Medical Genetics Commons^™

Ape-Gen20: Expanding Rapid Class I Peptide-Major Histocompatibility Complex Modeling To Post-Translational Modifications And Noncanonical Peptide Geometries, Romanos Fasoulis, Mauricio M Rigo, Gregory Lizée, Dinler A Antunes, Lydia E Kavraki

Faculty, Staff and Student Publications

The recognition of peptides bound to class I major histocompatibility complex (MHC-I) receptors by T-cell receptors (TCRs) is a determinant of triggering the adaptive immune response. While the exact molecular features that drive the TCR recognition are still unknown, studies have suggested that the geometry of the joint peptide–MHC (pMHC) structure plays an important role. As such, there is a definite need for methods and tools that accurately predict the structure of the peptide bound to the MHC-I receptor. In the past few years, many pMHC structural modeling tools have emerged that provide high-quality modeled structures in the general case. …

Grb2 Stabilizes Rad51 At Reversed Replication Forks Suppressing Genomic Instability And Innate Immunity Against Cancer, Zu Ye, Shengfeng Xu, Yin Shi, Xueqian Cheng, Yuan Zhang, Sunetra Roy, Sarita Namjoshi, Michael A Longo, Todd M Link, Katharina Schlacher, Guang Peng, Dihua Yu, Bin Wang, John A Tainer, Zamal Ahmed

Faculty, Staff and Student Publications

Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adapter for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS-STING pathway to trigger pro-inflammatory cytokine production. Moreover in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment …

Protein Biomarkers And Alternatively Methylated Cell-Free Dna Detect Early Stage Pancreatic Cancer, Roni Ben-Ami, Qiao-Li Wang, Jinming Zhang, Julianna G Supplee, Johannes F Fahrmann, Roni Lehmann-Werman, Lauren K Brais, Jonathan Nowak, Chen Yuan, Maureen Loftus, Ana Babic, Ehsan Irajizad, Tal Davidi, Aviad Zick, Ayala Hubert, Daniel Neiman, Sheina Piyanzin, Ofer Gal-Rosenberg, Amit Horn, Ruth Shemer, Benjamin Glaser, Natalia Boos, Kunal Jajoo, Linda Lee, Thomas E Clancy, Douglas A Rubinson, Kimmie Ng, John A Chabot, Fay Kastrinos, Michael Kluger, Andrew J Aguirre, Pasi A Jänne, Nabeel Bardeesy, Ben Stanger, Mark H O'Hara, Jacob Till, Anirban Maitra, Erica L Carpenter, Andrea J Bullock, Jeanine Genkinger, Samir M Hanash, Cloud P Paweletz, Yuval Dor, Brian M Wolpin

Faculty, Staff and Student Publications

Objective: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed.

Design: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites.

Results: Comparative methylome analysis identified nine loci that were differentially …

Safety, Tolerability, And Dose-Limiting Toxicity Of Lacosamide In Patients With Painful Chronic Pancreatitis: Protocol For A Phase 1 Clinical Trial To Determine Safety And Identify Side Effects, Evan L Fogel, Jeffrey J Easler, Ying Yuan, Dhiraj Yadav, Darwin L Conwell, Santhi Swaroop Vege, Samuel Y Han, Walter Park, Vanessa Patrick, Fletcher A White

Faculty, Staff and Student Publications

Background: Chronic abdominal pain is the hallmark symptom of chronic pancreatitis (CP), with 50% to 80% of patients seeking medical attention for pain control. Although several management options are available, outcomes are often disappointing, and opioids remain a mainstay of therapy. Opioid-induced hyperalgesia is a phenomenon resulting in dose escalation, which may occur partly because of the effects of opioids on voltage-gated sodium channels associated with pain. Preclinical observations demonstrate that the combination of an opioid and the antiseizure drug lacosamide diminishes opioid-induced hyperalgesia and improves pain control.

Objective: In this phase 1 trial, we aim to determine the safety, …

One Form And Two Functions: Mbd Of Setdb2 Is A Protein-Interacting Domain, Jujun Zhou, Taiping Chen, Xiaodong Cheng

Faculty, Staff and Student Publications

In this issue of Structure, Mahana et al.1 present their structural characterization of an annotated methyl-CpG-binding domain (MBD) from the histone H3 lysine 9 methyltransferase SETDB2. This study reveals that, rather than binding DNA as previously hypothesized, this domain instead interacts with a cystine-rich domain from C11orf46, highlighting its involvement in protein-protein interactions.

Haploinsufficiency Of Zfhx3, Encoding A Key Player In Neuronal Development, Causes Syndromic Intellectual Disability, María Del Rocío Pérez Baca, Eva Z Jacobs, Lies Vantomme, Pontus Leblanc, Elke Bogaert, Annelies Dheedene, Laurenz De Cock, Sadegheh Haghshenas, Aidin Foroutan, Michael A Levy, Jennifer Kerkhof, Haley Mcconkey, Chun-An Chen, Nurit Assia Batzir, Xia Wang, María Palomares, Marieke Carels, Zfhx3 Consortium, Bart Dermaut, Bekim Sadikovic, Björn Menten, Bo Yuan, Sarah Vergult, Bert Callewaert

Faculty, Staff and Students Publications

Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. Here, we identify loss-of-function (LoF) variation in ZFHX3 as a cause for syndromic intellectual disability (ID). ZFHX3 is a zinc-finger homeodomain transcription factor involved in various biological processes, including cell differentiation and tumorigenesis. We describe 42 individuals with protein-truncating variants (PTVs) or (partial) deletions of ZFHX3, exhibiting variable intellectual disability and autism spectrum disorder, recurrent facial features, relative short stature, brachydactyly, and, rarely, cleft palate. ZFHX3 LoF associates with a specific methylation profile in whole blood extracted DNA. Nuclear abundance of ZFHX3 increases during human brain development and …

Inhibition Of Mer Proto-Oncogene Tyrosine Kinase By An Antisense Oligonucleotide Enhances Treatment Efficacy Of Immunoradiotherapy, Yun Hu, Alexey Revenko, Hampartsoum Barsoumian, Genevieve Bertolet, Natalie Wall Fowlkes, Hadi Maazi, Morgan Maureen Green, Kewen He, Duygu Sezen, Tiffany A Voss, Claudia S Kettlun Leyton, Fatemeh Masrorpour, Zahid Rafiq, Nahum Puebla-Osorio, Carola Leuschner, Robert Macleod, Maria Angelica Cortez, James W Welsh

Faculty, Staff and Student Publications

Background: The combination of radiotherapy and immunotherapy (immunoradiotherapy) has been increasingly used for treating a wide range of cancers. However, some tumors are resistant to immunoradiotherapy. We have previously shown that MER proto-oncogene tyrosine kinase (MerTK) expressed on macrophages mediates resistance to immunoradiotherapy. We therefore sought to develop therapeutics that can mitigate the negative impact of MerTK. We designed and developed a MerTK specific antisense oligonucleotide (ASO) and characterized its effects on eliciting an anti-tumor immune response in mice.

Methods: 344SQR cells were injected into the right legs on day 0 and the left legs on day 4 of 8-12 …

Transcriptomic, Proteomic, And Genomic Mutational Fraction Differences Based On Hpv Status Observed In Patient-Derived Xenograft Models Of Penile Squamous Cell Carcinoma, Niki M Zacharias, Luis Segarra, Keiko Akagi, Natalie Wall Fowlkes, Huiqin Chen, Angelita Alaniz, Carolyn De La Cerda, Pedro Pesquera, Yuanxin Xi, Jing Wang, Jad Chahoud, Xin Lu, Priya Rao, Magaly Martinez-Ferrer, Curtis A Pettaway

Faculty, Staff and Student Publications

Simple Summary

Penile cancer is a rare but aggressive cancer. After it metastasizes, the median survival time is less than 12 months. The overall response rate to common first-line combination chemotherapy treatments is approximately 50%. There is an urgent need in advanced-penile-cancer treatment to find novel therapies that would generate better response rates than standard chemotherapy thus far and have less toxicity. Partially due to its rarity, there are few animal models and cell lines of penile cancer. We report on the generation of seven penile cancer animal models that were created by directly implanting human tumor tissue into immunocompromised …

Potential Protein Signatures For Recurrence Prediction Of Ischemic Stroke, Chengyi Zhang, Yang Liu, Huimin Zhu, Xinying Huang, Cang Guo, Si Cheng, Meng Yuan, Yong Jiang, Xia Meng, S Claiborne Johnston, Yongjun Wang, Wei-Na Jin, Fu-Dong Shi

Faculty, Staff and Student Publications

Background: Acute ischemic stroke is a major cause of mortality and disability worldwide, with approximately 7.4% to 7.7% recurrence within the first 3 months. This study aimed to identify potential biomarkers for predicting stroke recurrence.

Methods and results: We conducted a nested case-control study using a hospital-based cohort from the Third China National Stroke Registry selecting 214 age- and sex-matched patients with ischemic stroke with hypertension and no history of diabetes or heart disease. Using data-independent acquisition for discovery and multiple reaction monitoring for quantitative validation, we identified 26 differentially expressed proteins in large-artery atherosclerosis (Causative Classification of Ischemic Stroke …

Eef1a2 Promotes Pten-Gsk3Β-Scf Complex-Dependent Degradation Of Aurora Kinase A And Is Inactivated In Breast Cancer, Warapen Treekitkarnmongkol, Luisa M Solis, Deivendran Sankaran, Mihai Gagea, Pankaj K Singh, Ragini Mistry, Tristian Nguyen, Kazuharu Kai, Jiajun Liu, Kaori Sasai, Yoshimi Jitsumori, Jianwen Liu, Norio Nagao, Fabio Stossi, Michael A Mancini, Ignacio I Wistuba, Alastair M Thompson, Jonathan M Lee, Juan Cadiñanos, Kwong-Kwok Wong, Catherine M Abbott, Aysegul A Sahin, Suyu Liu, Hiroshi Katayama, Subrata Sen

Faculty, Staff and Student Publications

The translation elongation factor eEF1A promotes protein synthesis. Its methylation by METTL13 increases its activity, supporting tumor growth. However, in some cancers, a high abundance of eEF1A isoforms is associated with a good prognosis. Here, we found that eEF1A2 exhibited oncogenic or tumor-suppressor functions depending on its interaction with METTL13 or the phosphatase PTEN, respectively. METTL13 and PTEN competed for interaction with eEF1A2 in the same structural domain. PTEN-bound eEF1A2 promoted the ubiquitination and degradation of the mitosis-promoting Aurora kinase A in the S and G2 phases of the cell cycle. eEF1A2 bridged the interactions between the SKP1-CUL1-FBXW7 (SCF) ubiquitin …

Efficacy Of Single-Agent Chemotherapy In Endocrine Therapy-Refractory Metastatic Invasive Lobular Carcinoma, Jason A Mouabbi, Wei Qaio, Yu Shen, Akshara Singareeka Raghavendra, Debasish Tripathy, Rachel M Layman

Faculty, Staff and Student Publications

Background: Hormone receptor (HR)-positive, HER2-negative metastatic invasive lobular breast cancer (mILC) is distinct from invasive ductal cancer (IDC) in clinicopathologic and molecular characteristics, impacting its response to systemic therapy. While endocrine therapy (ET) combined with targeted therapies has shown efficacy in ET-sensitive mILC, data on chemotherapy in ET-refractory mILC remain limited. We investigated the efficacy of single-agent capecitabine (CAP) versus taxanes (TAX) in ET-refractory HR+ HER2-negative patients with mILC.

Materials and methods: Using data from the MD Anderson prospectively collected breast cancer database, we identified patients with HR+ HER2-negative mILC who received prior ET and first-time chemotherapy in the metastatic …

Differential Treatment Effects Of Subgroup Analyses In Phase 3 Oncology Trials From 2004 To 2020, Alexander D Sherry, Andrew W Hahn, Zachary R Mccaw, Joseph Abi Jaoude, Ramez Kouzy, Timothy A Lin, Bruce Minsky, C David Fuller, Tomer Meirson, Pavlos Msaouel, Ethan B Ludmir

Faculty, Staff and Student Publications

Importance: Subgroup analyses are often performed in oncology to investigate differential treatment effects and may even constitute the basis for regulatory approvals. Current understanding of the features, results, and quality of subgroup analyses is limited.

Objective: To evaluate forest plot interpretability and credibility of differential treatment effect claims among oncology trials.

Design, setting, and participants: This cross-sectional study included randomized phase 3 clinical oncology trials published prior to 2021. Trials were screened from ClinicalTrials.gov.

Main outcomes and measures: Missing visual elements in forest plots were defined as a missing point estimate or use of a linear x-axis scale for hazard …

The Identification Of A Distinct Astrocyte Subtype That Diminishes In Alzheimer's Disease, Haichao Wei, Joseph Withrow, Jyotirmoy Rakshit, Faiz Ul Amin, Joshua Nahm, Francesca E Mowry, Zhengmei Mao, Meenakshi B Bhattacharjee, Jay-Jiguang Zhu, Yongjie Yang, Jia Qian Wu

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is characterized by the presence of two hallmark pathologies: the accumulation of Amyloid beta (Aβ) and tau proteins in the brain. There is a growing body of evidence suggesting that astrocytes, a type of glial cell in the brain, play crucial roles in clearing Aβ and binding to tau proteins. However, due to the heterogeneity of astrocytes, the specific roles of different astrocyte subpopulations in response to Aβ and tau remain unclear. To enhance the understanding of astrocyte subpopulations in AD, we investigated astrocyte lineage cells based on single-nuclei transcriptomic data obtained from both human and mouse …

Germline Genetic Testing And Survival Outcomes Among Children With Rhabdomyosarcoma: A Report From The Children's Oncology Group, Bailey A Martin-Giacalone, He Li, Michael E Scheurer, Dana L Casey, Shannon Dugan-Perez, Deborah A Marquez-Do, Donna Muzny, Richard A Gibbs, Donald A Barkauskas, David Hall, Douglas R Stewart, Joshua D Schiffman, Matthew T Mcevoy, Javed Khan, David Malkin, Corinne M Linardic, Brian D Crompton, Jack F Shern, Stephen X Skapek, Rajkumar Venkatramani, Douglas S Hawkins, Aniko Sabo, Sharon E Plon, Philip J Lupo

Faculty, Staff and Students Publications

IMPORTANCE: Determining the impact of germline cancer-predisposition variants (CPVs) on outcomes could inform novel approaches to testing and treating children with rhabdomyosarcoma.

OBJECTIVE: To assess whether CPVs are associated with outcome among children with rhabdomyosarcoma.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, data were obtained for individuals, aged 0.01-23.23 years, newly diagnosed with rhabdomyosarcoma who were treated across 171 Children's Oncology Group sites from March 15, 1999, to December 8, 2017. Data analysis was performed from June 16, 2021, to May 15, 2023.

EXPOSURE: The presence of a CPV in 24 rhabdomyosarcoma-associated cancer-predisposition genes (CPGs) or an expanded set …

Congenital Tooth Agenesis And Risk Of Early-Onset Cancer, Saga Elise Eiset, Jeremy Schraw, Gitte Vrelits Sørensen, Pernille Axél Gregersen, Sonja A Rasmussen, Cecilia H Ramlau-Hansen, Philip J Lupo, Henrik Hasle

Faculty, Staff and Students Publications

IMPORTANCE: There is some evidence that tooth agenesis (congenital absence of 1 or more teeth) is associated with cancer risk, especially carcinomas of the colon and ovaries, but results of previous studies are conflicting, and associations have not yet been evaluated in a population-based setting.

OBJECTIVE: To examine the association between tooth agenesis and specific cancer types before 40 years of age.

DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used linking data from nationwide registries in Denmark to assess all Danish live-born singletons born from January 1, 1977, to December 31, 2018, and followed up for up to 40 …

Expanded Clinical Phenotype And Untargeted Metabolomics Analysis In Rars2-Related Mitochondrial Disorder: A Case Report, Ameya S Walimbe, Keren Machol, Stephen F Kralik, Elizabeth A Mizerik, Yoel Gofin, Mir Reza Bekheirnia, Charul Gijavanekar, Sarah H Elsea, Lisa T Emrick, Fernando Scaglia

Faculty, Staff and Students Publications

Background

RARS2-related mitochondrial disorder is an autosomal recessive mitochondrial encephalopathy caused by biallelic pathogenic variants in the gene encoding the mitochondrial arginyl-transfer RNA synthetase 2 (RARS2, MIM *611524, NM_020320.5). RARS2 catalyzes the transfer of L-arginine to its cognate tRNA during the translation of mitochondrially-encoded proteins. The classical presentation of RARS2-related mitochondrial disorder includes pontocerebellar hypoplasia (PCH), progressive microcephaly, profound developmental delay, feeding difficulties, and hypotonia. Most patients also develop severe epilepsy by three months of age, which consists of focal or generalized seizures that frequently become pharmacoresistant and lead to developmental and epileptic encephalopathy (DEE). …

Integrating Genome Sequencing And Untargeted Metabolomics In Monozygotic Twins With A Rare Complex Neurological Disorder, Rulan Shaath, Aljazi Al-Maraghi, Haytham Ali, Jehan Alrayahi, Adam D Kennedy, Karen L Debalsi, Sura Hussein, Najwa Elbashir, Sujitha S Padmajeya, Sasirekha Palaniswamy, Sarah H Elsea, Ammira A Akil, Noha A Yousri, Khalid A Fakhro

Faculty, Staff and Students Publications

Multi-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools in the diagnosis of rare diseases. We used untargeted metabolomics and whole-genome sequencing (WGS) to gain a more comprehensive understanding of a rare disease with a complex presentation affecting female twins from a consanguineous family. The sisters presented with polymicrogyria, a Dandy–Walker malformation, respiratory distress, and multiorgan dysfunctions. Through WGS, we identified two rare homozygous variants in both subjects, a pathogenic variant in ADGRG1(p.Arg565Trp) and a novel variant in CNTNAP1(p.Glu910Val). These genes have been previously associated with autosomal recessive polymicrogyria and hypomyelinating neuropathy with/without …

Genetic Sex Validation For Sample Tracking In Next-Generation Sequencing Clinical Testing, Jianhong Hu, Viktoriya Korchina, Hana Zouk, Maegan V Harden, David Murdock, Alyssa Macbeth, Steven M Harrison, Niall Lennon, Christie Kovar, Adithya Balasubramanian, Lan Zhang, Gauthami Chandanavelli, Divya Pasham, Robb Rowley, Ken Wiley, Maureen E Smith, Adam Gordon, Gail P Jarvik, Patrick Sleiman, Melissa A Kelly, Harris T Bland, Mullai Murugan, Eric Venner, Eric Boerwinkle, Emerge Iii Consortium, Cynthia Prows, Lisa Mahanta, Heidi L Rehm, Richard A Gibbs, Donna M Muzny

Faculty, Staff and Students Publications

OBJECTIVE: Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups.

RESULTS: Precise SNP tracking showed no sample swap errors within the clinical testing laboratories. In contrast, when comparing predicted sex-by-genotype to the provided sex on the test requisition, we identified 110 inconsistencies from 25,015 clinical samples (0.44%), that …

The Fatigue-Inducing Effects Of Cancer And Its Therapy Are Characterized By Decreased Physical Activity In The Absence Of Any Motivational Deficit, Thien T Phan, Kiersten S Scott, Brandon Chelette, A Phillip West, Robert Dantzer

Faculty, Staff and Student Publications

Although cancer and its therapy are well known to be associated with fatigue, the exact nature of cancer-related fatigue remains ill-defined. We previously reported that fatigue-like behavior induced independently by tumor growth and by the chemotherapeutic agent cisplatin is characterized by reduced voluntary wheel running and an intact motivation to expand effort for food rewards. The present set of experiments was initiated to characterize the functional consequences of fatigue induced by chemoradiotherapy in tumor-bearing mice and relate them to changes in the expression of genes coding for inflammation, mitochondria dynamics and metabolism. Two syngeneic murine models of cancer were selected …

Genome-Wide Gene-Environment Interaction Analyses To Understand The Relationship Between Red Meat And Processed Meat Intake And Colorectal Cancer Risk, Mariana C Stern, Joel Sanchez Mendez, Andre E Kim, Mireia Obón-Santacana, Ferran Moratalla-Navarro, Vicente Martín, Victor Moreno, Yi Lin, Stephanie A Bien, Conghui Qu, Yu-Ru Su, Emily White, Tabitha A Harrison, Jeroen R Huyghe, Catherine M Tangen, Polly A Newcomb, Amanda I Phipps, Claire E Thomas, Eric S Kawaguchi, Juan Pablo Lewinger, John L Morrison, David V Conti, Jun Wang, Duncan C Thomas, Elizabeth A Platz, Kala Visvanathan, Temitope O Keku, Christina C Newton, Caroline Y Um, Anshul Kundaje, Anna Shcherbina, Neil Murphy, Marc J Gunter, Niki Dimou, Nikos Papadimitriou, Stéphane Bézieau, Franzel J B Van Duijnhoven, Satu Männistö, Gad Rennert, Alicja Wolk, Michael Hoffmeister, Hermann Brenner, Jenny Chang-Claude, Yu Tian, Loïc Le Marchand, Michelle Cotterchio, Konstantinos K Tsilidis, D Timothy Bishop, Yohannes Adama Melaku, Brigid M Lynch, Daniel D Buchanan, Cornelia M Ulrich, Jennifer Ose, Anita R Peoples, Andrew J Pellatt, Li Li, Matthew A M Devall, Peter T Campbell, Demetrius Albanes, Stephanie J Weinstein, Sonja I Berndt, Stephen B Gruber, Edward Ruiz-Narvaez, Mingyang Song, Amit D Joshi, David A Drew, Jessica L Petrick, Andrew T Chan, Marios Giannakis, Ulrike Peters, Li Hsu, W James Gauderman

Faculty, Staff and Student Publications

Background: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations.

Methods: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan.

Results: Meta-analyses confirmed positive associations between increased consumption of red meat and …

Identification Of Pancreatic Cancer Germline Risk Variants With Effects That Are Modified By Smoking, Huili Zhu, Jaihee Choi, Naishu Kui, Tianzhong Yang, Peng Wei, Donghui Li, Ryan Sun

Faculty, Staff and Student Publications

Purpose: Pancreatic cancer (PC) is a deadly disease most often diagnosed in late stages. Identification of high-risk subjects could both contribute to preventative measures and help diagnose the disease at earlier timepoints. However, known risk factors, assessed independently, are currently insufficient for accurately stratifying patients. We use large-scale data from the UK Biobank (UKB) to identify genetic variant-smoking interaction effects and show their importance in risk assessment.

Methods: We draw data from 15,086,830 genetic variants and 315,512 individuals in the UKB. There are 765 cases of PC. Crucially, robust resampling corrections are used to overcome well-known challenges in hypothesis testing …

Personal History Of Cancer As A Risk Factor For Second Primary Lung Cancer: Implications For Lung Cancer Screening, Sara Nofal, Jiangong Niu, Paul Resong, Jeff Jin, Kelly W Merriman, Xiuning Le, Hormuzd Katki, John Heymach, Mara B Antonoff, Edwin Ostrin, Jia Wu, Jianjun Zhang, Iakovos Toumazis

Faculty, Staff and Student Publications

Background: Personal history of cancer is an independent risk factor for lung cancer but is omitted from existing lung cancer screening eligibility criteria. In this study, we assess the lung cancer risk among cancer survivors and discuss potential implications for screening.

Methods: This was a retrospective, secondary analysis of data from the Surveillance, Epidemiology and End Results (SEER) registry and the MD Anderson Cancer Center (MDACC). We estimated the standardized incidence ratios (SIRs) for lung cancer by site of first primary cancer using data from SEER. We assessed the lung cancer risk among head and neck cancer survivors from MDACC …

Systematic Evaluation Of Mri-Based Characterization Of Tumor-Associated Vascular Morphology And Hemodynamics Via A Dynamic Digital Phantom, Chengyue Wu, David A Hormuth, Ty Easley, Federico Pineda, Gregory S Karczmar, Thomas E Yankeelov

Faculty, Staff and Student Publications

Purpose: Validation of quantitative imaging biomarkers is a challenging task, due to the difficulty in measuring the ground truth of the target biological process. A digital phantom-based framework is established to systematically validate the quantitative characterization of tumor-associated vascular morphology and hemodynamics based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Approach: A digital phantom is employed to provide a ground-truth vascular system within which 45 synthetic tumors are simulated. Morphological analysis is performed on high-spatial resolution DCE-MRI data (spatial/temporal resolution = 30 to 300μm/60s" role="presentation" style="box-sizing: inherit; display: inline-block; line-height: 0; font-size: 18.08px; font-size-adjust: none; overflow-wrap: normal; word-spacing: normal; text-wrap-mode: …

Comprehensive Immunogenomic Profiling Of Idh1-/2-Altered Cholangiocarcinoma, Shalini Makawita, Sunyoung Lee, Elisabeth Kong, Lawrence N Kwong, Zeyad Abouelfetouh, Anaemy Danner De Armas, Lianchun Xiao, Karthikeyan Murugesan, Natalie Danziger, Dean Pavlick, Anil Korkut, Jeffrey S Ross, Milind Javle

Faculty, Staff and Student Publications

Purpose: Isocitrate dehydrogenase (IDH)1/2 genomic alterations (GA) occur in 20% of intrahepatic cholangiocarcinoma (iCCA); however, the immunogenomic landscape of IDH1-/2-mutated iCCA is largely unknown.

Methods: Comprehensive genomic profiling (CGP) was performed on 3,067 cases of advanced iCCA. Tumor mutational burden (TMB), PD-L1 expression (Dako 22C3), microsatellite instability (MSI), and genomic loss of heterozygosity (gLOH) as a surrogate marker for homologous recombination deficiency were examined. RNA sequencing of 73 patient samples was analyzed for differences in stromal/immune cell infiltration, immune marker expression, and T-cell inflammation. Tissue microarray arrays were subjected to multiplex immunohistochemistry and colocalization …

Tongue Electrical Impedance Myography Correlates With Functional, Neurophysiologic, And Clinical Outcome Measures In Long-Term Oropharyngeal Cancer Survivors With And Without Hypoglossal Neuropathy: An Exploratory Study, Nathan J Hansen, Karin Woodman, Sheila Buoy, Shitong Mao, Carly E A Barbon, Stephen Y Lai, C David Fuller, Katherine A Hutcheson, Benjamin Sanchez

Faculty, Staff and Student Publications

Background: This pilot study analyzed correlations between tongue electrical impedance myography (EIM), standard tongue electromyography (EMG), and tongue functional measures in N = 4 long-term oropharyngeal cancer (OPC) survivors.

Methods: Patients were screened for a supportive care trial (NCT04151082). Hypoglossal nerve function was evaluated with genioglossus needle EMG, functional measures with the Iowa oral performance instrument (IOPI), and multi-frequency tissue composition with tongue EIM.

Results: Tongue EIM conductivity was higher for patients with EMG-confirmed cranial nerve XII neuropathy than those without (p = 0.005) and in patients with mild versus normal EMG reinnervation ratings (16 kHz EIM: p …

Patients With Advanced Cancer And Their Spouses Parenting Minor Children: The Role Of The Relationship Context In Parenting Concerns, Kathrin Milbury, Sujin Ann-Yi, Morgan Jones, Yisheng Li, Meagan Whisenant, Sania Yousuf, Victoria Necroto, Mariana Chavez Mac Gregor, Eduardo Bruera

Faculty, Staff and Student Publications

Objective: Patients with advanced cancer who parent minor children report parenting concerns and increased psychological distress. This cross-sectional study seeks to understand parenting-related issues in patients and spousal caregivers from a relationship perspective.

Methods: Patients with a metastatic solid malignancy and their spouses independently completed cross-sectional assessments of psychological distress (Hospital Anxiety and Depression Scale), parenting concerns (Parenting Concern Questionnaire) and efficacy (Cancer-Related Parenting Self-Efficacy Scale), and relationship measures (DAS-7, Couples' Illness Communication Scale, and Family Relationship Index).

Results: Of the 51 patients (57% female, 49% NHW, mean age 42 years) and spouses (43% female, 43% NHW, mean age of …

Correcting Ct Misregistration In Data-Driven Gated (Ddg) Pet With Pet Self-Gating And Deformable Image Registration, Peng Sun, M Allan Thomas, Dershan Luo, Tinsu Pan

Faculty, Staff and Student Publications

Background: Misregistration between CT and PET data can result in mis-localization and inaccurate quantification of functional uptake in whole body PET/CT imaging. This problem is exacerbated when an abnormal inspiration occurs during the free-breathing helical CT (FB CT) used for attenuation correction of PET data. In data-driven gated (DDG) PET, the data selected for reconstruction is typically derived from the end-expiration (EE) phase of the breathing cycle, making this potential issue worse.

Purpose: The objective of this study is to develop a deformable image registration (DIR)-based respiratory motion model to improve the registration and quantification between misregistered FB CT and …

Desirability Of Outcome Ranking For Obstetrical Trials: Illustration And Application To The Arrive Trial, Grecio J Sandoval, William A Grobman, Scott R Evans, Madeline M Rice, Rebecca G Clifton, Suneet P Chauhan, Maged M Costantine, Kelly S Gibson, Monica Longo, Torri D Metz, Emily S Miller, Samuel Parry, Uma M Reddy, Dwight J Rouse, Hyagriv N Simhan, John M Thorp, Alan T N Tita, George R Saade

Faculty, Staff and Student Publications

BACKGROUND: In randomized trials, 1 primary outcome is typically chosen to evaluate the consequences of an intervention, whereas other important outcomes are relegated to secondary outcomes. This issue is amplified for many obstetrical trials in which an intervention may have consequences for both the pregnant person and the child. In contrast, desirability of outcome ranking, a paradigm shift for the design and analysis of clinical trials based on patient-centric evaluation, allows multiple outcomes-including from >1 individual-to be considered concurrently.

OBJECTIVE: This study aimed to describe desirability of outcome ranking methodology tailored to obstetrical trials and to apply the methodology to …

Reducing Frame Rate And Pulse Rate For Routine Diagnostic Cerebral Angiography: Alara Principles In Practice, Arvin R Wali, Sarath Pathuri, Michael G Brandel, Ryan W Sindewald, Brian R Hirshman, Javier A Bravo, Jeffrey A Steinberg, Scott E Olson, Jeffrey S Pannell, Alexander Khalessi, David Santiago-Dieppa

Faculty, Staff and Student Publications

Objective: Diagnostic cerebral angiograms (DCAs) are widely used in neurosurgery due to their high sensitivity and specificity to diagnose and characterize pathology using ionizing radiation. Eliminating unnecessary radiation is critical to reduce risk to patients, providers, and health care staff. We investigated if reducing pulse and frame rates during routine DCAs would decrease radiation burden without compromising image quality.

Methods: We performed a retrospective review of prospectively acquired data after implementing a quality improvement protocol in which pulse rate and frame rate were reduced from 15 p/s to 7.5 p/s and 7.5 f/s to 4.0 f/s respectively. Radiation doses and …

Examining Psychometric Properties Of The Metacognitions About Smoking Questionnaire Among Young E-Cigarette Users, Aslesha Sumbe, Robert Suchting, Baojiang Chen, Anna V Wilkinson, Bara Bataineh, Stephanie L Clendennen, Melissa B Harrell

Faculty, Staff and Student Publications

Objective: Metacognition can be understood as 'cognition of cognition' or 'thinking about thinking'. Metacognition research has primarily focused on cigarette smoking, while e-cigarette use has been relatively unexplored. The study sought to examine the properties of the Metacognitions about Smoking Questionnaire (MSQ), as it was adapted for use among adolescent and young adult e-cigarette users. Further, the study sought to examine the ability of the Metacognitions about Smoking Questionnaire (MSQ) to predict past 30-day e-cigarette use among adolescent and young adult e-cigarette users.

Methods: The study analyzed data collected by the Texas Adolescent Tobacco and Marketing Surveillance System (TATAMS) in …