Medicine and Health Sciences Commons^™

Mir-142: A Master Regulator In Hematological Malignancies And Therapeutic Opportunities, Wilson Huang, Doru Paul, George A Calin, Recep Bayraktar

Student and Faculty Publications

MicroRNAs (miRNAs) are a type of non-coding RNA whose dysregulation is frequently associated with the onset and progression of human cancers. miR-142, an ultra-conserved miRNA with both active -3p and -5p mature strands and wide-ranging physiological targets, has been the subject of countless studies over the years. Due to its preferential expression in hematopoietic cells, miR-142 has been found to be associated with numerous types of lymphomas and leukemias. This review elucidates the multifaceted role of miR-142 in human physiology, its influence on hematopoiesis and hematopoietic cells, and its intriguing involvement in exosome-mediated miR-142 transport. Moreover, we offer a comprehensive …

Altered Outer Retinal Structure, Electrophysiology And Visual Perception In Parkinson's Disease., Katie K N Tran, Pei Ying Lee, David I Finkelstein, Allison M Mckendrick, Bao N Nguyen, Bang V Bui, Christine T O Nguyen

Student and Faculty Publications

BACKGROUND: Visual biomarkers of Parkinson's disease (PD) are attractive as the retina is an outpouching of the brain. Although inner retinal neurodegeneration in PD is well-established this has overlap with other neurodegenerative diseases and thus outer retinal (photoreceptor) measures warrant further investigation.

OBJECTIVE: To examine in a cross-sectional study whether clinically implementable measures targeting outer retinal function and structure can differentiate PD from healthy ageing and whether these are sensitive to intraday levodopa (L-DOPA) dosing.

METHODS: Centre-surround perceptual contrast suppression, macular visual field sensitivity, colour discrimination, light-adapted electroretinography and optical coherence tomography (OCT) were tested in PD participants (n = …

Glp1 Receptor Agonists-Effects Beyond Obesity And Diabetes, Sydney S Wilbon, Mikhail G Kolonin

Student and Faculty Publications

Glucagon-like peptide-1 receptor agonists (GLP1RA) have been transformative for patients and clinicians in treating type-2 diabetes and obesity. Drugs of this class, the bioavailability of which is continuously improving, enable weight loss and control blood glucose with minimal unwanted side effects. Since adopting GLP1RA for treating metabolic diseases, animal and clinical studies have revealed their beneficial effects on several other pathologies, including cardiovascular diseases, neurodegeneration, kidney disease, and cancer. A notable commonality between these diseases is their association with older age. Clinical trials and preclinical data suggest that GLP1RA may improve outcomes in these aging-related diseases. Some of the benefits …

Simvastatin In Critically Ill Patients With Covid-19, Thomas E Hills, Elizabeth Lorenzi, Lindsay R Berry, Murali Shyamsundar, Farah Al-Beidh, Djillali Annane, Yaseen Arabi, Diptesh Aryal, Carly Au, Abigail Beane, Zahra Bhimani, Marc Bonten, Charlotte A Bradbury, Frank M Brunkhorst, Aidan Burrell, Meredith Buxton, Carolyn S Calfee, Maurizio Cecconi, Allen C Cheng, Matthew E Cove, Michelle A Detry, Lise J Estcourt, Mark Fitzgerald, Ewan C Goligher, Herman Goossens, Cameron Green, Rashan Haniffa, David A Harrison, Madiha Hashmi, Alisa M Higgins, Christopher Horvat, David T Huang, Nao Ichihara, Deva Jayakumar, Peter S Kruger, François Lamontagne, Lamprini Lampro, Patrick R Lawler, John C Marshall, Alexina J Mason, Anna Mcglothlin, Shay Mcguinness, Zoe K Mcquilten, Bryan J Mcverry, Paul R Mouncey, Srinivas Murthy, Matthew D Neal, Alistair D Nichol, Cecilia M O'Kane, Rachael L Parke, Jane C Parker, Ebenezer Rabindrarajan, Luis F Reyes, Kathryn M Rowan, Hiroki Saito, Marlene Santos, Christina T Saunders, Christopher W Seymour, Manu Shankar-Hari, Pratik Sinha, B Taylor Thompson, Alexis F Turgeon, Anne M Turner, Frank Van De Veerdonk, Sebastian Weis, Ian S Young, Ryan Zarychanski, Roger J Lewis, Colin J Mcarthur, Derek C Angus, Scott M Berry, Lennie P G Derde, Steve A Webb, Anthony C Gordon, Daniel F Mcauley

Student and Faculty Publications

BACKGROUND: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.

METHODS: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical …

Colonization Of Larval Zebrafish (Danio Rerio) With Adherent-Invasive Escherichia Coli Prevents Recovery Of The Intestinal Mucosa From Drug-Induced Enterocolitis, Erika Flores, Soumita Dutta, Rachel Bosserman, Ambro Van Hoof, Anne-Marie Krachler

Student and Faculty Publications

Although inflammatory bowel diseases are on the rise, what factors influence IBD risk and severity, and the underlying mechanisms remain to be fully understood. Although host genetics, microbiome, and environmental factors have all been shown to correlate with the development of IBD, cause and effect are difficult to disentangle in this context. For example, AIEC is a known pathobiont found in IBD patients, but it remains unclear if gut inflammation during IBD facilitates colonization with AIEC, or if AIEC colonization makes the host more susceptible to pro-inflammatory stimuli. It is critical to understand the mechanisms that contribute to AIEC infections …

Bacterial Outer Membrane Vesicles Provide An Alternative Pathway For Trafficking Of Escherichia Coli O157 Type Iii Secreted Effectors To Epithelial Cells, Natalie Sirisaengtaksin, Eloise J O'Donoghue, Sara Jabbari, Andrew J Roe, Anne Marie Krachler

Student and Faculty Publications

Outer membrane vesicles (OMVs) are proteoliposomes shed by Gram-negative bacteria. Their secretion is enhanced by the transition into the intra-host milieu, and OMVs play critical roles during pathogenesis. Enterohemorrhagic Escherichia coli O157 (EHEC) can cause diarrheal disease in humans, and soluble toxins including Shiga-like toxins that contribute to disease severity and clinical complications like hemolytic uremic syndrome have been shown to be OMV associated. In addition to Shiga-like toxins, EHEC produces a type III secretion system (T3SS), and T3SS effectors are associated with colonization and disease severity in vivo. Here, we show that type III secreted substrates including translocators …

Targeted Therapeutic Strategies For Melanoma, Shiwei Zhang, Ruxin Xie, Ai Zhong, Junjie Chen

Student and Faculty Publications

Melanoma accounts for a small proportion of skin cancers diagnosed each year, but it has a high degree of malignancy and rapid progression, resulting in a short survival period for patients. The incidence of melanoma continues to rise, and now melanoma accounts for 1.7% of cancer diagnoses worldwide and is the fifth most common cancer in the United States. With the development of high-throughput sequencing technologies, the understanding of the pathophysiology of melanoma had also been improved. The most common activating mutations in melanoma cells are BRAF , NRAS , and KIT mutations, which disrupt cell signaling pathways related to …

Prmt Blockade Induces Defective Dna Replication Stress Response And Synergizes With Parp Inhibition, Yang Li, Lacey E Dobrolecki, Christina Sallas, Xudong Zhang, Travis D Kerr, Deepa Bisht, Yalong Wang, Sharad Awasthi, Babita Kaundal, Siqi Wu, Weiyi Peng, Marc L Mendillo, Yiling Lu, Collene R Jeter, Guang Peng, Jinsong Liu, Shannon N Westin, Anil K Sood, Michael T Lewis, Jishnu Das, S Stephen Yi, Mark T Bedford, Daniel J Mcgrail, Nidhi Sahni

Student and Faculty Publications

Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous …

Interlaboratory Comparison Of Pseudomonas Aeruginosa Phage Susceptibility Testing, Krupa Parmar, Lauren Komarow, Damon W Ellison, Andrey A Filippov, Mikeljon P Nikolich, Joseph R Fackler, Martin Lee, Anjna Nair, Priyesh Agrawal, Pranita D Tamma, Maria Souli, Scott R Evans, Kerryl E Greenwood-Quaintance, Scott A Cunningham, Robin Patel, Antibacterial Resistance Leadership Group

Student and Faculty Publications

Standardized approaches to phage susceptibility testing (PST) are essential to inform selection of phages for study in patients with bacterial infections. There is no reference standard for assessing bacterial susceptibility to phage. We compared agreement between PST performed at three centers: two centers using a liquid assay standardized between the sites with the third, a plaque assay. Four Pseudomonas aeruginosa phages: PaWRA01ø11 (EPa11), PaWRA01ø39 (EPa39), PaWRA02ø83 (EPa83), PaWRA02ø87 (EPa87), and a cocktail of all four phages were tested against 145 P. aeruginosa isolates. Comparisons were made within measurements at the two sites performing the liquid assay and between these …

Genetic And Epigenetic Features Of Bilateral Wilms Tumor Predisposition In Patients From The Children’S Oncology Group Aren18b5-Q, Andrew J Murphy, Changde Cheng, Justin Williams, Timothy I Shaw, Emilia M Pinto, Karissa Dieseldorff-Jones, Jack Brzezinski, Lindsay A Renfro, Brett Tornwall, Vicki Huff, Andrew L Hong, Elizabeth A Mullen, Brian Crompton, Jeffrey S Dome, Conrad V Fernandez, James I Geller, Peter F Ehrlich, Heather Mulder, Ninad Oak, Jamie Maciezsek, Carolyn M Jablonowski, Andrew M Fleming, Prahalathan Pichavaram, Christopher L Morton, John Easton, Kim E Nichols, Michael R Clay, Teresa Santiago, Jinghui Zhang, Jun Yang, Gerard P Zambetti, Zhaoming Wang, Andrew M Davidoff, Xiang Chen

Student and Faculty Publications

Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of …

Bayesian Longitudinal Tensor Response Regression For Modeling Neuroplasticity, Suprateek Kundu, Alec Reinhardt, Serena Song, Joo Han, M Lawson Meadows, Bruce Crosson, Venkatagiri Krishnamurthy

Student and Faculty Publications

A major interest in longitudinal neuroimaging studies involves investigating voxel-level neuroplasticity due to treatment and other factors across visits. However, traditional voxel-wise methods are beset with several pitfalls, which can compromise the accuracy of these approaches. We propose a novel Bayesian tensor response regression approach for longitudinal imaging data, which pools information across spatially distributed voxels to infer significant changes while adjusting for covariates. The proposed method, which is implemented using Markov chain Monte Carlo (MCMC) sampling, utilizes low-rank decomposition to reduce dimensionality and preserve spatial configurations of voxels when estimating coefficients. It also enables feature selection via joint credible …

Variations Of The Trapezius Branch Of The Accessory Nerve: An Anatomic Study, Matthew E Lin, Celeste Kim, Adam Howard, Niels Kokot

Student and Faculty Publications

Although modified radical neck dissections have increased in popularity to reduce morbidity secondary to intraoperative accessory nerve damage, inadvertent injury still often occurs. As this phenomenon is thought to be due to anatomic variation in the trapezius branch of the accessory nerve, it is imperative to better understand the nuances of these anatomic variations to better inform surgical decision-making. A total of 24 accessory nerves were dissected, exposed, and traced in 15 cadavers. Three aspects of the accessory nerve were identified and recorded: the course of the trapezius branch in relation to the sternocleidomastoid, the number of trapezius branches at …

Oncogenic Kras Drives Lipofibrogenesis To Promote Angiogenesis And Colon Cancer Progression, Wen-Hao Hsu, Kyle A Labella, Yiyun Lin, Ping Xu, Rumi Lee, Cheng-En Hsieh, Lei Yang, Ashley Zhou, Jonathan M Blecher, Chang-Jiun Wu, Kangyu Lin, Xiaoying Shang, Shan Jiang, Denise J Spring, Yan Xia, Peiwen Chen, John Paul Shen, Scott Kopetz, Ronald A Depinho

Student and Faculty Publications

Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer, KRAS* suppresses antitumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAF) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) that upregulates the expression of the proadipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce VEGFA to spur angiogenesis. In KRAS*-driven colorectal cancer mouse models, genetic or pharmacologic neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. …

Labour Market Participation After Sickness Absence Due To Cancer: A Dynamic Cohort Study In Catalonia (Spain), Amaya Ayala-Garcia, Fernando G Benavides, Laura Serra

Student and Faculty Publications

BACKGROUND: The consequences of cancer on working until retirement age remain unclear. This study aimed to analyse working life considering all possible labour market states in a sample of workers after sickness absence (SA) due to cancer and to compare their working life paths to those of a sample of workers without SA and with an SA due to other diseases.

METHODS: This was a retrospective dynamic cohort study among social security affiliates in Catalonia from 2012-2018. Cases consisted of workers with an SA due to cancer between 2012-2015 (N = 516) and were individually age- and sex-matched with those …

Metformin: A Potential Treatment For Acne, Hidradenitis Suppurativa And Rosacea, Minah Cho, Yu Ri Woo, Sang Hyun Cho, Jeong Deuk Lee, Hei Sung Kim

Student and Faculty Publications

Metformin is a widely used drug for treatment of diabetes mellitus, due to its safety and efficacy. In addition to its role as an antidiabetic drug, numerous beneficial effects of metformin have enabled its use in various diseases. Considering the anti-androgenic, anti-angiogenic, anti-fibrotic and antioxidant properties of metformin, it may have the potential to improve chronic inflammatory skin diseases. However, further evidence is needed to confirm the efficacy of metformin in dermatological conditions, This review focuses on exploring the therapeutic targets of metformin in acne vulgaris, hidradenitis suppurativa and rosacea, by studying their pathogeneses.

Phenotyping Emt And Met Cellular States In Lung Cancer Patient Liquid Biopsies At A Personalized Level Using Mass Cytometry, Loukia G Karacosta, Danny Pancirer, Jordan S Preiss, Jalen A Benson, Winston Trope, Joseph B Shrager, Arthur Wai Sung, Joel W Neal, Sean C Bendall, Heather Wakelee, Sylvia K Plevritis

Student and Faculty Publications

Malignant pleural effusions (MPEs) can be utilized as liquid biopsy for phenotyping malignant cells and for precision immunotherapy, yet MPEs are inadequately studied at the single-cell proteomic level. Here we leverage mass cytometry to interrogate immune and epithelial cellular profiles of primary tumors and pleural effusions (PEs) from early and late-stage non-small cell lung cancer (NSCLC) patients, with the goal of assessing epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) states in patient specimens. By using the EMT-MET reference map PHENOSTAMP, we observe a variety of EMT states in cytokeratin positive (CK+) cells, and report for the first time MET-enriched CK+ …

Novel Sox10 Indel Mutations Drive Schwannomas Through Impaired Transactivation Of Myelination Gene Programs, Erik A Williams, Ajay Ravindranathan, Rohit Gupta, Nicholas O Stevers, Abigail K Suwala, Chibo Hong, Somang Kim, Jimmy Bo Yuan, Jasper Wu, Jairo Barreto, Calixto-Hope G Lucas, Emily Chan, Melike Pekmezci, Philip E Leboit, Thaddeus Mully, Arie Perry, Andrew Bollen, Jessica Van Ziffle, W Patrick Devine, Alyssa T Reddy, Nalin Gupta, Kristen M Basnet, Robert J B Macaulay, Patrick Malafronte, Han Lee, William H Yong, Kevin Jon Williams, Tareq A Juratli, Douglas A Mata, Richard S P Huang, Matthew C Hiemenz, Dean C Pavlick, Garrett M Frampton, Tyler Janovitz, Jeffrey S Ross, Susan M Chang, Mitchel S Berger, Line Jacques, Jun S Song, Joseph F Costello, David A Solomon

Student and Faculty Publications

BACKGROUND: Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.

METHODS: We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a …

Rab1a Haploinsufficiency Phenocopies The 2p14-P15 Microdeletion And Is Associated With Impaired Neuronal Differentiation, Jonathan J Rios, Yang Li, Nandina Paria, Ryan J Bohlender, Chad Huff, Jill A Rosenfeld, Pengfei Liu, Weimin Bi, Kentaro Haga, Mitsunori Fukuda, Shayal Vashisth, Kiran Kaur, Maria H Chahrour, Michael B Bober, Angela L Duker, Farah A Ladha, Neil A Hanchard, Kristhen Atala, Anas M Khanshour, Linsley Smith, Carol A Wise, Mauricio R Delgado

Student and Faculty Publications

Hereditary spastic parapareses (HSPs) are clinically heterogeneous motor neuron diseases with variable age of onset and severity. Although variants in dozens of genes are implicated in HSPs, much of the genetic basis for pediatric-onset HSP remains unexplained. Here, we re-analyzed clinical exome-sequencing data from siblings with HSP of unknown genetic etiology and identified an inherited nonsense mutation (c.523C>T [p.Arg175Ter]) in the highly conserved RAB1A. The mutation is predicted to produce a truncated protein with an intact RAB GTPase domain but without two C-terminal cysteine residues required for proper subcellular protein localization. Additional RAB1A mutations, including two frameshift mutations and …

Archery: A Prospective Observational Study Of Artificial Intelligence-Based Radiotherapy Treatment Planning For Cervical, Head And Neck And Prostate Cancer – Study Protocol, Ajay Aggarwal, Laurence Edward Court, Peter Hoskin, Isabella Jacques, Mariana Kroiss, Sarbani Laskar, Yolande Lievens, Indranil Mallick, Rozita Abdul Malik, Elizabeth Miles, Issa Mohamad, Claire Murphy, Matthew Nankivell, Jeannette Parkes, Mahesh Parmar, Carol Roach, Hannah Simonds, Julie Torode, Barbara Vanderstraeten, Ruth Langley

Student and Faculty Publications

INTRODUCTION: Fifty per cent of patients with cancer require radiotherapy during their disease course, however, only 10%-40% of patients in low-income and middle-income countries (LMICs) have access to it. A shortfall in specialised workforce has been identified as the most significant barrier to expanding radiotherapy capacity. Artificial intelligence (AI)-based software has been developed to automate both the delineation of anatomical target structures and the definition of the position, size and shape of the radiation beams. Proposed advantages include improved treatment accuracy, as well as a reduction in the time (from weeks to minutes) and human resources needed to deliver radiotherapy. …

Mitochondrial Dna Variants At Low-Level Heteroplasmy And Decreased Copy Numbers In Chronic Kidney Disease (Ckd) Tissues With Kidney Cancer, Yuki Kanazashi, Kazuhiro Maejima, Todd A Johnson, Shota Sasagawa, Ryosuke Jikuya, Hisashi Hasumi, Naomichi Matsumoto, Shigekatsu Maekawa, Wataru Obara, Hidewaki Nakagawa

Student and Faculty Publications

The human mitochondrial genome (mtDNA) is a circular DNA molecule with a length of 16.6 kb, which contains a total of 37 genes. Somatic mtDNA mutations accumulate with age and environmental exposure, and some types of mtDNA variants may play a role in carcinogenesis. Recent studies observed mtDNA variants not only in kidney tumors but also in adjacent kidney tissues, and mtDNA dysfunction results in kidney injury, including chronic kidney disease (CKD). To investigate whether a relationship exists between heteroplasmic mtDNA variants and kidney function, we performed ultra-deep sequencing (30,000×) based on long-range PCR of DNA from 77 non-tumor kidney …

Chromosome 10q24.32 Variants Associate With Brain Arterial Diameters In Diverse Populations: A Genome-Wide Association Study, Minghua Liu, Farid Khasiyev, Sanjeev Sariya, Antonio Spagnolo-Allende, Danurys L Sanchez, Howard Andrews, Qiong Yang, Alexa Beiser, Ye Qiao, Emy A Thomas, Jose Rafael Romero, Tatjana Rundek, Adam M Brickman, Jennifer J Manly, Mitchell Sv Elkind, Sudha Seshadri, Christopher Chen, Saima Hilal, Bruce A Wasserman, Giuseppe Tosto, Myriam Fornage, Jose Gutierrez

Student and Faculty Publications

Background: Brain arterial diameters (BADs) are novel imaging biomarkers of cerebrovascular disease, cognitive decline, and dementia. Traditional vascular risk factors have been associated with BADs, but whether there may be genetic determinants of BADs is unknown.

Methods and results: The authors studied 4150 participants from 6 geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). Brain arterial diameters for 13 segments were measured and averaged to obtain a global measure of BADs as well as the posterior and anterior circulations. A genome-wide association study revealed 14 variants at one locus associated with global BAD at genome-wide …

An Efficacy And Safety Evaluation Of Montelukast + Fluticasone Propionate Vs. Fluticasone Propionate In The Treatment Of Cough Variant Asthma In Children: A Meta-Analysis, Zhengbo Wei, Sheng Li

Student and Faculty Publications

PURPOSE: This study aimed to evaluate the efficacy and safety of montelukast (Mon) + fluticasone propionate (Flu) versus Flu in the treatment of cough variant asthma (CVA) in children.

METHODS: Eligible documents were selected from various databases. Weighted mean difference (WMD) and 95% confidence interval (CI) were used to evaluate continuous variables, and categorical variables were evaluated using risk ratio (RR) and 95% CI. Heterogeneity analysis was performed using Cochran's Q test and I

RESULTS: Nine studies were included, and Flu + Mon was found to significantly improve the total effective rate and reduce cough recurrence compared to Flu. The …

Improving Radiotherapy In Immunosuppressive Microenvironments By Targeting Complement Receptor C5ar1, Callum Beach, David Maclean, Dominika Majorova, Stavros Melemenidis, Dhanya K Nambiar, Ryan K Kim, Gabriel N Valbuena, Silvia Guglietta, Carsten Krieg, Mahnaz Darvish-Damavandi, Tatsuya Suwa, Alistair Easton, Lily Vs Hillson, Ashley K Mcculloch, Ross K Mcmahon, Kathryn Pennel, Joanne Edwards, Sean M O'Cathail, Campbell S Roxburgh, Enric Domingo, Eui Jung Moon, Dadi Jiang, Yanyan Jiang, Qingyang Zhang, Albert C Koong, Trent M Woodruff, Edward E Graves, Tim Maughan, Simon Ja Buczacki, Manuel Stucki, Quynh-Thu Le, Simon J Leedham, Amato J Giaccia, Monica M Olcina

Student and Faculty Publications

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased …

Influenza Viral Infection Is A Risk Factor For Severe Illness In Covid-19 Patients: A Nationwide Population-Based Cohort Study, Jeong-Hwan Hwang, Yeon Seok You, Sang Woo Yeom, Min Gyu Lee, Jong-Hwan Lee, Min Gul Kim, Jong Seung Kim

Student and Faculty Publications

In order to prepare for the twindemic of influenza and SARS-CoV-2 infection, we investigated the association between influenza infection and subsequent severity of SARS-CoV-2 infection. A population-based nationwide cohort study was performed using data from the National Health Insurance Service (NHIS) in the Republic of Korea. This study included 274,126 individuals who underwent SARS-CoV-2 PCR testing between 20 January 2020 and 1 October 2020. Among these patients, 28,338 tested positive for SARS-CoV-2, and 4,003 of these individuals had a history of influenza. The control group was selected through 1:1 propensity score matching. In the group of 4,003 COVID-19-positive individuals with …

The Androgen Receptor Does Not Directly Regulate The Transcription Of Dna Damage Response Genes, Sylwia Hasterok, Thomas G Scott, Devin G Roller, Adam Spencer, Arun B Dutta, Kizhakke M Sathyan, Daniel E Frigo, Michael J Guertin, Daniel Gioeli

Student and Faculty Publications

UNLABELLED: The clinical success of combined androgen deprivation therapy (ADT) and radiotherapy (RT) in prostate cancer created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at a steady state and in response to ionizing radiation (IR). In this study, we sought to determine which immediate transcriptional changes are induced by IR in an AR-dependent manner. Using PRO-seq to quantify …

Pathomic Features Reveal Immune And Molecular Evolution From Lung Preneoplasia To Invasive Adenocarcinoma, Pingjun Chen, Frank R Rojas, Xin Hu, Alejandra Serrano, Bo Zhu, Hong Chen, Lingzhi Hong, Rukhmini Bandyoyadhyay, Muhammad Aminu, Neda Kalhor, J Jack Lee, Siba El Hussein, Joseph D Khoury, Harvey I Pass, Andre L Moreira, Vamsidhar Velcheti, Daniel H Sterman, Junya Fukuoka, Kazuhiro Tabata, Dan Su, Lisha Ying, Don L Gibbons, John V Heymach, Ignacio I Wistuba, Junya Fujimoto, Luisa M Solis Soto, Jianjun Zhang, Jia Wu

Student and Faculty Publications

Recent statistics on lung cancer, including the steady decline of advanced diseases and the dramatically increasing detection of early-stage diseases and indeterminate pulmonary nodules, mark the significance of a comprehensive understanding of early lung carcinogenesis. Lung adenocarcinoma (ADC) is the most common histologic subtype of lung cancer, and atypical adenomatous hyperplasia is the only recognized preneoplasia to ADC, which may progress to adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) and eventually to invasive ADC. Although molecular evolution during early lung carcinogenesis has been explored in recent years, the progress has been significantly hindered, largely due to insufficient materials …

Crispr-Cas9-Based Functional Interrogation Of Unconventional Translatome Reveals Human Cancer Dependency On Cryptic Non-Canonical Open Reading Frames, Caishang Zheng, Yanjun Wei, Peng Zhang, Kangyu Lin, Dandan He, Hongqi Teng, Ganiraju Manyam, Zhao Zhang, Wen Liu, Hye Rin Lindsay Lee, Ximing Tang, Wei He, Nelufa Islam, Antrix Jain, Yulun Chiu, Shaolong Cao, Yarui Diao, Sherita Meyer-Gauen, Magnus Höök, Anna Malovannaya, Wenbo Li, Ming Hu, Wenyi Wang, Han Xu, Scott Kopetz, Yiwen Chen

Student and Faculty Publications

Emerging evidence suggests that cryptic translation beyond the annotated translatome produces proteins with developmental or physiological functions. However, functions of cryptic non-canonical open reading frames (ORFs) in cancer remain largely unknown. To fill this gap and systematically identify colorectal cancer (CRC) dependency on non-canonical ORFs, we apply an integrative multiomic strategy, combining ribosome profiling and a CRISPR-Cas9 knockout screen with large-scale analysis of molecular and clinical data. Many such ORFs are upregulated in CRC compared to normal tissues and are associated with clinically relevant molecular subtypes. We confirm the in vivo tumor-promoting function of the microprotein SMIMP, encoded by a …

In Severe Alcohol-Related Hepatitis, Acute Kidney Injury Is Prevalent, Associated With Mortality Independent Of Liver Disease Severity, And Can Be Predicted Using Il-8 And Micro-Rnas, Luke D Tyson, Stephen Atkinson, Robert W Hunter, Michael Allison, Andrew Austin, James W Dear, Ewan Forrest, Tong Liu, Emma Lord, Steven Masson, Joao Nunes, Paul Richardson, Stephen D Ryder, Mark Wright, Mark Thursz, Nikhil Vergis

Student and Faculty Publications

BACKGROUND: The prevalence, prediction and impact of acute kidney injury (AKI) in alcohol-related hepatitis (AH) is uncertain.

AIMS: We aimed to determine AKI incidence; association with mortality; evaluate serum biomarkers and the modifying effects of prednisolone and pentoxifylline in the largest AH cohort to date.

METHODS: Participants in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial with day zero (D0) creatinine available were included. AKI was defined by modified International Club of Ascites criteria; incident AKI as day 7 (D7) AKI without D0-AKI. Survival was compared by Kaplan-Meier; mortality associations by Cox regression; associations with AKI by binary logistic regression; …

An Ace2 Decamer Viral Trap As A Durable Intervention Solution For Current And Future Sars-Cov, Hailong Guo, Bomsoo Cho, Paul R Hinton, Sijia He, Yongjun Yu, Ashwin Kumar Ramesh, Jwala Priyadarsini Sivaccumar, Zhiqiang Ku, Kristen Campo, Sarah Holland, Sameer Sachdeva, Christopher Mensch, Mohamed Dawod, Annalis Whitaker, Philip Eisenhauer, Allison Falcone, Rebekah Honce, Jason W Botten, Stephen F Carroll, Bruce A Keyt, Andrew W Womack, William R Strohl, Kai Xu, Ningyan Zhang, Zhiqiang An, Sha Ha, John W Shiver, Tong-Ming Fu

Student and Faculty Publications

The capacity of SARS-CoV-2 to evolve poses challenges to conventional prevention and treatment options such as vaccination and monoclonal antibodies, as they rely on viral receptor binding domain (RBD) sequences from previous strains. Additionally, animal CoVs, especially those of the SARS family, are now appreciated as a constant pandemic threat. We present here a new antiviral approach featuring inhalation delivery of a recombinant viral trap composed of ten copies of angiotensin-converting enzyme 2 (ACE2) fused to the IgM Fc. This ACE2 decamer viral trap is designed to inhibit SARS-CoV-2 entry function, regardless of viral RBD sequence variations as shown by …

Enhanced Tp53 Reactivation Disrupts Myc Transcriptional Program And Overcomes Venetoclax Resistance In Acute Myeloid Leukemias, Yuki Nishida, Jo Ishizawa, Edward Ayoub, Rafael Heinz Montoya, Lauren B Ostermann, Muharrem Muftuoglu, Vivian R Ruvolo, Tallie Patsilevas, Darah A Scruggs, Shayaun Khazaei, Po Yee Mak, Wenjing Tao, Bing Z Carter, Steffen Boettcher, Benjamin L Ebert, Naval G Daver, Marina Konopleva, Takahiko Seki, Kensuke Kojima, Michael Andreeff

Student and Faculty Publications

The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a …