Digital Commons Network^™

Antioxidant Activity And Total Phenolic Compounds Of Commiphora Gileadensis Extracts Obtained By Ultrasonic-Assisted Extraction, With Monitoring Antiaging And Cytotoxicity Activities, Hani Ahmed, Marwan M A Rashed, Marwan Almoiliqy, Mohammed Abdalla, Mohanad Bashari, Mohamed Y Zaky, Zhu Hailin, Taha A A Naji, Ahmed Eibaid, Jinpeng Wang, Li-Ping Jiang

Faculty, Staff and Student Publications

Commiphora gileadensis (C. gileadensis) has been identified and linked with various health benefits and pharmaceutical potential for its phytochemical activities and chemical constituents. This study aimed to evaluate ultrasonic‐assisted extraction (USE) technique for total phenols content from C. gileadensis leaf compared to the hydrodistillation extraction (HDE). Our results showed that the USE operating conditions were identified as: MeOH·H2O solvent‐to‐fresh sample ratio of 80:20 (v/v); ultrasonic power/frequency at 150 W/20 kHz; and a temperature of 40 ± 1°C; subjected to acoustic waves intermittently for a calculated time (5 min) during the total programmed time of 12 min. The USE …

Patient-Reported Fatigue And Pain In Erdheim-Chester Disease: A Registry-Based, Mixed Methods Study, Anne S Reiner, Dana Bossert, Justin J Buthorn, Allison M Sigler, Selin Gonen, Deanna Fournier, Kathleen Brewer, Jessica Corkran, Gaurav Goyal, Carl E Allen, Kenneth L Mcclain, Thomas M Atkinson, Kathleen A Lynch, Jun J Mao, Katherine S Panageas, Eli L Diamond

Faculty, Staff and Students Publications

No abstract provided.

Discordant Calls Across Genotype Discovery Approaches Elucidate Variants With Systematic Errors, Elizabeth G Atkinson, Mykyta Artomov, Alexander A Loboda, Heidi L Rehm, Daniel G Macarthur, Konrad J Karczewski, Benjamin M Neale, Mark J Daly

Faculty, Staff and Students Publications

Large-scale high-throughput sequencing data sets have been transformative for informing clinical variant interpretation and for use as reference panels for statistical and population genetic efforts. Although such resources are often treated as ground truth, we find that in widely used reference data sets such as the Genome Aggregation Database (gnomAD), some variants pass gold-standard filters, yet are systematically different in their genotype calls across genotype discovery approaches. The inclusion of such discordant sites in study designs involving multiple genotype discovery strategies could bias results and lead to false-positive hits in association studies owing to technological artifacts rather than a true …

The Voltage-Gated Sodium Channel In Drosophila, Para, Localizes To Dendrites As Well As Axons In Mechanosensitive Chordotonal Neurons, Thomas A Ravenscroft, Ashleigh Jacobs, Mingxue Gu, Daniel F Eberl, Hugo J Bellen

Faculty, Staff and Students Publications

The fruit fly Drosophila melanogaster has provided important insights into how sensory information is transduced by transient receptor potential (TRP) channels in the peripheral nervous system (PNS). However, TRP channels alone have not been able to completely model mechanosensitive transduction in mechanoreceptive chordotonal neurons (CNs). Here, we show that, in addition to TRP channels, the sole voltage-gated sodium channel (NaV) in Drosophila, Para, is localized to the dendrites of CNs. Para is localized to the distal tip of the dendrites in all CNs, from embryos to adults, and is colocalized with the mechanosensitive TRP channels No mechanoreceptor potential C …

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 …

Pan-Cancer T Cell Atlas Links A Cellular Stress Response State To Immunotherapy Resistance, Yanshuo Chu, Enyu Dai, Yating Li, Guangchun Han, Guangsheng Pei, Davis R Ingram, Krupa Thakkar, Jiang-Jiang Qin, 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 …

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, Deanna M Glassman, Amir A Jazaeri, Jose A Rauh-Hain, 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 …

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 …

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, Yang Yu, Walter V Velasco, Kwanghyuk Lee, 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 …

Smooth Muscle-Alpha Actin R149c Pathogenic Variant Downregulates Integrin Recruitment At Cell-Matrix Adhesions And Decreases Cellular Contractility, Krishna R Ojha, Hyoseon Kim, Samuel Padgham, Laura Hopkins, Robert J Zamen, Abhijnan Chattopadhyay, Gang Han, Dianna M Milewicz, Michael P Massett, Andreea Trache

Faculty, Staff and Student Publications

Thoracic aortic aneurysm is found in patients with ACTA2 pathogenic variants. ACTA2 missense variants are associated with impaired aortic smooth muscle cell (SMC) contraction. This study tested the hypothesis that the Acta2R149C/+ variant alters actin isoform expression and decreases integrin recruitment, thus, reducing aortic contractility. Stress relaxation measurements in thoracic aortic rings showed two functional regimes with a reduction of stress relaxation in the aorta from Acta2R149C/+ mice at low tension, but not at high tension values. Contractile responses to phenylephrine and potassium chloride were 50% lower in Acta2R149C/+ mice than in wild-type (WT) mice. Additionally, SMC were immunofluorescently labeled …

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 …

Integration Of Remote Symptom And Biometric Monitoring Into The Care Of Adult Patients With Cancer Receiving Chemotherapy-A Decentralized Feasibility Pilot Study, Anaeze C Offodile, Domenica Delgado, Yu-Li Lin, Danielle Geyen, Christopher J Miller, Sanchita Jain, Janice P Finder, Sanjay Shete, Frank V Fossella, Michael J Overman, Susan K Peterson

Faculty, Staff and Student Publications

PURPOSE: Although electronic patient-reported outcomes (ePROs) are efficacious in symptom management, much is unknown about the utility of vital signs surveillance. We examined the feasibility of a remote patient monitoring platform that integrates ePROs and biometrics into the ambulatory management of symptom burden.

METHODS: Using a decentralized workflow, patients with gastrointestinal or thoracic cancer were approached for a 1-month study. Patients reported symptom burden via ePROs and biometrics (blood pressure, oxygen saturation, pulse, weight, and temperature) using bluetooth-enabled devices daily. Alerts on the basis of prespecified thresholds were managed via nurse-led triage. Adherence was defined as the completion of > 70% …

Trpv4 Expression In The Renal Tubule Is Necessary For Maintaining Whole Body K+ Homeostasis, Anna Stavniichuk, Kyrylo Pyrshev, Oleg Zaika, Viktor N Tomilin, Mariya Kordysh, Monika Lakk, David Križaj, Oleh Pochynyuk

Faculty, Staff and Student Publications

The Ca2+-permeable transient receptor potential vanilloid type 4 (TRPV4) channel serves as the sensor of tubular flow, thus being well suited to govern mechanosensitive K+ transport in the distal renal tubule. Here, we directly tested whether the TRPV4 function is significant in affecting K+ balance. We used balance metabolic cage experiments and systemic measurements with different K+ feeding regimens [high (5% K+), regular (0.9% K+), and low (<0.01% K+)] in newly created transgenic mice with selective TRPV4 deletion in the renal tubule (TRPV4fl/fl-Pax8Cre) and their littermate controls (TRPV4fl/fl). Deletion was verified by the absence of TRPV4 protein expression and lack of TRPV4-dependent Ca2+ influx. There were no differences in plasma electrolytes, urinary volume, and K+ levels at baseline. In contrast, plasma K+ levels were significantly elevated in TRPV4fl/fl-Pax8Cre mice on high K+ intake. K+-loaded knockout mice exhibited lower urinary K+ levels than TRPV4fl/fl mice, which was accompanied by higher aldosterone levels by day 7. Moreover, TRPV4fl/fl-Pax8Cre mice had more efficient renal K+ conservation and higher plasma K+ levels in the state of dietary K+ deficiency. H+-K+-ATPase levels were significantly increased in TRPV4fl/fl-Pax8Cre mice …

Efficacy Of Systemic Chemotherapy In Patients With Low-Grade Mucinous Appendiceal Adenocarcinoma: A Randomized Crossover Trial, John Paul Shen, Abdelrahman M Yousef, Fadl A Zeineddine, Mohammad A Zeineddine, Rebecca S Tidwell, Karen A Beaty, Lisa C Scofield, Safia Rafeeq, Nicholas Hornstein, Elizabeth Lano, Cathy Eng, Aurelio Matamoros, Wai Chin Foo, Abhineet Uppal, Christopher Scally, Paul Mansfield, Melissa Taggart, Kanwal P Raghav, Michael J Overman, Keith Fournier

Faculty, Staff and Student Publications

IMPORTANCE: Appendiceal adenocarcinoma is a rare tumor, and given the inherent difficulties in performing prospective trials in such a rare disease, there are currently minimal high-quality data to guide treatment decisions, highlighting the need for more preclinical and clinical investigation for this disease.

OBJECTIVE: To prospectively evaluate the effectiveness of fluoropyrimidine-based systemic chemotherapy in patients with inoperable low-grade mucinous appendiceal adenocarcinoma.

DESIGN, SETTING, AND PARTICIPANTS: This open-label randomized crossover trial recruited patients at a single tertiary care comprehensive cancer center from September 2013 to January 2021. The data collection cutoff was May 2022. Enrollment of up to 30 patients was …

Ovarian Cancer Pathology Characteristics As Predictors Of Variant Pathogenicity In Brca1 And Brca2, Denise G O'Mahony, Susan J Ramus, Melissa C Southey, Nicola S Meagher, Andreas Hadjisavvas, Esther M John, Ute Hamann, Evgeny N Imyanitov, Irene L Andrulis, Priyanka Sharma, Mary B Daly, Christopher R Hake, Jeffrey N Weitzel, Anna Jakubowska, Andrew K Godwin, Adalgeir Arason, Anita Bane, Jacques Simard, Penny Soucy, Maria A Caligo, Phuong L Mai, Kathleen B M Claes, Manuel R Teixeira, Wendy K Chung, Conxi Lazaro, Peter J Hulick, Amanda E Toland, Inge Sokilde Pedersen, Susan L Neuhausen, Ana Vega, Miguel De La Hoya, Heli Nevanlinna, Mallika Dhawan, Valentina Zampiga, Rita Danesi, Liliana Varesco, Viviana Gismondi, Valerio Gaetano Vellone, Paul A James, Ramunas Janavicius, Liene Nikitina-Zake, Finn Cilius Nielsen, Thomas Van Overeem Hansen, Tanja Pejovic, Ake Borg, Johanna Rantala, Kenneth Offit, Marco Montagna, Katherine L Nathanson, Susan M Domchek, Ana Osorio, María J García, Beth Y Karlan, Gemo Study Collaborators, Anna De Fazio, David Bowtell, Aocs Group, Lesley Mcguffog, Michael T Parsons, Thilo Dörk, Lisa-Marie Speith, Elizabeth Santana Dos Santos, Alexandre André B A Da Costa, Paolo Radice, Paolo Peterlongo, Laura Papi, Christoph Engel, Eric Hahnen, Rita K Schmutzler, Barbara Wappenschmidt, Douglas F Easton, Marc Tischkowitz, Christian F Singer, Yen Yen Tan, Alice S Whittemore, Weiva Sieh, James D Brenton, Drakoulis Yannoukakos, Florentia Fostira, Irene Konstantopoulou, Jana Soukupova, Michal Vocka, Czecanca Consortium, Georgia Chenevix-Trench, Paul D P Pharoah, Antonis C Antoniou, David E Goldgar, Amanda B Spurdle, Kyriaki Michailidou, Consortium Of Investigators Of Modifiers Of Brca1/2, Evidence-Based Network For The Interpretation Of Germline Mutant Alleles Consortium, Hebon Investigators, Goska Leslie

Faculty, Staff and Student Publications

BACKGROUND: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.

METHODS: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with …

Uptake And Outcomes Of Neoadjuvant Chemotherapy Among Us Patients With Less Common Epithelial Ovarian Carcinomas, Koji Matsuo, Shinya Matsuzaki, Michihide Maeda, Alesandra R Rau, Kosuke Yoshihara, Ryo Tamura, Muneaki Shimada, Hiroko Machida, Mikio Mikami, Maximilian Klar, Lynda D Roman, Jason D Wright, Anil K Sood, David M Gershenson

Faculty, Staff and Student Publications

Importance: Randomized clinical trials examining the effectiveness of neoadjuvant chemotherapy (NACT) for advanced ovarian cancer predominantly included patients with high-grade serous carcinomas. The use and outcomes of NACT in less common epithelial carcinomas are understudied.

Objective: To investigate the uptake and survival outcomes in treatment with NACT for less common histologic subtypes of epithelial ovarian cancer.

Design, setting, and participants: A retrospective cohort study and systematic literature review with meta-analysis was conducted using the National Cancer Database from 2006 to 2017 and the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2006 to 2019. Data analysis was performed …

Dusp22 Rearrangement Is Associated With A Distinctive Immunophenotype But Not Outcome In Patients With Systemic Alk-Negative Anaplastic Large Cell Lymphoma, Lianqun Qiu, Guilin Tang, Shaoying Li, Francisco Vega, Pei Lin, Sa A Wang, Wei Wang, Swaminathan P Iyer, Luis Malpica, Roberto N Miranda, Sergej Konoplev, Zhenya Tang, Hong Fang, L Jeffrey Medeiros, Jie Xu

Faculty, Staff and Student Publications

DUSP22 rearrangement (R) has been associated with a favorable outcome in systemic ALK-negative anaplastic large cell lymphoma (ALCL). However, a recent study found that patients with DUSP22-R ALK-negative ALCL have a poorer prognosis than was reported initially. In this study, we compared the clinicopathological features and outcomes of patients with ALKnegative ALCL with DUSP22-R (n=22) versus those without DUSP22-R (DUSP22-NR; n=59). Patients with DUSP22-R ALCL were younger than those with DUSP22-NR neoplasms (P=0.049). DUSP22-R ALK-negative ALCL cases were more often positive for CD15, CD8, and less frequently expressed pSTAT3Tyr705, PD-L1, granzyme B and EMA (all P0.05), but was significantly shorter …

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 …

Neuroaffective Reactivity Profiles Are Associated With Vulnerability To E-Cigarette Use, Francesco Versace, George Kypriotakis, Dustin Pluta

Faculty, Staff and Student Publications

BACKGROUND: We tested whether neuroaffective responses to motivationally salient stimuli are associated with vulnerability to cue-induced e-cigarette use in e-cigarette naïve adults who smoke daily. We hypothesized that individuals with stronger neuroaffective responses to nicotine-related cues than to pleasant stimuli (the C>P reactivity profile) would be more vulnerable to cue-induced nicotine self-administration than individuals with stronger neuroaffective responses to pleasant stimuli than to nicotine-related cues (the P>C reactivity profile).

METHODS: We used event-related potentials (ERPs, a direct measure of cortical activity) to measure neuroaffective reactivity to pleasant, unpleasant, neutral, and nicotine-related cues indicating the opportunity to use an …

5s Rrna Pseudogene Transcripts Are Associated With Interferon Production And Inflammatory Responses In Alcohol-Associated Hepatitis, Jianguo Wu, Adam Kim, Xiaoqin Wu, Semanti Ray, Daniela S Allende, Nicole Welch, Annette Bellar, Jaividhya Dasarathy, Srinivasan Dasarathy, Laura E Nagy

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Interferon (IFN) signaling is critical to the pathogenesis of alcohol-associated hepatitis (AH), yet the mechanisms for activation of this system are elusive. We hypothesize that host-derived 5S rRNA pseudogene (RNA5SP) transcripts regulate IFN production and modify immunity in AH.

APPROACH AND RESULTS: Mining of transcriptomic datasets revealed that in patients with severe alcohol-associated hepatitis (sAH), hepatic expression of genes regulated by IFNs was perturbed and gene sets involved in IFN production were enriched. RNA5SP transcripts were also increased and correlated with expression of type I IFNs. Interestingly, inflammatory mediators upregulated in sAH, but not in other liver …

Camonsertib In Dna Damage Response-Deficient Advanced Solid Tumors: Phase 1 Trial Results, Timothy A Yap, Elisa Fontana, Elizabeth K Lee, David R Spigel, Martin Højgaard, Stephanie Lheureux, Niharika B Mettu, Benedito A Carneiro, Louise Carter, Ruth Plummer, Gregory M Cote, Funda Meric-Bernstam, Joseph O'Connell, Joseph D Schonhoft, Marisa Wainszelbaum, Adrian J Fretland, Peter Manley, Yi Xu, Danielle Ulanet, Victoria Rimkunas, Mike Zinda, Maria Koehler, Ian M Silverman, Jorge S Reis-Filho, Ezra Rosen

Faculty, Staff and Student Publications

Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia-mutated (ATM) kinase, and preclinical studies have identified ATRi-sensitizing alterations in other DNA damage response (DDR) genes. Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors harboring LOF alterations in DDR genes, predicted by chemogenomic CRISPR screens to sensitize tumors to ATRi. Primary objectives were to determine safety and propose …

Targeting Fatty Acid Reprogramming Suppresses Carm1-Expressing Ovarian Cancer, Simona Lombardi, Aaron R Goldman, Hsin-Yao Tang, Andrew V Kossenkov, Heng Liu, Wei Zhou, Meenhard Herlyn, Jianhuang Lin, Rugang Zhang

Faculty, Staff and Student Publications

The arginine methyltransferase CARM1 exhibits high expression levels in several human cancers, with the trend also observed in ovarian cancer. However, therapeutic approaches targeting tumors that overexpress CARM1 have not been explored. Cancer cells exploit metabolic reprogramming such as fatty acids for their survival. Here we report that CARM1 promotes monounsaturated fatty acid synthesis and fatty acid reprogramming represents a metabolic vulnerability for CARM1-expressing ovarian cancer. CARM1 promotes the expression of genes encoding rate-limiting enzymes of de novo fatty acid metabolism such as acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN). In addition, CARM1 upregulates stearoyl-CoA desaturase 1 (SCD1) …

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 …

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 …

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 …

Prospective Validation Of Diffusion-Weighted Mri As A Biomarker Of Tumor Response And Oncologic Outcomes In Head And Neck Cancer: Results From An Observational Biomarker Pre-Qualification Study, Abdallah S R Mohamed, Abdelrahman Abusaif, Renjie He, Kareem A Wahid, Vivian Salama, Sara Youssef, Brigid A Mcdonald, Mohamed Naser, Yao Ding, Travis C Salzillo, Moamen A Abobakr, Jihong Wang, Stephen Y Lai, Clifton D Fuller

Faculty, Staff and Student Publications

PURPOSE: To determine DWI parameters associated with tumor response and oncologic outcomes in head and neck (HNC) patients treated with radiotherapy (RT).

METHODS: HNC patients in a prospective study were included. Patients had MRIs pre-, mid-, and post-RT completion. We used T2-weighted sequences for tumor segmentation which were co-registered to respective DWIs for extraction of apparent diffusion coefficient (ADC) measurements. Treatment response was assessed at mid- and post-RT and was defined as: complete response (CR) vs. non-complete response (non-CR). The Mann-Whitney U test was used to compare ADC between CR and non-CR. Recursive partitioning analysis (RPA) was performed to identify …

Anaplastic Transformation In Thyroid Cancer Revealed By Single-Cell Transcriptomics, Lina Lu, Jennifer Rui Wang, Ying C Henderson, Shanshan Bai, Jie Yang, Min Hu, Cheng-Kai Shiau, Timothy Pan, Yuanqing Yan, Tuan M Tran, Jianzhuo Li, Rachel Kieser, Xiao Zhao, Jiping Wang, Roza Nurieva, Michelle D Williams, Maria E Cabanillas, Ramona Dadu, Naifa Lamki Busaidy, Mark Zafereo, Nicholas Navin, Stephen Y Lai, Ruli Gao

Faculty, Staff and Student Publications

The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC); however, the complex intratumor transformation process is poorly understood. We investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single-cell transcriptomic and genetic alteration data from patients with different subtypes of thyroid cancer. The resulting spectrum of ATC transformation included stress-responsive DTC cells, inflammatory ATC cells (iATCs), and mitotic-defective ATC cells and extended all the way to mesenchymal ATC cells (mATCs). Furthermore, our analysis identified 2 important milestones: (a) a diploid stage, in which iATC cells were diploids with inflammatory …

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 …