Huang, Yan Wang, Xin Zhao, Junjun Nan, Yuxin Meng, Mingcong Deng, Yuancong Li, Zirui Zhuang, Hanyi He, Dan Zu, Yuke Zhong, Chunkai Zhang, Bing Wang, Ran Li, Yanhua He, Qihan Wang, Min Liu, John A Tainer, Yin Shi, Xiangdong Cheng, Ji Jing, Zu Ye

Faculty, Staff and Student Publications

Dysregulation of cell cycle checkpoints is a cancer hallmark, with ubiquitination-controlled protein stability playing a pivotal role. Although p21, a key cyclin-dependent kinase inhibitor, is tightly regulated by ubiquitin-mediated degradation, the key upstream modulators of its ubiquitination remain incompletely defined. Here, we identify poly(ADP-ribose) glycohydrolase (PARG) as a regulator of p21 stability in gastric cancer (GC) cells. We show that PARG expression is markedly upregulated in GC tissues and correlates with poor patient prognosis. Functional assays revealed that genetic depletion of PARG triggers G2/M phase arrest and impairs GC cell proliferation. Mechanistically, we demonstrate that PARG loss enhances p21 PARylation, …

Mechanometabolism Instructs Hematopoietic Stem Cell Specification, Paulina D Horton, Alina Syed, Michelle Winkler, Abishek B Vaidya, Michael Rariden, Neha Arora, Yong Zhou, Michihiro Kobayashi, Momoko Yoshimoto, Hyun Jung Lee, Hyun-Eui Kim, John P Hagan, Catherine Denicourt, Travis I Moore, Pamela L Wenzel

Faculty, Staff and Student Publications

Mechanical force generated by blood flow stimulates emergence of the first hematopoietic stem cells (HSCs) that populate the blood system. Force drives the transition of HSC precursors from an endothelial to hematopoietic identity, yet the molecular regulation of this fate switch remains poorly understood. We report that shear stress triggers adaptation in mitochondrial composition, ultrastructure, and function, which are essential for hematopoietic fate and engraftment potential. Shear stress remodels mitochondria in hemogenic endothelium by promoting mitochondrial gene transcription and protein synthesis. Laminar flow selectively initiates translation of 5' terminal polypyrimidine (5'TOP) motif-containing transcripts, which commonly encode ribosome and translation machinery. …

Segmental And Multifocal Isolated Dystonias: Similarities And Differences, Hyder A Jinnah, Vittorio Velucci, Daniele Belvisi, Gamze Kilic-Berkmen, Joel S Perlmutter, Laura J Wright, Christine Klein, Jeanne S Feuerstein, Steven Bellows, Joseph Jankovic, Cynthia Comella, Richard L Barbano, Aparna Wagle Shukla, Stephen G Reich, Mark S Ledoux, Alberto J Espay, Kevin R Duque, Florence C F Chang, Victor S C Fung, Sarah Pirio-Richardson, Carmen Terranova, Emile S Moukheiber, Sarah Idrissi, Barbara Vitucci, Susan H Fox, Samuel Frank, Natividad Stover, Brian D Berman, Rachel Saunders-Pullman, William G Ondo, Christopher L Groth, Marcello Esposito, Laura Avanzino, Francesco Bono, Roberto Erro, Marcello Mario Mascia, Antonella Muroni, Alfredo Berardelli, Giovanni Defazio

Faculty, Staff and Students Publications

Background: Whether the traditional distinction between segmental and multifocal dystonia is clinically or scientifically useful remains unclear.

Objective: To evaluate whether idiopathic isolated adult-onset segmental and multifocal dystonia can be differentiated based on clinical features other than the contiguity of affected body regions.

Methods: We compared data on segmental and multifocal dystonia from two large dystonia databases established in the USA and Italy that used similar criteria for patient recruitment and assessment.

Results: Compared to segmental dystonia, multifocal dystonia was characterized by a higher proportion of men, a younger age at dystonia onset, a greater frequency of upper limb dystonia, …

Impulsivity In Cerebellar Ataxia: An Online, Multidimensional Assessment, Brooke Chasalow, Yakov Flaumenhaft, Yael De Picciotto, Chi-Ying R Lin, Leila Montaser-Kouhsari, William Saban

Faculty, Staff and Students Publications

While considered a motor control structure, the cerebellum contributes to non-motor functions, including impulsivity. However, whether it contributes to impulsivity in a domain-specific manner remains unknown. Studies on cerebellar ataxia (CA), a common model for cerebellar dysfunction, typically have small sample sizes, limiting robustness. In a multicenter cross-sectional study, we investigated the cerebellum's role in various forms of impulsivity by comparing large cohorts of CA to age- and education-matched neurotypical healthy (NH) controls. Additionally, to examine the ability to identify individuals with CA using impulsivity features alone, we developed supervised machine learning (ML) models. In experiment 1 (CA = 140, …

Lonp1 Variants Are Associated With Clinically Diverse Phenotypes, Randee E Young, Lu Qiao, Rebecca Hernan, David A Sweetser, Jessica L Waxler, Daryl A Scott, Tiana M Scott, Seema R Lalani, Mahshid S Azamian, Jill A Rosenfeld, Bret Bostwick, Lindsay C Burrage, Lance H Rodan, Bianca E Russell, Marina Dutra-Clarke, Michael Kruer, Somayeh Bakhtiarim, Hossein Darvish, David J Amor, Shamima Rahman, Karen Stals, Lisa Bradley, Susan Byrne, Leandra K Tolusso, Beatrix Wong, Laura Benedict, Kimberly Wallis, Kestutis Micke, Cindy Colson, Thomas Smol, Sabrina V Southwick, Kristen A Miller, Michelle L Kush, Odelia Chorin, Annick Rothschild, Wei Wang, Yufeng Shen, Wendy K Chung

Faculty, Staff and Students Publications

LONP1 encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in LONP1 are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies syndrome (CODAS), congenital diaphragmatic hernia (CDH), and neurodevelopmental disorders (NDD), with some individuals exhibiting features of mitochondrial encephalopathy. We report 16 novel LONP1 variants identified in 16 individuals (11 with NDD, 5 with CDH), further expanding the clinical spectrum. Structural mapping of disease-associated missense variants revealed phenotype-specific clustering, with CODAS variants enriched in the proteolytic chamber and NDD variants more broadly distributed. CODAS is caused by biallelic …

Comparison Of Variant Callers Using 60 532 Multi-Ancestry Whole Genome Sequences, Hufeng Zhou, Zilin Li, Derek Shyr, Xihao Li, Haoyu Yang, Rounak Dey, Yushi Tang, Robert Maier, Eric Boerwinkle, Steve Buyske, Mark Daly, Adam Felsenfeld, Richard A Gibbs, Namrata Gupta, Ira M Hall, Tara Matise, Ginger A Metcalf, Albert Smith, Catherine Reeves, Heidi J Sofia, Nathan O Stitziel, Michael C Zody, Nhgri Genome Sequencing Program (Gsp) Consortium, Benjamin Neale, Xihong Lin

Faculty, Staff and Students Publications

Whole genome sequencing (WGS) studies play a pivotal role in studying the genetic underpinnings of human diseases and traits. High quality and reproducible variant calling is the cornerstone for the success of downstream analyses, including WGS association studies and polygenic risk prediction. This paper compares the data quality, performance, and concordance of two widely used WGS variant callers, the Genome Analysis Toolkit (GATK) and Variant Tool set that discovers short variants (VT), using 60 532 multi-ancestry whole genomes sequenced by the Centers for Common Disease Genomics (CCDGs) of the NHGRI Genome Sequencing Program. Our findings show that both QCed GATK …

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 …

Beyond Short Microhomologies: Mismatch-Compatible Pol Θ-Mediated Dna Damage Repair, Yuzhen Li, Richard D Wood

Faculty, Staff and Student Publications

DNA polymerase θ (Pol θ)-mediated end-joining (TMEJ), one of several pathways for repairing DNA double-strand breaks, is traditionally thought to initiate via anchoring at short, consecutive, and perfectly matched microhomologies (MHs). Emerging evidence indicates that Pol θ can utilize MHs containing mismatches both in vitro and in vivo. This revised definition of MH provides a mechanistic explanation for a broader spectrum of Pol θ-dependent repair outcomes. Here, we summarize recent findings on the revised definition of MHs utilized by Pol θ, assess the applicability of this concept across species, and compare TMEJ with other (micro)hom(e)ology-mediated repair pathways. We explore how …

Spatial Profiling Reveals Distinct Molecular And Immune Evolution Of Mouse Lung Adenocarcinoma Precancers With Or Without Carcinogen Exposure, Bo Zhu, Muhammad Aminu, Pingjun Chen, Jian-Rong Li, Chuanpeng Dong, Chenyang Li, Yanhua Tian, Shao-Wei Lu, Hong Chen, Chenxi Ma, Xin Hu, Jie Ye, Andrew Y Liu, Beibei Huang, Frank R Rojas, Parra Cuentas Edwin Roger, Ou Shi, Monique B Nilsson, Alissa Poteete, Khaja B Khan, Wei Lu, Luisa M Solis Soto, Junya Fujimoto, Cara Haymaker, Ignacio I Wistuba, Zhubo Wei, Linghua Wang, Don L Gibbons, Ken Chen, Alexandre Reuben, Jason M Schenkel, John V Heymach, Chao Cheng, Jia Wu, Jianjun Zhang

Faculty, Staff and Student Publications

Tumor evolution involves genetic, transcriptional, and phenotypic alterations that shape cancer cell behavior and interactions with the microenvironment. While single‐cell technologies have advanced our understanding of this process, spatial dynamics remain incompletely characterized. Here, whole‐exome sequencing (WES), imaging mass cytometry (IMC), and spatial transcriptomics (ST) were integrated to study molecular evolution and immune responses in two lung adenocarcinoma (LUAD) mouse models: a genetically engineered model (129S4/Sv‐KrasLSL‐G12D, termed 129S4 K) and a carcinogen‐induced precancer model (129S4 U). Compared to 129S4 K, 129S4 U tumors exhibited higher mutational, neoantigen but lower copy number variation (CNV) burdens at matched developmental timepoints, consistent with …

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 …

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 …

Linkage Disequilibrium Score Regression Identifies Genetic Correlations Between Hepatocellular Carcinoma And Clinically Relevant Traits, Younghun Han, Vikram R Shaw, Jinyoung Byun, Aaron P Thrift, Catherine Zhu, Donghui Li, Rikita I Hatia, Robin Kate Kelley, Sean P Cleary, Anna S Lok, Paige M Bracci, Jennifer B Permuth, Roxana Bucur, Jennifer Knox, Jian-Min Yuan, Amit G Singal, Prasun K Jalal, R Mark Ghobrial, Yuko Kono, Dimpy P Shah, Mindie H Nguyen, Neehar D Parikh, Richard Kim, Hui-Chen Wu, Hashem El-Serag, Ping Chang, Yun Shin Chun, Jian Gu, Chad Huff, Asif Rashid, Lu-Yu Hwang, Alison P Klein, Saira A Khaderi, Ahmed O Kaseb, Kathrine A Mcglynn, Lewis R Roberts, Manal M Hassan, Christopher I Amos

Faculty, Staff and Students Publications

Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome-wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co-development with hepatitis C virus-negative (HCV-negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV-negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale …

Classification Of Major Depressive Disorder Using Vertex-Wise Brain Sulcal Depth, Curvature, And Thickness With A Deep And A Shallow Learning Model, Roberto Goya-Maldonado, Tracy Erwin-Grabner, Ling-Li Zeng, Christopher R K Ching, Andre Aleman, Alyssa R Amod, Zeynep Basgoze, Francesco Benedetti, Bianca Besteher, Katharina Brosch, Robin Bülow, Romain Colle, Colm G Connolly, Emmanuelle Corruble, Baptiste Couvy-Duchesne, Kathryn Cullen, Udo Dannlowski, Christopher G Davey, Annemiek Dols, Jan Ernsting, Jennifer W Evans, Lukas Fisch, Paola Fuentes-Claramonte, Ali Saffet Gonul, Ian H Gotlib, Hans J Grabe, Nynke A Groenewold, Dominik Grotegerd, Tim Hahn, J Paul Hamilton, Laura K M Han, Ben J Harrison, Tiffany C Ho, Neda Jahanshad, Alec J Jamieson, Andriana Karuk, Tilo Kircher, Bonnie Klimes-Dougan, Sheri-Michelle Koopowitz, Thomas Lancaster, Ramona Leenings, Meng Li, David E J Linden, Frank P Macmaster, David M A Mehler, Susanne Meinert, Elisa Melloni, Bryon A Mueller, Benson Mwangi, Igor Nenadić, Amar Ojha, Yasumasa Okamoto, Mardien L Oudega, Brenda W J H Penninx, Sara Poletti, Edith Pomarol-Clotet, Maria J Portella, Joaquim Radua, Elena Rodríguez-Cano, Matthew D Sacchet, Raymond Salvador, Anouk Schrantee, Kang Sim, Jair C Soares, Aleix Solanes, Dan J Stein, Frederike Stein, Aleks Stolicyn, Sophia I Thomopoulos, Yara J Toenders, Aslihan Uyar-Demir, Eduard Vieta, Yolanda Vives-Gilabert, Henry Völzke, Martin Walter, Heather C Whalley, Sarah Whittle, Nils Winter, Katharina Wittfeld, Margaret J Wright, Mon-Ju Wu, Tony T Yang, Carlos Zarate, Dick J Veltman, Lianne Schmaal, Paul M Thompson, Enigma Major Depressive Disorder Working Group

Faculty, Staff and Student Publications

Major depressive disorder (MDD) is a complex psychiatric disorder that affects the lives of hundreds of millions of individuals around the globe. Even today, researchers debate if morphological alterations in the brain are linked to MDD, likely due to the heterogeneity of this disorder. The application of deep learning tools to neuroimaging data, capable of capturing complex non-linear patterns, has the potential to provide diagnostic and predictive biomarkers for MDD. However, previous attempts to demarcate MDD patients and healthy controls (HC) based on segmented cortical features via linear machine learning approaches have reported low accuracies. In this study, we used …

Frontotemporal Network Interactions Causally Support Rapid Concreteness Judgments During Reading, Elliot Murphy, Oscar Woolnough, Cale W Morse, Xavier Scherschligt, Nitin Tandon

Faculty, Staff and Student Publications

Neurobiological models of conceptual processing have been limited in spatiotemporal resolution, and uncertainty remains about the causal role of specific regions in concept representation. We utilized intracranial recordings in human neurosurgical patients with epilepsy (n = 19) during a concreteness judgement paradigm of single word reading. Concrete concepts showed greater high-frequency activation across a frontal and ventrotemporal network, while greater activation for abstract words was found in lateral posterior middle temporal cortex. Intercortical communications, measured by high-frequency partial direct coherence, revealed bidirectional frontal and ventral plus lateral temporal interactions. Words occupying the middle range of the concreteness scale (e.g., "profit") …

Quantifying Rate-Limiting Genetic Variation In Breast And Ovarian Tumourigenesis, Kathleen E Houlahan, Mahad Bihie, Yves Greatti, Julián Grandvallet Contreras, Daniel J Fulop, Gonzalo Lopez, Marc Williams, Hsin-Hsiung Huang, Peter Van Loo, Paul C Boutros, Kuan-Lin Huang

Faculty, Staff and Student Publications

Background: The number and type of genetic alterations required to initiate breast and ovarian cancer remain unclear. While germline BRCA1/2 carriers show markedly elevated cancer risk, it is uncertain whether point mutations or copy number alterations constitute the rate-limiting events of tumourigenesis.

Methods: We developed a statistical framework extending prior incidence-mutation models to estimate the minimal number and type of driver events required for cancer initiation. Somatic mutation and copy-number data from >3000 breast and ovarian cancers in TCGA and METABRIC were compared between germline BRCA1/2 carriers and non-carriers matched on subtypes. Results were validated through analyses of evolutionary timing …

Cd44v9 As A Therapeutic Target For Antibody-Drug Conjugate In Advanced Breast Cancer, Dileep R Reddy, Mckenna E Flynn, Yasuaki Anami, Zhaoxuan Yang, Jayden Aleman, Minji Seo, Kyoji Tsuchikama, Jennifer A Maynard, Naoto T Ueno, Jangsoon Lee

Faculty, Staff and Student Publications

Antibody-drug conjugates (ADCs) have revolutionized breast cancer therapy. HER2 is the only validated biomarker guiding ADC therapy in breast cancer. However, their clinical benefit remains confined to HER2- and TROP2-targeted therapies. Tumor heterogeneity and acquired resistance often limit durable responses, underscoring the need for novel, tumor-specific ADC targets. CD44 variant isoform 9 (CD44v9), a splice variant of the CD44 family, is largely absent in normal tissues but enriched in aggressive breast cancers, where it contributes to stemness, redox regulation, and therapy resistance. In this study, we developed a chimeric monoclonal antibody against CD44v9 (clone SUM24.1, IgG1) and conjugated it to …

Tuscan: Tumor Segmentation And Classification Analysis In Spatial Transcriptomics, Chenxuan Zang, Charles C Guo, Yaohong Wang, Peng Wei, Ziyi Li

Faculty, Staff and Student Publications

The identification of tumor cells is pivotal for understanding tumor heterogeneity and the tumor microenvironment. Recent advances in spatially resolved transcriptomics (SRT) have revolutionized the way that transcriptomic profiles are characterized and have enabled the simultaneous quantification of transcript locations in intact tissue samples. SRT is a promising alternative method to study gene expression patterns in spatial domains. Nevertheless, the precise detection of tumor regions within intact tissue remains a great challenge. A common strategy for identifying tumor cells is via tumor-specific marker gene expression signatures, which are highly dependent on marker accuracy. Another effective approach is through aneuploid copy …

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 …

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 …

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 …

Segmental Tracheal Resection For Thyroid Cancer: Perioperative Morbidity, Locoregional Control, And Survival, Anastasios Maniakas, David C Wilde, Isabelle Fournier, Emily K Hyde, Li Xu, Jennifer R Wang, Neil D Gross, Erich M Sturgis, Victoria Banuchi, Naifa L Busaidy, Maria E Cabanillas, Priyanka Iyer, Ramona Dadu, Steven G Waguespack, Mimi I Hu, G Brandon Gunn, Michael Kwon, Salmaan Ahmed, Michelle D Williams, Mark E Zafereo

Faculty, Staff and Student Publications

Background: Segmental tracheal resection is rarely needed for advanced thyroid cancer but is among the most complex, high-risk thyroid surgeries.

Methods: Retrospective study of patients undergoing segmental tracheal resection for thyroid cancer at MD Anderson Cancer Center (2005-2024).

Results: We identified 120 patients with a median follow-up of 4.6 years (range 0.02-16.38). Papillary thyroid cancer was most common (68%). The median number of tracheal rings resected was 4 (range 1-9). Seventeen (14%) patients had a new tracheostomy placed at the time of surgery, with 11 (9%) remaining trach-dependent at last follow-up. Twenty-six (22%) patients had a return to the operating …

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, …

Physical Activity In Osteosarcoma Patients During And Post Therapy: A Single Site Prospective Observational Study, Elysia R Cohen, Clark Andersen, Karen Moody, Maria C Swartz, Michael C Robertson, Alakh Rajan, Theresa Honey, Sandra Lugo, Grace Waterman, Keri Schadler

Faculty, Staff and Student Publications

PURPOSE: Osteosarcoma is the most common primary bone tumor in childhood and adolescence. Many patients face long-term impairments in their mobility and function after treatment, leading to a decrease in their quality of life. Exercise has been shown to improve functional recovery and improve quality of life in patients with cancer, though data specific to children with osteosarcoma are sparse. Exercise has also been shown to be feasible in patients undergoing chemotherapy, with numerous potential benefits to health and quality of life. To design the most effective exercise interventions for children and adolescents with osteosarcoma, we must first understand the …