Digital Commons Network^™

Axl/Mertk Inhibitor Ono-7475 Potently Synergizes With Venetoclax And Overcomes Venetoclax Resistance To Kill F Lt 3-Itd Acute Myeloid Leukemia, Sean M Post, Huaxian Ma, Prerna Malaney, Xiaorui Zhang, Marisa J L Aitken, Po Yee Mak, Vivian R Ruvolo, Tomoko Yasuhiro, Ryohei Kozaki, Lauren E Chan, Lauren B Ostermann, Marina Konopleva, Bing Z Carter, Courtney Dinardo, Michael D Andreeff, Joseph D Khoury, Peter P Ruvolo

Faculty, Staff and Student Publications

FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in acute myeloid leukemia (AML). The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor, ONO-7475, kills FLT3-mutant AML cells with targets including Extracellular- signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that …

Maximal Activation Of Apoptosis Signaling By Cotargeting Antiapoptotic Proteins In Bh3 Mimetic-Resistant Aml And Aml Stem Cells, Bing Z Carter, Po Yee Mak, Wenjing Tao, Qi Zhang, Vivian Ruvolo, Vinitha M Kuruvilla, Xiangmeng Wang, Duncan H Mak, Venkata L Battula, Marina Konopleva, Elias J Jabbour, Paul E Hughes, Xiaoyue Chen, Phuong K Morrow, Michael Andreeff

Faculty, Staff and Student Publications

MCL-1 is known to play a major role in resistance to BCL-2 inhibition, but the contribution of other BCL-2 family proteins has not been fully explored. We, here, demonstrate the ineffectiveness of MCL-1 inhibitor AMG176 in venetoclax-resistant, and conversely, of venetoclax in AMG176-resistant acute myelogenous leukemia (AML). Like cells with acquired resistance to venetoclax, cells with acquired resistance to AMG176 express increased MCL-1. Both cells with acquired resistance to venetoclax and to AMG176 express increased levels of BCL-2 and BCL-2A1, decreased BAX, and/or altered levels of other BCL-2 proteins. Cotargeting BCL-2 and MCL-1 was highly synergistic in AML cell lines …

The Life Cycle Of Polyploid Giant Cancer Cells And Dormancy In Cancer: Opportunities For Novel Therapeutic Interventions, Jinsong Liu, Na Niu, Xiaoran Li, Xudong Zhang, Anil K Sood

Faculty, Staff and Student Publications

Recent data suggest that most genotoxic agents in cancer therapy can lead to shock of genome and increase in cell size, which leads whole genome duplication or multiplication, formation of polyploid giant cancer cells, activation of an early embryonic program, and dedifferentiation of somatic cells. This process is achieved via the giant cell life cycle, a recently proposed mechanism for malignant transformation of somatic cells. Increase in both cell size and ploidy allows cells to completely or partially restructures the genome and develop into a blastocyst-like structure, similar to that observed in blastomere-stage embryogenesis. Although blastocyst-like structures with reprogrammed genome …

Pityriasis Rosea-Like Rash After Messenger Rna Covid-19 Vaccination: A Case Report And Review Of The Literature, Jordan E Buckley, Laura N Landis, Ronald P Rapini

Faculty, Staff and Student Publications

A spectrum of cutaneous reactions to SARs-CoV-2 (COVID-19) vaccines have been reported in the literature. We present a case of a pityriasis rosea-like rash occurring after Pfizer COVID-19 vaccination and review cases of pityriasis rosea (PR)/PR-like eruption (PR-LE) after mRNA COVID-19 vaccine published in the medical literature. Of the 30 cases found, none experienced severe adverse effects and the rash resolved in an average of 5.6 weeks. It is important for physicians to be aware of this self-limited reaction so they can reassure and appropriately counsel patients that it is safe to receive subsequent vaccine doses despite the cutaneous eruption. …

Role Of The Chemokine System In Liver Fibrosis: A Narrative Review, Kyle L Poulsen, Christina K Cajigas-Du Ross, Jarod K Chaney, Laura E Nagy

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVE: Liver fibrosis is a disease with characteristics of an aberrant wound healing response. Fibrosis is commonly the end-stage for chronic liver diseases like alcohol-associated liver disease (ALD), metabolic-associated liver disease, viral hepatitis, and hepatic autoimmune disease. Innate immunity contributes to the progression of many diseases through multiple mechanisms including production of pro-inflammatory mediators, leukocyte infiltration and tissue injury. Chemokines and their receptors orchestrate accumulation and activation of immune cells in tissues and are associated with multiple liver diseases; however, much less is known about their potential roles in liver fibrosis. This is a narrative review of current …

Are Thyrotropin-Releasing Hormone (Trh) And Analog Taltirelin Viable Reversal Agents Of Opioid-Induced Respiratory Depression?, Marieke Hyke Algera, Joseph F Cotten, Monique Van Velzen, Marieke Niesters, Martijn Boon, Daniel S Shoham, Kaye E Dandrea, Rutger Van Der Schrier, Albert Dahan

Faculty, Staff and Student Publications

Opioid-induced respiratory depression (OIRD) is a potentially life-threatening complication of opioid consumption. Apart from naloxone, an opioid antagonist that has various disadvantages, a possible reversal strategy is treatment of OIRD with the hypothalamic hormone and neuromodulator thyrotropin-releasing hormone (TRH). In this review, we performed a search in electronic databases and retrieved 52 papers on the effect of TRH and TRH-analogs on respiration and their efficacy in the reversal of OIRD in awake and anesthetized mammals, including humans. Animal studies show that TRH and its analog taltirelin stimulate breathing via an effect at the preBötzinger complex, an important respiratory rhythm generator …

The Pendulum Of Fontan Fenestration, Nadia Hernandez, Sudipta Sen, Johanna Blair De Haan, Stephen Haskins, Amit Pawa

Faculty, Staff and Student Publications

No abstract provided.

Androgen Receptor Blockade Promotes Response To Braf/Mek-Targeted Therapy, Christopher P Vellano, Michael G White, Miles C Andrews, Manoj Chelvanambi, Russell G Witt, Joseph R Daniele, Mark Titus, Jennifer L Mcquade, Fabio Conforti, Elizabeth M Burton, Matthew J Lastrapes, Gabriel Ologun, Alexandria P Cogdill, Golnaz Morad, Peter Prieto, Alexander J Lazar, Yanshuo Chu, Guangchun Han, M A Wadud Khan, Beth Helmink, Michael A Davies, Rodabe N Amaria, Jeffrey J Kovacs, Scott E Woodman, Sapna Patel, Patrick Hwu, Michael Peoples, Jeffrey E Lee, Zachary A Cooper, Haifeng Zhu, Guang Gao, Hiya Banerjee, Mike Lau, Jeffrey E Gershenwald, Anthony Lucci, Emily Z Keung, Merrick I Ross, Laura Pala, Eleonora Pagan, Rossana Lazcano Segura, Qian Liu, Mikayla S Borthwick, Eric Lau, Melinda S Yates, Shannon N Westin, Khalida Wani, Michael T Tetzlaff, Lauren E Haydu, Mikhila Mahendra, Xiaoyan Ma, Christopher Logothetis, Zachary Kulstad, Sarah Johnson, Courtney W Hudgens, Ningping Feng, Lorenzo Federico, Georgina V Long, P Andrew Futreal, Swathi Arur, Hussein A Tawbi, Amy E Moran, Linghua Wang, Timothy P Heffernan, Joseph R Marszalek, Jennifer A Wargo

Faculty, Staff and Student Publications

Treatment with BRAF/MEK-targeted therapy has revolutionized care in melanoma and other cancers, however therapeutic resistance is common and innovative treatment strategies are needed1,2. We studied a group of melanoma patients treated with neoadjuvant BRAF/MEK-targeted therapy (NCT02231775, n=51), and observed significantly higher rates of major pathologic response (MPR= <10% viable tumor at resection) and improved recurrence-free survival (RFS) in females versus males (MPR-66% versus 14%, p=0.001; RFS-64% versus 32% at 2 years, p=0.021). Findings were validated in a several additional cohorts2–4 patients with unresectable metastatic melanoma treated with BRAF and/or MEK-targeted therapy (n=664 patients in total), demonstrating improved progression-free survival (PFS) and overall survival (OS) in females versus males in several of these studies. Studies in pre-clinical models demonstrated significantly impaired anti-tumor activity in male …

Sik2 Inhibition Enhances Parp Inhibitor Activity Synergistically In Ovarian And Triple-Negative Breast Cancers, Zhen Lu, Weiqun Mao, Hailing Yang, Janice M Santiago-O'Farrill, Philip J Rask, Jayanta Mondal, Hu Chen, Cristina Ivan, Xiuping Liu, Chang-Gong Liu, Yuanxin Xi, Kenta Masuda, Eli M Carrami, Meng Chen, Yitao Tang, Lan Pang, David S Lakomy, George A Calin, Han Liang, Ahmed A Ahmed, Hariprasad Vankayalapati, Robert C Bast

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP inhibitors are selectively active in cells with homologous recombination DNA repair deficiency caused by mutations in BRCA1/2 and other DNA repair pathway genes. Cancers with homologous recombination DNA repair proficiency respond poorly to PARP inhibitors. Cancers that initially respond to PARP inhibitors eventually develop drug resistance. We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and …

Factors Impacting Adolescent And Young Adult Cancer Patients’ Decision To Pursue Genetic Counseling And Testing, Megan Morand, Michael Roth, Susan K Peterson, Erica M Bednar, Aarti Ramdaney, J Andrew Livingston, Angela Yarbrough, Jessica Corredor

Faculty, Staff and Student Publications

Purpose: Adolescent and young adult (AYA) cancer patients face challenges when navigating cancer treatment and survivorship. Many are at risk for cancer predisposition syndromes; however, factors influencing pursuit of genetic counseling and testing have not been reported. We describe AYA cancer patients' decision-making process, including motivational factors and barriers, as it relates to utilization of genetic services.

Methods: Thirty AYAs diagnosed with cancer previously referred for cancer predisposition genetic counseling completed semi-structured interviews via audio-only Zoom calls. Thematic analysis was used to perform qualitative analysis and identify major themes.

Results: The sample comprised 21 AYAs who had genetic counseling and …

Comprehensive Characterization Of Tumor Immune Landscape Following Oncolytic Virotherapy By Single-Cell Rna Sequencing, Divya Ravirala, Guangsheng Pei, Zhongming Zhao, Xiaoliu Zhang

Faculty, Staff and Student Publications

An important mechanism of oncolytic virotherapy in ameliorating cancer immunotherapy is by inducing significant changes in the immune landscape in the tumor microenvironment (TME). Despite this notion and the potential therapeutic implications, a comprehensive analysis of the immune changes in carcinomas induced by virotherapy has not yet been elucidated. We conducted single-cell RNA sequencing analysis on carcinomas treated with an HSV-2-based oncolytic virus to characterize the immunogenic changes in the TME. We specifically analyzed and compared the immune cell composition between viral treated and untreated tumors. We also applied CellChat to analyze the complex interactions among the infiltrated immune cells. …

Peripheral Blood Gene Expression Profiling Shows Predictive Significance For Response To Mycophenolate In Systemic Sclerosis-Related Interstitial Lung Disease, Shervin Assassi, Elizabeth R Volkmann, W Jim Zheng, Xuan Wang, Holly Wilhalme, Marka A Lyons, Michael D Roth, Donald P Tashkin

Faculty, Staff and Student Publications

OBJECTIVES: To characterise the peripheral blood cell (PBC) gene expression changes ensuing from mycophenolate mofetil (MMF) or cyclophosphamide (CYC) treatment and to determine the predictive significance of baseline PBC transcript scores for response to immunosuppression in systemic sclerosis (SSc)-related interstitial lung disease (ILD).

METHODS: PBC RNA samples from baseline and 12-month visits, corresponding to the active treatment period of both arms in Scleroderma Lung Study II, were investigated by global RNA sequencing. Joint models were created to examine the predictive significance of

RESULTS: 134 patients with SSc-ILD (CYC=69 and MMF=65) were investigated. CYC led to an upregulation of erythropoiesis, inflammation …

Does Gender Impact A Diagnosis Of Ankylosing Spondylitis?, Mark C Hwang, Martin Rozycki, David Kauffman, Theresa Arndt, Esther Yi, Michael H Weisman

Faculty, Staff and Student Publications

Objective: The study objective was to explore differences in ankylosing spondylitis (AS) diagnosis experiences between men and women by examining the coding of health events over the 2 years preceding AS diagnosis.

Methods: Claims data (January 2006-April 2019) from the MarketScan databases were examined. Patients who had received two or more AS diagnoses at least 30 days apart and had at least 2 years of insurance enrollment before their first AS diagnosis were analyzed. Men were matched 1:1 to women by age, diagnosis date, insurance type, and enrollment duration. Health events (diagnosis and provider codes) were examined over 2 years …

Atf4/Txnip/Redd1/Mtor Signaling Mediates The Antitumor Activities Of Liver X Receptor In Pancreatic Cancers, Zhikang Chen, Xiaobo Lai, Hui Ding, Aijun Zhang, Yufei Sun, Jianhua Ling, Paul J Chiao, Zihua Chen, Xuefeng Xia

Faculty, Staff and Student Publications

Background: Limited by difficulties in early detection and availabilities of effective treatments, pancreatic cancer is a highly malignant disease with poor prognosis. Nuclear receptors are a family of ligand-dependent transcription factors that are highly druggable therapeutic targets playing critical roles in human physiological and pathological development, including cancer. In this study, we explored the therapeutic potential as well as the molecular mechanisms of liver X receptor (LXR) agonist GW3965 in pancreatic cancer.

Methods: Soft-agar colony formation assay, xenograft tumors, Oligonucleotide microarray, Reverse transcription real-time polymerase chain reaction, Western immunoblotting and Immunohistochemistry were used in this study.

Results: We demonstrated pleotropic …

Cooking After Cancer: The Structure And Implementation Of A Community-Based Cooking Program For Cancer Survivors, Margaret Raber, Molly Costigan, Joya Chandra, Karen Basen-Engquist

Faculty, Staff and Student Publications

Cancer survivors are a growing population that may particularly benefit from nutrition and lifestyle interventions. Community-based programs teaching healthy cooking skills are increasingly popular and offer an opportunity to support survivors within communities. The objective of this study is to describe the curriculum and implementation of a cooking class program designed for cancer survivors, housed within an established community-based organization. First, we evaluated the class curriculum for specific constructs. An evidence-based measure of healthy cooking constructs, the Healthy Cooking Index (HCI), was used to analyze included recipes and revealed both summative cooking quality scores and individual constructs underlying the overall …

A Phase 1 Trial Of 8-Chloro-Adenosine In Relapsed/Refractory Acute Myeloid Leukemia: An Evaluation Of Safety And Pharmacokinetics, Rong Chen, Yuling Chen, Ping Xiong, Daniella Zheleva, David Blake, Michael J Keating, William G Wierda, William Plunkett

Faculty, Staff and Student Publications

Fadraciclib (CYC065) is a second-generation aminopurine CDK2/9 inhibitor with increased potency and selectivity toward CDK2 and CDK9 compared to seliciclib (R-roscovitine). In chronic lymphocytic leukemia (CLL), a disease that depends on the over-expression of anti-apoptotic proteins for its survival, inhibition of CDK9 by fadraciclib reduced phosphorylation of the C-terminal domain of RNA polymerase II and blocked transcription in vitro; these actions depleted the intrinsically short-lived anti-apoptotic protein Mcl-1 and induced apoptosis. While the simulated bone marrow and lymph node microenvironments induced Mcl-1 expression and protected CLL cells from apoptosis, these conditions did not prolong the turnover rate of Mcl-1, and …

The Androgen Receptor Is A Therapeutic Target In Desmoplastic Small Round Cell Sarcoma, Salah-Eddine Lamhamedi-Cherradi, Mayinuer Maitituoheti, Brian A Menegaz, Sandhya Krishnan, Amelia M Vetter, Pamela Camacho, Chia-Chin Wu, Hannah C Beird, Robert W Porter, Davis R Ingram, Vandhana Ramamoorthy, Sana Mohiuddin, David Mccall, Danh D Truong, Branko Cuglievan, P Andrew Futreal, Alejandra Ruiz Velasco, Nazanin Esmaeili Anvar, Budi Utama, Mark Titus, Alexander J Lazar, Wei-Lien Wang, Cristian Rodriguez-Aguayo, Ravin Ratan, J Andrew Livingston, Kunal Rai, A Robert Macleod, Najat C Daw, Andrea Hayes-Jordan, Joseph A Ludwig

Faculty, Staff and Student Publications

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the …

Association Of Driver Oncogene Variations With Outcomes In Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Chemoradiation And Consolidative Durvalumab, Yufei Liu, Zhe Zhang, Waree Rinsurongkawong, Carl M Gay, Xiuning Le, Matthew S Ning, Jeff Lewis, Vadeerat Rinsurongkawong, J Jack Lee, Jack Roth, Stephen Swisher, Saumil Gandhi, Percy P Lee, Don L Gibbons, Ara A Vaporciyan, John V Heymach, Jianjun Zhang, Steven H Lin

Faculty, Staff and Student Publications

Importance: Consolidative durvalumab after definitive chemoradiation for unresectable locally advanced non-small cell lung cancer (NSCLC) can significantly improve progression-free survival (PFS) and overall survival (OS), as shown in the PACIFIC trial. However, whether patients with driver variations derive equal benefit from this regimen remains unclear.

Objectives: To compare outcomes of patients with locally advanced NSCLC with and without driver variations treated with the PACIFIC regimen.

Design, setting, and participants: This cohort study examined 104 patients with unresectable locally advanced NSCLC with mutational profiling treated at a tertiary cancer center with definitive chemoradiation and consolidative durvalumab from June 2017 through May …

Outcomes After Definitive Surgery For Mandibular Osteoradionecrosis, Kevin J Contrera, Steven B Chinn, Randal S Weber, Dianna Roberts, Jeffery N Myers, Stephen Y Lai, Carol M Lewis, Amy C Hessel, Ann M Gillenwater, Collin F Mulcahy, Peirong Yu, Matthew M Hanasono, Clifton D Fuller, Mark S Chambers, Mark E Zafereo

Faculty, Staff and Student Publications

Objectives: To analyze charges, complications, survival, and functional outcomes for definitive surgery of mandibular osteoradionecrosis (ORN).

Materials and methods: Retrospective analysis of 76 patients who underwent segmental mandibulectomy with reconstruction from 2000 to 2009.

Results: Complications occurred in 49 (65%) patients and were associated with preoperative drainage (odds ratio [OR] 4.40, 95% confidence interval [CI] 1.01-19.27). The adjusted median charge was $343 000, and higher charges were associated with double flap reconstruction (OR 8.15, 95% CI 2.19-30.29) and smoking (OR 5.91, 95% CI 1.69-20.72). Improved swallow was associated with age <67 years (OR 3.76, 95% CI 1.16-12.17) and preoperative swallow (OR 3.42, 95% CI 1.23-9.51). Five-year ORN-recurrence-free survival was 93% while overall survival was 63% and associated with pulmonary disease (HR [hazard ratio] 3.57, 95% CI 1.43-8.94).

Conclusions: Although recurrence of ORN is rare, surgical complications are …

Prognosticators Of Visual Acuity After Indirect Traumatic Optic Neuropathy, Alex J Wright, Joanna H Queen, Emilio P Supsupin, Alice Z Chuang, John J Chen, Rod Foroozan, Ore-Ofe O Adesina

Faculty, Staff and Student Publications

BACKGROUND: The purpose of this study is to determine whether there are radiographic and systemic clinical characteristics that can predict final visual outcomes in patients with indirect traumatic optic neuropathy (iTON).

METHODS: This study is a retrospective, multicenter case series of adult patients with iTON treated initially at large, urban, and/or academic trauma centers with follow-up at an affiliated ophthalmology clinic. In addition to detailed cranial computed tomography characteristics, demographics, systemic comorbidities, coinjuries, blood products administered, and intracranial pressure, along with other factors, were gathered. LogMAR visual acuity (VA) at the initial presentation to the hospital and up to 12 …

Differential Effects Of Dietary Macronutrients On The Development Of Oncogenic Kras-Mediated Pancreatic Ductal Adenocarcinoma, Liang Zhu, Juntao Ji, Jianjia Ma, Dan Wang, Muyun Liu, James Xianxing Du, Rong Chen, Wei Hou, James L Abbruzzese, Craig D Logsdon, Vincent W Yang, Yongde Luo, Weiqin Lu

Faculty, Staff and Student Publications

KRAS mutations are prevalent in patients with pancreatic ductal adenocarcinoma (PDAC) and are critical to fostering tumor growth in part by aberrantly rewiring glucose, amino acid, and lipid metabolism. Obesity is a modifiable risk factor for pancreatic cancer. Corroborating this epidemiological observation, mice harboring mutant KRAS are highly vulnerable to obesogenic high-fat diet (HFD) challenges leading to the development of PDAC with high penetrance. However, the contributions of other macronutrient diets, such as diets rich in carbohydrates that are regarded as a more direct source to fuel glycolysis for cancer cell survival and proliferation than HFD, to pancreatic tumorigenesis remain …

Cardiovascular Outcomes In Aortopathy: Gentac Registry Of Genetically Triggered Aortic Aneurysms And Related Conditions, Kathryn W Holmes, Sheila Markwardt, Kim A Eagle, Richard B Devereux, Jonathan W Weinsaft, Federico M Asch, Scott A Lemaire, Cheryl L Maslen, Howard K Song, Dianna M Milewicz, Siddharth K Prakash, Dongchuan Guo, Shaine A Morris, Reed E Pyeritz, Rita C Milewski, William J Ravekes, H C Dietz, Ralph V Shohet, Michael Silberbach, Mary J Roman

Faculty, Staff and Student Publications

BACKGROUND: The GenTAC (Genetically Triggered Thoracic Aortic Aneurysm and Cardiovascular Conditions) Registry enrolled patients with genetic aortopathies between 2007 and 2016.

OBJECTIVES: The purpose of this study was to compare age distribution and probability of elective surgery for proximal aortic aneurysm, any dissection surgery, and cardiovascular mortality among aortopathy etiologies.

METHODS: The GenTAC study had a retrospective/prospective design. Participants with bicuspid aortic valve (BAV) with aneurysm (n = 879), Marfan syndrome (MFS) (n = 861), nonsyndromic heritable thoracic aortic disease (nsHTAD) (n = 378), Turner syndrome (TS) (n = 298), vascular Ehlers-Danlos syndrome (vEDS) (n = 149), and Loeys-Dietz syndrome …

Detoxification Role Of Metabolic Glutathione S-Transferase (Gst) Genes In Blood Lead Concentrations Of Jamaican Children With And Without Autism Spectrum Disorder, Mohammad H Rahbar, Maureen Samms-Vaughan, Sori Kim, Sepideh Saroukhani, Jan Bressler, Manouchehr Hessabi, Megan L Grove, Sydonnie Shakspeare-Pellington, Katherine A Loveland

Faculty, Staff and Student Publications

Glutathione S-transferases (GST) are involved in the detoxification of exogenous chemicals including lead (Pb). Using data from 344 pairs of autism spectrum disorder (ASD) cases and age- and sex-matched typically developing (TD) controls (2−8 years old) from Jamaica, we investigated the interaction between three GST genes and ASD status as determinants of blood Pb concentrations (BPbCs). We found that ASD cases had lower geometric mean BPbCs than TD children (1.74 vs. 2.27 µg/dL, p < 0.01). Using a co-dominant genetic model, ASD cases with the Ile/Val genotype for the GSTP1 Ile105Val polymorphism had lower GM BPbCs than TD controls, after adjusting for a known interaction between GSTP1 and GSTT1, child’s parish, socioeconomic status, consumption of lettuce, fried plantains, and canned fish (Ile/Val: 1.78 vs. 2.13 µg/dL, p = 0.03). Similarly, among carriers of the I/I or I/D (I*) genotype for GSTT1 and GSTM1, ASD cases had lower adjusted GM BPbCs than TD controls (GSTT1 I*: 1.61 vs. 1.91 µg/dL, p = 0.01; GSTM1 I*: 1.71 vs. 2.04 µg/dL, p = 0.01). Our findings suggest that genetic polymorphisms in GST genes may influence detoxification of Pb by the enzymes they encode in Jamaican children with and without ASD.

Tumor Immunology And Immunotherapy Of Non-Small-Cell Lung Cancer, Tina Cascone, Jared Fradette, Monika Pradhan, Don L Gibbons

Faculty, Staff and Student Publications

Historically, non-small-cell lung cancer (NSCLC) has been regarded as a nonimmunogenic tumor; however, recent studies have shown that NSCLCs are among the most responsive cancers to monoclonal antibody immune checkpoint inhibitors (ICIs). ICIs have dramatically improved clinical outcomes for a subset of patients (∼20%) with locally advanced and metastatic NSCLC, and they have also demonstrated promise as neoadjuvant therapy for early-stage resectable disease. Nevertheless, the majority of patients with NSCLC are refractory to ICIs for reasons that are poorly understood. Thus, major questions are: how do we initially identify the patients most likely to derive significant clinical benefit from these …

Food Insecurity And Health-Related Concerns Among Elementary Schoolteachers During The Covid-19 Pandemic, Fangyu Li, Nivedhitha Parthasarathy, Feng Zhang, Ru-Jye Chuang, Mallika Mathur, Mike Pomeroy, Jacqueline Noyola, Christine M Markham, Shreela V Sharma

Faculty, Staff and Student Publications

INTRODUCTION: US school systems underwent major upheaval, including closures, implementation of virtual and/or hybrid learning, and stringent infection mitigation protocols, during the initial phase of the COVID-19 pandemic. We aimed to examine the association between food insecurity and perceived health, perceived stress, and social determinants of health concerns among elementary schoolteachers serving predominantly low-income children during the COVID-19 pandemic.

METHODS: Brighter Bites, a nonprofit organization that weekly distributes fresh fruits and vegetables and nutrition education materials to more than 300 schools serving racial and ethnic minority populations with low income, conducts annual surveys of participating teachers to help determine subsequent …

Resistant Maltodextrin Consumption In A Double-Blind, Randomized, Crossover Clinical Trial Induces Specific Changes In Potentially Beneficial Gut Bacteria, Volker Mai, Alyssa M Burns, Rebecca J Solch, Jennifer C Dennis-Wall, Maria Ukhanova, Bobbi Langkamp-Henken

Faculty, Staff and Student Publications

Background: We have previously reported that the addition of resistant maltodextrin (RMD), a fermentable functional fiber, to the diet increases fecal weight as well as the amount of fecal bifidobacteria. Here, we report on the targeted analysis of changes in potentially beneficial gut bacteria associated with the intervention. Objective: The primary objective of this study was to determine the effect of adding 0, 15 and 25 g RMD to the diets of healthy free-living adults on potentially beneficial gut bacteria. Methods: We expanded on our previously reported microbiota analysis in a double-blind, placebo-controlled feeding study (NCT02733263) by performing additional qPCR …

Association Study Between Mucin 4 (Muc4) Polymorphisms And Idiopathic Recurrent Pregnancy Loss In A Korean Population, Ji-Hyang Kim, Han-Sung Park, Jeong-Yong Lee, Eun-Ju Ko, Young-Ran Kim, Hee-Young Cho, Woo-Sik Lee, Eun-Hee Ahn, Nam-Keun Kim

Faculty, Staff and Student Publications

Recurrent pregnancy loss (RPL) is the loss of two or more consecutive pregnancies before 20 weeks of gestational age. Our study investigated whether mucin 4 (MUC4) polymorphisms are associated with RPL. MUC polymorphisms (rs882605 C>A, rs1104760 A>G, rs2688513 A>G, rs2258447 C>T, and rs2291652 A>G) were genotyped in 374 women with RPL and 239 controls of Korean ethnicity using polymerase chain reaction-restriction fragment length polymorphism analysis and the TaqMan probe SNP genotyping assay. Differences in genotype frequencies between cases of RPL and the controls were compared. MUC4 rs882605 C>A and rs1104760 A>G polymorphisms were …

A Nickase Cas9 Gene-Drive System Promotes Super-Mendelian Inheritance In Drosophila, Víctor López Del Amo, Sara Sanz Juste, Valentino M Gantz

Faculty, Staff and Student Publications

CRISPR-based gene-drives have been proposed for managing insect populations, including disease-transmitting mosquitoes, due to their ability to bias their inheritance toward super-Mendelian rates (>50%). Current technologies use a Cas9 that introduces DNA double-strand breaks into the opposing wild-type allele to replace it with a copy of the gene-drive allele via DNA homology-directed repair. However, the use of different Cas9 versions is unexplored, and alternative approaches could increase the available toolkit for gene-drive designs. Here, we report a gene-drive that relies on Cas9 nickases that generate staggered paired nicks in DNA to propagate the engineered gene-drive cassette. We show that …

Impact Of Estrogen Receptor Expression On Prognosis Of Ovarian Cancer According To Antibody Clone Used For Immunohistochemistry: A Meta-Analysis, Chun Wai Ng, Kwong-Kwok Wong

Faculty, Staff and Student Publications

Background: The prognostic value of the expression of estrogen receptor (ER) subtypes ER⍺ and ERβ in ovarian cancer has previously been evaluated by meta-analyses. However, the results are contradictory and controversial.

Methods: We conducted an updated meta-analysis with stringent inclusion criteria to ensure homogeneous studies to determine the effect of ER subtypes on ovarian cancer prognosis. Articles were retrieved by systematic search of PubMed and Web of Science for articles dated up to June 2021. Only studies with known hazard ratio (HR) and antibody clone for immunochemistry (IHC) were included. Pooled HRs with the corresponding 95% confidence intervals (CIs) were …

Electrographic Seizures In Neonates With A High Risk Of Encephalopathy, Wan-Hsuan Chen, Oi-Wa Chan, Jainn-Jim Lin, Ming-Chou Chiang, Shao-Hsuan Hsia, Huei-Shyong Wang, En-Pei Lee, Yi-Shan Wang, Cheng-Yen Kuo, Kuang-Lin Lin, On The Behalf Of The Icns Group

Faculty, Staff and Student Publications

Background: Neonatal encephalopathy is caused by a wide variety of acute brain insults in newborns and presents with a spectrum of neurologic dysfunction, such as consciousness disturbance, seizures, and coma. The increased excitability in the neonatal brain appears to be highly susceptible to seizures after a variety of insults, and seizures may be the first clinical sign of a serious neurologic disorder. Subtle seizures are common in the neonatal period, and abnormal clinical paroxysmal events may raise the suspicion of neonatal seizures. Continuous video electroencephalographic (EEG) monitoring is the gold standard for the diagnosis of neonatal seizures. The aim of …