Medical Genetics Commons^™

Prediction Of Disease Progression To Upfront Pembrolizumab Monotherapy In Advanced Non-Small-Cell Lung Cancer With High Pd-L1 Expression Using Baseline Ct Disease Quantification And Smoking Pack Years, Ali Silver, Cheryl Ho, Qian Ye, Jianjun Zhang, Ian Janzen, Montgomery Martin, Ying Wang, Stephen Lam, Calum Macaulay, Barbara Melosky, Ren Yuan

Faculty, Staff and Student Publications

Health Canada approved pembrolizumab in the first-line setting for advanced non-small-cell lung cancer with PD-L1 ≥ 50% and no EGFR/ALK aberration. The keynote 024 trial showed 55% of such patients progress with pembrolizumab monotherapy. We propose that the combination of baseline CT and clinical factors can help identify those patients who may progress. In 138 eligible patients from our institution, we retrospectively collected their baseline variables, including baseline CT findings (primary lung tumor size and metastatic site), smoking pack years, performance status, tumor pathology, and demographics. The treatment response was assessed via RECIST 1.1 using the baseline and first follow-up …

Germline Genetic Variants And Pediatric Rhabdomyosarcoma Outcomes: A Report From The Children’S Oncology Group, Pagna Sok, Meredith Yeager, Deborah A Marquez-Do, Donald A Barkauskas, David Hall, Matthew T Mcevoy, Austin L Brown, Aniko Sabo, Paul Scheet, Chad D Huff, Stephen X Skapek, Douglas S Hawkins, Rajkumar Venkatramani, Lisa Mirabello, Philip J Lupo

Faculty, Staff and Student Publications

BACKGROUND: Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with RMS.

METHODS: The study included 920 individuals with newly diagnosed RMS who were enrolled in Children's Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards models, adjusted for clinical …

Noncoding Rnas: Hope And Hype At 30 Years, George A Calin

Faculty, Staff and Student Publications

No abstract provided.

Decoding The Regulatory Roles Of Non-Coding Rnas In Cellular Metabolism And Disease, Yuru Zong, Xuliang Wang, Bing Cui, Xiaowei Xiong, Andrew Wu, Yaohua Zhang

Faculty, Staff and Student Publications

Non-coding RNAs, including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are being studied extensively in a variety of fields. Their roles in metabolism have received increasing attention in recent years but are not yet clear. The regulation of glucose, fatty acid, and amino acid metabolism is an imperative physiological process that occurs in living organisms and takes part in cancer and cardiovascular diseases. Here, we summarize the important roles played by non-coding RNAs in glucose metabolism, fatty acid metabolism, and amino acid metabolism, as well as the mechanisms involved. We also summarize the therapeutic advances for non-coding …

Non-Homologous End-Joining Pathway Genotypes Significantly Associated With Nasopharyngeal Carcinoma Susceptibility, Chia-Wen Tsai, Liang-Chun Shih, Wen-Shin Chang, Che-Lun Hsu, Jie-Long He, Yun-Chi Wang, Da-Tian Bau

Faculty, Staff and Student Publications

Defects in the non-homologous end-joining (NHEJ) DNA repair pathway lead to genomic instability and carcinogenesis. However, the roles of individual NHEJ genes in nasopharyngeal carcinoma (NPC) etiology are not well-understood. The aim of this study was to assess the contribution of NHEJ genotypes, including XRCC4 (rs6869366, rs3734091, rs28360071, rs28360317, rs1805377), XRCC5 (rs828907, rs11685387, rs9288518), XRCC6 (rs5751129, rs2267437, rs132770, rs132774), XRCC7 rs7003908, and Ligase4 rs1805388, to NPC risk, with 208 NPC patients and 416 controls. Genotype-phenotype correlations were also investigated by measuring mRNA and protein expression in adjacent normal tissues and assessing the NHEJ repair capacity in blood lymphocytes from 43 …

17Β-Estradiol Promotes Extracellular Vesicle Release And Selective Mirna Loading In Erα-Positive Breast Cancer, Rares Drula, Barbara Pardini, Xiao Fu, Mireia Cruz De Los Santos, Ancuta Jurj, Sherien M El-Daly, Erik Knutsen, Mihnea P Dragomir, Recep Bayraktar, Yongfeng Li, Meng Chen, Filippo Del Vecchio, Léa Berland, Jessica Dae, Daniel Fan, Masayoshi Shimizu, Anh M Tran, Mercedes Barzi, Carlotta Pioppini, Angelica M Gutierrez, Cristina Ivan, Salyna Meas, Carolyn S Hall, Suresh K Alahari, Ioana Berindan-Neagoe, Muller Fabbri, Anthony Lucci, Banu Arun, Simone Anfossi, George A Calin

Faculty, Staff and Student Publications

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor-positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7's miRNAs into EVs. In multiple patient cohorts, …

Targeting Cxcr4 Abrogates Resistance To Trastuzumab By Blocking Cell Cycle Progression And Synergizes With Docetaxel In Breast Cancer Treatment, Shuying Liu, Shelly M Xie, Wenbin Liu, Mihai Gagea, Ariella B Hanker, Akshara Singareeka Raghavendra, Fuliang Chu, Sattva S Neelapu, Adriano Marchese, Samir Hanash, Johann Zimmermann, Carlos L Arteaga, Debasish Tripathy

Faculty, Staff and Student Publications

Background: Although trastuzumab and other HER2-targeted therapies have significantly improved survival in patients with HER2 overexpressed or amplified (HER2+) breast cancer, a significant proportion of patients do not respond or eventually develop clinical resistance. Strategies to reverse trastuzumab resistance remain a high clinical priority. We were the first to report the role of CXCR4 in trastuzumab resistance. The present study aims to explore the therapeutic potential of targeting CXCR4 and better understand the associated mechanisms.

Methods: Immunofluorescent staining, confocal microscopy analysis, and immunoblotting were used to analyze CXCR4 expression. BrdU incorporation assays and flow cytometry were used to analyze dynamic …

Tubectomy With Delayed Oophorectomy As An Alternative To Risk-Reducing Salpingo-Oophorectomy In High-Risk Women To Assess The Safety Of Prevention: The Tuba-Wisp Ii Study Protocol, Miranda P Steenbeek, Majke H D Van Bommel, Joanna Inthout, Christine B Peterson, Michiel Simons, Marleen Kets, Elizabeth M Swisher, Rosella P M G Hermens, Tuba-Wisp Ii Consortium, Karen H Lu, Joanne A De Hullu

Faculty, Staff and Student Publications

Background: Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy.

Primary objective: To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk.

Study hypothesis: We hypothesize that postponement of oophorectomy after salpingectomy, to the age of 40-45 (BRCA1) …

Studies On Diketopiperazine And Dipeptide Analogs As Opioid Receptor Ligands, Siavash Shahbazi Nia, Mohammad Anwar Hossain, Guangchen Ji, Sravan K Jonnalagadda, Samuel Obeng, Ali Ehsan Sifat, Collin Blackwell, Dhavalkumar Patel, Jon Thompson, Scott Runyon, Takato Hiranita, Christopher R Mccurdy, Lance Mcmahon, Thomas J Abbruscato, Paul C Trippier, Volker Neugebauer, Nadezhda A German

Faculty, Staff and Student Publications

Using the structure of gliotoxin as a starting point, we have prepared two different chemotypes with selective affinity to the kappa opioid receptor (KOR). Using medicinal chemistry approaches and structure-activity relationship (SAR) studies, structural features required for the observed affinity were identified, and advanced molecules with favorable Multiparameter Optimization (MPO) and Ligand Lipophilicity (LLE) profiles were prepared. Using the Thermal Place Preference Test (TPPT), we have shown that compound2 blocks the antinociceptive effect of U50488, a known KOR agonist. Multiple reports suggest that modulation of KOR signaling is a promising therapeutic strategy in treating neuropathic pain (NP). As a …

Irinotecan- Vs Oxaliplatin-Based Doublets In Krasg12c-Mutated Metastatic Colorectal Cancer—A Multicentre Propensity-Score-Matched Retrospective Analysis, Vincenzo Formica, Cristina Morelli, Veronica Conca, Maria Alessandra Calegari, Jessica Lucchetti, Marta Schirripa, Lisa Salvatore, Federica Lo Prinzi, Giovanni Dima, Giovanni Trovato, Silvia Riondino, Mario Roselli, Ferdinandos Skoulidis, Hendrik-Tobias Arkenau, Chiara Cremolini

Faculty, Staff and Student Publications

Background: KRASG12C-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRASG12C-inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown.

Methods: A multicentre retrospective analysis was conducted including KRASG12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/- bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis …

Utility Of Patient-Reported Symptom And Functional Outcomes To Indicate Recovery After First 90 Days Of Radical Cystectomy: A Longitudinal Study, Xin Shelley Wang, Kelly K Bree, Neema Navai, Mona Kamal, Shu-En Shen, Charles S Cleeland, Vijaya Gottumukkala

Faculty, Staff and Student Publications

This is a longitudinal prospective study that tracked multiple symptom burden and functioning status for bladder cancer (BLC) patients for 3 months post-radical cystectomy at The University of Texas MD Anderson Cancer Center, using a validated disease-specific patient-reported outcome measure (PROM) tool, the MD Anderson Symptom Inventory (the MDASI-PeriOp-BLC). The feasibility of collecting an objective measure for physical functioning, using "Timed Up & Go test" (TUGT) and PRO scores at baseline, discharge and end of study, was tested. Patients (

Cxcr2 Expression During Melanoma Tumorigenesis Controls Transcriptional Programs That Facilitate Tumor Growth, J Yang, K Bergdorf, C Yan, W Luo, S C Chen, Q Liu, M Boothby, V L Weiss, S M Groves, A N Oleskie, X Zhang, D Y Maeda, J A Zebala, V Quaranta, A Richmond

Faculty, Staff and Student Publications

Background: Though the CXCR2 chemokine receptor is known to play a key role in cancer growth and response to therapy, a direct link between expression of CXCR2 in tumor progenitor cells during induction of tumorigenesis has not been established.

Methods: To characterize the role of CXCR2 during melanoma tumorigenesis, we generated tamoxifen-inducible tyrosinase-promoter driven BrafV600E/Pten-/-/Cxcr2-/- and NRasQ61R/INK4a-/-/Cxcr2-/- melanoma models. In addition, the effects of a CXCR1/CXCR2 antagonist, SX-682, on melanoma tumorigenesis were evaluated in BrafV600E/Pten-/- and NRasQ61R/INK4a-/- mice and in melanoma cell lines. Potential mechanisms by which Cxcr2 affects melanoma tumorigenesis in these murine models were explored using RNAseq, mMCP-counter, …

Clinical Implications Of Tumor-Based Next-Generation Sequencing In High-Grade Epithelial Ovarian Cancer, Katherine I Foster, Kenna R M Shaw, Jeff Jin, Shannon N Westin, Timothy A Yap, Amir A Jazaeri, Sanghoon Lee, Bryan M Fellman, Zhenlin Ju, Yuexin Liu, Nicole D Fleming, Anil K Sood

Faculty, Staff and Student Publications

Background: Tumor-based next-generation sequencing is used inconsistently as a tool to tailor treatment of ovarian cancer, yet beyond detection of somatic BRCA1 and BRCA2 mutations, the clinical benefit is not well established. This study aimed to assess the clinical relevance of tumor-based next-generation sequencing (tbNGS) in patients with ovarian cancer.

Methods: This retrospective study included patients with high-grade epithelial ovarian carcinoma. tbNGS results were identified in the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected. Progression-free survival (PFS) and overall survival were calculated and compared using log-rank tests. Multivariate Cox …

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 …

Flt3 Inhibitors Upregulate Cxcr4 And E-Selectin Ligands Via Erk Suppression In Aml Cells And Cxcr4/E-Selectin Inhibition Enhances Anti-Leukemia Efficacy Of Flt3-Targeted Therapy In Aml, Yannan Jia, Weiguo Zhang, Mahesh Basyal, Kyung Hee Chang, Lauren Ostermann, Charlie Ly, Qi Zhang, Xin Han, William E Fogler, John L Magnani, Arnaud Lesegretain, Anna A Zal, Tomasz Zal, Michael Andreeff

Faculty, Staff and Student Publications

No abstract provided.

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, Gilson Gonçalves Dos Santos, 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, Brenna M Henn

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 …

Cumulative Burden Of Late, Major Surgical Intervention In Survivors Of Childhood Cancer: A Report From The Childhood Cancer Survivor Study (Ccss) Cohort, Bryan V Dieffenbach, Andrew J Murphy, Qi Liu, Duncan C Ramsey, Erik J Geiger, Rebecca M Howell, Leslie L Robison, Yutaka Yasui, Gregory T Armstrong, Eric J Chow, Brent R Weil, Christopher B Weldon

Faculty, Staff and Student Publications

Background: Multimodal cancer therapy places childhood cancer survivors at increased risk for chronic health conditions, subsequent malignancies, and premature mortality as they age. We aimed to estimate the cumulative burden of late (>5 years from cancer diagnosis), major surgical interventions among childhood cancer survivors, compared with their siblings, and to examine associations between specific childhood cancer treatments and the burden of late surgical interventions.

Methods: We analysed data from the Childhood Cancer Survivor Study (CCSS), a retrospective cohort study with longitudinal prospective follow-up of 5-year survivors of childhood cancer (diagnosed before age 21 years) treated at 31 institutions in …

An Fbn1 Deep Intronic Variant Is Associated With Pseudoexon Formation And A Variable Marfan Phenotype In A Five Generation Family, Dong-Chuan Guo, Xueyan Duan, Kathleen Mimnagh, Alana C Cecchi, Isabella C Marin, Walter V Velasco, Xue Zhu, David R Murdock, Suzanne M Leal, Marsha M Wheeler, Josh Smith, Michael J Bamshad, Dianna M Milewicz

Faculty, Staff and Student Publications

Exome sequencing of genes associated with heritable thoracic aortic disease (HTAD) failed to identify a pathogenic variant in a large family with Marfan syndrome (MFS). A genome-wide linkage analysis for thoracic aortic disease identified a peak at 15q21.1, and genome sequencing identified a novel deep intronic FBN1 variant that segregated with thoracic aortic disease in the family (LOD score 2.7) and was predicted to alter splicing. RT-PCR and bulk RNA sequencing of RNA harvested from fibroblasts explanted from the affected proband revealed an insertion of a pseudoexon between exons 13 and 14 of the FBN1 transcript, predicted to lead to …

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

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 …

Improving Prediction Of Late Symptoms Using Lstm And Patient-Reported Outcomes For Head And Neck Cancer Patients, Yaohua Wang, Lisanne Van Dijk, Abdallah S R Mohamed, Mohamed Naser, Clifton David Fuller, G Elisabeta Marai

Faculty, Staff and Student Publications

Patient-Reported Outcomes (PRO) are collected directly from the patients using symptom questionnaires. In the case of head and neck cancer patients, PRO surveys are recorded every week during treatment with each patient's visit to the clinic and at different follow-up times after the treatment has concluded. PRO surveys can be very informative regarding the patient's status and the effect of treatment on the patient's quality of life (QoL). Processing PRO data is challenging for several reasons. First, missing data is frequent as patients might skip a question or a questionnaire altogether. Second, PROs are patient-dependent, a rating of 5 for …

Pan-Cancer T Cell Atlas Links A Cellular Stress Response State To Immunotherapy Resistance, Yanshuo Chu, Enyu Dai, Yating Li, Guangchun Han, Guangsheng Pei, Krupa Thakkar, Minghao Dang, Xiuning Le, Can Hu, Qing Deng, Ansam Sinjab, Pravesh Gupta, Ruiping Wang, Dapeng Hao, Fuduan Peng, Xinmiao Yan, Yunhe Liu, Shumei Song, Shaojun Zhang, John V Heymach, Alexandre Reuben, Yasir Y Elamin, Melissa P Pizzi, Yang Lu, Rossana Lazcano, Jian Hu, Mingyao Li, Michael Curran, Andrew Futreal, Anirban Maitra, Amir A Jazaeri, Jaffer A Ajani, Charles Swanton, Xiang-Dong Cheng, Hussein A Abbas, Maura Gillison, Krishna Bhat, Alexander J Lazar, Michael Green, Kevin Litchfield, Humam Kadara, Cassian Yee, Linghua Wang

Faculty, Staff and Student Publications

Tumor-infiltrating T cells offer a promising avenue for cancer treatment, yet their states remain to be fully characterized. Here we present a single-cell atlas of T cells from 308,048 transcriptomes across 16 cancer types, uncovering previously undescribed T cell states and heterogeneous subpopulations of follicular helper, regulatory and proliferative T cells. We identified a unique stress response state, TSTR, characterized by heat shock gene expression. TSTR cells are detectable in situ in the tumor microenvironment across various cancer types, mostly within lymphocyte aggregates or potential tertiary lymphoid structures in tumor beds or surrounding tumor edges. T cell states/compositions correlated with …

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, Razelle Kurzrock, 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 …

2021 Aapm Equity, Diversity, And Inclusion Climate Survey Executive Summary, Kristi R G Hendrickson, Stephen M Avery, Richard Castillo, Laura Cervino, Ashley Cetnar, Wendy Harris, Megan E Lipford, Nadia Octave, Kelly C Paradis, Angélica Pérez-Andújar, Surendra Prajapati, Julianne Pollard-Larkin

Faculty, Staff and Student Publications

Purpose: The American Association of Physicists in Medicine (AAPM) shares the results, conclusions, and recommendations from the initial Equity, Diversity, and Inclusion Climate Survey conducted in 2021.

Methods and materials: The climate survey targeted medical physicists who are full members of the AAPM and included demographic inquiries and questions intended to assess the working environmental climate in terms of a sense of belonging and inclusion, experiences of discrimination and harassment, and obstacles to participation within the AAPM. The survey invitation was sent to 5,500 members. Responses were collected from 1385 members (response rate of 25%) between January and February 2021. …

Causal Linkage Of Presence Of Mutant Npm1 To Efficacy Of Novel Therapeutic Agents Against Aml Cells With Mutant Npm1, Christopher P Mill, Warren Fiskus, Kaberi Das, John A Davis, Christine E Birdwell, Courtney D Dinardo, Koichi Takahashi, Koji Sasaki, Gerard M Mcgeehan, Xinjia Ruan, Xiaoping Su, Sanam Loghavi, Hagop Kantarjian, Kapil N Bhalla

Faculty, Staff and Student Publications

In AML with NPM1 mutation causing cytoplasmic dislocation of NPM1, treatments with Menin inhibitor (MI) and standard AML chemotherapy yield complete remissions. However, the causal and mechanistic linkage of mtNPM1 to the efficacy of these agents has not been definitively established. Utilizing CRISPR-Cas9 editing to knockout (KO) or knock-in a copy of mtNPM1 in AML cells, present studies demonstrate that KO of mtNPM1 from AML cells abrogates sensitivity to MI, selinexor (exportin-1 inhibitor), and cytarabine. Conversely, the knock-in of a copy of mtNPM1 markedly sensitized AML cells to treatment with MI or cytarabine. Following AML therapy, most elderly patients with …

Coffee Intake, Caffeine Metabolism Genotype, And Survival Among Men With Prostate Cancer, Justin R Gregg, Jeri Kim, Christopher Logothetis, Sam Hanash, Xiaotao Zhang, Kenneth Muir, 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 …

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 …

Targeting Glutaminase Is Therapeutically Effective In Ibrutinib-Resistant Mantle Cell Lymphoma, Lingzhi Li, Lei Nie, Alexa Jordan, Qingsong Cai, Yang Liu, Yuxuan Che, 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, David S Miller, 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, …

Leveraging A Surrogate Outcome To Improve Inference On A Partially Missing Target Outcome, Zachary R Mccaw, Sheila M Gaynor, Ryan Sun, Xihong Lin

Faculty, Staff and Student Publications

Sample sizes vary substantially across tissues in the Genotype-Tissue Expression (GTEx) project, where considerably fewer samples are available from certain inaccessible tissues, such as the substantia nigra (SSN), than from accessible tissues, such as blood. This severely limits power for identifying tissue-specific expression quantitative trait loci (eQTL) in undersampled tissues. Here we propose Surrogate Phenotype Regression Analysis (Spray) for leveraging information from a correlated surrogate outcome (eg, expression in blood) to improve inference on a partially missing target outcome (eg, expression in SSN). Rather than regarding the surrogate outcome as a proxy for the target outcome, Spray jointly models the …