Medical Genetics Commons^™

Framework For Quality Assurance Of Ultrahigh Dose Rate Clinical Trials Investigating Flash Effects And Current Technology Gaps, Wei Zou, Rongxiao Zhang, Emil Schüler, Paige A Taylor, Anthony E Mascia, Eric S Diffenderfer, Tianyu Zhao, Ahmet S Ayan, Manju Sharma, Shu-Jung Yu, Weiguo Lu, Walter R Bosch, Christina Tsien, Murat Surucu, Julianne M Pollard-Larkin, Jan Schuemann, Eduardo G Moros, Magdalena Bazalova-Carter, David J Gladstone, Heng Li, Charles B Simone, Kristoffer Petersson, Stephen F Kry, Amit Maity, Billy W Loo, Lei Dong, Peter G Maxim, Ying Xiao, Jeffrey C Buchsbaum

Faculty, Staff and Student Publications

FLASH radiation therapy (FLASH-RT), delivered with ultrahigh dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared with currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology …

Divergent Structures Of Mammalian And Gammaherpesvirus Uracil Dna Glycosylases Confer Distinct Dna Binding And Substrate Activity, Yunxiang Mu, Monika A Zelazowska, Zaowen Chen, Joshua B Plummer, Qiwen Dong, Laurie T Krug, Kevin M Mcbride

Faculty, Staff and Student Publications

Uracil DNA glycosylase (UNG) removes mutagenic uracil base from DNA to initiate base excision repair (BER). The result is an abasic site (AP site) that is further processed by the high-fidelity BER pathway to complete repair and maintain genome integrity. The gammaherpesviruses (GHVs), human Kaposi sarcoma herpesvirus (KSHV), Epstein-Barr virus (EBV), and murine gammaherpesvirus 68 (MHV68) encode functional UNGs that have a role in viral genome replication. Mammalian and GHVs UNG share overall structure and sequence similarity except for a divergent amino-terminal domain and a leucine loop motif in the DNA binding domain that varies in sequence and length. To …

Effect Of Sotagliflozin On Early Mortality And Heart Failure-Related Events: A Post Hoc Analysis Of Soloist-Whf, Bertram Pitt, Deepak L Bhatt, Michael Szarek, Christopher P Cannon, Lawrence A Leiter, Darren K Mcguire, Julia B Lewis, Matthew C Riddle, Adriaan A Voors, Marco Metra, Lars H Lund, Michel Komajda, Jeffrey M Testani, Christopher S Wilcox, Piotr Ponikowski, Renato D Lopes, Justin A Ezekowitz, Franklin Sun, Michael J Davies, Subodh Verma, Mikhail N Kosiborod, Ph Gabriel Steg, Soloist-Whf Investigators

Faculty, Staff and Student Publications

Background: Approximately 25% of patients admitted to hospitals for worsening heart failure (WHF) are readmitted within 30 days.

Objectives: The authors conducted a post hoc analysis of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post-WHF) trial to evaluate the efficacy of sotagliflozin versus placebo to decrease mortality and HF-related events among patients who began study treatment on or before discharge from their index hospitalization.

Methods: The main endpoint of interest was cardiovascular death or HF-related event (HF hospitalization or urgent care visit) occurring within 90 and 30 days after discharge for the index …

Life-Threatening Hemoptysis In Patients With Metastatic Kidney Cancer, Viral M Patel, Roy Elias, Annapoorani Asokan, Akanksha Sharma, Alana Christie, Ivan Pedrosa, Hsienchang Chiu, Scott Reznik, Raquibul Hannan, Robert Timmerman, James Brugarolas

Faculty, Staff and Student Publications

Hemoptysis is a complication of intrathoracic tumors, both primary and metastatic, and the risk may be increased by procedural interventions as well as Stereotactic Ablative Radiation (SAbR). The risk of hemoptysis with SAbR for lung cancer is well characterized, but there is a paucity of data about intrathoracic metastases. Here, we sought to evaluate the incidence of life-threatening/fatal hemoptysis (LTH) in patients with renal cell carcinoma (RCC) chest metastases with a focus on SAbR. We systematically evaluated patients with RCC at UT Southwestern Medical Center (UTSW) Kidney Cancer Program (KCP) from July 2005 to March 2020. We queried Kidney Cancer …

Open Innovation: The Key To Advancing Brain Health, Harris A Eyre, Jason Searfoss, Malcolm Hopwood, Michael Berk, Shuo Chen, Jeffrey Cummings, Francois Veron, Vicki Zikopoulou, Agustin Ibanez, Kacie Kelly, Jair C Soares, Erin Smith, Barnabas J Gilbert

Faculty, Staff and Student Publications

With the exponential growth in investment attention to brain health-solutions spanning brain wellness to mental health to neurological disorders-tech giants, payers, and biotechnology companies have been making forays into this field to identify technology solutions and pharmaceutical amplifiers. So far, their investments have had mixed results. The concept of open innovation (OI) was first coined by Henry Chesbrough to describe the paradigm by which enterprises allow free flow of ideas, products, and services from the outside to the inside and vice versa in order to remain competitive, particularly in rapidly evolving fields where there is abundant, relevant knowledge outside the …

Tumor Thickness In Mesothelioma Predicts Differential Response To Neoadjuvant Therapy And Survival, Nicolas Zhou, Cynthia S Bell, Hope A Feldman, Cara L Haymaker, Wayne L Hofstetter, Anne S Tsao, Reza J Mehran, David C Rice, Boris Sepesi

Faculty, Staff and Student Publications

Objective: Neoadjuvant systemic therapy in resectable malignant pleural mesothelioma remains controversial and demonstrates variable responses. We sought to evaluate tumor thickness as a predictor of response to neoadjuvant therapy and as a prognostic marker for overall survival.

Methods: Data from patients who underwent neoadjuvant therapy followed by cytoreductive surgery from 2002 to 2019 were reviewed. Baseline and postneoadjuvant therapy tumor thickness were measured on computed tomography. Radiological tumor response was categorized as progressive disease (≥20% increase), partial response (≥30% decrease), or stable disease (in between). Tumor response outcomes were modeled using logistic regression and multinomial regression models. Overall survival was …

Mesothelin-Targeting T Cell Receptor Fusion Construct Cell Therapy In Refractory Solid Tumors: Phase 1/2 Trial Interim Results, Raffit Hassan, Marcus Butler, Roisin E O'Cearbhaill, David Y Oh, Melissa Johnson, Kevin Zikaras, Munisha Smalley, Michael Ross, Janos L Tanyi, Azam Ghafoor, Nirali N Shah, Babak Saboury, Liang Cao, Alfonso Quintás-Cardama, David Hong

Faculty, Staff and Student Publications

The T cell receptor fusion construct (TRuC) gavocabtagene autoleucel (gavo-cel) consists of single-domain anti-mesothelin antibody that integrates into the endogenous T cell receptor (TCR) and engages the signaling capacity of the entire TCR upon mesothelin binding. Here we describe phase 1 results from an ongoing phase1/2 trial of gavo-cel in patients with treatment-refractory mesothelin-expressing solid tumors. The primary objectives were to evaluate safety and determine the recommended phase 2 dose (RP2D). Secondary objectives included efficacy. Thirty-two patients received gavo-cel at increasing doses either as a single agent (n = 3) or after lymphodepletion (LD, n = 29). Dose-limiting toxicities of …

Pathologist-Initiated Reflex Testing For Biomarkers In Non-Small-Cell Lung Cancer: Expert Consensus On The Rationale And Considerations For Implementation, J R Gosney, L Paz-Ares, P Jänne, K M Kerr, N B Leighl, M D Lozano, U Malapelle, T Mok, B S Sheffield, A Tufman, I I Wistuba, S Peters

Faculty, Staff and Student Publications

Biomarker tests in lung cancer have been traditionally ordered by the treating oncologist upon confirmation of an appropriate pathological diagnosis. The delay this introduces prolongs yet further what is already a complex, multi-stage, pre-treatment pathway and delays the start of first-line systemic treatment, which is crucially informed by the results of such analysis. Reflex testing, in which the responsibility for testing for an agreed range of biomarkers lies with the pathologist, has been shown to standardise and expedite the process. Twelve experts discussed the rationale and considerations for implementing reflex testing as standard clinical practice.

A Splicing Transcriptome-Wide Association Study Identifies Novel Altered Splicing For Alzheimer’S Disease Susceptibility, Yanfa Sun, Ye Eun Bae, Jingjing Zhu, Zichen Zhang, Hua Zhong, Jie Yu, Chong Wu, Lang Wu

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a common neurodegenerative disease in aging individuals. Alternative splicing is reported to be relevant to AD development while their roles in etiology of AD remain largely elusive. We performed a comprehensive splicing transcriptome-wide association study (spTWAS) using intronic excision expression genetic prediction models of 12 brain tissues developed through three modelling strategies, to identify candidate susceptibility splicing introns for AD risk. A total of 111,326 (46,828 proxy) cases and 677,663 controls of European ancestry were studied. We identified 343 associations of 233 splicing introns (143 genes) with AD risk after Bonferroni correction (0.05/136,884 = 3.65 × …

Mitotic Rate In Primary Cutaneous Melanoma: Cell Division Matters, Jeffrey E Gershenwald

Faculty, Staff and Student Publications

No abstract provided.

Ramucirumab Plus Erlotinib Versus Placebo Plus Erlotinib In Previously Untreated Egfr-Mutated Metastatic Non-Small-Cell Lung Cancer (Relay): Exploratory Analysis Of Next-Generation Sequencing Results, E B Garon, M Reck, K Nishio, J V Heymach, M Nishio, S Novello, L Paz-Ares, S Popat, S Ponce Aix, H Graham, B D Butts, C Visseren-Grul, K Nakagawa

Faculty, Staff and Student Publications

Background: Ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) over placebo + ERL (PBO + ERL) in the phase III RELAY study of patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (EGFR+ mNSCLC; NCT02411448). Next-generation sequencing (NGS) was used to identify clinically relevant alterations in circulating tumor DNA (ctDNA) and explore their impact on treatment outcomes.

Patients and methods: Eligible patients with EGFR+ mNSCLC were randomized 1 : 1 to ERL (150 mg/day) plus RAM (10 mg/kg)/PBO every 2 weeks. Liquid biopsies were to be prospectively collected at baseline, cycle 4 (C4), and …

Poziotinib In Treatment-Naive Nsclc Harboring Her2 Exon 20 Mutations: Zenith20-4, A Multicenter, Multicohort, Open-Label, Phase 2 Trial (Cohort 4), Robin Cornelissen, Arsela Prelaj, Sophie Sun, Christina Baik, Mirjana Wollner, Eric B Haura, Hirva Mamdani, Jonathan W Riess, Federico Cappuzzo, Marina C Garassino, John V Heymach, Mark A Socinski, Szu-Yun Leu, Gajanan Bhat, Francois Lebel, Xiuning Le, Zenith20-4 Investigators

Faculty, Staff and Student Publications

Introduction: ERBB2 or HER2 alterations are found in approximately 2% to 5% of NSCLCs; most are exon 20 insertion mutations. The efficacy and safety of poziotinib, an oral tyrosine kinase inhibitor, were assessed in patients with treatment-naive NSCLC whose tumors harbor HER2 exon 20 insertions.

Methods: ZENITH20 is an open-label, multicohort, multicenter, global, phase 2 trial. ZENITH20-C4 enrolled treatment-naive patients with NSCLC with tumors harboring HER2 exon 20 insertions. Poziotinib was administered 16 mg once daily (QD) or 8 mg twice daily (BID). The primary end point was objective response rate (ORR) by independent central review. Secondary and exploratory end …

Vincristine Enhances The Efficacy Of Mek Inhibitors In Preclinical Models Of Kras-Mutant Colorectal Cancer, Susmita Ghosh, Fan Fan, Reid T Powell, Jason Roszik, Yong Sung Park, Clifford Stephan, Manu Sebastian, Lin Tan, Alexey V Sorokin, Philip L Lorenzi, Scott Kopetz, Lee M Ellis, Rajat Bhattacharya

Faculty, Staff and Student Publications

Mutations in KRAS are found in more than 50% of tumors from patients with metastatic colorectal cancer (mCRC). However, direct targeting of most KRAS mutations is difficult; even the recently developed KRASG12C inhibitors failed to show significant benefit in patients with mCRC. Single agents targeting mitogen-activated protein kinase kinase (MEK), a downstream mediator of RAS, have also been ineffective in colorectal cancer. To identify drugs that can enhance the efficacy of MEK inhibitors, we performed unbiased high-throughput screening using colorectal cancer spheroids. We used trametinib as the anchor drug and examined combinations of trametinib with the NCI-approved Oncology Library version …

Development And Validation Of An Automated Image-Based Deep Learning Platform For Sarcopenia Assessment In Head And Neck Cancer, Zezhong Ye, Anurag Saraf, Yashwanth Ravipati, Frank Hoebers, Paul J Catalano, Yining Zha, Anna Zapaishchykova, Jirapat Likitlersuang, Christian Guthier, Roy B Tishler, Jonathan D Schoenfeld, Danielle N Margalit, Robert I Haddad, Raymond H Mak, Mohamed Naser, Kareem A Wahid, Jaakko Sahlsten, Joel Jaskari, Kimmo Kaski, Antti A Mäkitie, Clifton D Fuller, Hugo J W L Aerts, Benjamin H Kann

Faculty, Staff and Student Publications

Importance: Sarcopenia is an established prognostic factor in patients with head and neck squamous cell carcinoma (HNSCC); the quantification of sarcopenia assessed by imaging is typically achieved through the skeletal muscle index (SMI), which can be derived from cervical skeletal muscle segmentation and cross-sectional area. However, manual muscle segmentation is labor intensive, prone to interobserver variability, and impractical for large-scale clinical use.

Objective: To develop and externally validate a fully automated image-based deep learning platform for cervical vertebral muscle segmentation and SMI calculation and evaluate associations with survival and treatment toxicity outcomes.

Design, setting, and participants: For this prognostic study, …

Myelodysplastic Syndromes: 2023 Update On Diagnosis, Risk-Stratification, And Management, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Disease overview: The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy.

Diagnosis: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry, and molecular genetics is usually complementary and may help refine diagnosis. A new WHO classification of MDS was proposed in 2022. Under this classification, …

Pitfalls In Machine Learning-Based Assessment Of Tumor-Infiltrating Lymphocytes In Breast Cancer: A Report Of The International Immuno-Oncology Biomarker Working Group On Breast Cancer, Jeppe Thagaard, Glenn Broeckx, David B Page, Chowdhury Arif Jahangir, Sara Verbandt, Zuzana Kos, Rajarsi Gupta, Reena Khiroya, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Guray Akturk, Jonas S Almeida, Isabel Alvarado-Cabrero, Mohamed Amgad, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Eva Balslev, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Najat Bouchmaa, Octavio Burgues, Alexandros Chardas, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Anders B Dahl, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Johan Doré Hansen, Sarah N Dudgeon, Thomas Ebstrup, Mahmoud Elghazawy, Claudio Fernandez-Martín, Stephen B Fox, William M Gallagher, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Steven N Hart, Johan Hartman, Søren Hauberg, Stephen Hewitt, Akira I Hida, Hugo M Horlings, Zaheed Husain, Evangelos Hytopoulos, Sheeba Irshad, Emiel Am Janssen, Mohamed Kahila, Tatsuki R Kataoka, Kosuke Kawaguchi, Durga Kharidehal, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Amy Ly, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S Mcdonald, Ravi Mehrotra, Stefan Michiels, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Arman Rahman, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Jorge S Reis-Filho, Joana M Ribeiro, David Rimm, Anne Roslind, Anne Vincent-Salomon, Manuel Salto-Tellez, Joel Saltz, Shahin Sayed, Ely Scott, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Susan Fineberg, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen Van Der Laak, Paul J Van Diest, Gregory E Verghese, Giuseppe Viale, Michael Vieth, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, Reena Md Zin, Sylvia Adams, John Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Roberto Salgado, Elisabeth Specht Stovgaard

Faculty, Staff and Student Publications

The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. …

Spatial Analyses Of Immune Cell Infiltration In Cancer: Current Methods And Future Directions: A Report Of The International Immuno-Oncology Biomarker Working Group On Breast Cancer, David B Page, Glenn Broeckx, Chowdhury Arif Jahangir, Sara Verbandt, Rajarsi R Gupta, Jeppe Thagaard, Reena Khiroya, Zuzana Kos, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Guray Akturk, Jonas S Almeida, Isabel Alvarado-Cabrero, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Najat Bouchmaa, Octavio Burgues, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Sarah N Dudgeon, Mahmoud Elghazawy, Scott Ely, Claudio Fernandez-Martín, Susan Fineberg, Stephen B Fox, William M Gallagher, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Alexandros Hardas, Steven N Hart, Johan Hartman, Stephen Hewitt, Akira I Hida, Hugo M Horlings, Zaheed Husain, Evangelos Hytopoulos, Sheeba Irshad, Emiel Am Janssen, Mohamed Kahila, Tatsuki R Kataoka, Kosuke Kawaguchi, Durga Kharidehal, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Amy Ly, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S Mcdonald, Ravi Mehrotra, Stefan Michiels, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Arman Rahman, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Jorge S Reis-Filho, Joana M Ribeiro, David Rimm, Anne Vincent-Salomon, Manuel Salto-Tellez, Joel Saltz, Shahin Sayed, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen Van Der Laak, Paul J Van Diest, Gregory E Verghese, Giuseppe Viale, Michael Vieth, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, Sylvia Adams, John Mark Seaverns Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Roberto Salgado, Elisabeth Specht Stovgaard

Faculty, Staff and Student Publications

Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical …

Generative Pre-Trained Transformers (Gpt) And Space Health: A Potential Frontier In Astronaut Health During Exploration Missions, Ethan Waisberg, Joshua Ong, Mouayad Masalkhi, Nasif Zaman, Sharif Amit Kamran, Prithul Sarker, Andrew G Lee, Alireza Tavakkoli

Faculty, Staff and Student Publications

In anticipation of space exploration where astronauts are traveling away from Earth, and for longer durations with an increasing communication lag, artificial intelligence (AI) frameworks such as large language learning models (LLMs) that can be trained on Earth can provide real-time answers. This emerging technology may be helpful for acute medical emergencies, particularly in austere and distant space environments. In this manuscript, we provide an overview of generative pre-trained transformer (GPT) technology, a rapidly emerging AI technology, and implications, considerations, and limitations of such technology for space health.

Predictive Model Of Liver Toxicity To Aid The Personalized Selection Of Proton Versus Photon Therapy In Hepatocellular Carcinoma, Ibrahim Chamseddine, Yejin Kim, Brian De, Issam El Naqa, Dan G Duda, John A Wolfgang, Jennifer Pursley, Jennifer Y Wo, Theodore S Hong, Harald Paganetti, Eugene J Koay, Clemens Grassberger

Faculty, Staff and Student Publications

Purpose: Our objective was to develop an externally validated model for predicting liver toxicity after radiation therapy in patients with hepatocellular carcinoma (HCC) that can integrate both photon and proton dose distributions with patient-specific characteristics.

Methods and materials: Training data consisted of all patients with HCC treated between 2008 and 2019 at our institution (n = 117, 60%/40% photon/proton). We developed a shallow convolutional neural network (CNN) to predict posttreatment liver dysfunction from the differential dose-volume histogram (DVH) and baseline liver metrics. To reduce bias and improve robustness, we used ensemble learning (CNNE). After a preregistered study analysis plan, we …

Ultrasensitive Ngs Mrd Assessment In Ph+ All: Prognostic Impact And Correlation With Rt-Pcr For Bcr::Abl1, Nicholas J Short, Elias Jabbour, Walid Macaron, Farhad Ravandi, Nitin Jain, Rashmi Kanagal-Shamanna, Keyur P Patel, Sanam Loghavi, Fadi G Haddad, Musa Yilmaz, Ghayas C Issa, Partow Kebriaei, Steven M Kornblau, Sarah Pelletier, Wilmer Flores, Jairo Matthews, Rebecca Garris, Hagop Kantarjian

Faculty, Staff and Student Publications

Reverse transcription polymerase chain reaction (RT-PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL); however, RT-PCR may not be an optimal measure of MRD in many cases of Ph+ ALL. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay (sensitivity of 10-6 ) and its correlation with RT-PCR for BCR::ABL1 in patients with Ph+ ALL. Overall, 32% of patients had a discordance between MRD assessment by RT-PCR and NGS, and 31% of patients who achieved NGS MRD negativity were …

Ddx41 Mutations In Patients With Non-Myeloid Hematologic Neoplasms, Fatima Zahra Jelloul, Mark J Routbort, Courtney D Dinardo, Carlos E Bueso-Ramos, Rashmi Kanagal-Shamanna, Beenu Thakral, Zhuang Zuo, C Cameron Yin, Sanam Loghavi, Chi Young Ok, Sa A Wang, Zhenya Tang, M James You, Keyur P Patel, L Jeffrey Medeiros, Andrés E Quesada

Faculty, Staff and Student Publications

No abstract provided.

Artificial Mirnas Derived From Mir-181 Family Members Have Potential In Cancer Therapy Due To An Altered Spectrum Of Target Mrnas, Sergiu Chira, Cristina Ciocan, Cecilia Bica, George A Calin, Ioana Berindan-Neagoe

Faculty, Staff and Student Publications

miRNAs are a class of noncoding RNAs with gene regulation properties, and they function as key factors in cell homeostasis. The interaction of miRNAs with their target mRNAs is largely considered to rely on sequence complementarity; however, some evidence indicates that mature miRNAs can adopt diverse conformations with implications for their function. Using the oncogenic miR-181 family as a study model, we suggest that a potential relationship between the primary sequence and secondary structure of miRNAs may have an impact on the number and spectrum of targeted cellular transcripts. We further emphasize that specific alterations in miR-181 primary sequences might …

Gwas-Identified Telomere Length Associated Genetic Variants Predict Risk Of Recurrence Of Hpv-Positive Oropharyngeal Cancer After Definitive Radiotherapy, Peng Sun, Peng Wei, Hongliang Liu, Jia Wu, Neil D Gross, Andrew G Sikora, Qingyi Wei, Sanjay Shete, Mark E Zafereo, Jisheng Liu, Guojun Li

Faculty, Staff and Student Publications

Background: Lymphocyte telomere length (LTL)-related genetic variants may modulate LTL and affect recurrence of squamous cell carcinoma of the oropharynx (SCCOP).

Methods: A total of 1013 patients with incident SCCOP were recruited and genotyped for 16 genome-wide association study (GWAS)-identified TL-related polymorphisms. Of these patients, 489 had tumour HPV16 status determination. Univariate and multivariate analyses were performed to evaluate associations.

Findings: Of the 16 TL-related polymorphisms, four were significantly associated with LTL: rs1920116, rs3027234, rs6772228, and rs11125529, and the patients with putatively favourable genotypes had approximately 1.5-3 times the likelihood of shorter LTL compared with patients with the corresponding risk …

Rewiring Cancer Drivers To Activate Apoptosis, Sai Gourisankar, Andrey Krokhotin, Wenzhi Ji, Xiaofan Liu, Chiung-Ying Chang, Samuel H Kim, Zhengnian Li, Wendy Wenderski, Juste M Simanauskaite, Haopeng Yang, Hannes Vogel, Tinghu Zhang, Michael R Green, Nathanael S Gray, Gerald R Crabtree

Faculty, Staff and Student Publications

Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers1-4. Independent studies have identified cell death pathways that eliminate cells for the good of the organism5,6. The coexistence of cell death pathways with driver mutations suggests that the cancer driver could be rewired to activate cell death using chemical inducers of proximity (CIPs). Here we describe a new class of molecules called transcriptional/epigenetic CIPs (TCIPs) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes, thereby activating their expression. We focused on diffuse …

Durable Control Of Metastases In An Hla-A2+ Patient With Refractory Melanoma After Low-Dose Radiotherapy In Combination With Mage-A4 T Cell Therapy: A Case Report, Kewen He, David S Hong, Danxia Ke, Partow Kebriaei, Tianjiao Wang, Hassan Danesi, Genevieve Bertolet, Carola Leuschner, Nahum Puebla-Osorio, Tiffany A Voss, Quan Lin, Elliot Norry, Paula M Fracasso, James W Welsh

Faculty, Staff and Student Publications

There is no currently approved adoptive cellular therapy for solid tumors. Pre-clinical and clinical studies have demonstrated that low-dose radiotherapy (LDRT) can enhance intratumoral T cell infiltration and efficacy. This case report describes a 71-year-old female patient with rectal mucosal melanoma that had developed metastases to liver, lung, mediastinum, axillary nodes, and brain. After systemic therapies had failed, she enrolled in the radiation sub-study of our phase-I clinical trial exploring the safety and efficacy of afamitresgene autoleucel (afami-cel), genetically engineered T cells with a T cell receptor (TCR) targeting the MAGE-A4 tumor antigen in patients with advanced malignancies (NCT03132922). Prior …

Statin Use And Chemoradiation In Esophageal Squamous Cell Carcinomas: Ready For Prime Time?, Steven H Lin

Faculty, Staff and Student Publications

No abstract provided.

Single-Cell Transcriptomic Analysis Uncovers Intratumoral Heterogeneity And Drug-Tolerant Persister In Alk-Rearranged Lung Adenocarcinoma, Hoi-Hin Kwok, Huiyu Li, Jiashuang Yang, Junyang Deng, Nerissa Chui-Mei Lee, Timmy Wing-Kuk Au, Alva Ko-Yung Sit, Michael Kuan-Yew Hsin, Stephanie Kwai-Yee Ma, Lydia Wai-Ting Cheung, Luc Girard, Junya Fujimoto, Ignacio Ivan Wistuba, Boning Gao, John Dorrance Minna, David Chi-Leung Lam

Faculty, Staff and Student Publications

No abstract provided.

Zeb1 Is Regulated By K811 Acetylation To Promote Stability, Nurd Complex Interactions, Emt, And Nsclc Metastasis, Mabel Perez-Oquendo, Roxsan Manshouri, Yanhua Tian, Jared J Fradette, B Leticia Rodriguez, Samrat T Kundu, Don L Gibbons

Faculty, Staff and Student Publications

Epithelial-to-mesenchymal transition results in loss of specialized epithelial cell contacts and acquisition of mesenchymal invasive capacity. The transcription repressor zinc finger E-box-binding homeobox 1 (ZEB1) binds to E-boxes of gene promoter regions to suppress the expression of epithelial genes. ZEB1 has inconsistent molecular weights, which have been attributed to posttranslational modifications (PTM). We performed mass spectrometry and identified K811 acetylation as a novel PTM in ZEB1. To define the role of ZEB1 acetylation in regulating function, we generated ZEB1 acetyl-mimetic (K811Q) and acetyl-deficient (K811R) mutant-expressing non-small cell lung cancer cell lines (NSCLC). We demonstrate that the K811R ZEB1 (125 kDa) …

Cation Leak Through The Atp1a3 Pump Causes Spasticity And Intellectual Disability, Daniel G Calame, Cristina Moreno Vadillo, Seth Berger, Timothy Lotze, Marwan Shinawi, Javaher Poupak, Corina Heller, Julie Cohen, Richard Person, Aida Telegrafi, Chalongchai Phitsanuwong, Kaylene Fiala, Isabelle Thiffault, Florencia Del Viso, Dihong Zhou, Emily A Fleming, Tomi Pastinen, Ali Fatemi, Sruthi Thomas, Samuel I Pascual, Rosa J Torres, Carmen Prior, Clara Gómez-González, Saskia Biskup, James R Lupski, Dragan Maric, Miguel Holmgren, Debra Regier, Sho T Yano

Faculty, Staff and Students Publications

ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear.

We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3 …

Multiscale Analysis Of Pangenomes Enables Improved Representation Of Genomic Diversity For Repetitive And Clinically Relevant Genes, Chen-Shan Chin, Sairam Behera, Asif Khalak, Fritz J Sedlazeck, Peter H Sudmant, Justin Wagner, Justin M Zook

Faculty, Staff and Students Publications

Advancements in sequencing technologies and assembly methods enable the regular production of high-quality genome assemblies characterizing complex regions. However, challenges remain in efficiently interpreting variation at various scales, from smaller tandem repeats to megabase rearrangements, across many human genomes. We present a PanGenome Research Tool Kit (PGR-TK) enabling analyses of complex pangenome structural and haplotype variation at multiple scales. We apply the graph decomposition methods in PGR-TK to the class II major histocompatibility complex demonstrating the importance of the human pangenome for analyzing complicated regions. Moreover, we investigate the Y-chromosome genes, DAZ1/DAZ2/DAZ3/DAZ4, of which structural variants have been linked to …