Digital Commons Network^™

An End-To-End In-Silico And In-Vitro Drug Repurposing Pipeline For Glioblastoma, Ko-Hong Lin, Jay-Jiguang Zhu, Judith A Smith, Yejin Kim, Xiaoqian Jiang

Faculty, Staff and Student Publications

Our study aims to address the challenges in drug development for glioblastoma, a highly aggressive brain cancer with poor prognosis. We propose a computational framework that utilizes machine learning-based propensity score matching to estimate counterfactual treatment effects and predict synergistic effects of drug combinations. Through our in-silico analysis, we identified promising drug candidates and drug combinations that warrant further investigation. To validate these computational findings, we conducted in-vitro experiments on two GBM cell lines, U87 and T98G. The experimental results demonstrated that some of the identified drugs and drug combinations indeed exhibit strong suppressive effects on GBM cell growth. Our …

The Tgf-Β Superfamily As Potential Therapeutic Targets In Pancreatic Cancer, William A Grobman, Grecio J Sandoval, Torri D Metz, Tracy A Manuck, Rebecca G Clifton, Brenna L Hughes, George R Saade, Monica Longo, Amber Sowles, Kelly Clark, Hyagriv N Simhan, Dwight J Rouse, Hector Mendez-Figueroa, Cynthia Gyamfi-Bannerman, Jennifer L Bailit, Maged M Costantine, Harish M Sehdev, Alan T N Tita, George A Macones

Faculty, Staff and Student Publications

OBJECTIVE: To evaluate whether preterm birth rates changed in relation to the onset of the coronavirus disease 2019 (COVID-19) pandemic and whether any change depended on socioeconomic status.

METHODS: This is an observational cohort study of pregnant individuals with a singleton gestation who delivered in the years 2019 and 2020 at 1 of 16 U.S. hospitals of the Maternal-Fetal Medicine Units Network. The frequency of preterm birth for those who delivered before the onset of the COVID-19 pandemic (ie, in 2019) was compared with that of those who delivered after its onset (ie, in 2020). Interaction analyses were performed for …

Dural Sinus Narrowing In Patients With Spontaneous Anterior Skull Base Cerebrospinal Fluid Leak, Karim W Asi, Brian H Cameron, Elliot R Friedman, Jeffrey P Radabaugh, Martin J Citardi, Amber U Luong, William C Yao

Faculty, Staff and Student Publications

OBJECTIVES: Current evidence suggests a link between idiopathic intracranial hypertension (IIH) and spontaneous cerebrospinal fluid (sCSF) leak, as well as between IIH and dural venous sinus (DVS) narrowing. However, there are limited data linking DVS narrowing and sCSF leak. This study aims to determine the prevalence of DVS narrowing in patients with sCSF leak.

METHODS: A retrospective review of all patients with sCSF leak that presented to a tertiary academic center from 2008 to 2019. Preoperative imaging was independently reviewed by two neuroradiologists to evaluate for DVS narrowing. Available literature was used to estimate the prevalence of DVS narrowing in …

Patient-Reported Outcomes During And After Hepatitis C Virus Direct-Acting Antiviral Treatment Among People Who Inject Drugs, Qinglu Cheng, Evan B Cunningham, Sophy Shih, Janaki Amin, Julie Bruneau, Adelina A Artenie, Jeff Powis, Alain H Litwin, Curtis Cooper, Olav Dalgard, Margaret Hellard, Philip Bruggmann, Philippa Marks, Karine Lacombe, Catherine Stedman, Phillip Read, Behzad Hajarizadeh, Adrian J Dunlop, Brian Conway, Jordan J Feld, Gregory J Dore, Jason Grebely

Faculty, Staff and Student Publications

Objectives: People who inject drugs (PWID) are at a high risk of hepatitis C virus (HCV) infection. HCV cure is associated with improved patient-reported outcomes (PROs), but there are little data among PWID. This study aimed to assess the change in PROs during and after HCV direct-acting antiviral (DAA) treatment.

Methods: This analysis used data from 2 clinical trials of DAA treatment in PWID. PROs assessed included health-related quality of life, social functioning, psychological distress, housing, and employment. Generalized estimating equations and group-based trajectory modeling were used to assess changes in PROs over time.

Results: No significant changes in the …

Analysis Of Relative Error In Perturbation Monte Carlo Simulations Of Radiative Transport, Mahsa Parsanasab, Carole Hayakawa, Jerome Spanier, Yanning Shen, Vasan Venugopalan

Faculty, Staff and Student Publications

SIGNIFICANCE: Perturbation and differential Monte Carlo (pMC/dMC) methods, used in conjunction with nonlinear optimization methods, have been successfully applied to solve inverse problems in diffuse optics. Application of pMC to systems over a large range of optical properties requires optimal "placement" of baseline conventional Monte Carlo (cMC) simulations to minimize the pMC variance. The inability to predict the growth in pMC solution uncertainty with perturbation size limits the application of pMC, especially for multispectral datasets where the variation of optical properties can be substantial.

AIM: We aim to predict the variation of pMC variance with perturbation size without explicit computation …

Hybrid Repair Strategies For Acute Type B Aortic Dissection Complicating Prior Standard And Complex Endovascular Aortic Repair, Jesse Chait, Bernardo C Mendes, Lily E Johnston, Fahad Shuja, Gustavo S Oderich, Manju Kalra

Faculty, Staff and Student Publications

Type B aortic dissection (TBAD) in the presence of an existing aortic endograft is a rare, but potentially catastrophic, event. False lumen pressurization and propagation leads to several failure modes. Endograft collapse can lead to spinal cord, visceral, or lower extremity ischemia, and rupture of a previously sealed aneurysm sac is often fatal. A successful treatment strategy must incorporate the patient's symptoms, urgency of intervention, extent of dissection, and the location and status of the existing graft. In this series, we present three cases of TBAD complicating prior endovascular aortic repairs-infrarenal, iliac branched, and thoracoabdominal branched endografts-successfully treated with tailored, …

Artificial Intelligence Cad Tools In Trauma Imaging: A Scoping Review From The American Society Of Emergency Radiology (Aser) Ai/Ml Expert Panel, David Dreizin, Pedro V Staziaki, Garvit D Khatri, Nicholas M Beckmann, Zhaoyong Feng, Yuanyuan Liang, Zachary S Delproposto, Maximiliano Klug, J Stephen Spann, Nathan Sarkar, Yunting Fu

Faculty, Staff and Student Publications

BACKGROUND: AI/ML CAD tools can potentially improve outcomes in the high-stakes, high-volume model of trauma radiology. No prior scoping review has been undertaken to comprehensively assess tools in this subspecialty.

PURPOSE: To map the evolution and current state of trauma radiology CAD tools along key dimensions of technology readiness.

METHODS: Following a search of databases, abstract screening, and full-text document review, CAD tool maturity was charted using elements of data curation, performance validation, outcomes research, explainability, user acceptance, and funding patterns. Descriptive statistics were used to illustrate key trends.

RESULTS: A total of 4052 records were screened, and 233 full-text …

Sex And Gender Differences In Acute Stroke Care: Metrics, Access To Treatment And Outcome A Territorial Analysis Of The Stroke Code System Of Catalonia, Yolanda Silva, Laura Sánchez-Cirera, Mikel Terceño, Laura Dorado, Adrián Valls, Marina Martínez, Sònia Abilleira, Marta Rubiera, Helena Quesada, Laura Llull, Ana Rodríguez-Campello, Joan Martí-Fàbregas, Laia Seró, Francisco Purroy, Iago Payo, Sònia García, David Cánovas, Jurek Krupinski, Natalia Mas, Ernest Palomeras, Dolores Cocho, Maria Àngels Font, Esther Catena, Elsa Puiggròs, Claudia Pedroza, Gemma Marín, Dolors Carrión, Xavier Costa, Mari Cruz Almendros, Ivan Torres, Carla Colom, John Alejandro Velasquez, Gloria Diaz, Xavier Jiménez, Teresa Subirats, Anna Deulofeu, Verónica Hidalgo, Mercè Salvat-Plana, Natalia Pérez De La Ossa, Catalan Stroke Code And Reperfusion Consortium (Cat-Scr)

Faculty, Staff and Student Publications

INTRODUCTION: Previous studies have reported differences in the management and outcome of women stroke patients in comparison with men. We aim to analyze sex and gender differences in the medical assistance, access to treatment and outcome of acute stroke patients in Catalonia.

PATIENTS AND METHODS: Data were obtained from a prospective population-based registry of stroke code activations in Catalonia (CICAT) from January/2016 to December/2019. The registry includes demographic data, stroke severity, stroke subtype, reperfusion therapy, and time workflow. Centralized clinical outcome at 90 days was assessed in patients receiving reperfusion therapy.

RESULTS: A total of 23,371 stroke code activations were …

Coronary Artery Disease As An Independent Predictor Of Cardiovascular Mortality In Covid-19 Patients, Hywel Soney, Nathan Deron, Lucas Wang, Lawrence Hoang, Mujahed Abualfoul, Yi Zhao, Kristopher Aten, Victor Canela, Sri Prathivada, Michael Vu, Manavjot Sidhu

Faculty, Staff and Student Publications

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with increased risk of cardiovascular mortality. However, little is known about the combined effect of coronary artery disease (CAD) and COVID-19 on mortality. We aimed to investigate the incidence of cardiovascular and all-cause mortality in COVID-19 patients with CAD.

METHODS: This multicenter retrospective study identified 3,336 COVID-19 patients admitted between March and December 2020. Data points were manually reviewed in the patients' electronic health records. Multivariate logistic regression was used to assess whether CAD and its subtypes were associated with mortality.

RESULTS: This study shows that CAD was not an independent predictor of …

Sedation And Analgesia For Reduction Of Pediatric Ileocolic Intussusception, Naveen Poonai, Daniel M Cohen, Doug Macdowell, Rakesh D Mistry, Santiago Mintegi, Simon Craig, Damian Roland, Michael Miller, Itai Shavit, Paediatric Emergency Research Networks (Pern) Paint Study Group;, Yvette Wang, Alan Nager, Theodore Heyming, Rebekah Burns, Indi Trehan, Matthew Lipshaw, Carmen Sulton, Joyce Li, Aderonke Ojo, Susan Kelly, Matthew Thornton, Kerry Caperell, Iluonose Amoni, Anna Abrams, Myto Duong, Muhammad Wassem, Adrienne Davis, Jocelyn Gravel, Evelyne Doyon Trottier, Neta Bar Am, Graham Thompson, Vikram Sabhaney, Garth Meckler, Rini Jain, Samina Ali, Silvia Bressan, Tiziana Zangardi, Giovanna Villa, Martina Giacalone, Michelle Seiler, Cyril Sahyoun, Fabrizio Romano, Zsolt Bognar, Szofia Hajosi-Kalcakosz, Lisa Amir, Said Hachimi-Idrissi, Zanda Pucuka, Astra Zviedre, Emilija Zeltina, Natalie Phillips, Meredith Borland, Sharon O'Brien, Jeanette Marchant, Amit Kochar, Shane George, Victoria Pennington, Mark Lyttle, Jen Browning, Anna Mcloughlin, Stuart Hartshorn, Chaman Urooj, Lucy Johnston, Emily Walton, Deepika Subrahmanyam Puthucode, Phil Peacock, James Conroy, Rafael Marañon, Silvia Garcia, Nuria Cahís, Amaia Cámara-Otegui, Arantxa Gomez, Maria Carbonero, Carlos Angelats-Romero, Adriana Yock-Corrales, Gabriela Hualde, Fabian Spigariol, Alex Donas, Cinthia Gübeli Linné, Alessia Rocchi, Alessia Pedrazzini, Giorgio Cozzi, Dino Barbi, Laura Baggio, Giovana La Fauci, Angela Mauro, Matthew Steimle, Danilo Buonsenso, Irma Ugalde, Gaby Nieva, Charlotte Harper, Idanna Sforzi, Shobhit Jain

Faculty, Staff and Student Publications

IMPORTANCE: Ileocolic intussusception is an important cause of intestinal obstruction in children. Reduction of ileocolic intussusception using air or fluid enema is the standard of care. This likely distressing procedure is usually performed without sedation or analgesia, but practice variation exists.

OBJECTIVE: To characterize the prevalence of opioid analgesia and sedation and assess their association with intestinal perforation and failed reduction.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study reviewed medical records of children aged 4 to 48 months with attempted reduction of ileocolic intussusception at 86 pediatric tertiary care institutions in 14 countries from January 2017 to December 2019. Of …

Real-World Safety Of Neurohormonal Antagonist Initiation Among Older Adults Following A Heart Failure Hospitalization, Parag Goyal, Andrew R Zullo, Barbara Gladders, Chukwuma Onyebeke, Min Ji Kwak, Larry A Allen, Emily B Levitan, Monika M Safford, Lauren Gilstrap

Faculty, Staff and Student Publications

AIMS: To optimize guideline-directed medical therapy for heart failure, patients may require the initiation of multiple neurohormonal antagonists (NHAs) during and following hospitalization. The safety of this approach for older adults is not well established.

METHODS AND RESULTS: We conducted an observational cohort study of 207 223 Medicare beneficiaries discharged home following a hospitalization for heart failure with reduced ejection fraction (HFrEF) (2008-2015). We performed Cox proportional hazards regression to examine the association between the count of NHAs initiated within 90 days of hospital discharge (as a time-varying exposure) and all-cause mortality, all-cause rehospitalization, and fall-related adverse events over the …

A Role For Protein Arginine Methyltransferase 7 In Repetitive And Mild Traumatic Brain Injury, Christina H Acosta, Garrett A Clemons, Cristiane T Citadin, William C Carr, Mariana Sayuri Berto Udo, Vesna Tesic, Henry W Sanicola, Anne H Freelin, Jamie B Toms, J Dedrick Jordan, Bharat Guthikonda, Celeste Yin-Chieh Wu, Reggie Hui-Chao Lee, Hung Wen Lin

Faculty, Staff and Student Publications

Mild traumatic brain injury affects the largest proportion of individuals in the United States and world-wide. Pre-clinical studies of repetitive and mild traumatic brain injury (rmTBI) have been limited in their ability to recapitulate human pathology (i.e. diffuse rotational injury). We used the closed-head impact model of engineered rotation acceleration (CHIMERA) to simulate rotational injury observed in patients and to study the pathological outcomes post-rmTBI using C57BL/6J mice. Enhanced cytokine production was observed in both the cortex and hippocampus to suggest neuroinflammation. Furthermore, microglia were assessed via enhanced iba1 protein levels and morphological changes using immunofluorescence. In addition, LC/MS analyses …

Mini-Hyper-Cvd Plus Inotuzumab Ozogamicin, With Or Without Blinatumomab, In The Subgroup Of Older Patients With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphocytic Leukaemia: Long-Term Results Of An Open-Label Phase 2 Trial, Elias Jabbour, Nicholas J Short, Jayastu Senapati, Nitin Jain, Xuelin Huang, Naval Daver, Courtney D Dinardo, Naveen Pemmaraju, William Wierda, Guillermo Garcia-Manero, Guillermo Montalban Bravo, Koji Sasaki, Tapan M Kadia, Joseph Khoury, Sa A Wang, Fadi G Haddad, Jovitta Jacob, Rebecca Garris, Farhad Ravandi, Hagop M Kantarjian

Faculty, Staff and Student Publications

Background: The outcome of older patients with B-cell acute lymphocytic leukaemia is inferior to that in younger patients due to the adverse disease biology and their inability to tolerate intensive therapy. We aimed to study the long-term outcomes of inotuzumab ozogamicin with or without blinatumomab in combination with low-intensity chemotherapy in these patients.

Methods: For this open-label phase 2 trial, patients aged 60 years or older with newly diagnosed, Philadelphia-chromosome negative, B-cell acute lymphocytic leukaemia, and an ECOG performance status of 3 or lower were eligible. This study was conducted at the University of Texas MD Anderson Cancer Center. The …

Targeting Glutaminase Is Therapeutically Effective In Ibrutinib-Resistant Mantle Cell Lymphoma, Lingzhi Li, Lei Nie, Alexa Jordan, Qingsong Cai, Yang Liu, Yijing Li, Yuxuan Che, Jovanny Vargas, Zhihong Chen, Angela Leeming, Wei Wang, Yixin Yao, Michael Wang, Vivian Changying Jiang

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma characterized by frequent relapses. The development of resistance to ibrutinib therapy remains a major challenge in MCL. We previously showed that glutaminolysis is associated with resistance to ibrutinib. In this study, we confirmed that glutaminase (GLS), the first enzyme in glutaminolysis, is overexpressed in ibrutinib-resistant MCL cells, and that its expression correlates well with elevated glutamine dependency and glutaminolysis. Furthermore, we discovered that GLS expression correlates with MYC expression and the functioning of the glutamine transporter ASCT2. Depletion of glutamine or GLS significantly reduced cell growth, while GLS overexpression enhanced …

Lenvatinib Plus Pembrolizumab In Previously Treated Advanced Endometrial Cancer: Updated Efficacy And Safety From The Randomized Phase Iii Study 309/Keynote-775, Vicky Makker, Nicoletta Colombo, Antonio Casado Herráez, Bradley J Monk, Helen Mackay, Alessandro D Santin, David S Miller, Richard G Moore, Sally Baron-Hay, Isabelle Ray-Coquard, Kimio Ushijima, Kan Yonemori, Yong Man Kim, Eva M Guerra Alia, Ulus A Sanli, Steven Bird, Robert Orlowski, Jodi Mckenzie, Chinyere Okpara, Gianmaria Barresi, Domenica Lorusso

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

We report the final prespecified analysis for overall survival (OS), along with updated progression-free survival (PFS) and objective response rate (ORR), and safety from the open-label, randomized, phase III Study 309/KEYNOTE-775. In total, 827 patients with advanced, …

Inference For Set-Based Effects In Genetic Association Studies With Interval-Censored Outcomes, Ryan Sun, Liang Zhu, Yimei Li, Yutaka Yasui, Leslie Robison

Faculty, Staff and Student Publications

The rapid acceleration of genetic data collection in biomedical settings has recently resulted in the rise of genetic compendiums filled with rich longitudinal disease data. One common feature of these data sets is their plethora of interval-censored outcomes. However, very few tools are available for the analysis of genetic data sets with interval-censored outcomes, and in particular, there is a lack of methodology available for set-based inference. Set-based inference is used to associate a gene, biological pathway, or other genetic construct with outcomes and is one of the most popular strategies in genetics research. This work develops three such tests …

Coffee Intake, Caffeine Metabolism Genotype, And Survival Among Men With Prostate Cancer, Justin R Gregg, Jeri Kim, Christopher Logothetis, Sam Hanash, Xiaotao Zhang, Ganiraju Manyam, Kenneth Muir, Graham G Giles, Janet L Stanford, Sonja I Berndt, Manolis Kogevinas, Hermann Brenner, Rosalind A Eeles, Practical Consortium, Peng Wei, Carrie R Daniel

Faculty, Staff and Student Publications

Background: Coffee intake may lower prostate cancer risk and progression, but postdiagnosis outcomes by caffeine metabolism genotype are not well characterized.

Objective: To evaluate associations between coffee intake, caffeine metabolism genotype, and survival in a large, multicenter study of men with prostate cancer.

Design, setting, and participants: Data from The PRACTICAL Consortium database for 5727 men with prostate cancer from seven US, Australian, and European studies were included. The cases included had data available for the CYP1A2 -163C>A rs762551 single-nucleotide variant associated with caffeine metabolism, coffee intake, and >6 mo of follow-up.

Outcome measurements and statistical analysis: Multivariable-adjusted Cox …

Test-Retest Reliability Of Virtual Reality Devices In Quantifying For Relative Afferent Pupillary Defect, Prithul Sarker, Nasif Zaman, Joshua Ong, Phani Paladugu, Molly Aldred, Ethan Waisberg, Andrew G Lee, Alireza Tavakkoli

Faculty, Staff and Student Publications

Background: The swinging flashlight test (SFT) is one of the most prominent clinical tests for detecting the relative afferent pupillary defect (RAPD). A positive RAPD localizes the lesion to the affected afferent pupil pathway and is a critical part of any ophthalmic exam. Testing for an RAPD, however, can be challenging (especially when small), and there is significant intrarater and interrater variability.

Methods: Prior studies have shown that the pupillometer can improve the detection and measurement of RAPD. In our previous research, we have demonstrated an automatic SFT by utilizing virtual reality (VR), named VR-SFT. We applied our methods to …

Targeting Chemotherapy Resistance In Mesenchymal Triple-Negative Breast Cancer: A Phase Ii Trial Of Neoadjuvant Angiogenic And Mtor Inhibition With Chemotherapy, Nour Abuhadra, Ryan Sun, Roland L Bassett, Lei Huo, Jeffrey T Chang, Mediget Teshome, Alyson R Clayborn, Jason B White, Elizabeth E Ravenberg, Beatriz E Adrada, Rosalind P Candelaria, Wei Yang, Qingqing Ding, W Fraser Symmans, Banu Arun, Senthil Damodaran, Kimberly B Koenig, Rachel M Layman, Bora Lim, Jennifer K Litton, Alastair Thompson, Naoto T Ueno, Helen Piwnica-Worms, Gabriel N Hortobagyi, Vicente Valero, Debu Tripathy, Gaiane M Rauch, Stacy Moulder, Clinton Yam

Faculty, Staff and Student Publications

Background:: Metaplastic histology and mesenchymal differentiation have been associated with chemotherapy resistance in triple-negative breast cancer (TNBC). In the neoadjuvant setting, suboptimal on-treatment clinical response to chemotherapy is associated with low rates of pathological complete response (pCR). Given the previously demonstrated activity of pegylated liposomal doxorubicin, bevacizumab, and mTOR inhibition with temsirolimus (DAT) or everolimus (DAE) in metastatic, metaplastic TNBC, we conducted a phase II study of DAT/DAE as the second phase of neoadjuvant therapy in patients with metaplastic and/or mesenchymal TNBC experiencing suboptimal clinical response to neoadjuvant doxorubicin and cyclophosphamide (AC) (NCT02456857).

Patients and Methods:: Patients received …

Characterization Of Gafchromictm Ebt4 Film With Clinical Kv/Mv Photons And Mev Electrons, Fada Guan, Huixiao Chen, Emily Draeger, Yuting Li, Resat Aydin, Christopher J Tien, Zhe Chen

Faculty, Staff and Student Publications

Objective: A newly developed GafchromicTM EBT4 film model was released recently. According to the vendor-stated specifications, this new model maintains major features of its more recent predecessor, EBT3, but has a great improvement in the signal-to-noise ratio (SNR). The purpose of this study was to fully characterize the EBT4 model by testing its dose response dependence on beam energy using clinical photon and electron beams and validating its improvement in SNR.

Methods: In the beam energy dependence experiments, 6 MV and 15 MV photon beams, 6 MeV, 12 MeV and 20 MeV electron beams, 120 kVp and two 250 kVp …

A Nasal Inflammatory Cytokine Signature Is Associated With Early Graft-Versus-Host Disease Of The Lung After Allogeneic Hematopoietic Cell Transplantation: Proof Of Concept, Edwin J Ostrin, Nicholas L Rider, Amin M Alousi, Ehsan Irajizad, Liang Li, Qian Peng, Sang T Kim, Lara Bashoura, Muhammad H Arain, Laila Z Noor, Nikul Patel, Rohtesh Mehta, Uday R Popat, Chitra Hosing, Robert R Jenq, Gabriela Rondon, Samir M Hanash, Sophie Paczesny, Elizabeth J Shpall, Richard E Champlin, Burton F Dickey, Ajay Sheshadri

Faculty, Staff and Student Publications

Respiratory inflammation in bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation (HCT) is poorly understood. Clinical criteria for early-stage BOS (stage 0p) often capture HCT recipients without BOS. Measuring respiratory tract inflammation may help identify BOS, particularly early BOS. We conducted a prospective observational study in HCT recipients with new-onset BOS (n = 14), BOS stage 0p (n = 10), and recipients without lung impairment with (n = 3) or without (n = 8) chronic graft-versus-host disease and measured nasal inflammation using nasosorption at enrollment and then every 3 mo for 1 y. We divided BOS stage 0p into impairment …

Aibp Regulates Trpv1 Activation In Chemotherapy-Induced Peripheral Neuropathy By Controlling Lipid Raft Dynamics And Proximity To Tlr4 In Dorsal Root Ganglion Neurons, Juliana M Navia-Pelaez, Julia Borges Paes Lemes, Leonardo Gonzalez, Lauriane Delay, Luciano Dos Santos Aggum Capettini, Jenny W Lu, Gilson Gonçalves Dos Santos, Ann M Gregus, Patrick M Dougherty, Tony L Yaksh, Yury I Miller

Faculty, Staff and Student Publications

Nociceptive afferent signaling evoked by inflammation and nerve injury is mediated by the opening of ligand-gated and voltage-gated receptors or channels localized to cholesterol-rich lipid raft membrane domains. Dorsal root ganglion (DRG) nociceptors express high levels of toll-like receptor 4 (TLR4), which also localize to lipid rafts. Genetic deletion or pharmacologic blocking of TLR4 diminishes pain associated with chemotherapy-induced peripheral neuropathy (CIPN). In DRGs of mice with paclitaxel-induced CIPN, we analyzed DRG neuronal lipid rafts, expression of TLR4, activation of transient receptor potential cation channel subfamily V member 1 (TRPV1), and TLR4-TRPV1 interaction. Using proximity ligation assay, flow cytometry, and …

Impact Of Cross-Ancestry Genetic Architecture On Gwass In Admixed Populations, Rachel Mester, Kangcheng Hou, Yi Ding, Gillian Meeks, Kathryn S Burch, Arjun Bhattacharya, Brenna M Henn, Bogdan Pasaniuc

Faculty, Staff and Student Publications

Genome-wide association studies (GWASs) have identified thousands of variants for disease risk. These studies have predominantly been conducted in individuals of European ancestries, which raises questions about their transferability to individuals of other ancestries. Of particular interest are admixed populations, usually defined as populations with recent ancestry from two or more continental sources. Admixed genomes contain segments of distinct ancestries that vary in composition across individuals in the population, allowing for the same allele to induce risk for disease on different ancestral backgrounds. This mosaicism raises unique challenges for GWASs in admixed populations, such as the need to correctly adjust …

Beta-Blocker Use Is Associated With Worse Relapse-Free Survival In Patients With Head And Neck Cancer, Hannah Y Chen, Weilu Zhao, Shorook Na'ara, Frederico O Gleber-Netto, Tongxin Xie, Shahrukh Ali, Zachary M Thompson, Jane Buell, Haleigh Stafford, Priyadharsini Nagarajan, Michael Davies, Michael K Wong, Michael R Migden, Padmanee Sharma, Jeffrey N Myers, Neil D Gross, Moran Amit

Faculty, Staff and Student Publications

PURPOSE: Although beta-blockers (BBs) have been hypothesized to exert a beneficial effect on cancer survival through inhibition of beta-adrenergic signaling pathways, clinical data on this issue have been inconsistent. We investigated the impact of BBs on survival outcomes and efficacy of immunotherapy in patients with head and neck squamous cell carcinoma (HNSCC), non-small-cell lung cancer (NSCLC), melanoma, or squamous cell carcinoma of the skin (skin SCC), independent of comorbidity status or cancer treatment regimen.

METHODS: Patients (N = 4,192) younger than 65 years with HNSCC, NSCLC, melanoma, or skin SCC treated at MD Anderson Cancer Center from 2010 to 2021 …

Comparison Of Mammography Ai Algorithms With A Clinical Risk Model For 5-Year Breast Cancer Risk Prediction: An Observational Study, Vignesh A Arasu, Laurel A Habel, Ninah S Achacoso, Diana S M Buist, Jason B Cord, Laura J Esserman, Nola M Hylton, M Maria Glymour, John Kornak, Lawrence H Kushi, Donald A Lewis, Vincent X Liu, Caitlin M Lydon, Diana L Miglioretti, Daniel A Navarro, Albert Pu, Li Shen, Weiva Sieh, Hyo-Chun Yoon, Catherine Lee

Faculty, Staff and Student Publications

Background Although several clinical breast cancer risk models are used to guide screening and prevention, they have only moderate discrimination. Purpose To compare selected existing mammography artificial intelligence (AI) algorithms and the Breast Cancer Surveillance Consortium (BCSC) risk model for prediction of 5-year risk. Materials and Methods This retrospective case-cohort study included data in women with a negative screening mammographic examination (no visible evidence of cancer) in 2016, who were followed until 2021 at Kaiser Permanente Northern California. Women with prior breast cancer or a highly penetrant gene mutation were excluded. Of the 324 009 eligible women, a random subcohort …

Hes1 Marks Peri-Condensation Mesenchymal Cells That Generate Both Chondrocytes And Perichondrial Cells In Early Bone Development, Yuki Matsushita, Hiroaki Manabe, Takahiro Ohyama, Shogo Nakamura, Mizuki Nagata, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

Bone development starts with condensations of undifferentiated mesenchymal cells that set a framework for future bones within the primordium. In the endochondral pathway, mesenchymal cells inside the condensation differentiate into chondrocytes and perichondrial cells in a SOX9-dependent mechanism. However, the identity of mesenchymal cells outside the condensation and how they participate in developing bones remain undefined. Here we show that mesenchymal cells surrounding the condensation contribute to both cartilage and perichondrium, robustly generating chondrocytes, osteoblasts, and marrow stromal cells in developing bones. Single-cell RNA-seq analysis of Prrx1-cre-marked limb bud mesenchymal cells at E11.5 reveals that Notch effector Hes1 is …

Circulating Succinate-Modifying Metabolites Accurately Classify And Reflect The Status Of Fumarate Hydratase-Deficient Renal Cell Carcinoma, Liang Zheng, Zi-Ran Zhu, Tal Sneh, Wei-Tuo Zhang, Zao-Yu Wang, Guang-Yu Wu, Wei He, Hong-Gang Qi, Hang Wang, Xiao-Yu Wu, Jonatan Fernández-García, Ifat Abramovich, Yun-Ze Xu, Jin Zhang, Eyal Gottlieb

Faculty, Staff and Student Publications

Germline or somatic loss-of-function mutations of fumarate hydratase (FH) predispose patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection there is no effective therapy for metastatic FH-deficient RCC, an accurate method for early diagnosis is needed. Although MRI or CT scans are offered, they cannot differentiate FH-deficient tumors from other RCCs. Therefore, finding noninvasive plasma biomarkers suitable for rapid diagnosis, screening, and surveillance would improve clinical outcomes. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed plasma metabolomics analysis and identified 2 tumor-derived metabolites, succinyl-adenosine and succinic-cysteine, as excellent …

Addition Of Metastasis-Directed Therapy To Intermittent Hormone Therapy For Oligometastatic Prostate Cancer: The Extend Phase 2 Randomized Clinical Trial, Chad Tang, Alexander D Sherry, Cara Haymaker, Tharakeswara Bathala, Suyu Liu, Bryan Fellman, Lorenzo Cohen, Ana Aparicio, Amado J Zurita, Alexandre Reuben, Enrica Marmonti, Stephen G Chun, Jay P Reddy, Amol Ghia, Sean Mcguire, Eleni Efstathiou, Jennifer Wang, Jianbo Wang, Patrick Pilie, Craig Kovitz, Weiliang Du, Samantha J Simiele, Rachit Kumar, Yerko Borghero, Zheng Shi, Brian Chapin, Daniel Gomez, Ignacio Wistuba, Paul G Corn

Faculty, Staff and Student Publications

IMPORTANCE: Despite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial.

OBJECTIVE: To determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone.

DESIGN, SETTING, PARTICIPANTS: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical …

High-Yield Deterministic Focused Ion Beam Implantation Of Quantum Defects Enabled By In Situ Photoluminescence Feedback, Vigneshwaran Chandrasekaran, Michael Titze, Anthony R Flores, Deanna Campbell, Jacob Henshaw, Andrew C Jones, Edward S Bielejec, Han Htoon

Faculty, Staff and Student Publications

Focused ion beam implantation is ideally suited for placing defect centers in wide bandgap semiconductors with nanometer spatial resolution. However, the fact that only a few percent of implanted defects can be activated to become efficient single photon emitters prevents this powerful capability to reach its full potential in photonic/electronic integration of quantum defects. Here an industry adaptive scalable technique is demonstrated to deterministically create single defects in commercial grade silicon carbide by performing repeated low ion number implantation and in situ photoluminescence evaluation after each round of implantation. An array of 9 single defects in 13 targeted locations is …

Efficacy And Safety Of Nivolumab Plus Ipilimumab Vs Nivolumab Alone For Treatment Of Recurrent Or Metastatic Squamous Cell Carcinoma Of The Head And Neck: The Phase 2 Checkmate 714 Randomized Clinical Trial, Kevin J Harrington, Robert L Ferris, Maura Gillison, Makoto Tahara, Athanasios Argiris, Jérôme Fayette, Michael Schenker, Åse Bratland, John W T Walker, Peter Grell, Caroline Even, Christine H Chung, Rebecca Redman, Alexandre Coutte, Sébastien Salas, Cliona Grant, Sergio De Azevedo, Denis Soulières, Aaron R Hansen, Li Wei, Tariq Aziz Khan, Karen Miller-Moslin, Mustimbo Roberts, Robert Haddad

Faculty, Staff and Student Publications

IMPORTANCE: There remains an unmet need to improve clinical outcomes in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

OBJECTIVE: To evaluate clinical benefit of first-line nivolumab plus ipilimumab vs nivolumab alone in patients with R/M SCCHN.

DESIGN, SETTING, AND PARTICIPANTS: The CheckMate 714, double-blind, phase 2 randomized clinical trial was conducted at 83 sites in 21 countries between October 20, 2016, and January 23, 2019. Eligible participants were aged 18 years or older and had platinum-refractory or platinum-eligible R/M SCCHN and no prior systemic therapy for R/M disease. Data were analyzed from …