Digital Commons Network^™

Cd73-Dependent Adenosine Signaling Through Adora2b Drives Immunosuppression In Ductal Pancreatic Cancer, Erika Y Faraoni, Kanchan Singh, Vidhi Chandra, Olivereen Le Roux, Yulin Dai, Ismet Sahin, Baylee J O'Brien, Lincoln N Strickland, Le Li, Emily Vucic, Amanda N Warner, Melissa Pruski, Trent Clark, George Van Buren, Nirav C Thosani, John S Bynon, Curtis J Wray, Dafna Bar-Sagi, Kyle L Poulsen, Lana A Vornik, Michelle I Savage, Shizuko Sei, Altaf Mohammed, Zhongming Zhao, Powel H Brown, Tingting Mills, Holger K Eltzschig, Florencia Mcallister, Jennifer M Bailey-Lundberg

Faculty, Staff and Student Publications

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin-dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar cells. …

Il6 Mediates Suppression Of T- And Nk-Cell Function In Emt-Associated Tki-Resistant Egfr-Mutant Nsclc, Sonia A Patel, Monique B Nilsson, Yan Yang, Xiuning Le, Hai T Tran, Yasir Y Elamin, Xiaoxing Yu, Fahao Zhang, Alissa Poteete, Xiaoyang Ren, Li Shen, Jing Wang, Seyed Javad Moghaddam, Tina Cascone, Michael Curran, Don L Gibbons, John V Heymach

Faculty, Staff and Student Publications

Purpose: Patients with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are initially responsive to tyrosine kinase inhibitors (TKI). However, therapeutic resistance eventually emerges, often via secondary EGFR mutations or EGFR-independent mechanisms such as epithelial-to-mesenchymal transition. Treatment options after EGFR-TKI resistance are limited as anti-PD-1/PD-L1 inhibitors typically display minimal benefit. Given that IL6 is associated with worse outcomes in patients with NSCLC, we investigate whether IL6 in part contributes to this immunosuppressed phenotype.

Experimental design: We utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR-mutant NSCLC to investigate the effects of IL6 on the tumor microenvironment and …

Dna Damage Repair Kinase Dna-Pk And Cgas Synergize To Induce Cancer-Related Inflammation In Glioblastoma, Clara Taffoni, Johanna Marines, Hanane Chamma, Soumyabrata Guha, Mathilde Saccas, Amel Bouzid, Ana-Luiza Chaves Valadao, Clément Maghe, Jane Jardine, Mi Kyung Park, Katarzyna Polak, Mara De Martino, Claire Vanpouille-Box, Maguy Del Rio, Celine Gongora, Julie Gavard, Nicolas Bidère, Min Sup Song, Donovan Pineau, Jean-Philippe Hugnot, Karima Kissa, Laura Fontenille, Fabien P Blanchet, Isabelle K Vila, Nadine Laguette

Faculty, Staff and Student Publications

Cytosolic DNA promotes inflammatory responses upon detection by the cyclic GMP-AMP (cGAMP) synthase (cGAS). It has been suggested that cGAS downregulation is an immune escape strategy harnessed by tumor cells. Here, we used glioblastoma cells that show undetectable cGAS levels to address if alternative DNA detection pathways can promote pro-inflammatory signaling. We show that the DNA-PK DNA repair complex (i) drives cGAS-independent IRF3-mediated type I Interferon responses and (ii) that its catalytic activity is required for cGAS-dependent cGAMP production and optimal downstream signaling. We further show that the cooperation between DNA-PK and cGAS favors the expression of chemokines that promote …

Longitudinal Global Transcriptomic Profiling Of Preclinical Systemic Sclerosis Reveals Molecular Changes Associated With Disease Progression, Chiara Bellocchi, Lorenzo Beretta, Xuan Wang, Marka A Lyons, Maurizio Marchini, Maurizio Lorini, Vincenzo Carbonelli, Nicola Montano, Shervin Assassi

Faculty, Staff and Student Publications

Objective: To investigate peripheral blood cell (PBCs) global gene expression profile of SSc at its preclinical stage (PreSSc) and to characterize the molecular changes associated with progression to a definite disease over time.

Material and methods: Clinical data and PBCs of 33 participants with PreSSc and 16 healthy controls (HCs) were collected at baseline and follow-up (mean 4.2 years). Global gene expression profiling was conducted by RNA sequencing and a modular analysis was performed.

Results: Comparison of baseline PreSSc to HCs revealed 2889 differentially expressed genes. Interferon signalling was the only activated pathway among top over-represented pathways. Moreover, 10 modules …

Increases In Group A Streptococcal Infections In The Pediatric Population In Houston, Tx, 2022, Aya Aboulhosn, Misu A Sanson, Luis Alberto Vega, Maria G Segura, Lauren M Summer, Marritta Joseph, J Chase Mcneil, Anthony R Flores

Faculty, Staff and Student Publications

Beginning in October 2022, we observed a substantial increase in the total number of cases of invasive GAS disease (iGAS) in the pediatric population in Houston, TX. Emm12 GAS strains were disproportionately represented but the overall proportion of iGAS infections observed during the current spike was similar to pre-pandemic years.

Inhibition Of Stat6 With Antisense Oligonucleotides Enhances The Systemic Antitumor Effects Of Radiotherapy And Anti-Pd-1 In Metastatic Non-Small Cell Lung Cancer, Kewen He, Hampartsoum B Barsoumian, Nahum Puebla-Osorio, Yun Hu, Duygu Sezen, Mark D Wasley, Genevieve Bertolet, Jie Zhang, Carola Leuschner, Liangpeng Yang, Claudia S Kettlun Leyton, Natalie Wall Fowlkes, Morgan Maureen Green, Lisa Hettrick, Dawei Chen, Fatemeh Masrorpour, Meidi Gu, Hadi Maazi, Alexey S Revenko, Maria Angelica Cortez, James W Welsh

Faculty, Staff and Student Publications

Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non-small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells-such as M2 tumor-associated macrophages (TAM)-thereby establishing an immunosuppressive tumor microenvironment that contributes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti-PD-1-resistant 344SQ lung …

Increases In Group A Streptococcal Infections In The Pediatric Population In Houston, Tx, 2022, Aya Aboulhosn, Misu A Sanson, Luis Alberto Vega, Maria G Segura, Lauren M Summer, Marritta Joseph, J Chase Mcneil, Anthony R Flores

Faculty, Staff and Student Publications

Beginning in October 2022, we observed a substantial increase in the total number of cases of invasive GAS disease (iGAS) in the pediatric population in Houston, TX. Emm12 GAS strains were disproportionately represented but the overall proportion of iGAS infections observed during the current spike was similar to pre-pandemic years.

Lecanemab For Patients With Early Alzheimer Disease: Bayesian Analysis Of A Phase 2b Dose-Finding Randomized Clinical Trial, Donald A Berry, Shobha Dhadda, Michio Kanekiyo, David Li, Chad J Swanson, Michael Irizarry, Lynn D Kramer, Scott M Berry

Faculty, Staff and Student Publications

IMPORTANCE: Bayesian clinical trial designs are increasingly common; given their promotion by the US Food and Drug Administration, the future use of the bayesian approach will only continue to increase. Innovations possible when using the bayesian approach improve the efficiency of drug development and the accuracy of clinical trials, especially in the context of substantial data missingness.

OBJECTIVE: To explain the foundations, interpretations, and scientific justification of the bayesian approach in the setting of lecanemab trial 201, a bayesian-designed phase 2 dose-finding trial; to demonstrate the efficiency of using a bayesian design; and to show how it accommodates innovations in …

Dysregulation And Epigenetic Reprogramming Of Nrf2 Signaling Axis Promote Acquisition Of Cisplatin Resistance And Metastasis In Head And Neck Squamous Cell Carcinoma, Abdullah A Osman, Emre Arslan, Mason Bartels, Chieko Michikawa, Antje Lindemann, Katarzyna Tomczak, Wangjie Yu, Vlad Sandulache, Wencai Ma, Li Shen, Jing Wang, Anand K Singh, Mitchell J Frederick, Nakia D Spencer, Jeffery Kovacs, Timothy Heffernan, William F Symmans, Kunal Rai, Jeffrey N Myers

Faculty, Staff and Student Publications

PURPOSE: Cisplatin (CDDP)-based chemotherapy is a first-line treatment for patients with advanced head and neck squamous cell carcinomas (HNSCC), despite a high rate of treatment failures, acquired resistance, and subsequent aggressive behavior. The purpose of this study was to study the mechanism of CDDP resistance and metastasis in HNSCC. We investigated the role of NRF2 pathway activation as a driven event for tumor progression and metastasis of HNSCC.

EXPERIMENTAL DESIGN: Human HNSCC cell lines that are highly resistant to CDDP were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of NRF2 …

Independent Reproduction Of The Flash Effect On The Gastrointestinal Tract: A Multi-Institutional Comparative Study, Anet Valdés Zayas, Neeraj Kumari, Kevin Liu, Denae Neill, Abagail Delahoussaye, Patrik Gonçalves Jorge, Reiner Geyer, Steven H Lin, Claude Bailat, François Bochud, Raphael Moeckli, Albert C Koong, Jean Bourhis, Cullen M Taniguchi, Fernanda G Herrera, Emil Schüler

Faculty, Staff and Student Publications

FLASH radiation therapy (RT) is a promising new paradigm in radiation oncology. However, a major question that remains is the robustness and reproducibility of the FLASH effect when different irradiators are used on animals or patients with different genetic backgrounds, diets, and microbiomes, all of which can influence the effects of radiation on normal tissues. To address questions of rigor and reproducibility across different centers, we analyzed independent data sets from The University of Texas MD Anderson Cancer Center and from Lausanne University (CHUV). Both centers investigated acute effects after total abdominal irradiation to C57BL/6 animals delivered by the FLASH …

Decs: A Tool For Systematic Cell Type Annotations Of Single-Cell Rna Sequencing Data Among Human Tissues, Guangsheng Pei, Fangfang Yan, Lukas M Simon, Yulin Dai, Peilin Jia, Zhongming Zhao

Faculty, Staff and Student Publications

Single-cell RNA sequencing (scRNA-seq) is revolutionizing the study of complex and dynamic cellular mechanisms. However, cell type annotation remains a main challenge as it largely relies on a priori knowledge and manual curation, which is cumbersome and subjective. The increasing number of scRNA-seq datasets, as well as numerous published genetic studies, has motivated us to build a comprehensive human cell type reference atlas.Here, we present decoding Cell type Specificity (deCS), an automatic cell type annotation method augmented by a comprehensive collection of human cell type expression profiles and marker genes. We used deCS to annotate scRNA-seq data from various tissue …

An Untrained Deep Learning Method For Reconstructing Dynamic Mr Images From Accelerated Model-Based Data, Kalina P Slavkova, Julie C Dicarlo, Viraj Wadhwa, Sidharth Kumar, Chengyue Wu, John Virostko, Thomas E Yankeelov, Jonathan I Tamir

Faculty, Staff and Student Publications

PURPOSE: To implement physics-based regularization as a stopping condition in tuning an untrained deep neural network for reconstructing MR images from accelerated data.

METHODS: The ConvDecoder (CD) neural network was trained with a physics-based regularization term incorporating the spoiled gradient echo equation that describes variable-flip angle data. Fully-sampled variable-flip angle k-space data were retrospectively accelerated by factors of R = {8, 12, 18, 36} and reconstructed with CD, CD with the proposed regularization (CD + r), locally low-rank (LR) reconstruction, and compressed sensing with L1-wavelet regularization (L1). Final images from CD + r training were evaluated at the "argmin" of …

Causal Effects On Complex Traits Are Similar For Common Variants Across Segments Of Different Continental Ancestries Within Admixed Individuals, Kangcheng Hou, Yi Ding, Ziqi Xu, Yue Wu, Arjun Bhattacharya, Rachel Mester, Gillian M Belbin, Steve Buyske, David V Conti, Burcu F Darst, Myriam Fornage, Chris Gignoux, Xiuqing Guo, Christopher Haiman, Eimear E Kenny, Michelle Kim, Charles Kooperberg, Leslie Lange, Ani Manichaikul, Kari E North, Ulrike Peters, Laura J Rasmussen-Torvik, Stephen S Rich, Jerome I Rotter, Heather E Wheeler, Genevieve L Wojcik, Ying Zhou, Sriram Sankararaman, Bogdan Pasaniuc

Faculty, Staff and Student Publications

Individuals of admixed ancestries (for example, African Americans) inherit a mosaic of ancestry segments (local ancestry) originating from multiple continental ancestral populations. This offers the unique opportunity of investigating the similarity of genetic effects on traits across ancestries within the same population. Here we introduce an approach to estimate correlation of causal genetic effects (radmix) across local ancestries and analyze 38 complex traits in African-European admixed individuals (N = 53,001) to observe very high correlations (meta-analysis radmix = 0.95, 95% credible interval 0.93-0.97), much higher than correlation of causal effects across continental ancestries. We replicate our results using regression-based methods …

Quantification Of The Role Of Lead Foil In Flattening Filter Free Beam Reference Dosimetry, Song Gao, Christopher Nelson, Congjun Wang, Vindu Kathriarachchi, Michael Choi, Rishik Saxena, Robin Kendall, Peter Balter

Faculty, Staff and Student Publications

PURPOSE: To quantify the potential error in outputs for flattening filter free (FFF) beams associated with use of a lead foil in beam quality determination per the addendum protocol for TG-51, we examined differences in measurements of the beam quality conversion factor k

METHODS: Two FFF beams, a 6 MV FFF and a 10 MV FFF, were calibrated on eight Varian TrueBeams and two Elekta Versa HD linear accelerators (linacs) according to the TG-51 addendum protocol by using Farmer ionization chambers [TN 30013 (PTW) and SNC600c (Sun Nuclear)] with traceable absorbed dose-to-water calibrations. In determining k

RESULTS: Differences in %dd(10)x …

Prediction Of Brain Metastases Development In Patients With Lung Cancer By Explainable Artificial Intelligence From Electronic Health Records, Zhao Li, Rongbin Li, Yujia Zhou, Laila Rasmy, Degui Zhi, Ping Zhu, Antonio Dono, Xiaoqian Jiang, Hua Xu, Yoshua Esquenazi, W Jim Zheng

Faculty, Staff and Student Publications

PURPOSE: Early detection of brain metastases (BMs) is critical for prompt treatment and optimal control of the disease. In this study, we seek to predict the risk of developing BM among patients diagnosed with lung cancer on the basis of electronic health record (EHR) data and to understand what factors are important for the model to predict BM development through explainable artificial intelligence approaches accurately.

MATERIALS AND METHODS: We trained a recurrent neural network model, REverse Time AttentIoN (RETAIN), to predict the risk of developing BM using structured EHR data. To interpret the model's decision process, we analyzed the attention …

Why Is Biomedical Informatics Hard? A Fundamental Framework, Todd R Johnson, Elmer V Bernstam

Faculty, Staff and Student Publications

Building on previous work to define the scientific discipline of biomedical informatics, we present a framework that categorizes fundamental challenges into groups based on data, information, and knowledge, along with the transitions between these levels. We define each level and argue that the framework provides a basis for separating informatics problems from non-informatics problems, identifying fundamental challenges in biomedical informatics, and provides guidance regarding the search for general, reusable solutions to informatics problems. We distinguish between processing data (symbols) and processing meaning. Computational systems, that are the basis for modern information technology (IT), process data. In contrast, many important challenges …

De Novo Mutations Disturb Early Brain Development More Frequently Than Common Variants In Schizophrenia, Toshiyuki Itai, Peilin Jia, Yulin Dai, Jingchun Chen, Xiangning Chen, Zhongming Zhao

Faculty, Staff and Student Publications

Investigating functional, temporal, and cell-type expression features of mutations is important for understanding a complex disease. Here, we collected and analyzed common variants and de novo mutations (DNMs) in schizophrenia (SCZ). We collected 2,636 missense and loss-of-function (LoF) DNMs in 2,263 genes across 3,477 SCZ patients (SCZ-DNMs). We curated three gene lists: (a) SCZ-neuroGenes (159 genes), which are intolerant to LoF and missense DNMs and are neurologically important, (b) SCZ-moduleGenes (52 genes), which were derived from network analyses of SCZ-DNMs, and (c) SCZ-commonGenes (120 genes) from a recent GWAS as reference. To compare temporal gene expression, we used the BrainSpan …

Renal-Hepatic-Pancreatic Dysplasia Type 2: Perinatal Lethal Condition Or A Multisystemic Disorder With Variable Expressivity, Kathryn Gunther, Essam M Imseis, Joyce P Samuel, Elizabeth A Hillman, Tiina H Ojala, Timo Jahnukainen, Paul R Hillman

Faculty, Staff and Student Publications

BACKGROUND: Renal-hepatic-pancreatic dysplasia type 2 (RHPD2) is a rare condition that has been described in the literature disproportionately in perinatal losses. The main features of liver and kidney involvement are well described, with cardiac malformations and cardiomyopathy adding additional variation to the phenotype. Many patients reported are within larger cohorts of congenital anomalies of kidney and urinary tract (CAKUT) or liver failure, and with minimal phenotypic and clinical course data.

METHODS: An independent series of phenotypes and prognosis was aggregated from the literature. In this literature review, we describe an additional patient with RHPD2, provide a clinical update on the …

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 …

Myosin Light-Chain 4 Gene-Transfer Attenuates Atrial Fibrosis While Correcting Autophagic Flux Dysregulation, Yuan Zhong, Kai Tang, Stanley Nattel, Ming Zhai, Shiyu Gong, Qing Yu, Yanxi Zeng, Guangxi E, Nuerbiyemu Maimaitiaili, Jun Wang, Yawei Xu, Wenhui Peng, Hailing Li

Faculty, Staff and Student Publications

OBJECTIVES: To determine the role of MYL4 regulation of lysosomal function and its disturbance in fibrotic atrial cardiomyopathy.

BACKGROUND: We have previously demonstrated that the atrial-specific essential light chain protein MYL4 is required for atrial contractile, electrical, and structural integrity. MYL4 mutation/dysfunction leads to atrial fibrosis, standstill, and dysrhythmia. However, the underlying pathogenic mechanisms remain unclear.

METHODS AND RESULTS: Rats subjected to knock-in of a pathogenic MYL4 mutant (p.E11K) developed fibrotic atrial cardiomyopathy. Proteome analysis and single-cell RNA sequencing indicate enrichment of autophagy pathways in mutant-MYL4 atrial dysfunction. Immunofluorescence and electron microscopy revealed undegraded autophagic vesicles accumulated in MYL4

CONCLUSIONS: …

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 …

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 …

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 …

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 …