Digital Commons Network^™

Hyperphosphorylated Tau In Mesial Temporal Lobe Epilepsy: A Neuropathological And Cognitive Study, Eliana C B Toscano, Érica L M Vieira, Lea T Grinberg, Natalia P Rocha, Joseane A S Brant, Regina S Paradela, Alexandre V Giannetti, Claudia K Suemoto, Renata E P Leite, Ricardo Nitrini, Milene A Rachid, Antonio L Teixeira

Faculty, Staff and Student Publications

Temporal lobe epilepsy (TLE) often courses with cognitive deficits, but its underlying neuronal basis remains unclear. Confluent data suggest that epilepsy share pathophysiological mechanisms with neurodegenerative diseases. However, as most studies analyze subjects 60 years old and older, it is challenging to rule out that neurodegenerative changes arise from age-related mechanisms rather than epilepsy in these individuals. To fill this gap, we conducted a neuropathological investigation of the hippocampal formation of 22 adults with mesial TLE and 20 age- and sex-matched controls (both younger than 60 years). Moreover, we interrogated the relationship between these neuropathological metrics and cognitive performance. Hippocampal …

Genomic-Transcriptomic Evolution In Lung Cancer And Metastasis, Carlos Martínez-Ruiz, James R M Black, Clare Puttick, Mark S Hill, Jonas Demeulemeester, Elizabeth Larose Cadieux, Kerstin Thol, Thomas P Jones, Selvaraju Veeriah, Cristina Naceur-Lombardelli, Antonia Toncheva, Paulina Prymas, Andrew Rowan, Sophia Ward, Laura Cubitt, Foteini Athanasopoulou, Oriol Pich, Takahiro Karasaki, David A Moore, Roberto Salgado, Emma Colliver, Carla Castignani, Michelle Dietzen, Ariana Huebner, Maise Al Bakir, Miljana Tanić, Thomas B K Watkins, Emilia L Lim, Ali M Al-Rashed, Danny Lang, James Clements, Daniel E Cook, Rachel Rosenthal, Gareth A Wilson, Alexander M Frankell, Sophie De Carné Trécesson, Philip East, Nnennaya Kanu, Kevin Litchfield, Nicolai J Birkbak, Allan Hackshaw, Stephan Beck, Peter Van Loo, Mariam Jamal-Hanjani, Charles Swanton, Nicholas Mcgranahan

Faculty, Staff and Student Publications

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression …

The Evolution Of Non-Small Cell Lung Cancer Metastases In Tracerx, Maise Al Bakir, Ariana Huebner, Carlos Martínez-Ruiz, Kristiana Grigoriadis, Thomas B K Watkins, Oriol Pich, David A Moore, Selvaraju Veeriah, Sophia Ward, Joanne Laycock, Diana Johnson, Andrew Rowan, Maryam Razaq, Mita Akther, Cristina Naceur-Lombardelli, Paulina Prymas, Antonia Toncheva, Sonya Hessey, Michelle Dietzen, Emma Colliver, Alexander M Frankell, Abigail Bunkum, Emilia L Lim, Takahiro Karasaki, Christopher Abbosh, Crispin T Hiley, Mark S Hill, Daniel E Cook, Gareth A Wilson, Roberto Salgado, Emma Nye, Richard Kevin Stone, Dean A Fennell, Gillian Price, Keith M Kerr, Babu Naidu, Gary Middleton, Yvonne Summers, Colin R Lindsay, Fiona H Blackhall, Judith Cave, Kevin G Blyth, Arjun Nair, Asia Ahmed, Magali N Taylor, Alexander James Procter, Mary Falzon, David Lawrence, Neal Navani, Ricky M Thakrar, Sam M Janes, Dionysis Papadatos-Pastos, Martin D Forster, Siow Ming Lee, Tanya Ahmad, Sergio A Quezada, Karl S Peggs, Peter Van Loo, Caroline Dive, Allan Hackshaw, Nicolai J Birkbak, Simone Zaccaria, Tracerx Consortium, Mariam Jamal-Hanjani, Nicholas Mcgranahan, Charles Swanton

Faculty, Staff and Student Publications

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% …

The Evolution Of Lung Cancer And Impact Of Subclonal Selection In Tracerx, Alexander M Frankell, Michelle Dietzen, Maise Al Bakir, Emilia L Lim, Takahiro Karasaki, Sophia Ward, Selvaraju Veeriah, Emma Colliver, Ariana Huebner, Abigail Bunkum, Mark S Hill, Kristiana Grigoriadis, David A Moore, James R M Black, Wing Kin Liu, Kerstin Thol, Oriol Pich, Thomas B K Watkins, Cristina Naceur-Lombardelli, Daniel E Cook, Roberto Salgado, Gareth A Wilson, Chris Bailey, Mihaela Angelova, Robert Bentham, Carlos Martínez-Ruiz, Christopher Abbosh, Andrew G Nicholson, John Le Quesne, Dhruva Biswas, Rachel Rosenthal, Clare Puttick, Sonya Hessey, Claudia Lee, Paulina Prymas, Antonia Toncheva, Jon Smith, Wei Xing, Jerome Nicod, Gillian Price, Keith M Kerr, Babu Naidu, Gary Middleton, Kevin G Blyth, Dean A Fennell, Martin D Forster, Siow Ming Lee, Mary Falzon, Madeleine Hewish, Michael J Shackcloth, Eric Lim, Sarah Benafif, Peter Russell, Ekaterini Boleti, Matthew G Krebs, Jason F Lester, Dionysis Papadatos-Pastos, Tanya Ahmad, Ricky M Thakrar, David Lawrence, Neal Navani, Sam M Janes, Caroline Dive, Fiona H Blackhall, Yvonne Summers, Judith Cave, Teresa Marafioti, Javier Herrero, Sergio A Quezada, Karl S Peggs, Roland F Schwarz, Peter Van Loo, Daniël M Miedema, Nicolai J Birkbak, Crispin T Hiley, Allan Hackshaw, Simone Zaccaria, Mariam Jamal-Hanjani, Nicholas Mcgranahan, Charles Swanton

Faculty, Staff and Student Publications

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) …

Evolutionary Characterization Of Lung Adenocarcinoma Morphology In Tracerx, Takahiro Karasaki, David A Moore, Selvaraju Veeriah, Cristina Naceur-Lombardelli, Antonia Toncheva, Neil Magno, Sophia Ward, Maise Al Bakir, Thomas B K Watkins, Kristiana Grigoriadis, Ariana Huebner, Mark S Hill, Alexander M Frankell, Christopher Abbosh, Clare Puttick, Haoran Zhai, Francisco Gimeno-Valiente, Sadegh Saghafinia, Nnennaya Kanu, Michelle Dietzen, Oriol Pich, Emilia L Lim, Carlos Martínez-Ruiz, James R M Black, Dhruva Biswas, Brittany B Campbell, Claudia Lee, Emma Colliver, Katey S S Enfield, Sonya Hessey, Crispin T Hiley, Simone Zaccaria, Kevin Litchfield, Nicolai J Birkbak, Elizabeth Larose Cadieux, Jonas Demeulemeester, Peter Van Loo, Prasad S Adusumilli, Kay See Tan, Waseem Cheema, Francisco Sanchez-Vega, David R Jones, Natasha Rekhtman, William D Travis, Allan Hackshaw, Teresa Marafioti, Roberto Salgado, John Le Quesne, Andrew G Nicholson, Tracerx Consortium, Nicholas Mcgranahan, Charles Swanton, Mariam Jamal-Hanjani

Faculty, Staff and Student Publications

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions …

Autologous Stem Cell Transplantation For Patients With Multiple Myeloma With Translocation (4;14): The Md Anderson Cancer Center Experience, Oren Pasvolsky, Mahmoud R Gaballa, Denái R Milton, Adeel Masood, Sophiya S Sami, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Jeremy Ramdial, Yago Nieto, Guilin Tang, Pei Lin, Hans C Lee, Krina K Patel, Partow Kebriaei, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Elizabeth J Shpall, Richard E Champlin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Translocation between chromosomes 4 and 14, t(4;14), has been reported in 15% of patients with multiple myeloma (MM) and is considered a high-risk cytogenetic abnormality associated with inferior outcomes. Autologous hematopoietic stem cell transplantation (auto-HCT) is standard of care for patients with high-risk MM, yet there are scarce data on post-transplantation outcomes of patients with t(4;14) MM. The aim of the present study was to evaluate outcomes of MM patients with t(4;14) who underwent auto-HCT and received contemporary anti-myeloma agents for induction and post-transplantation maintenance. We conducted a retrospective analysis of MM patients with t(4;14), detected by fluorescence in situ …

Fear Of Recurrence, Emotional Well-Being And Quality Of Life Among Long-Term Advanced Ovarian Cancer Survivors, Kathryn Osann, Lari Wenzel, Chelsea Mckinney, Lynne Wagner, David Cella, Giulia Fulci, Mary J Scroggins, Heather A Lankes, Victoria Wang, Kenneth P Nephew, George L Maxwell, Samuel C Mok, Thomas P Conrads, Austin Miller, Michael Birrer

Faculty, Staff and Student Publications

OBJECTIVE: Although advanced stage epithelial ovarian cancer is widely considered life-threatening, 17% of women with advanced disease will survive long-term. Little is known about the health-related quality of life (QOL) of long-term ovarian cancer survivors, or how fear of recurrence might affect QOL.

METHODS: 58 long-term survivors with advanced disease participated in the study. Participants completed standardized questionnaires to capture cancer history, QOL, and fear of recurrent disease (FOR). Statistical analyses included multivariable linear models.

RESULTS: Participants averaged 52.8 years at diagnosis and had survived >8 years (mean:13.5); 64% had recurrent disease. Mean FACT-G, FACT-O, and FACT-O-TOI (TOI) scores were …

The Glycoprotein Cd147 Defines Mirna-Enriched Extracellular Vesicles That Derive From Cancer Cells, Song Yi Ko, Wonjae Lee, Melanie Weigert, Eric Jonasch, Ernst Lengyel, Honami Naora

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) are ideal for liquid biopsy, but distinguishing cancer cell‐derived EVs and subpopulations of biomarker‐containing EVs in body fluids has been challenging. Here, we identified that the glycoproteins CD147 and CD98 define subpopulations of EVs that are distinct from classical tetraspanin+ EVs in their biogenesis. Notably, we identified that CD147+ EVs have substantially higher microRNA (miRNA) content than tetraspanin+ EVs and are selectively enriched in miRNA through the interaction of CD147 with heterogeneous nuclear ribonucleoprotein A2/B1. Studies using mouse xenograft models showed that CD147+ EVs predominantly derive from cancer cells, whereas the majority of tetraspanin+ EVs are not …

Emerging Role Of Tak1 In The Regulation Of Skeletal Muscle Mass, Anirban Roy, Vihang A Narkar, Ashok Kumar

Faculty, Staff and Student Publications

Maintenance of skeletal muscle mass and strength throughout life is crucial for heathy living and longevity. Several signaling pathways have been implicated in the regulation of skeletal muscle mass in adults. TGF-β-activated kinase 1 (TAK1) is a key protein, which coordinates the activation of multiple signaling pathways. Recently, it was discovered that TAK1 is essential for the maintenance of skeletal muscle mass and myofiber hypertrophy following mechanical overload. Forced activation of TAK1 in skeletal muscle causes hypertrophy and attenuates denervation-induced muscle atrophy. TAK1-mediated signaling in skeletal muscle promotes protein synthesis, redox homeostasis, mitochondrial health, and integrity of neuromuscular junctions. In …

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 …

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 …

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 …

Interstitial Lung Disease In Veterans: Leveraging Big Data To Bridge Evidence And Practice Gaps, Bhavika Kaul, Laura A Petersen, Ivan O Rosas, Joyce S Lee, Fernando J Martinez, Venkata D Bandi, Drew A Helmer, Paul J Wolters, Harold R Collard, Mary A Whooley

Faculty, Staff and Students Publications

No abstract provided.

Paving The Road For Chimeric Antigen Receptor T Cells: American Society For Transplantation And Cellular Therapy 80/20 Task Force Consensus On Challenges And Solutions To Improving Efficiency Of Clinical Center Certification And Maintenance Of Operations For Commercially Approved Immune Effector Cell Therapies, Sarah Nikiforow, Matthew J Frigault, Noelle V Frey, Rebecca A Gardner, Krishna V Komanduri, Miguel-Angel Perales, Partow Kebriaei, Phyllis Irene Warkentin, Marcelo Pasquini, Joy Lynn Aho, Bruce L Levine, Helen E Heslop, Tracey L Hlucky, Karen Habucky, Mecide Gharibo, Madan Jagasia, Frederick L Locke

Faculty, Staff and Students Publications

As the number and type of regulatory authority-approved cellular therapies grow, clinical treatment centers face a heavy burden of duplicative documentation around initial qualification, ongoing auditing, and reporting, with overlapping requirements from each manufacturer to ensure safe use of their specific product, which in the United States are stipulated under individual Food and Drug Administration (FDA) Biologic License Applications. The American Society for Transplantation and Cellular Therapy (ASTCT) convened the 80/20 Task Force to consider challenges and potential solutions to these issues. The Task Force proposed that 80% of manufacturers' requirements for onboarding and ongoing operations of commercially available products …

Associations Between Perceived Racial Discrimination, Racial Residential Segregation, And Cancer Screening Adherence Among Low-Income African Americans: A Multilevel, Cross-Sectional Analysis, Lynn N Ibekwe, Maria Eugenia Fernández-Esquer, Sandi L Pruitt, Nalini Ranjit, Maria E Fernández

Faculty, Staff and Student Publications

OBJECTIVES: African Americans suffer disproportionately from cancer compared to their White counterparts. Racism may be an important determinant, but the literature on its association with cancer screening is limited. We examine associations between racism and cancer screening among a sample of African Americans.

DESIGN: Guided by the Public Health Critical Race Praxis and the Behavioral Model of Health Services Use, we conducted a multilevel, cross-sectional study using cancer risk assessment data collected from 405 callers to the 2-1-1 Texas helpline. We merged these data with contextual data from the U.S. Census Bureau. We assessed perceived racial discrimination using the Experiences …

Accurate Detection Of Α-Synuclein Seeds In Cerebrospinal Fluid From Isolated Rapid Eye Movement Sleep Behavior Disorder And Patients With Parkinson's Disease In The Denovo Parkinson (Denopa) Cohort, Luis Concha-Marambio, Sandrina Weber, Carly M Farris, Mohammed Dakna, Elisabeth Lang, Tamara Wicke, Yihua Ma, Maritta Starke, Jens Ebentheuer, Friederike Sixel-Döring, Maria-Lucia Muntean, Sebastian Schade, Claudia Trenkwalder, Claudio Soto, Brit Mollenhauer

Faculty, Staff and Student Publications

BACKGROUND: Misfolded α-synuclein (αSyn) aggregates (αSyn-seeds) in cerebrospinal fluid (CSF) are biomarkers for synucleinopathies such as Parkinson's disease (PD). αSyn-seeds have been detected in prodromal cases with isolated rapid eye movement sleep behavior disorder (iRBD).

OBJECTIVES: The objective of this study was to determine the accuracy of the αSyn-seed amplification assay (αS-SAA) in a comprehensively characterized cohort with a high proportion of PD and iRBD CSF samples collected at baseline.

METHODS: We used a high-throughput αS-SAA to analyze 233 blinded CSF samples from 206 participants of the DeNovo Parkinson Cohort (DeNoPa) (113 de novo PD, 64 healthy controls, 29 iRBD …

Integrative Clinical And Genomic Characterization Of Mtap-Deficient Metastatic Urothelial Cancer, Omar Alhalabi, Yueting Zhu, Ameer Hamza, Wei Qiao, Yiyun Lin, Raymond M Wang, Amishi Y Shah, Matthew T Campbell, Vijaykumar Holla, Ashish Kamat, Wei-Lien Wang, Jennifer Wang, Jianfeng Chen, Jieru Meng, Miao Zhang, Jolanta Bondaruk, Mark Titus, Giannicola Genovese, Bogdan A Czerniak, Kenna R Shaw, Funda Meric-Bernstam, Charles C Guo, Christopher J Logothetis, Arlene Siefker-Radtke, Pavlos Msaouel, Linghua Wang, Jiyan Liu, Jianjun Gao

Faculty, Staff and Student Publications

Deficiency of MTAP (MTAPdef) mainly occurs because of homozygous loss of chromosome 9p21, which is the most common copy-number loss in metastatic urothelial cancer (mUC). We characterized the clinical and genomic features of MTAPdef mUC in 193 patients treated at MD Anderson Cancer Center (MDACC) and 298 patients from the phase 2 IMvigor210 trial, which investigated atezolizumab in cisplatin-ineligible and platinum-refractory disease. In the MDACC cohort, visceral metastases were significantly more common for MTAPdef (n = 48) than for MTAP-proficient (MTAPprof; n = 145) patients (75% vs 55.2%; p = 0.02). MTAPdef was associated with poor prognosis (median overall …

Impact Of Common Vitamin D-Binding Protein Isoforms On Supplemental Vitamin D3 And/Or Calcium Effects On Colorectal Adenoma Recurrence Risk: A Secondary Analysis Of A Randomized Clinical Trial, David Corley Gibbs, Elizabeth L Barry, Veronika Fedirko, John A Baron, Roberd M Bostick

Faculty, Staff and Student Publications

IMPORTANCE: Variants in the vitamin D-binding protein (DBP) gene (GC) encode DBP isoforms that may affect vitamin D metabolism. However, whether these isoforms modify the effects of vitamin D3 and/or calcium supplementation on colorectal adenoma recurrence is unclear. We hypothesized that supplementation effects may be stronger among those with the DBP2 isoform (encoded by the rs4588*A allele), which is associated with vitamin D deficiency and modified the associations of circulating vitamin D with risk for colorectal neoplasms in observational studies.

OBJECTIVE: To estimate supplemental vitamin D3 and/or calcium effects on colorectal adenoma recurrence according to 3 common DBP isoforms (DBP1s, …

Emotional, Behavioral, And Physical Health Consequences Of Loneliness In Young Adult Survivors Of Childhood Cancer: Results From The Childhood Cancer Survivor Study, Chiara Papini, Ameera A Fayad, Mingjuan Wang, Fiona S M Schulte, I-Chan Huang, Yu-Ping Chang, Rebecca M Howell, Deokumar Srivastava, Wendy M Leisenring, Gregory T Armstrong, Todd M Gibson, Leslie L Robison, Kevin C Oeffinger, Kevin R Krull, Tara M Brinkman

Faculty, Staff and Student Publications

Background: Young adults in the general population are at risk of experiencing loneliness, which has been associated with physical and mental health morbidities. The prevalence and consequences of loneliness in young adult survivors of childhood cancer remain unknown.

Methods: A total of 9664 young adult survivors of childhood cancer (median age at diagnosis 10.5 years [interquartile range (IQR), 5-15], 27.1 years at baseline [IQR, 23-32]) and 2221 siblings enrolled in the Childhood Cancer Survivor Study completed a self-reported survey question assessing loneliness on the Brief Symptom Inventory-18 at baseline and follow-up (median follow-up, 6.6 years). Multivariable models evaluated the prevalence …

Data Partitioning And Statistical Considerations For Association Of Radiomic Features To Biological Underpinnings: What Is Needed, Michael A Jacobs

Faculty, Staff and Student Publications

No abstract provided.

Letter To The Editor: Quality Criteria For Computational Models Predicting Individual Outcomes In Car-T Cell Therapy, Anna M Mc Laughlin, Cassian Yee

Faculty, Staff and Student Publications

No abstract provided.

Quality Assurance Assessment Of Intra-Acquisition Diffusion-Weighted And T2-Weighted Magnetic Resonance Imaging Registration And Contour Propagation For Head And Neck Cancer Radiotherapy, Mohamed A Naser, Kareem A Wahid, Sara Ahmed, Vivian Salama, Cem Dede, Benjamin W Edwards, Ruitao Lin, Brigid Mcdonald, Travis C Salzillo, Renjie He, Yao Ding, Moamen Abobakr Abdelaal, Daniel Thill, Nicolette O'Connell, Virgil Willcut, John P Christodouleas, Stephen Y Lai, Clifton D Fuller, Abdallah S R Mohamed

Faculty, Staff and Student Publications

BACKGROUND/PURPOSE: Adequate image registration of anatomical and functional magnetic resonance imaging (MRI) scans is necessary for MR-guided head and neck cancer (HNC) adaptive radiotherapy planning. Despite the quantitative capabilities of diffusion-weighted imaging (DWI) MRI for treatment plan adaptation, geometric distortion remains a considerable limitation. Therefore, we systematically investigated various deformable image registration (DIR) methods to co-register DWI and T2-weighted (T2W) images.

MATERIALS/METHODS: We compared three commercial (ADMIRE, Velocity, Raystation) and three open-source (Elastix with default settings [Elastix Default], Elastix with parameter set 23 [Elastix 23], Demons) post-acquisition DIR methods applied to T2W and DWI MRI images acquired during the same …

A Non-Antibiotic-Disrupted Gut Microbiome Is Associated With Clinical Responses To Cd19-Car-T Cell Cancer Immunotherapy, Christoph K Stein-Thoeringer, Neeraj Y Saini, Eli Zamir, Viktoria Blumenberg, Maria-Luisa Schubert, Uria Mor, Matthias A Fante, Sabine Schmidt, Eiko Hayase, Tomo Hayase, Roman Rohrbach, Chia-Chi Chang, Lauren Mcdaniel, Ivonne Flores, Rogier Gaiser, Matthias Edinger, Daniel Wolff, Martin Heidenreich, Paolo Strati, Ranjit Nair, Dai Chihara, Luis E Fayad, Sairah Ahmed, Swaminathan P Iyer, Raphael E Steiner, Preetesh Jain, Loretta J Nastoupil, Jason Westin, Reetakshi Arora, Michael L Wang, Joel Turner, Meghan Menges, Melanie Hidalgo-Vargas, Kayla Reid, Peter Dreger, Anita Schmitt, Carsten Müller-Tidow, Frederick L Locke, Marco L Davila, Richard E Champlin, Christopher R Flowers, Elizabeth J Shpall, Hendrik Poeck, Sattva S Neelapu, Michael Schmitt, Marion Subklewe, Michael D Jain, Robert R Jenq, Eran Elinav

Faculty, Staff and Student Publications

Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n = 66; United States, n = 106; total, n = 172), we demonstrate that wide-spectrum antibiotics treatment ('high-risk antibiotics') prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals …

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, …

Integrated Analysis Of Racial Disparities In Genomic Architecture Identifies A Trans-Ancestry Prognostic Subtype In Bladder Cancer, Baifeng Zhang, Peilin Jia, Jiayin Wang, Guangsheng Pei, Changxi Wang, Shimei Pei, Xiangchun Li, Zhongming Zhao, Xin Yi, Xin-Yuan Guan, Yi Huang

Faculty, Staff and Student Publications

The incidence of bladder cancer and patient survival vary greatly among different populations, but the influence of the associated molecular features and evolutionary processes on its clinical treatment and prognostication remains unknown. Here, we analyze the genomic architectures of 505 bladder cancer patients from Asian/Black/White populations. We identify a previously unknown association between AHNAK mutations and activity of the APOBEC-a mutational signature, the activity of which varied substantially across populations. All significantly mutated genes but only half of arm-level somatic copy number alterations (SCNAs) are enriched with clonal events, indicating large-scale SCNAs as rich sources of bladder cancer clonal diversities. …

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.

Evaluating The Causal Effect Of Tobacco Smoking On White Matter Brain Aging: A Two-Sample Mendelian Randomization Analysis In Uk Biobank, Chen Mo, Jingtao Wang, Zhenyao Ye, Hongjie Ke, Song Liu, Kathryn Hatch, Si Gao, Jessica Magidson, Chixiang Chen, Braxton D Mitchell, Peter Kochunov, L Elliot Hong, Tianzhou Ma, Shuo Chen

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Tobacco smoking is a risk factor for impaired brain function, but its causal effect on white matter brain aging remains unclear. This study aimed to measure the causal effect of tobacco smoking on white matter brain aging.

DESIGN: Mendelian randomization (MR) analysis using two non-overlapping data sets (with and without neuroimaging data) from UK Biobank (UKB). The group exposed to smoking and control group consisted of current smokers and never smokers, respectively. Our main method was generalized weighted linear regression with other methods also included as sensitivity analysis.

SETTING: United Kingdom.

PARTICIPANTS: The study cohort included 23 …

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 …

Dnmt3a-Coordinated Splicing Governs The Stem State Switch Towards Differentiation In Embryonic And Haematopoietic Stem Cells, Raghav Ramabadran, Jarey H Wang, Jaime M Reyes, Anna G Guzman, Sinjini Gupta, Carina Rosas, Lorenzo Brunetti, Michael C Gundry, Ayala Tovy, Hali Long, Tianpeng Gu, Sean M Cullen, Siddhartha Tyagi, Danielle Rux, Jean J Kim, Steven M Kornblau, Michael Kyba, Fabio Stossi, Rachel E Rau, Koichi Takahashi, Thomas F Westbrook, Margaret A Goodell

Faculty, Staff and Student Publications

Upon stimulation by extrinsic stimuli, stem cells initiate a programme that enables differentiation or self-renewal. Disruption of the stem state exit has catastrophic consequences for embryogenesis and can lead to cancer. While some elements of this stem state switch are known, major regulatory mechanisms remain unclear. Here we show that this switch involves a global increase in splicing efficiency coordinated by DNA methyltransferase 3α (DNMT3A), an enzyme typically involved in DNA methylation. Proper activation of murine and human embryonic and haematopoietic stem cells depends on messenger RNA processing, influenced by DNMT3A in response to stimuli. DNMT3A coordinates splicing through recruitment …

Whole Genome Analysis Of Venous Thromboembolism: The Trans-Omics For Precision Medicine Program, Amanda A Seyerle, Cecelia A Laurie, Brandon J Coombes, Deepti Jain, Matthew P Conomos, Jennifer Brody, Ming-Huei Chen, Stephanie M Gogarten, Kathleen M Beutel, Namrata Gupta, Susan R Heckbert, Rebecca D Jackson, Andrew D Johnson, Darae Ko, Joann E Manson, Barbara Mcknight, Ginger A Metcalf, Alanna C Morrison, Alexander P Reiner, Tamar Sofer, Weihong Tang, Kerri L Wiggins, Trans-Omics For Precision Medicine Program, Eric Boerwinkle, Mariza De Andrade, Stacey B Gabriel, Richard A Gibbs, Cathy C Laurie, Bruce M Psaty, Ramachandran S Vasan, Ken Rice, Charles Kooperberg, James S Pankow, Nicholas L Smith, Nathan Pankratz

Faculty, Staff and Student Publications

BACKGROUND: Risk for venous thromboembolism has a strong genetic component. Whole genome sequencing from the TOPMed program (Trans-Omics for Precision Medicine) allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies.

METHODS: The 3793 cases and 7834 controls (11.6% of cases were individuals of African, Hispanic/Latino, or Asian ancestry) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants).

RESULTS: Single variant analyses identified associations at 5 known loci. Aggregate …