Medicine and Health Sciences Commons^™

Elimination Of Oncogenic Kras In Genetic Mouse Models Eradicates Pancreatic Cancer By Inducing Fas-Dependent Apoptosis By Cd8+ T Cells, Krishnan K Mahadevan, Valerie S Lebleu, Elena V Ramirez, Yang Chen, Bingrui Li, Amari M Sockwell, Mihai Gagea, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K Jain, Ronald A Depinho, Anirban Maitra, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Oncogenic KrasG12D (Kras*) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC), and a known repressor of tumor immunity. Conditional elimination of Kras* in genetic mouse models of PDAC leads to reactivation of Fas, CD8+ T cell mediated apoptosis, and complete eradication of tumors. Kras* elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen presenting cells. Mechanistically, Kras* mediated immune evasion involves epigenetic regulation of the Fas death receptor in cancer cells, via methylation of its promoter region. Further, analysis of human RNA sequencing identifies that high KRAS expressing PDAC tumors show …

Stereotactic Ablative Radiotherapy With Or Without Immunotherapy For Early-Stage Or Isolated Lung Parenchymal Recurrent Node-Negative Non-Small-Cell Lung Cancer: An Open-Label, Randomised, Phase 2 Trial, Joe Y Chang, Steven H Lin, Wenli Dong, Zhongxing Liao, Saumil J Gandhi, Carl M Gay, Jianjun Zhang, Stephen G Chun, Yasir Y Elamin, Frank V Fossella, George Blumenschein, Tina Cascone, Xiuning Le, Jenny V Pozadzides, Anne Tsao, Vivek Verma, James W Welsh, Aileen B Chen, Mehmet Altan, Reza J Mehran, Ara A Vaporciyan, Stephen G Swisher, Peter A Balter, Junya Fujimoto, Ignacio I Wistuba, Lei Feng, J Jack Lee, John V Heymach

Faculty, Staff and Student Publications

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC.

METHODS: We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older …

Structures Of Ctcf-Dna Complexes Including All 11 Zinc Fingers, Jie Yang, John R Horton, Bin Liu, Victor G Corces, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

The CCCTC-binding factor (CTCF) binds tens of thousands of enhancers and promoters on mammalian chromosomes by means of its 11 tandem zinc finger (ZF) DNA-binding domain. In addition to the 12-15-bp CORE sequence, some of the CTCF binding sites contain 5' upstream and/or 3' downstream motifs. Here, we describe two structures for overlapping portions of human CTCF, respectively, including ZF1-ZF7 and ZF3-ZF11 in complex with DNA that incorporates the CORE sequence together with either 3' downstream or 5' upstream motifs. Like conventional tandem ZF array proteins, ZF1-ZF7 follow the right-handed twist of the DNA, with each finger occupying and recognizing …

Beyond The Symptom: The Biology Of Fatigue, David M Raizen, Janet Mullington, Christelle Anaclet, Gerard Clarke, Hugo Critchley, Robert Dantzer, Ronald Davis, Kelly L Drew, Josh Fessel, Patrick M Fuller, Erin M Gibson, Mary Harrington, W Ian Lipkin, Elizabeth B Klerman, Nancy Klimas, Anthony L Komaroff, Walter Koroshetz, Lauren Krupp, Anna Kuppuswamy, Julie Lasselin, Laura D Lewis, Pierre J Magistretti, Heidi Y Matos, Christine Miaskowski, Andrew H Miller, Avindra Nath, Maiken Nedergaard, Mark R Opp, Marylyn D Ritchie, Dragana Rogulja, Asya Rolls, John D Salamone, Clifford Saper, Vicky Whittemore, Glenn Wylie, Jarred Younger, Phyllis C Zee, H Craig Heller

Faculty, Staff and Student Publications

A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a …

Click Display: A Rapid And Efficient In Vitro Protein Display Method For Directed Evolution, Yu Zeng, Michael Woolley, Karuppiah Chockalingam, Benjamin Thomas, Srishtee Arora, Magnus Hook, Zhilei Chen

Faculty, Staff and Student Publications

We describe a novel method for in vitro protein display-click display-that does not depend on maintaining RNA integrity during biopanning and yields covalently linked protein-cDNA complexes from double-stranded input DNA within 2 h. The display is achieved in a one-pot format encompassing transcription, translation and reverse transcription reactions in series. Stable linkage between proteins and the encoding cDNA is mediated by a modified DNA linker-ML-generated via a click chemistry reaction between a puromycin-containing oligo and a cDNA synthesis primer. Biopanning of a click-displayed mock library coupled with next-generation sequencing analysis revealed >600-fold enrichment of target binders within a single round …

Modulation Of The Proteostasis Network Promotes Tumor Resistance To Oncogenic Kras Inhibitors, Xiangdong Lv, Xuan Lu, Jin Cao, Qin Luo, Yao Ding, Fanglue Peng, Apar Pataer, Dong Lu, Dong Han, Eric Malmberg, Doug W Chan, Xiaoran Wang, Sara R Savage, Sufeng Mao, Jingjing Yu, Fei Peng, Liang Yan, Huan Meng, Laure Maneix, Yumin Han, Yiwen Chen, Wantong Yao, Eric C Chang, Andre Catic, Xia Lin, George Miles, Pengxiang Huang, Zheng Sun, Bryan Burt, Huamin Wang, Jin Wang, Qizhi Cathy Yao, Bing Zhang, Jack A Roth, Bert W O'Malley, Matthew J Ellis, Mothaffar F Rimawi, Haoqiang Ying, Xi Chen

Faculty, Staff and Student Publications

Despite substantial advances in targeting mutant KRAS, tumor resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report proteostasis reprogramming as a key convergence point of multiple KRASi-resistance mechanisms. Inactivation of oncogenic KRAS down-regulated both the heat shock response and the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response, causing severe proteostasis disturbances. However, IRE1α was selectively reactivated in an ER stress-independent manner in acquired KRASi-resistant tumors, restoring proteostasis. Oncogenic KRAS promoted IRE1α protein stability through extracellular signal-regulated kinase (ERK)-dependent phosphorylation of IRE1α, leading to IRE1α disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase. In …

Braf V600e/Ras Mutations And Lynch Syndrome In Patients With Msi-H/Dmmr Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors, Raphael Colle, Sara Lonardi, Marine Cachanado, Michael J Overman, Elena Elez, Marwan Fakih, Francesca Corti, Priya Jayachandran, Magali Svrcek, Antoine Dardenne, Baptiste Cervantes, Alex Duval, Romain Cohen, Filippo Pietrantonio, Thierry André

Faculty, Staff and Student Publications

BACKGROUND: We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS).

PATIENTS AND METHODS: Patients were defined as LS-linked if germline mutation was detected and as sporadic if loss of MLH1/PMS2 expression with BRAFV600E mutation and/or MLH1 promoter hypermethylation, or biallelic somatic MMR genes mutations were found. Progression-free survival (PFS) and overall survival (OS) were adjusted on prognostic modifiers selected on unadjusted analysis (P < .2) if limited number of events.

RESULTS: Of 466 included patients, 305 (65.4%) and 161 (34.5%) received, respectively, anti-PD1 alone and anti-PD1+anti-CTLA4 …

Five-Year Follow-Up Of Keynote-087: Pembrolizumab Monotherapy For Relapsed/Refractory Classical Hodgkin Lymphoma, Philippe Armand, Pier Luigi Zinzani, Hun Ju Lee, Nathalie A Johnson, Pauline Brice, John Radford, Vincent Ribrag, Daniel Molin, Theodoros P Vassilakopoulos, Akihiro Tomita, Bastian Von Tresckow, Margaret A Shipp, Alex F Herrera, Jianxin Lin, Eunhee Kim, Samhita Chakraborty, Patricia Marinello, Craig H Moskowitz

Faculty, Staff and Student Publications

Previous analyses of the phase 2 KEYNOTE-087 (NCT02453594) trial of pembrolizumab monotherapy demonstrated effective antitumor activity with acceptable safety in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). However, long-term response durability and outcome of patients who receive a second course after treatment discontinuation after complete response (CR) remain of clinical interest. We present KEYNOTE-087 data after >5 years of median follow-up. Patients with R/R cHL and progressive disease (PD) after autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV; cohort 1), salvage chemotherapy and BV without ASCT (cohort 2), or ASCT without subsequent BV (cohort 3), received …

Seamless Phase Ii/Iii Design: A Useful Strategy To Reduce The Sample Size For Dose Optimization, Liyun Jiang, Ying Yuan

Faculty, Staff and Student Publications

Background: The traditional more-is-better dose selection paradigm, originally developed for cytotoxic chemotherapeutics, can be problematic when applied to the development of novel molecularly targeted agents. Recognizing this issue, the US Food and Drug Administration initiated Project Optimus to reform the dose optimization and selection paradigm in oncology drug development, emphasizing the need for greater attention to benefit-risk considerations.

Methods: We identify different types of phase II/III dose-optimization designs, classified according to trial objectives and endpoint types. Through computer simulations, we examine their operating characteristics and discuss the relevant statistical and design considerations for effective dose optimization.

Results: Phase II/III dose-optimization …

An Electronic Origin Of Charge Order In Infinite-Layer Nickelates, Hanghui Chen, Yi-Feng Yang, Guang-Ming Zhang, Hongquan Liu

Faculty, Staff and Student Publications

A charge order (CO) with a wavevector [Formula: see text] is observed in infinite-layer nickelates. Here we use first-principles calculations to demonstrate a charge-transfer-driven CO mechanism in infinite-layer nickelates, which leads to a characteristic Ni1+-Ni2+-Ni1+ stripe state. For every three Ni atoms, due to the presence of near-Fermi-level conduction bands, Hubbard interaction on Ni-d orbitals transfers electrons on one Ni atom to conduction bands and leaves electrons on the other two Ni atoms to become more localized. We further derive a low-energy effective model to elucidate that the CO state arises from a delicate competition between Hubbard interaction on Ni-d …

Clinically Conserved Genomic Subtypes Of Gastric Adenocarcinoma, Yun Seong Jeong, Young-Gyu Eun, Sung Hwan Lee, Sang-Hee Kang, Sun Young Yim, Eui Hyun Kim, Joo Kyung Noh, Bo Hwa Sohn, Seon Rang Woo, Moonkyoo Kong, Deok Hwa Nam, Hee-Jin Jang, Hyun-Sung Lee, Shumei Song, Sang Cheul Oh, Jeeyun Lee, Jaffer A Ajani, Ju-Seog Lee

Faculty, Staff and Student Publications

Gastric adenocarcinoma (GAC) is a lethal disease characterized by genomic and clinical heterogeneity. By integrating 8 previously established genomic signatures for GAC subtypes, we identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs). CGS1 have the poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 is enriched with canonical epithelial gene expression. CGS3 and CGS4 have high copy number alterations and low immune reactivity. However, CGS3 and CGS4 differ in that CGS3 has high HER2 activation, while CGS4 has high SALL4 and KRAS activation. CGS5 has the high mutation burden and moderately …

Stem-Like Cd4+T Cells In Perivascular Tertiary Lymphoid Structures Sustain Autoimmune Vasculitis, Yuki Sato, Abhinav Jain, Shozo Ohtsuki, Hirohisa Okuyama, Ines Sturmlechner, Yoshinori Takashima, Kevin-Phu C Le, Melanie C Bois, Gerald J Berry, Kenneth J Warrington, Jörg J Goronzy, Cornelia M Weyand

Faculty, Staff and Student Publications

Autoimmune vasculitis of the medium and large elastic arteries can cause blindness, stroke, aortic arch syndrome, and aortic aneurysm. The disease is often refractory to immunosuppressive therapy and progresses over decades as smoldering aortitis. How the granulomatous infiltrates in the vessel wall are maintained and how tissue-infiltrating T cells and macrophages are replenished are unknown. Single-cell and whole-tissue transcriptomic studies of immune cell populations in vasculitic arteries identified a CD4+ T cell population with stem cell-like features. CD4+ T cells supplying the tissue-infiltrating and tissue-damaging effector T cells survived in tertiary lymphoid structures around adventitial vasa vasora, expressed the transcription …

Patient-Reported Outcomes Of Omission Of Breast Surgery Following Neoadjuvant Systemic Therapy: A Nonrandomized Clinical Trial, Helen M Johnson, Heather Lin, Yu Shen, Emilia J Diego, Savitri Krishnamurthy, Wei T Yang, Benjamin D Smith, Vicente Valero, Anthony Lucci, Susie X Sun, Simona F Shaitelman, Melissa P Mitchell, Judy C Boughey, Richard L White, Gaiane M Rauch, Henry M Kuerer

Faculty, Staff and Student Publications

IMPORTANCE: Patients should have an active role in decisions about pursuing or forgoing specific therapies in treatment de-escalation trials.

OBJECTIVE: To evaluate longitudinal patient-reported outcomes (PROs) encompassing decisional comfort and health-related quality of life (HRQOL) among patients who elected to enroll in a clinical trial evaluating radiotherapy alone, without breast surgery, for invasive breast cancers with exceptional response to neoadjuvant systemic therapy (NST).

DESIGN, SETTING, AND PARTICIPANTS: Prospective, single-group, phase 2 clinical trial at 7 US medical centers. Women aged 40 years or older with invasive cT1-2 N0-1 M0 triple-negative or human epidermal growth factor receptor 2 (ERBB2)-positive breast cancer …

Epidermal Growth Factor Receptor-Targeted Neoantigen Peptide Vaccination For The Treatment Of Non-Small Cell Lung Cancer And Glioblastoma, Fenge Li, Huancheng Wu, Xueming Du, Yimo Sun, Barbara Nassif Rausseo, Amjad Talukder, Arjun Katailiha, Lama Elzohary, Yupeng Wang, Zhiyu Wang, Gregory Lizée

Faculty, Staff and Student Publications

The epidermal growth factor receptor (EGFR) plays crucial roles in several important biological functions such as embryogenesis, epithelial tissue development, and cellular regeneration. However, in multiple solid tumor types overexpression and/or activating mutations of the EGFR gene frequently occur, thus hijacking the EGFR signaling pathway to promote tumorigenesis. Non-small cell lung cancer (NSCLC) tumors in particular often contain prevalent and shared EGFR mutations that provide an ideal source for public neoantigens (NeoAg). Studies in both humans and animal models have confirmed the immunogenicity of some of these NeoAg peptides, suggesting that they may constitute viable targets for cancer immunotherapies. Peptide …

Genetic Susceptibility To Cognitive Decline Following Craniospinal Irradiation For Pediatric Central Nervous System Tumors, Austin L Brown, Pagna Sok, Kimberly P Raghubar, Philip J Lupo, Melissa A Richard, Alanna C Morrison, Jun J Yang, Clinton F Stewart, Mehmet Fatih Okcu, Murali M Chintagumpala, Amar Gajjar, Lisa S Kahalley, Heather Conklin, Michael E Scheurer

Faculty, Staff and Student Publications

BACKGROUND: Survivors of pediatric central nervous system (CNS) tumors treated with craniospinal irradiation (CSI) exhibit long-term cognitive difficulties. Goals of this study were to evaluate longitudinal effects of candidate and novel genetic variants on cognitive decline following CSI.

METHODS: Intelligence quotient (IQ), working memory (WM), and processing speed (PS) were longitudinally collected from patients treated with CSI (n = 241). Genotype-by-time interactions were evaluated using mixed-effects linear regression to identify common variants (minor allele frequency > 1%) associated with cognitive performance change. Novel variants associated with cognitive decline (P < 5 × 10-5) in individuals of European ancestry (n = 163) were considered replicated if they demonstrated consistent genotype-by-time interactions (P < .05) in individuals of non-European ancestries (n = 78) and achieved genome-wide statistical significance (P < 5 × 10-8) in a meta-analysis across ancestry groups.

RESULTS: Participants were mostly males (65%) diagnosed with embryonal tumors (98%) at …

Low-Grade Serous Ovarian Cancer: Expert Consensus Report On The State Of The Science, Rachel N Grisham, Brian M Slomovitz, Nicole Andrews, Susana Banerjee, Jubilee Brown, Mark S Carey, Herman Chui, Robert L Coleman, Amanda N Fader, Stephanie Gaillard, Charlie Gourley, Anil K Sood, Bradley J Monk, Kathleen N Moore, Isabelle Ray-Coquard, Ie-Ming Shih, Shannon N Westin, Kwong-Kwok Wong, David M Gershenson

Faculty, Staff and Student Publications

Compared with high-grade serous carcinoma, low-grade serous carcinoma of the ovary or peritoneum is a less frequent epithelial ovarian cancer type that is poorly sensitive to chemotherapy and affects younger women, many of whom endure years of ineffective treatments and poor quality of life. The pathogenesis of this disease and its management remain incompletely understood. However, recent advances in the molecular characterization of the disease and identification of novel targeted therapies with activity in low-grade serous carcinoma offer the promise of improved outcomes. To update clinicians regarding recent scientific and clinical trial advancements and discuss unanswered questions related to low-grade …

The Characterization And Evaluation Of The Soluble Triggering Receptor Expressed On Myeloid Cells-Like Transcript-1 In Stable Coronary Artery Disease, Zaida Bayrón-Marrero, Siobhan Branfield, Javier Menéndez-Pérez, Benjamín Nieves-López, Laura Ospina, Yadira Cantres-Rosario, Loyda M Melendez, Robert Hunter, Angelia Gibson, Gerónimo Maldonado-Martínez, A Valance Washington

Faculty, Staff and Student Publications

Platelets play crucial roles in the development and progression of coronary artery disease (CAD). The triggering receptor expressed in myeloid cells-like transcript-1 (TLT-1) is stored in platelet α granules, and activated platelets release a soluble fragment (sTLT-1). We set out to better characterize the constituent amino acids of sTLT-1 and to evaluate sTLT-1 for use as a biomarker in patients with stable CAD. We evaluated sTLT-1 release using immunoprecipitation and mass spectrometry and employed statistical methods to retrospectively correlate sTLT-1 concentrations, utilizing ELISA in plasma samples from 1510 patients with documented stable CAD. We identified TLT-1 residues to 133 in …

Evaluation Of In Vitro Antioxidant, Anti-Obesity, And Anti-Diabetic Activities Of, Alaa S Mohamed, Essam Mohamed Elsebaie, Wesam Mohammed Abdelrhman, Nabila Yahia Mahmoud Abdulmaguid, Rasha M Bahnasy, Manal Salah Abbas Elgendy, Arwa Mohamed Mohamed Mahmoud Elashry, Marwa Fawzy El-Hassanin, Nora Hamdy Mouhamed El-Wakeil, Azhar Mostafa Mohamed Khalil, Hesham F Amin

Faculty, Staff and Student Publications

Opuntia ficus cladodes (OFC) are considered one of the wastes that result from opuntia cultivation, and their disposal by traditional methods results in many environmental problems. Therefore, this study was conducted with two aims. The first was the production of OFC gel, and the evaluation of its in vitro antioxidant (by two methods, DPPH and ABTS), anti-obesity, and anti-diabetic activities. The second was an investigation of the effects of different concentrations of this gel (0, 50, and 100%) as an edible coating on the quality of shrimp during 8 days of refrigerated storage. The results showed that this gel was …

Taz2 Truncation Confers Overactivation Of P300 And Cellular Vulnerability To Hdac Inhibition, Longxia Xu, Hongwen Xuan, Wei He, Liang Zhang, Mengying Huang, Kuai Li, Hong Wen, Han Xu, Xiaobing Shi

Faculty, Staff and Student Publications

The histone acetyltransferase p300/CBP is composed of several conserved domains, among which, the TAZ2 domain is known as a protein-protein interaction domain that binds to E1A and various transcription factors. Here we show that TAZ2 has a HAT autoinhibitory function. Truncating p300/CBP at TAZ2 leads to hyperactive HAT and elevated histone H3K27 and H3K18 acetylation in cells. Mechanistically, TAZ2 cooperates with other HAT neighboring domains to maintain the HAT active site in a 'closed' state. Truncating TAZ2 or binding of transcription factors to TAZ2 induces a conformational change that 'opens' the active site for substrate acetylation. Importantly, genetic mutations that …

Aenmd: Annotating Escape From Nonsense-Mediated Decay For Transcripts With Protein-Truncating Variants, Jonathan Klonowski, Qianqian Liang, Zeynep Coban-Akdemir, Cecilia Lo, Dennis Kostka

Faculty, Staff and Student Publications

DNA changes that cause premature termination codons (PTCs) represent a large fraction of clinically relevant pathogenic genomic variation. Typically, PTCs induce transcript degradation by nonsense-mediated mRNA decay (NMD) and render such changes loss-of-function alleles. However, certain PTC-containing transcripts escape NMD and can exert dominant-negative or gain-of-function (DN/GOF) effects. Therefore, systematic identification of human PTC-causing variants and their susceptibility to NMD contributes to the investigation of the role of DN/GOF alleles in human disease. Here we present aenmd, a software for annotating PTC-containing transcript-variant pairs for predicted escape from NMD. aenmd is user-friendly and self-contained. It offers functionality not currently available …

Hospitalizations Among Adults With Ckd In Public Renal Specialty Practices: A Retrospective Study From Queensland, Australia, Vishal Diwan, Wendy E Hoy, Zaimin Wang, Jianzhen Zhang, Anne Cameron, Sree K Venuthurupalli, Robert G Fassett, Samuel Chan, Helen G Healy, Ken-Soon Tan, Richard Baer, Andrew J Mallett, Nicholas Gray, Murty Mantha, Roy Cherian, Clyson Mutatiri, Krishan Madhan, George Kan, Geoffrey Mitchell, Shahadat Hossain, Danielle Wu, Thin Han, Adrian Kark, Thomas Titus, Dwarakanatan Ranganathan, Ann Bonner, Sridevi Govindarajulu, Nhmrc Ckd.Cre And The Ckd.Qld Collaborative

Faculty, Staff and Student Publications

RATIONALE & OBJECTIVE: Little is known about hospital admissions in nondialysis patients with chronic kidney disease (CKD) before death or starting kidney replacement therapy (KRT).

STUDY DESIGN: Retrospective observational cohort study.

SETTING & PARTICIPANTS: Hospitalizations among 7,201 patients with CKD from 10 public renal clinics in Queensland (QLD), enrolled in the CKD.QLD registry starting in May 2011, were followed for 25,496.34 person-years until they started receiving KRT or died, or until June 30, 2018.

PREDICTORS: Demographic and clinical characteristics of patients with CKD.

OUTCOMES: Hospital admissions.

ANALYTICAL APPROACH: We evaluated the association of demographic and clinical features with hospitalizations, length …

Efficient Targeted Learning Of Heterogeneous Treatment Effects For Multiple Subgroups, Waverly Wei, Maya Petersen, Mark J Van Der Laan, Zeyu Zheng, Chong Wu, Jingshen Wang

Faculty, Staff and Student Publications

In biomedical science, analyzing treatment effect heterogeneity plays an essential role in assisting personalized medicine. The main goals of analyzing treatment effect heterogeneity include estimating treatment effects in clinically relevant subgroups and predicting whether a patient subpopulation might benefit from a particular treatment. Conventional approaches often evaluate the subgroup treatment effects via parametric modeling and can thus be susceptible to model mis-specifications. In this paper, we take a model-free semiparametric perspective and aim to efficiently evaluate the heterogeneous treatment effects of multiple subgroups simultaneously under the one-step targeted maximum-likelihood estimation (TMLE) framework. When the number of subgroups is large, we …

Mpla Case: How Do You Lead As A Lead Physicist?, Patricia Sansourekidou, Leonard Kim, Lee Xu, Mary Gronberg, Cassandra Stambaugh, Dongxu Wang

Faculty, Staff and Student Publications

This work of fiction is part of a case study series developed by the Medical Physics Leadership Academy (MPLA). It is intended to facilitate the discussion of the managerial and leadership challenges faced by a clinical medical physicist. In this case, a physicist David used to work in a clinic where he thrived and felt like a leader, despite not having the title. After a job change, he is now officially the "Lead Physicist" at a hospital newly affiliated with a large academic healthcare system. He believes he will be equally successful. Yet he struggles to bring about changes and …

Longitudinal Diffusion And Volumetric Kinetics Of Head And Neck Cancer Magnetic Resonance On A 15 T Mr-Linear Accelerator Hybrid System: A Prospective R-Ideal Stage 2a Imaging Biomarker Characterization/Pre-Qualification Study, Joint Head And Neck Radiation Therapy-Mri Development Cooperative, Mr-Linac Consortium Head And Neck Tumor Site Group

Faculty, Staff and Student Publications

OBJECTIVES: We aim to characterize the serial quantitative apparent diffusion coefficient (ADC) changes of the target disease volume using diffusion-weighted imaging (DWI) acquired weekly during radiation therapy (RT) on a 1.5 T MR-Linac and correlate these changes with tumor response and oncologic outcomes for head and neck squamous cell carcinoma (HNSCC) patients as part of a programmatic R-IDEAL biomarker characterization effort.

METHODS: Thirty patients with HNSCC who received curative-intent RT at MD Anderson Cancer Center, were included. Baseline and weekly MRI were obtained, and various ADC parameters were extracted from the regions of interest (ROIs). Baseline and weekly ADC parameters …

Going Circular: History, Present, And Future Of Circrnas In Cancer, Giuseppina Pisignano, David C Michael, Tanvi H Visal, Radu Pirlog, Michael Ladomery, George A Calin

Faculty, Staff and Student Publications

To date, thousands of highly abundant and conserved single-stranded RNA molecules shaped into ring structures (circRNAs) have been identified. CircRNAs are multifunctional molecules that have been shown to regulate gene expression transcriptionally and post-transcriptionally and exhibit distinct tissue- and development-specific expression patterns associated with a variety of normal and disease conditions, including cancer pathogenesis. Over the past years, due to their intrinsic stability and resistance to ribonucleases, particular attention has been drawn to their use as reliable diagnostic and prognostic biomarkers in cancer diagnosis, treatment, and prevention. However, there are some critical caveats to their utility in the clinic. Their …

Design Of A Phase Iii, Double-Blind, Randomised, Placebo-Controlled Trial Of Bi 1015550 In Patients With Progressive Pulmonary Fibrosis (Fibroneer-Ild), Toby M Maher, Shervin Assassi, Arata Azuma, Vincent Cottin, Anna-Maria Hoffmann-Vold, Michael Kreuter, Justin M Oldham, Luca Richeldi, Claudia Valenzuela, Marlies S Wijsenbeek, Carl Coeck, Christina Schlecker, Florian Voss, Daniel Wachtlin, Fernando J Martinez

Faculty, Staff and Student Publications

INTRODUCTION: Progressive pulmonary fibrosis (PPF) includes any diagnosis of progressive fibrotic interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF). However, disease progression appears comparable between PPF and IPF, suggesting a similar underlying pathology relating to pulmonary fibrosis. Following positive results in a phase II study in IPF, this phase III study will investigate the efficacy and safety of BI 1015550 in patients with PPF (FIBRONEER-ILD).

METHODS AND ANALYSIS: In this phase III, double-blind, placebo-controlled trial, patients are being randomised 1:1:1 to receive BI 1015550 (9 mg or 18 mg) or placebo twice daily over at least 52 weeks, …

Carm1 Arginine Methyltransferase As A Therapeutic Target For Cancer, Margarida Santos, Jee Won Hwang, Mark T Bedford

Faculty, Staff and Student Publications

Coactivator-associated arginine methyltransferase 1 (CARM1) is an arginine methyltransferase that posttranslationally modifies proteins that regulate multiple levels of RNA production and processing. Its substrates include histones, transcription factors, coregulators of transcription, and splicing factors. CARM1 is overexpressed in many different cancer types, and often promotes transcription factor programs that are co-opted as drivers of the transformed cell state, a process known as transcription factor addiction. Targeting these oncogenic transcription factor pathways is difficult but could be addressed by removing the activity of the key coactivators on which they rely. CARM1 is ubiquitously expressed, and its KO is less detrimental in …

Aerobic Exercise Alters The Melanoma Microenvironment And Modulates Erk5 S496 Phosphorylation, Hannah Savage, Sumedha Pareek, Jonghae Lee, Riccardo Ballarò, Darlan Conterno Minussi, Karma Hayek, Mumina Sadullozoda, Brooke S Lochmann, Jennifer L Mcquade, Emily C Lavoy, Enrica Marmonti, Hetal Patel, Guangyu Wang, Masaki Imanishi, Sivareddy Kotla, Jun-Ichi Abe, Keri Schadler

Faculty, Staff and Student Publications

Exercise changes the tumor microenvironment by remodeling blood vessels and increasing infiltration by cytotoxic immune cells. The mechanisms driving these changes remain unclear. Herein, we demonstrate that exercise normalizes tumor vasculature and upregulates endothelial expression of VCAM1 in YUMMER 1.7 and B16F10 murine models of melanoma but differentially regulates tumor growth, hypoxia, and the immune response. We found that exercise suppressed tumor growth and increased CD8+ T-cell infiltration in YUMMER but not in B16F10 tumors. Single-cell RNA sequencing and flow cytometry revealed exercise modulated the number and phenotype of tumor-infiltrating CD8+ T cells and myeloid cells. Specifically, exercise caused a …

Cytoreductive Nephrectomy For Patients With Metastatic Sarcomatoid And/Or Rhabdoid Renal Cell Carcinoma Treated With Immune Checkpoint Therapy, Andrew W Hahn, Ritesh R Kotecha, Paul V Viscuse, Alberto C Pieretti, Andrew J Wiele, Eric Jonasch, Chung-Han Lee, Jianjun Gao, Amado J Zurita, Amishi Y Shah, Matthew T Campbell, Padmanee Sharma, Robert J Motzer, Paul Russo, Christopher G Wood, Nizar M Tannir, Martin H Voss, Jose A Karam, A Ari Hakimi, Pavlos Msaouel

Faculty, Staff and Student Publications

BACKGROUND: Renal cell carcinoma (RCC) with sarcomatoid and/or rhabdoid (S/R) dedifferentiation is a highly aggressive tumor with a poor prognosis. Immune checkpoint therapy (ICT) has shown significant treatment efficacy in this subtype. There remains uncertainly regarding the role of cytoreductive nephrectomy (CN) for patients with metastatic RCC (mRCC) with S/R who received ICT.

OBJECTIVE: Here, we report the outcomes with ICT for patients with mRCC and S/R dedifferentiation by CN status.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective review was conducted of 157 patients with sarcomatoid, rhabdoid, or sarcomatoid plus rhabdoid dedifferentiation who received an ICT-based regimen at two cancer centers. …

Association Between Duration Of Smoking Abstinence Before Non-Small-Cell Lung Cancer Diagnosis And Survival: A Retrospective, Pooled Analysis Of Cohort Studies, Aline F Fares, Yao Li, Mei Jiang, M Catherine Brown, Andrew C L Lam, Reenika Aggarwal, Sabine Schmid, Natasha B Leighl, Frances A Shepherd, Zhichao Wang, Nancy Diao, Angela S Wenzlaff, Juntao Xie, Takashi Kohno, Neil E Caporaso, Curtis Harris, Hongxia Ma, Matthew J Barnett, Leticia Ferro Leal, G Fernandez-Tardon, Mónica Pérez-Ríos, Michael P A Davies, Fiona Taylor, Ben Schöttker, Paul Brennan, David Zaridze, Ivana Holcatova, Jolanta Lissowska, Beata Świątkowska, Dana Mates, Milan Savic, Hermann Brenner, Angeline Andrew, Angela Cox, John K Field, Alberto Ruano-Ravina, Sanjay S Shete, Adonina Tardon, Ying Wang, Loic Le Marchand, Rui Manuel Reis, Matthew B Schabath, Chu Chen, Hongbing Shen, Brid M Ryan, Maria Teresa Landi, Kouya Shiraishi, Jie Zhang, Ann G Schwartz, Ming S Tsao, David C Christiani, Ping Yang, Rayjean J Hung, Wei Xu, Geoffrey Liu

Faculty, Staff and Student Publications

BACKGROUND: The association between duration of smoking abstinence before non-small-cell lung cancer (NSCLC) diagnosis and subsequent survival can influence public health messaging delivered in lung-cancer screening. We aimed to assess whether the duration of smoking abstinence before diagnosis of NSCLC is associated with improved survival.

METHODS: In this retrospective, pooled analysis of cohort studies, we used 26 cohorts participating in Clinical Outcomes Studies of the International Lung Cancer Consortium (COS-ILCCO) at 23 hospitals. 16 (62%) were from North America, six (23%) were from Europe, three (12%) were from Asia, and one (4%) was from South America. Patients enrolled were diagnosed …