Medical Specialties Commons^™

A Comprehensive Investigation Of The Performance Of A Commercial Scintillator System For Applications In Electron Flash Radiotherapy, Kevin Liu, Shannon Holmes, Emil Schüler, Sam Beddar

Faculty, Staff and Student Publications

Background: Dosimetry in ultra-high dose rate (UHDR) beamlines is significantly challenged by limitations in real-time monitoring and accurate measurement of beam output, beam parameters, and delivered doses using conventional radiation detectors, which exhibit dependencies in ultra-high dose-rate (UHDR) and high dose-per-pulse (DPP) beamline conditions.

Purpose: In this study, we characterized the response of the Exradin W2 plastic scintillator (Standard Imaging, Inc.), a water-equivalent detector that provides measurements with a time resolution of 100 Hz, to determine its feasibility for use in UHDR electron beamlines.

Methods: The W2 scintillator was exposed to an UHDR electron beam with different beam parameters by …

Consolidation Osimertinib Versus Durvalumab Versus Observation After Concurrent Chemoradiation In Unresectable Egfr-Mutant Nsclc: A Multicenter Retrospective Cohort Study, Amin H Nassar, So Yeon Kim, Jacqueline V Aredo, Jamie Feng, Frances Shepherd, Chao Xu, David Kaldas, Jhanelle E Gray, Thomas J Dilling, Joel W Neal, Heather A Wakelee, Yufei Liu, Steven H Lin, Tariq Abuali, Arya Amini, Yunan Nie, Tejas Patil, Anastasiya Lobachov, Jair Bar, Bailey Fitzgerald, Yu Fujiwara, Thomas U Marron, Rohit Thummalapalli, Helena Yu, Dwight H Owen, John Sharp, Saira Farid, Pedro Rocha, Edurne Arriola, Angelica D'Aiello, Haiying Cheng, Ryan Whitaker, Kaushal Parikh, Yash Ashara, Luxi Chen, Kamya Sankar, Jeremy P Harris, Misako Nagasaka, Adanma Ayanambakkam, Ana I Velazquez, Meera Ragavan, Jessica J Lin, Zofia Piotrowska, Molly Wilgucki, Joshua Reuss, Heike Luders, Christian Grohe, Javier Baena Espinar, Ella Feiner, Salman R Punekar, Shruti Gupta, Ticiana Leal, David J Kwiatkowski, Raymond H Mak, Elio Adib, Abdul Rafeh Naqash, Sarah B Goldberg

Faculty, Staff and Student Publications

Introduction: Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown.

Methods: In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary end point) and overall survival (secondary end point). Treatment-related adverse events (trAEs) during consolidation treatment were defined using Common Terminology …

Presentation, Management, And Outcomes Of Norovirus In Adult And Pediatric Solid Organ And Hematopoietic Stem Cell Transplant Recipients: A Multicenter, Retrospective Study, Michelle Callegari, Lara A Danziger-Isakov, Anne Rose, Daniel Kaul, Kelly Shaffer, Pearlie P Chong, Diana Florescu, Kaci German, Robin Avery, M Hong Nguyen, Brett Wildfeuer, Marian G Michaels, Michael Green, Kexin Guo, Lihui Zhao, Amna Daud, Michael G Ison

Faculty, Staff and Student Publications

Background: Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients. Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients.

Methods: A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated.

Results: A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a …

Mortality In Recipients Of Allogeneic Haematopoietic Cell Transplantation In The Era Of Cytomegalovirus Primary Prophylaxis: A Single-Centre Retrospective Experience, Anthony Febres-Aldana, Fareed Khawaja, Oscar Morado-Aramburo, Terri Lynn Shigle, Gabriela Rondon, Joseph Sassine, Amy Spallone, Krithika Srinivasan, Jeremy Ramdial, Amin Alousi, Richard Champlin, George Chen, May Daher, Katayoun Rezvani, Ella J Ariza-Heredia, Elizabeth J Shpall, Roy F Chemaly

Faculty, Staff and Student Publications

Objectives: Allogeneic haematopoietic cell transplant (allo-HCT) recipients who are cytomegalovirus (CMV)-seronegative have better post-transplant outcomes than CMV-seropositive recipients. Letermovir (LTV) is approved for CMV primary prophylaxis in adults who are CMV-seropositive after allo-HCT, and its use is associated with improved long-term post-transplant outcomes. We analysed whether LTV has affected the relationship between CMV serostatus and post-transplant outcomes.

Methods: We conducted a retrospective single-centre cohort study of allo-HCT recipients, stratified according to donor (D) and recipient (R). CMV serostatus and the use of LTV: D-/R-, R+/LTV-, and R+/LTV+. Outcomes measured were all-cause and non-relapse mortality, clinically significant CMV infection, graft-versus-host disease, …

Immune Infiltration At The Primary Tumor Is Associated With Clinical Outcome Of Patients With Extranodal Extension Of Lymph Node Metastasis In Oral Cancer, Chieko Michikawa, Frederico O Gleber-Netto, Curtis R Pickering, Xiayu Rao, Jing Wang, Andrew G Sikora, Jeffrey N Myers, Mitchell J Frederick

Faculty, Staff and Student Publications

Background: Extranodal extension (ENE) of lymph node metastasis is one of the most reliable prognostic indicators for patients with locally advanced oral cancer. Although multiple reports have found a close relationship between immune infiltration of tumors and patient clinical outcomes, its association with ENE is unknown.

Methods: We identified 234 human papillomavirus-negative (HPV-) oral cavity squamous cell carcinoma (OSCC) patients in The Cancer Genome Atlas and investigated the immune infiltration profiles of primary tumors and their association with survival.

Results: Hierarchical clustering analysis clearly classified the overall immune infiltration status in OSCC into high immune or low immune groups. The …

Integrative Genomic And Transcriptomic Profiling Of Pulmonary Sarcomatoid Carcinoma Identifies Molecular Subtypes Associated With Distinct Immune Features And Clinical Outcomes, Sahil Seth, Runzhe Chen, Yang Liu, Junya Fujimoto, Lingzhi Hong, Alexandre Reuben, Susan Varghese, Carmen Behrens, Tina Mcdowell, Luisa Solis Soto, Cara Haymaker, Annikka Weissferdt, Neda Kalhor, Jia Wu, Xiuning Le, Natalie I Vokes, Chao Cheng, John V Heymach, Don L Gibbons, P Andrew Futreal, Ignacio I Wistuba, Humam Kadara, Jianhua Zhang, Cesar Moran, Jianjun Zhang

Faculty, Staff and Student Publications

BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of non-small cell lung cancer (NSCLC), characterized by the presence of epithelial and sarcoma-like components. The molecular and immune landscape of PSC has not been well defined.

METHODS: Multiomics profiling of 21 pairs of PSCs with matched normal lung tissues was performed through targeted high-depth DNA panel, whole-exome, and RNA sequencing. We describe molecular and immune features that define subgroups of PSC with disparate genomic and immunogenic features as well as distinct clinical outcomes.

RESULTS: In total, 27 canonical cancer gene mutations were identified, with

CONCLUSIONS: We provided detailed …

Ascc1 Structures And Bioinformatics Reveal A Novel Helix-Clasp-Helix Rna-Binding Motif Linked To A Two-Histidine Phosphodiesterase, Naga Babu Chinnam, Roopa Thapar, Andrew S Arvai, Altaf H Sarker, Jennifer M Soll, Tanmoy Paul, Aleem Syed, Daniel J Rosenberg, Michal Hammel, Albino Bacolla, Panagiotis Katsonis, Abhishek Asthana, Miaw-Sheue Tsai, Ivaylo Ivanov, Olivier Lichtarge, Robert H Silverman, Nima Mosammaparast, Susan E Tsutakawa, John A Tainer

Faculty, Staff and Student Publications

Activating signal co-integrator complex 1 (ASCC1) acts with ASCC-ALKBH3 complex in alkylation damage responses. ASCC1 uniquely combines two evolutionarily ancient domains: nucleotide-binding K-Homology (KH) (associated with regulating splicing, transcriptional, and translation) and two-histidine phosphodiesterase (PDE; associated with hydrolysis of cyclic nucleotide phosphate bonds). Germline mutations link loss of ASCC1 function to spinal muscular atrophy with congenital bone fractures 2 (SMABF2). Herein analysis of The Cancer Genome Atlas (TCGA) suggests ASCC1 RNA overexpression in certain tumors correlates with poor survival, Signatures 29 and 3 mutations, and genetic instability markers. We determined crystal structures of Alvinella pompejana (Ap) ASCC1 and Human (Hs) …

Vaccine Uptake And Intentions: Insights From A Texas Survey On Factors Influencing Covid-19 Vaccination Decisions, Yordanos M Tiruneh, Paula M Cuccaro, Kimberly S Elliott, Jing Xie, Journey Martinez, Mark Owens, Christian R Alvarado, Jose-Miguel Yamal

Faculty, Staff and Student Publications

The effectiveness of COVID-19 vaccines depends on widespread vaccine uptake. Employing a telephone-administered weighted survey with 19,502 participants, we examined the determinants of COVID-19 vaccine acceptance among adults in Texas. We used multiple regression analysis with LASSO-selected variables to identify factors associated with COVID-19 vaccine uptake and intentions to receive the vaccine among the unvaccinated. The prevalence of unvaccinated individuals (22%) was higher among those aged 18-39, males, White respondents, English speakers, uninsured individuals, those facing financial challenges, and individuals expressing no concern about contracting the illness. In a fully adjusted regression model, higher odds of being unvaccinated were observed …

Prediction Accuracy Of Soil Chemical Parameters By Field- And Laboratory-Obtained Vis-Nir Spectra After External Parameter Orthogonalization, Konrad Metzger, Frank Liebisch, Juan M Herrera, Thomas Guillaume, Luca Bragazza

Faculty, Staff and Student Publications

One challenge in predicting soil parameters using in situ visible and near infrared spectroscopy is the distortion of the spectra due to soil moisture. External parameter orthogonalization (EPO) is a mathematical method to remove unwanted variability from spectra. We created two different EPO correction matrices based on the difference between spectra collected in situ and, respectively, spectra collected from the same soil samples after drying and sieving and after drying, sieving and finely grinding. Spectra from 134 soil samples recorded with two different spectrometers were split into calibration and validation sets and the two EPO corrections were applied. Clay, organic …

Two Genome-Wide Interaction Loci Modify The Association Of Nonsteroidal Anti-Inflammatory Drugs With Colorectal Cancer, David A Drew, Andre E Kim, Yi Lin, Conghui Qu, John Morrison, Juan Pablo Lewinger, Eric Kawaguchi, Jun Wang, Yubo Fu, Natalia Zemlianskaia, Virginia Díez-Obrero, Stephanie A Bien, Niki Dimou, Demetrius Albanes, James W Baurley, Anna H Wu, Daniel D Buchanan, John D Potter, Ross L Prentice, Sophia Harlid, Volker Arndt, Elizabeth L Barry, Sonja I Berndt, Emmanouil Bouras, Hermann Brenner, Arif Budiarto, Andrea Burnett-Hartman, Peter T Campbell, Robert Carreras-Torres, Graham Casey, Jenny Chang-Claude, David V Conti, Matthew A M Devall, Jane C Figueiredo, Stephen B Gruber, Andrea Gsur, Marc J Gunter, Tabitha A Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R Huyghe, Mark A Jenkins, Kristina M Jordahl, Anshul Kundaje, Loic Le Marchand, Li Li, Brigid M Lynch, Neil Murphy, Rami Nassir, Polly A Newcomb, Christina C Newton, Mireia Obón-Santacana, Shuji Ogino, Jennifer Ose, Rish K Pai, Julie R Palmer, Nikos Papadimitriou, Bens Pardamean, Andrew J Pellatt, Anita R Peoples, Elizabeth A Platz, Gad Rennert, Edward Ruiz-Narvaez, Lori C Sakoda, Peter C Scacheri, Stephanie L Schmit, Robert E Schoen, Mariana C Stern, Yu-Ru Su, Duncan C Thomas, Yu Tian, Konstantinos K Tsilidis, Cornelia M Ulrich, Caroline Y Um, Fränzel J B Van Duijnhoven, Bethany Van Guelpen, Emily White, Li Hsu, Victor Moreno, Ulrike Peters, Andrew T Chan, W James Gauderman

Faculty, Staff and Student Publications

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit

The Kat Module Of The Saga Complex Maintains The Oncogenic Gene Expression Program In Mycn- Amplified Neuroblastoma, Clare F Malone, Nathaniel W Mabe, Alexandra B Forman, Gabriela Alexe, Kathleen L Engel, Ying-Jiun C Chen, Melinda Soeung, Silvi Salhotra, Allen Basanthakumar, Bin Liu, Sharon Y R Dent, Kimberly Stegmaier

Faculty, Staff and Student Publications

Pediatric cancers are frequently driven by genomic alterations that result in aberrant transcription factor activity. Here, we used functional genomic screens to identify multiple genes within the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as selective dependencies for MYCN-amplified neuroblastoma, a disease of dysregulated development driven by an aberrant oncogenic transcriptional program. We characterized the DNA recruitment sites of the SAGA complex in neuroblastoma and the consequences of loss of SAGA complex lysine acetyltransferase (KAT) activity on histone acetylation and gene expression. We demonstrate that loss of SAGA complex KAT activity is associated with reduced MYCN binding on chromatin, suppression of …

Using Patient-Specific 3d Modeling And Simulations To Optimize Microwave Ablation Therapy For Liver Cancer, Amirreza Heshmat, Caleb S O'Connor, Jessica Albuquerque Marques Silva, Iwan Paolucci, Aaron Kyle Jones, Bruno C Odisio, Kristy K Brock

Faculty, Staff and Student Publications

Microwave ablation (MWA) of liver tumors presents challenges like under- and over-ablation, potentially leading to inadequate tumor destruction and damage to healthy tissue. This study aims to develop personalized three-dimensional (3D) models to simulate MWA for liver tumors, incorporating patient-specific characteristics. The primary objective is to validate the predicted ablation zones compared to clinical outcomes, offering insights into MWA before therapy to facilitate accurate treatment planning. Contrast-enhanced CT images from three patients were used to create 3D models. The simulations used coupled electromagnetic wave propagation and bioheat transfer to estimate the temperature distribution, predicting tumor destruction and ablation margins. The …

Nivolumab Plus Relatlimab In Patients With Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase Ii Checkmate 142 Study, Michael J Overman, Fabio Gelsomino, Massimo Aglietta, Mark Wong, Maria Luisa Limon Miron, Gregory Leonard, Pilar García-Alfonso, Andrew G Hill, Antonio Cubillo Gracian, Eric Van Cutsem, Bassel El-Rayes, Stephen M Mccraith, Beilei He, Ming Lei, Sara Lonardi

Faculty, Staff and Student Publications

BACKGROUND: Programmed death-1 (PD-1) inhibitors, including nivolumab, have demonstrated long-term survival benefit in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC). PD-1 and lymphocyte-activation gene 3 (LAG-3) are distinct immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes and contribute to tumor-mediated T-cell dysfunction. Relatlimab is a LAG-3 inhibitor that has demonstrated efficacy in combination with nivolumab in patients with melanoma. Here, we present the results from patients with MSI-H/dMMR metastatic CRC treated with nivolumab plus relatlimab in the CheckMate 142 study.

METHODS: In this open-label, phase II study, previously treated patients with MSI-H/dMMR metastatic CRC …

Molecular Classification And Biomarkers Of Outcome With Immunotherapy In Extensive-Stage Small-Cell Lung Cancer: Analyses Of The Caspian Phase 3 Study, Mingchao Xie, Miljenka Vuko, Jaime Rodriguez-Canales, Johannes Zimmermann, Markus Schick, Cathy O'Brien, Luis Paz-Ares, Jonathan W Goldman, Marina Chiara Garassino, Carl M Gay, John V Heymach, Haiyi Jiang, J Carl Barrett, Ross A Stewart, Zhongwu Lai, Lauren A Byers, Charles M Rudin, Yashaswi Shrestha

Faculty, Staff and Student Publications

BACKGROUND: We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial.

METHODS: 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue …

Multiomics Analysis Of The Phlda Gene Family In Different Cancers And Their Clinical Prognostic Value, Safia Iqbal, Md Rezaul Karim, Shahnawaz Mohammad, Ramya Mathiyalagan, Md Niaj Morshed, Deok-Chun Yang, Hyocheol Bae, Esrat Jahan Rupa, Dong Uk Yang

Faculty, Staff and Student Publications

The PHLDA (pleckstrin homology-like domain family) gene family is popularly known as a potential biomarker for cancer identification, and members of the PHLDA family have become considered potentially viable targets for cancer treatments. The PHLDA gene family consists of PHLDA1, PHLDA2, and PHLDA3. The predictive significance of PHLDA genes in cancer remains unclear. To determine the role of pleckstrin as a prognostic biomarker in human cancers, we conducted a systematic multiomics investigation. Through various survival analyses, pleckstrin expression was evaluated, and their predictive significance in human tumors was discovered using a variety of online platforms. By analyzing the protein-protein interactions, …

Machine Learning Models For Predicting Blood Pressure Phenotypes By Combining Multiple Polygenic Risk Scores, Yana Hrytsenko, Benjamin Shea, Michael Elgart, Nuzulul Kurniansyah, Genevieve Lyons, Alanna C Morrison, April P Carson, Bernhard Haring, Braxton D Mitchell, Bruce M Psaty, Byron C Jaeger, C Charles Gu, Charles Kooperberg, Daniel Levy, Donald Lloyd-Jones, Eunhee Choi, Jennifer A Brody, Jennifer A Smith, Jerome I Rotter, Matthew Moll, Myriam Fornage, Noah Simon, Peter Castaldi, Ramon Casanova, Ren-Hua Chung, Robert Kaplan, Ruth J F Loos, Sharon L R Kardia, Stephen S Rich, Susan Redline, Tanika Kelly, Timothy O'Connor, Wei Zhao, Wonji Kim, Xiuqing Guo, Yii-Der Ida Chen, Trans-Omics In Precision Medicine Consortium, Tamar Sofer

Faculty, Staff and Student Publications

We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model's performance as percentage variance explained (PVE) on a held-out test …

Validation Of A Blood-Based Protein Biomarker Panel For A Risk Assessment Of Lethal Lung Cancer In The Physicians' Health Study, Lulu Song, Ehsan Irajizad, Andrew Rundle, Howard D Sesso, John Michael Gaziano, Jody V Vykoukal, Kim-Anh Do, Jennifer B Dennison, Edwin J Ostrin, Johannes F Fahrmann, Frederica Perera, Samir Hanash

Faculty, Staff and Student Publications

This study aimed to assess a four-marker protein panel (4MP)'s performance, including the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19, for predicting lung cancer in a cohort enriched with never- and ever-smokers. Blinded pre-diagnostic plasma samples collected within 2 years prior to a lung cancer diagnosis from 25 cases and 100 sex-, age-, and smoking-matched controls were obtained from the Physicians' Health Study (PHS). The 4MP yielded AUC performance estimates of 0.76 (95% CI: 0.61-0.92) and 0.69 (95% CI: 0.56-0.82) for predicting lung cancer within one year and within two years of diagnosis, respectively. …

Efficacy And Safety Of Atezolizumab And Bevacizumab In Appendiceal Adenocarcinoma, Nicholas J Hornstein, Mohammad A Zeineddine, Betul B Gunes, Andrew J Pellatt, Mark Knafl, Haifeng Zhu, Anneleis F Willett, Abdelrahman Yousef, Suyu Liu, Ryan Sun, Andrew Futreal, Scott E Woodman, Melissa W Taggart, Michael J Overman, Daniel M Halperin, Kanwal P Raghav, John Paul Shen

Faculty, Staff and Student Publications

PURPOSE: Appendiceal adenocarcinoma (AA) remains an orphan disease with limited treatment options for patients unable to undergo surgical resection. Evidence supporting the efficacy of combined VEGF and PD-1 inhibition in other tumor types provided a compelling rationale for investigating this combination in AA, where immune checkpoint inhibitors have not been explored previously.

EXPERIMENTAL DESIGN: We conducted a prospective, single-arm phase II study evaluating efficacy and safety of atezolizumab in conjunction with bevacizumab (Atezo+Bev) in advanced, unresectable AA.

RESULTS: Patients treated with the Atezo+Bev combination had 100% disease control rate (1 partial response, 15 stable disease) with progression-free survival (PFS) of …

Metabolic Alterations And Cellular Responses To Β-Hydroxybutyrate Treatment In Breast Cancer Cells, Hadas Fulman-Levy, Raichel Cohen-Harazi, Bar Levi, Lital Argaev-Frenkel, Ifat Abramovich, Eyal Gottlieb, Sarah Hofmann, Igor Koman, Elimelech Nesher

Faculty, Staff and Student Publications

BACKGROUND: The ketogenic diet (KD), based on high fat (over 70% of daily calories), low carbohydrate, and adequate protein intake, has become popular due to its potential therapeutic benefits for several diseases including cancer. Under KD and starvation conditions, the lack of carbohydrates promotes the production of ketone bodies (KB) from fats by the liver as an alternative source of metabolic energy. KD and starvation may affect the metabolism in cancer cells, as well as tumor characteristics. The aim of this study is to evaluate the effect of KD conditions on a wide variety of aspects of breast cancer cells …

An International Phantom Study Of Inter-Site Variability In Technetium-99m Image Quantification: Analyses From The Target Radioembolization Study, Grace Keane, Rob Van Rooij, Marnix Lam, S Cheenu Kappadath, Bilal Kovan, Stephanie Leon, Matthew Dreher, Kirk Fowers, Hugo De Jong

Faculty, Staff and Student Publications

BACKGROUND: Personalised multi-compartment dosimetry based on [

RESULTS: Regarding the LSF, inter-site variation with planar site-specific protocols was minimal, as determined by comparing computed LSF between sites (interquartile range 9.6-10.1%). A standardised protocol did not improve variation (interquartile range 8.4-9.0%) but did improve mean accuracy compared to the site-specific protocols (5.0% error for standardised protocol vs 8.8% error for site-specific protocols). Regarding the CRC, inter-system variation was notable for site-specific SPECT protocols and could not be improved by the standardised protocol (CRC interquartile range for 37 mm sphere 0.5-0.7 and 0.6-0.8 respectively), however the standardised protocol did improve accuracy of …

A Multicenter Study Of Venetoclax-Based Treatment For Patients With Richter Transformation Of Chronic Lymphocytic Leukemia, Paul J Hampel, Mahesh Swaminathan, Kerry A Rogers, Erin M Parry, Jan A Burger, Matthew S Davids, Wei Ding, Alessandra Ferrajoli, Jonathan M Hyak, Nitin Jain, Saad S Kenderian, Yucai Wang, William G Wierda, Jennifer A Woyach, Sameer A Parikh, Philip A Thompson

Faculty, Staff and Student Publications

Patients with chronic lymphocytic leukemia (CLL) who develop Richter transformation (RT) have a poor prognosis when treated with chemoimmunotherapy regimens used for de novo diffuse large B-cell lymphoma. Venetoclax, a BCL2 inhibitor, has single-agent efficacy in patients with RT and is potentially synergistic with chemoimmunotherapy. In this multicenter, retrospective study, we evaluated 62 patients with RT who received venetoclax-based treatment outside of a clinical trial, in combination with a Bruton tyrosine kinase inhibitor (BTKi; n=28), rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=13), or intensive chemoimmunotherapy other than R-CHOP (n=21). The best overall and complete response rates were 36%/25%, 54%/46%, and …

Loss Of Lpar6 And Cab39l Dysregulates The Basal-To-Luminal Urothelial Differentiation Program, Contributing To Bladder Carcinogenesis, Sangkyou Lee, Jolanta Bondaruk, Yishan Wang, Huiqin Chen, June Goo Lee, Tadeusz Majewski, Rachel D Mullen, David Cogdell, Jiansong Chen, Ziqiao Wang, Hui Yao, Pawel Kus, Joon Jeong, Ilkyun Lee, Woonyoung Choi, Neema Navai, Charles Guo, Colin Dinney, Keith Baggerly, Cathy Mendelsohn, David Mcconkey, Richard R Behringer, Marek Kimmel, Peng Wei, Bogdan Czerniak

Faculty, Staff and Student Publications

We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term "forerunner" genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two …

Smoking Cessation After Initial Treatment Failure With Varenicline Or Nicotine Replacement: A Randomized Clinical Trial, Paul M Cinciripini, Charles E Green, Sanjay Shete, Jennifer A Minnix, Jason D Robinson, Yong Cui, Seokhun Kim, George Kypriotakis, Diane Beneventi, Janice A Blalock, Francesco Versace, Maher Karam-Hage

Faculty, Staff and Student Publications

Importance: Most people who smoke do not quit on their initial attempt.

Objective: To determine the best subsequent strategy for nonabstinence following initial treatment with varenicline or combined nicotine replacement therapy (CNRT).

Design, setting, and participants: Using a double-blind, placebo-controlled, sequential multiple assignment randomized trial, 490 volunteers were randomized to receive 6 weeks of varenicline or CNRT. After 6 weeks, nonabstainers were rerandomized to continue, switch, or increase medication dosage for 6 additional weeks. The study was conducted from June 2015 through October 2019 in a Texas tobacco treatment clinic.

Interventions: The initial treatment was 2 mg/d of varenicline or …

Differentiation Syndrome Associated With Treatment With Idh2 Inhibitor Enasidenib: Pooled Analysis From Clinical Trials, Pau Montesinos, Amir T Fathi, Stéphane De Botton, Eytan M Stein, Amer M Zeidan, Yue Zhu, Thomas Prebet, Carlos E Vigil, Iryna Bluemmert, Xin Yu, Courtney D Dinardo

Faculty, Staff and Student Publications

Treatment with enasidenib, a selective mutant isocitrate dehydrogenase isoform 2 (IDH2) inhibitor, has been associated with the development of differentiation syndrome (DS) in patients with acute myeloid leukemia (AML). Studies on the incidence and clinical features of DS are limited in this setting, and diagnosis is challenging because of nonspecific symptoms. This study assessed the incidence, diagnostic criteria, risk factors, and correlation with clinical response of DS based on the pooled analysis of 4 clinical trials in patients with IDH2-mutated AML treated with enasidenib as monotherapy, or in combination with azacitidine or with chemotherapy. Across the total AML population, 67 …

Astrocytic Slc4a4 Regulates Blood-Brain Barrier Integrity In Healthy And Stroke Brains Via A Ccl2-Ccr2 Pathway And No Dysregulation, Qi Ye, Juyeon Jo, Chih-Yen Wang, Heavin Oh, Jiangshan Zhan, Tiffany J Choy, Kyoung In Kim, Angelo D'Alessandro, Yana K Reshetnyak, Sung Yun Jung, Zheng Chen, Sean P Marrelli, Hyun Kyoung Lee

Faculty, Staff and Student Publications

Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests that ion homeostasis is a cellular mechanism important for BBB integrity. In the current study, we investigated the function of an astrocyte-specific pH regulator, Slc4a4, in BBB maintenance and repair. We show that astrocytic Slc4a4 is required for normal astrocyte morphological complexity and BBB function. Multi-omics analyses identified increased astrocytic secretion of CCL2 coupled with dysregulated arginine-NO metabolism after Slc4a4 deletion. Using a model of ischemic stroke, we found that loss of Slc4a4 exacerbates …

Outcomes And Pattern Of Care For Spinal Myxopapillary Ependymoma In The Modern Era-A Population-Based Observational Study, Chenyang Wang, Michael K Rooney, Christopher Alvarez-Breckenridge, Thomas H Beckham, Caroline Chung, Brian S De, Amol J Ghia, David Grosshans, Nazanin K Majd, Mary F Mcaleer, Susan L Mcgovern, Robert Y North, Arnold C Paulino, Subha Perni, Jay P Reddy, Laurence D Rhines, Todd A Swanson, Claudio E Tatsui, Martin C Tom, Debra N Yeboa, Jing Li

Faculty, Staff and Student Publications

(1) Background: Myxopapillary ependymoma (MPE) is a rare tumor of the spine, typically slow-growing and low-grade. Optimal management strategies remain unclear due to limited evidence given the low incidence of the disease. (2) Methods: We analyzed data from 1197 patients with spinal MPE from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2020). Patient demographics, treatment modalities, and survival outcomes were examined using statistical analyses. (3) Results: Most patients were White (89.9%) with a median age at diagnosis of 42 years. Surgical resection was performed in 95% of cases. The estimated 10-year overall survival was 91.4%. Younger age (hazard ratio …

Plasmonic Nano-Aperture Label-Free Imaging Of Single Small Extracellular Vesicles For Cancer Detection, Nareg Ohannesian, Mohammad Sadman Mallick, Jianzhong He, Yawei Qiao, Nan Li, Simona F Shaitelman, Chad Tang, Eileen H Shinn, Wayne L Hofstetter, Alexei Goltsov, Manal M Hassan, Kelly K Hunt, Steven H Lin, Wei-Chuan Shih

Faculty, Staff and Student Publications

BACKGROUND: Small extracellular vesicle (sEV) analysis can potentially improve cancer detection and diagnostics. However, this potential has been constrained by insufficient sensitivity, dynamic range, and the need for complex labeling.

METHODS: In this study, we demonstrate the combination of PANORAMA and fluorescence imaging for single sEV analysis. The co-acquisition of PANORAMA and fluorescence images enables label-free visualization, enumeration, size determination, and enables detection of cargo microRNAs (miRs).

RESULTS: An increased sEV count is observed in human plasma samples from patients with cancer, regardless of cancer type. The cargo miR-21 provides molecular specificity within the same sEV population at the single …

Ver-Net: A Hybrid Transfer Learning Model For Lung Cancer Detection Using Ct Scan Images, Anindita Saha, Shahid Mohammad Ganie, Pijush Kanti Dutta Pramanik, Rakesh Kumar Yadav, Saurav Mallik, Zhongming Zhao

Faculty, Staff and Student Publications

BACKGROUND: Lung cancer is the second most common cancer worldwide, with over two million new cases per year. Early identification would allow healthcare practitioners to handle it more effectively. The advancement of computer-aided detection systems significantly impacted clinical analysis and decision-making on human disease. Towards this, machine learning and deep learning techniques are successfully being applied. Due to several advantages, transfer learning has become popular for disease detection based on image data.

METHODS: In this work, we build a novel transfer learning model (VER-Net) by stacking three different transfer learning models to detect lung cancer using lung CT scan images. …

Validation Of Human Telomere Length Multi-Ancestry Meta-Analysis Association Signals Identifies Pop5 And Kbtbd6 As Human Telomere Length Regulation Genes, Rebecca Keener, Surya B Chhetri, Carla J Connelly, Margaret A Taub, Matthew P Conomos, Joshua Weinstock, Bohan Ni, Benjamin Strober, Stella Aslibekyan, Paul L Auer, Lucas Barwick, Lewis C Becker, John Blangero, Eugene R Bleecker, Jennifer A Brody, Brian E Cade, Juan C Celedon, Yi-Cheng Chang, L Adrienne Cupples, Brian Custer, Barry I Freedman, Mark T Gladwin, Susan R Heckbert, Lifang Hou, Marguerite R Irvin, Carmen R Isasi, Jill M Johnsen, Eimear E Kenny, Charles Kooperberg, Ryan L Minster, Take Naseri, Satupa'itea Viali, Sergei Nekhai, Nathan Pankratz, Patricia A Peyser, Kent D Taylor, Marilyn J Telen, Baojun Wu, Lisa R Yanek, Ivana V Yang, Christine Albert, Donna K Arnett, Allison E Ashley-Koch, Kathleen C Barnes, Joshua C Bis, Thomas W Blackwell, Eric Boerwinkle, Esteban G Burchard, April P Carson, Zhanghua Chen, Yii-Der Ida Chen, Dawood Darbar, Mariza De Andrade, Patrick T Ellinor, Myriam Fornage, Bruce D Gelb, Frank D Gilliland, Jiang He, Talat Islam, Stefan Kaab, Sharon L R Kardia, Shannon Kelly, Barbara A Konkle, Rajesh Kumar, Ruth J F Loos, Fernando D Martinez, Stephen T Mcgarvey, Deborah A Meyers, Braxton D Mitchell, Courtney G Montgomery, Kari E North, Nicholette D Palmer, Juan M Peralta, Benjamin A Raby, Susan Redline, Stephen S Rich, Dan Roden, Jerome I Rotter, Ingo Ruczinski, David Schwartz, Frank Sciurba, M Benjamin Shoemaker, Edwin K Silverman, Moritz F Sinner, Nicholas L Smith, Albert V Smith, Hemant K Tiwari, Ramachandran S Vasan, Scott T Weiss, L Keoki Williams, Yingze Zhang, Elad Ziv, Laura M Raffield, Alexander P Reiner, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Hematology And Hemostasis Working Group, Topmed Structural Variation Working Group, Marios Arvanitis, Carol W Greider, Rasika A Mathias, Alexis Battle

Faculty, Staff and Student Publications

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of …

Brain Cell-Type Shifts In Alzheimer’S Disease, Autism, And Schizophrenia Interrogated Using Methylomics And Genetics, Chloe X Yap, Daniel D Vo, Matthew G Heffel, Arjun Bhattacharya, Cindy Wen, Yuanhao Yang, Kathryn E Kemper, Jian Zeng, Zhili Zheng, Zhihong Zhu, Eilis Hannon, Dorothea Seiler Vellame, Alice Franklin, Christa Caggiano, Brie Wamsley, Daniel H Geschwind, Noah Zaitlen, Alexander Gusev, Bogdan Pasaniuc, Jonathan Mill, Chongyuan Luo, Michael J Gandal

Faculty, Staff and Student Publications

Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimer's disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimer's disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial …