Medical Specialties Commons^™

Gsk-3484862 Targets Dnmt1 For Degradation In Cells, Qin Chen, Bigang Liu, Yang Zeng, Jee Won Hwang, Nan Dai, Ivan R Corrêa, Marcos R Estecio, Xing Zhang, Margarida A Santos, Taiping Chen, Xiaodong Cheng

Faculty, Staff and Student Publications

Maintenance of genomic methylation patterns at DNA replication forks by DNMT1 is the key to faithful mitotic inheritance. DNMT1 is often overexpressed in cancer cells and the DNA hypomethylating agents azacytidine and decitabine are currently used in the treatment of hematologic malignancies. However, the toxicity of these cytidine analogs and their ineffectiveness in treating solid tumors have limited wider clinical use. GSK-3484862 is a newly-developed, dicyanopyridine containing, non-nucleoside DNMT1-selective inhibitor with low cellular toxicity. Here, we show that GSK-3484862 targets DNMT1 for protein degradation in both cancer cell lines and murine embryonic stem cells (mESCs). DNMT1 depletion was rapid, taking …

Concomitant Targeting Of Flt3 And Btk Overcomes Flt3 Inhibitor Resistance In Acute Myeloid Leukemia Through The Inhibition Of Autophagy, Weiguo Zhang, Guopan Yu, Hongying Zhang, Mahesh Basyal, Charlie Ly, Bin Yuan, Vivian Ruvolo, Sujan Piya, Seemana Bhattacharya, Qi Zhang, Gautam Borthakur, Venkata Battula, Marina Konopleva, William G Rice, Michael Andreeff

Faculty, Staff and Student Publications

Strategies to overcome resistance to FMS-like tyrosine kinase 3 (FLT3)-targeted therapy in acute myeloid leukemia (AML) are urgently needed. We identified autophagy as one of the resistance mechanisms, induced by hypoxia and the bone marrow microenvironment via activation of Bruton tyrosine kinase (BTK). Suppressing autophagy/BTK sensitized FLT3- mutated AML to FLT3 inhibitor-induced apoptosis. Furthermore, co-targeting FLT3/BTK/aurora kinases with a novel multikinase inhibitor CG-806 (luxeptinib) induced profound apoptosis in FLT3-mutated AML by co-suppressing FLT3/BTK, antagonizing autophagy, and causing leukemia cell death in FLT3-wildtype AML by aurora kinase-mediated G2/M arrest and polyploidy, in addition to FLT3 inhibition. Thus, CG-806 exerted profound anti-leukemia …

A Phase Ii Study Of Neoadjuvant Atezolizumab And Nab-Paclitaxel In Patients With Anthracycline-Resistant Early-Stage Triple-Negative Breast Cancer, Clinton Yam, Elizabeth A Mittendorf, Haven R Garber, Ryan Sun, Senthil Damodaran, Rashmi K Murthy, David Ramirez, Meghan Karuturi, Rachel M Layman, Nuhad Ibrahim, Gaiane M Rauch, Beatriz E Adrada, Rosalind P Candelaria, Jason B White, Elizabeth Ravenberg, Alyson Clayborn, Qing Qing Ding, W Fraser Symmans, Sabitha Prabhakaran, Alastair M Thompson, Vicente Valero, Debu Tripathy, Lei Huo, Stacy L Moulder, Jennifer K Litton

Faculty, Staff and Student Publications

Purpose: Neoadjuvant anti-PD-(L)1 therapy improves the pathological complete response (pCR) rate in unselected triple-negative breast cancer (TNBC). Given the potential for long-term morbidity from immune-related adverse events (irAEs), optimizing the risk-benefit ratio for these agents in the curative neoadjuvant setting is important. Suboptimal clinical response to initial neoadjuvant therapy (NAT) is associated with low rates of pCR (2-5%) and may define a patient selection strategy for neoadjuvant immune checkpoint blockade. We conducted a single-arm phase II study of atezolizumab and nab-paclitaxel as the second phase of NAT in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02530489).

Methods: Patients …

The Lure Of Cardiac Metabolism In The Diagnosis, Prevention, And Treatment Of Heart Failure, Daniele Rodolico, Gabriele G Schiattarella, Heinrich Taegtmeyer

Faculty, Staff and Student Publications

Energy substrate metabolism and contractile function are tightly coupled in the heart. Within this framework, heart failure may be viewed as a state of impaired energy transfer. The metabolic changes in the failing heart are linked to functional and structural changes. A worthwhile goal is to measure metabolic flux and its regulation quantitatively, and to do this in a manner that leads to targeted interventions. For several good reasons, this goal has been elusive until now. The development of new analytical and imaging techniques offers the potential of exploring the landscape of metabolic changes across the different stages of heart …

Evaluation Of Alisertib Alone Or Combined With Fulvestrant In Patients With Endocrine-Resistant Advanced Breast Cancer: The Phase 2 Tbcrc041 Randomized Clinical Trial, Tufia C Haddad, Vera J Suman, Antonino B D'Assoro, Jodi M Carter, Karthik V Giridhar, Brendan P Mcmenomy, Katelyn Santo, Erica L Mayer, Meghan S Karuturi, Aki Morikawa, P Kelly Marcom, Claudine J Isaacs, Sun Young Oh, Amy S Clark, Ingrid A Mayer, Khandan Keyomarsi, Timothy J Hobday, Prema P Peethambaram, Ciara C O'Sullivan, Roberto A Leon-Ferre, Minetta C Liu, James N Ingle, Matthew P Goetz

Faculty, Staff and Student Publications

IMPORTANCE: Aurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i-resistant MBC is unknown.

OBJECTIVE: To assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC.

DESIGN, SETTING, AND PARTICIPANTS: This phase …

Efficacy And Adverse Effects Of Ketamine Versus Electroconvulsive Therapy For Major Depressive Disorder: A Systematic Review And Meta-Analysis, Debora De A Simoes Moreira, Luís Eduardo Gauer, Guilherme Teixeira, Amanda Carolina Fonseca Da Silva, Stefanie Cavalcanti, João Quevedo

Faculty, Staff and Student Publications

Background: ECT is considered the fastest and most effective treatment for TRD. Ketamine seems to be an attractive alternative due to its rapid-onset antidepressant effects and impact on suicidal thoughts. This study aimed to compare efficacy and tolerability of ECT and ketamine for different depression outcomes (PROSPERO/CRD42022349220).

Methods: We searched MEDLINE, Web of Science, Embase, PsycINFO, Google Scholar, Cochrane Library and trial registries, which were the ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Platform, without restrictions on publication date.

Selection criteria: randomized controlled trials or cohorts comparing ketamine versus ECT in patients with TRD.

Results: Eight studies …

Antibody Toolkit To Investigate Eef1a Methylation Dynamics In Mrna Translation Elongation, Robert Mealey-Farr, Jinho Jeong, Juhyung Park, Shuo Liu, Simone Hausmann, Joel W Francis, Maria Angulo Ibanez, Joonseok Cho, Katrin Chua, Pawel K Mazur, Or Gozani

Faculty, Staff and Student Publications

Protein synthesis is a fundamental step in gene expression, with modulation of mRNA translation at the elongation step emerging as an important regulatory node in shaping cellular proteomes. In this context, five distinct lysine methylation events on eukaryotic elongation factor 1A (eEF1A), a fundamental nonribosomal elongation factor, are proposed to influence mRNA translation elongation dynamics. However, a lack of affinity tools has hindered progress in fully understanding how eEF1A lysine methylation impacts protein synthesis. Here we develop and characterize a suite of selective antibodies to investigate eEF1A methylation and provide evidence that methylation levels decline in aged tissue. Determination of …

Targeting Unc51-Like Autophagy Activating Kinase 1 (Ulk1) Overcomes Adaptive Drug Resistance In Acute Myelogenous Leukemia, Seemana Bhattacharya, Sujan Piya, Huaxian Ma, Priyanka Sharma, Qi Zhang, Natalia Baran, Vivian R Ruvolo, Teresa Mcqueen, R Eric Davis, Rasoul Pourebrahim, Marina Konopleva, Hagop Kantarjian, Nicholas D P Cosford, Michael Andreeff, Gautam Borthakur

Faculty, Staff and Student Publications

UNLABELLED: Despite effective new therapies, adaptive resistance remains the main obstacle in acute myelogenous leukemia (AML) therapy. Autophagy induction is a key mechanism for adaptive resistance. Leukemic blasts at diagnosis express higher levels of the apical autophagy kinase ULK1 compared with normal hematopoietic cells. Exposure to chemotherapy and targeted agents upregulate ULK1, hence we hypothesize that developing ULK1 inhibitors may present the unique opportunity for clinical translation of autophagy inhibition. Accordingly, we demonstrate that ULK1 inhibition, by genetic and pharmacologic means, suppresses treatment-induced autophagy, overcomes adaptive drug-resistance, and synergizes with chemotherapy and emerging antileukemia agents like venetoclax (ABT-199). The study …

A Bayesian Feature Allocation Model For Identifying Cell Subpopulations Using Cytof Data, Arthur Lui, Juhee Lee, Peter F Thall, May Daher, Katy Rezvani, Rafet Basar

Faculty, Staff and Student Publications

A Bayesian feature allocation model (FAM) is presented for identifying cell subpopulations based on multiple samples of cell surface or intracellular marker expression level data obtained by cytometry by time of flight (CyTOF). Cell subpopulations are characterized by differences in marker expression patterns, and cells are clustered into subpopulations based on their observed expression levels. A model-based method is used to construct cell clusters within each sample by modeling subpopulations as latent features, using a finite Indian buffet process. Non-ignorable missing data due to technical artifacts in mass cytometry instruments are accounted for by defining a static missingship mechanism. In …

Selective Immune Suppression Using Interleukin-6 Receptor Inhibitors For Management Of Immune-Related Adverse Events, Faisal Fa'ak, Maryam Buni, Adewunmi Falohun, Huifang Lu, Juhee Song, Daniel H Johnson, Chrystia M Zobniw, Van A Trinh, Muhammad Osama Awiwi, Nourel Hoda Tahon, Khaled M Elsayes, Kaysia Ludford, Emma J Montazari, Julia Chernis, Maya Dimitrova, Sabina Sandigursky, Jeffrey A Sparks, Osama Abu-Shawer, Osama Rahma, Uma Thanarajasingam, Ashley M Zeman, Rafee Talukder, Namrata Singh, Sarah H Chung, Petros Grivas, May Daher, Ala Abudayyeh, Iman Osman, Jeffrey Weber, Jean H Tayar, Maria E Suarez-Almazor, Noha Abdel-Wahab, Adi Diab

Faculty, Staff and Student Publications

BACKGROUND: Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs.

METHODS: We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment.

RESULTS: We identified a total of 92 patients …

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 …

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 …

Phase I/Ii Sequencing Study Of Azacitidine, Epacadostat, And Pembrolizumab In Advanced Solid Tumors, Jason J Luke, Marwan Fakih, Charles Schneider, E Gabriela Chiorean, Johanna Bendell, Rebecca Kristeleit, Razelle Kurzrock, Sarah P Blagden, Irene Brana, Laura W Goff, Kevin O'Hayer, Ryan Geschwindt, Michael Smith, Feng Zhou, Aung Naing

Faculty, Staff and Student Publications

Background: Indoleamine 2,3-dioxygenase 1 (IDO1), an interferon-inducible enzyme, contributes to tumor immune intolerance. Immune checkpoint inhibition may increase interferon levels; combining IDO1 inhibition with immune checkpoint blockade represents an attractive strategy. Epigenetic agents trigger interferon responses and may serve as an immunotherapy priming method. We evaluated whether epigenetic therapy plus IDO1 inhibition and immune checkpoint blockade confers clinical benefit to patients with advanced solid tumors.

Methods: ECHO-206 was a Phase I/II study where treatment-experienced patients with advanced solid tumors (N = 70) received azacitidine plus an immunotherapy doublet (epacadostat [IDO1 inhibitor] and pembrolizumab). Sequencing of treatment was also assessed. Primary …

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 …

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 …

Towards Neuromarkers For Tailored Smoking Cessation Treatments, Francesco Versace, Jason D Robinson, Paul M Cinciripini

Faculty, Staff and Student Publications

Vulnerability to compulsive drug use stems from dysregulated activity within the neural networks that underlie reward and executive functions. Empirical evidence suggests that a) attributing high motivational salience to drug-related stimuli leads to compulsive drug seeking and b) cognitive control deficits lead to compulsive drug taking. Noninvasive neuroimaging techniques enable brain activity monitoring during affective and cognitive processing and are paving the way to precision medicine for substance use disorders. Identifying robust neuromarkers of affective and cognitive dysregulation would allow clinicians to personalize treatments by targeting individual psychophysiological vulnerabilities. However, methodological choices have biased the field toward experimental paradigms that …

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 …

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 …

Adjuvant Therapy With Oncolytic Adenovirus Delta-24-Rgdox After Intratumoral Adoptive T-Cell Therapy Promotes Antigen Spread To Sustain Systemic Antitumor Immunity, Hong Jiang, Dong Ho Shin, Yanhua Yi, Xuejun Fan, Joy Gumin, Jiasen He, Andrew G Gillard, Frederick F Lang, Candelaria Gomez-Manzano, Juan Fueyo

Faculty, Staff and Student Publications

Cancer cell heterogeneity and immunosuppressive tumor microenvironment (TME) pose a challenge in treating solid tumors with adoptive cell therapies targeting limited tumor-associated antigens (TAA), such as chimeric antigen receptor T-cell therapy. We hypothesize that oncolytic adenovirus Delta-24-RGDOX activates the TME and promote antigen spread to potentiate the abscopal effect of adoptive TAA-targeting T cells in localized intratumoral treatment. Herein, we used C57BL/6 mouse models with disseminated tumors derived from B16 melanoma cell lines to assess therapeutic effects and antitumor immunity. gp100-specific pmel-1 or ovalbumin (OVA)-specific OT-I T cells were injected into the first subcutaneous tumor, followed by three injections of …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

Publisher Correction: Targeting Pd-L2-Rgmb Overcomes Microbiome-Related Immunotherapy Resistance, Joon Seok Park, Francesca S Gazzaniga, Meng Wu, Amalia K Luthens, Jacob Gillis, Wen Zheng, Martin W Lafleur, Sarah B Johnson, Golnaz Morad, Elizabeth M Park, Yifan Zhou, Stephanie S Watowich, Jennifer A Wargo, Gordon J Freeman, Dennis L Kasper, Arlene H Sharpe

Faculty, Staff and Student Publications

No abstract provided.

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 …

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, …

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 …