Digital Commons Network^™

An Integrative Genomics Approach For The Discovery Of Potential Clinically Actionable Diagnostic And Prognostic Biomarkers In Colorectal Cancer, Mark Fertel, Duaa Mohammad Alawad, Chindo Hicks

School of Graduate Studies Faculty Publications

Background: Despite remarkable progress in clinical management of patients and intensified screening, colorectal cancer remains the second most common cause of cancer-related death in the United States. The recent surge of next generation sequencing has enabled genomic analysis of colorectal cancer genomes. However, to date, there is little information about leveraging gene expression data and integrating it with somatic mutation information to discover potential biomarkers and therapeutic targets. Here, we integrated gene expression data with somatic mutation information to discover potential diagnostic and prognostic biomarkers and molecular drivers of colorectal cancer. Methods: We used publicly available gene expression and somatic …

Low Premorbid Iq May Exacerbate The Cognitive Effects Of Apolipoprotein Ε4 (Apoe Ε4): A Multi-Ethnic Cross-Sectional Study From Habs-Hd, Lubnaa B. Abdullah, Zhengyang Zhou, Ney Alex Alliey, Robert Barber, James Hall, Sid O’Bryant

Psychological Science Faculty Publications

Introduction: Apolipoprotein allele 4 (APOE ε4) is associated with lower IQ scores during childhood and adolescence, but the influence of APOE ε4 and low IQ on late-life cognition is unknown. This study examines the association between APOE ε4 and cognitive outcomes based on premorbid intellectual ability (pIQ) and ethnic background.

Methods: Participants were drawn from the Health & Aging Brain Study–Health Disparities (HABS-HD), categorized by low (z ≤ −2.00) or average (z = 0.00 ± 1.00) pIQ based on word reading scores. Statistical analyses were conducted to evaluate whether APOE ε4 was associated with the cognitive domains of …

Convergent Reduction Of Olfactory Genes And Olfactory Bulb Size In Mammalian Species At Altitude, Allie M Graham, Elysia Saputra, Bogdan Kirilenko, Jason S Presnell, Arianna Harrington, Chad Huff, Michael Hiller, Nathan Clark

Faculty, Staff and Student Publications

The invasion of specialized ecological niches can cause drastic changes to selection regimes, resulting in genomic and phenotypic transformation.

Risk Of Pancreatic Cancer In Glycemically Defined New-Onset Diabetes: A Prospective Cohort Study, Suresh T Chari, Bechien Wu, Camden Lopez, Eva Lustigova, Qiaoling Chen, Stephen K Van Den Eeden, Amethyst D Leimpeter, William Fisher, Amy Wood, Ashley S Alexander, John Valenta, Santhi Swaroop Vege, Erin E Carlson, Kari G Rabe, Phil A Hart, Lu Qian, Ying-Qi Zhao, Nadia Yosuf, Lynn Matrisian, Barbara Kenner, Jo Ann Rinaudo, Anirban Maitra, Ziding Feng

Faculty, Staff and Student Publications

Background & aims: The increased 3-year incidence of pancreatic cancer after new-onset diabetes observed in retrospective studies needs prospective validation. It is unknown whether incidence varies by race and ethnicity.

Methods: In a prospective, observational study using active real-time surveillance of electronic health records, we identified 18,838 adults 50 years or older with glycemically defined new-onset diabetes (GNOD). In this interim analysis, we report 3-year Kaplan-Meier estimates of the proportion diagnosed with pancreatic cancer after GNOD (absolute incidence [95% CI]) and associated standardized incidence ratio (SIR) by race and ethnicity, overall 3-year incidence of pancreatic cancer adjusting for racial distribution …

Sex-Specific Effects Of Early-Life Unpredictability On Hippocampal And Amygdala Responses To Novelty In Adolescents, Elysia Poggi Davis, Bianca T. Leonard, Robert J. Jirsaraie, David B. Keator, Steven L. Small, Curt A. Sandman, Victoria B. Risbrough, Hal S. Stern, Laura M. Glynn, Michael A. Yassa, Tallie Z. Baram, Jerod M. Rasmussen

Psychology Faculty Articles and Research

Background

Unpredictable childhood experiences are an understudied form of early-life adversity that impact neurodevelopment. The neurobiological processes by which exposure to early-life unpredictability impact development and vulnerability to psychopathology remain poorly understood. In the current study, we investigated the sex-specific consequences of early-life unpredictability on the limbic network, focusing on the hippocampus and the amygdala.

Methods

Participants included 150 youths (54% female). Early-life unpredictability was assessed using the Questionnaire of Unpredictability in Childhood (QUIC). Participants engaged in 1 or more task–functional magnetic resonance imaging scans between the ages of 8 and 17 (223 total observations) measuring blood oxygen level–dependent (BOLD) …

Accounting For Competing Risks In The Assessment Of Prognostic Biomarkers' Discriminative Accuracy, Xinran Huang, Xinyang Jiang, Ruosha Li, Jing Ning

Faculty, Staff and Student Publications

The discriminative performance of biomarkers often changes over time and exhibits heterogeneity across subgroups defined by patient characteristics. Assessing how this performance varies with these factors is crucial for a comprehensive evaluation of biomarkers and to identify areas for improvement in sub-populations with poor performance. Additionally, the presence of competing risks complicates the assessment of discriminative performance. Ignoring competing risks can lead to misleading conclusions, as the biomarker's performance for the event of interest, such as disease onset, may be confounded by its performance for competing events, such as death. To address these challenges, we develop a regression model to …

Du Undergraduate Showcase Abstracts: Research, Scholarship, And Creative Works, Kabe Aberle, Nadia Kako, Kateri Mcrae, Brooke Agulnek, Sky Palmon, Yasmine Ramirez, Francisca Aguirre Beltran, Ashley Juarez, Bridget Kim, Tessa Appel, Sterling Kerr, Spencer Ingley, Gabe Meyer, Robin Tinghitella, Dale Broder, Lily Baeza, Chloe Beers, Julia Coakley, Whitney Kelsey, Sydney Gainforth, Gabi Wing, Audrey Martin, Aaliyah Amore Berry, Brooke Watley, Kiruthika Venkatesan, Rachel Bienstock, Annabella Brotherston, Madison Bryant, Mia Burgener, Emma P. Lieb, Rachel A. Johnson, Jennifer L. Hoffman, Kania Campbell, Kiena Campbell, Courtney Cassidy, Sage Krzyzkowski, Maddox Jones, Skylar Abookire, Luke Hawkins, Sunnah Yoon, Andrea Chu, Yan Qin, Nyah Cubbison, Brian Gearity, Daniel Mcintosh, Mariely Cruz, Edward Garrido, Grady Dionne, Nicole Doris, Lyndsie Salvagio, Ann-Charlotte Granholm-Bentley, Anna Dymov, Hannah Eckert, Gabrielle Welsh, Erica Larson, Charlie Ernst, Anna Zhou, Sarah Watamura, Larissa Fedorovich-Klein, Georgie Fields, Kimberly A. Guevara, Aven Mccall, Ben Peltier, Feruz Yahia, Patrick Flores, Jadyn Floyd, Sophia Forcier, J. Von R. Monteza, Peter Sokol-Hessner, Gwendolyn Geiger, Scott Nichols, Camryn Gunter, Kendal Hengst, Charlie Bednarz, Issy Garside, Addison Baker, Rachel Mina, Brooke Hermanson, Amanda Klingler, William Highfill, Sydney Jaques, Kerstin Lewey, Allison Grossery, Daniel Linseman, Ethan Lim, Jagger Livengood, Owen Mantelli, Gabby Pappas, Abby Mcdonald, Madeleine Dierking, Eve Miller, Emma Loeber, Anna Marlow, Michael Kerwin, Ella Mathews, Hillary Hamann, Khadija Mohamed, Vivian Nguyen, Gabri Notov, Ifunayachi Ogbonna-Ukuku, Sunil Kumar, Charles Baysah, Sarah Olson, Don Sullivan, Anna Paradiso, Jay Parrish, Mira Pronobis, Alisha Pravasi, Kerstin Haring, Diego Ramirez, Christopher Reardon, Juliana Ramirez, Casey Doherty, Ella Kestner, Teagan Weindel, Cate Billings, Pablo Torre-Walter, Lucy Rand, Samantha Reynolds, Mark Siemens, Khadeeja Rashid, Laine Satterlee, Piper Heilbronner, Lily Pound, Ben Whitehurst, Anna Respet, Lizzie Lesoing, Sydney Hertel, Aya Saad-Masri, Brooke Ballenger, Max Proske, Hannah Rosenberg, Ellia Nakahara, Sophia Espinoza, Ivan Woolhouse, Simon Ruland, Gorkem Er, Timothy Sweeny, Melaku Saketa, Michela Schenk, Maren Lynch, Madi Hamm, Grace Schroeder, Michelle Rozenman, Rana Seif, Jackson Hall, Marisela Simental, Daniel Paredes, Aaron Mena, Preston Spaan, Evelyn Stovin, David Andrew Swartz, Anh Tran, Daniel Pittman, Luke Farchione, Emily Boyer, Ukari Verner, Lacey Conrad, Jonathan Velotta, James Weiner, Jagger Gossett, Noah Sherry, Sam Proud, Ben Block, Avi Narayana, Zoey Weiss, Alyssa Wilson, Gabrielle Walsh, David Zonana, Keely Wright, Kena Riveria, Lillybelle Deer, Jena Doom, Elysia Davis, Isabelle Yaremenko, Caitlyn Young

DU Undergraduate Research Journal Archive

Abstracts from the DU Undergraduate Research Showcase.

Small Policy Changes Can Accelerate The Adoption Of Improved On-Farm Storage Among Smallholder Farmers, Michael Brander, Zewdu Abro, Menale Kassie, Wolfgang Mittmann, Lukas Stiefel, Matthias Huss

All Peer-Reviewed Publications

Reducing food losses is a significant and often overlooked opportunity to bolster global food security and enhancing the resilience and sustainability of global food systems. Food losses are highest in low-income countries where millions of smallholder farming households remain particularly vulnerable. As yet, smallholders’ adoption of loss-minimizing storage technologies, such as hermetic storage bags, remains low. Here, we study the effects of two types of policy options on the adoption of improved on-farm storage in the case of Ethiopia. Using a randomized controlled trial, we show that a small partial subsidy, which mirrors the current fiscal burden on these technologies, …

Planetary Thinking: Hellbenders As Emissaries Of Appalachia, Tierra R. Curry

Critical Humanities

Hellbenders are prehistoric salamanders that have thrived in cold rivers since before the continents divided. Once found throughout Appalachian watersheds, due to exploitation and habitat degradation only a few dozen healthy populations survive. Monstrous yet fascinating, hellbenders were often reviled historically, but in recent decades they have gained iconic status and are now celebrated as charismatic indicators for clean rivers. Hellbenders are symbols of the wild because of their ancient history, elusive nature, and contribution to ecosystem resilience. The same forces that drove the decline of these amphibian sentinels have sacrificed public health in Appalachia. Their demise echoes the struggle …

Preliminary Investigation Of The Association Between Epigenetic Aging Acceleration And Amyloid Biomarkers In Bipolar Disorder, Gabriel R Fries, Steven De La Garza, Ning O Zhao, Andres W Bass, Camila N C Lima, Nobuhide Kobori, Tatiana Barichello, Gustavo Turecki, Paul E Schulz, Breno S Diniz, Jair C Soares

Faculty, Staff and Student Publications

Objectives: Bipolar disorder (BD) has been associated with an elevated risk of Alzheimer's Disease (AD). We assessed AD biomarkers in BD and tested whether epigenetic aging (EA) acceleration is associated with changes in these markers.

Design, setting, participants: Cross-sectional study of n = 58 living individuals with BD and n = 20 age- and sex-matched control participants, as well as analyses of postmortem brain samples (Brodmann area 9/46) from n = 46 individuals with BD.

Measurements: Amyloid beta (Aβ)40, Aβ42, and total Tau levels were measured in plasma from individuals with BD and controls, and Aβ42 levels were measured in …

Vigorous Physical Activity As A Potential Environmental Risk Factor In Renal Medullary Carcinoma, Daniel D Shapiro, Sagar S Mukhida, Andrew W Hahn, Ayman Isahaku, Schyler M Turner, Jessica P Cheng, Pankaj K Chauhan, Susan S Thomas, Beei Chan, Zita D Lim, Nizar M Tannir, Maria Chang Swartz, Pavlos Msaouel

Faculty, Staff and Student Publications

Purpose: Renal medullary carcinoma (RMC) is a rare but aggressive kidney cancer affecting young individuals with sickle hemoglobinopathies. Prior retrospective case-control and mouse modeling studies suggest a mechanism linking vigorous intensity physical activity to increased RMC risk in individuals with sickle hemoglobinopathies. This study aimed to prospectively investigate the association between vigorous intensity exercise and RMC.

Materials and methods: This study used a validated questionnaire to prospectively assess reported physical activity in a large cohort of patients with RMC compared to the activity of individuals without RMC. Between 2022 and 2024, patients with RMC (N = 39) were prospectively surveyed …

Fish Assemblages And Flow Regimes Upstream And Downstream Of Falcon Reservoir, Christopher J. Austin, Christopher Taylor

School of Integrative Biological & Chemical Sciences Faculty Publications

The lower Rio Grande is regulated by Falcon and Amistad dams, as well as series of smaller dams and rock weirs. Several native fish species that rely on a natural flow regime for habitat and spawning are imperiled in the region. We analyzed streamflow discharge above and below Falcon Reservoir to assess potential impacts of dam impoundment on the fishes and flow regime. Fish collections were conducted by seine, and river discharge data was provided by the International Boundaries and Water Commission. We found significant differences in fish assemblages above vs below Falcon Reservoir, and the flow regime was significantly …

Supporting Patients With Advanced Cancer And Their Spouses In Parenting Minor Children: Results Of A Randomized Controlled Trial, Kathrin Milbury, Sujin Ann-Yi, Meagan S Whisenant, Morgan Jones, Yisheng Li, Victoria Necroto, Sania D Yousuf, Mariana Chavez-Macgregor, Larrisa Meyers, Eduardo Bruera

Faculty, Staff and Student Publications

Introduction: Patients with advanced cancer and their spousal caregivers who parent minor children report unmet parenting concerns and increased psychological distress. Seeking to address these important supportive care needs, this RCT examined the feasibility, acceptability, and initial evidence for the efficacy of a novel psychosocial intervention.

Patients and methods: Patients with a metastatic solid malignancy and their spouses completed self-reported validated assessments of psychological symptoms and cancer-related parenting outcomes and were then randomized to the parent support intervention or a usual care (UC) group. Both groups were reassessed 6 and 12 weeks later. Dyads randomized to the counselor-led intervention attended …

Improving Genetics Equity: Identifying Women Eligible For Genetic Care Services Using Mammography Clinics In Underserved Areas As Screening Hubs, Darya Kizub, Rachel Bluebond, Sierra Green, Jessica Duckworth, Sreejesh Shanker, Autumn Vara, Banu Arun

Faculty, Staff and Student Publications

PURPOSE: Fewer than 20% of underserved individuals undergo guideline-concordant hereditary breast and ovarian cancer (HBOC) genetic testing (GT). Our study aimed to determine the proportion of women eligible for HBOC GT using a cancer genetics risk assessment (CGRA) tool at breast cancer (BC) screening clinics in underserved communities and to describe the program's impact.

METHODS: Participants were women who presented for BC screening at The Rose clinics, serving low-income underserved communities in southeast Texas, and completed the CGRA. High-risk individuals received bilingual educational materials and a saliva-based GT kit. Those with a pathogenic variant (PV) or a variant of uncertain …

Pan-Cancer Immune And Stromal Deconvolution Predicts Clinical Outcomes And Mutation Profiles, Bhavneet Bhinder, Verena Friedl, Sunantha Sethuraman, Davide Risso, Kami E Chiotti, R Jay Mashl, Kyle P Ellrott, Jordan A Lee, Christopher K Wong, Kofi Gyan, Aditya Deshpande, Marcin Imielinski, Rohan Bareja, Josh Stuart, Myron Peto, Katherine A Hoadley, Alexander J Lazar, Andrew D Cherniack, Jingchun Zhu, Shaolong Cao, Mark Rubin, Wenyi Wang, Oliver F Bathe, Nicolas Robine, Li Ding, Peter W Laird, Wanding Zhou, Hui Shen, Vésteinn Thorsson, Jen Jen Yeh, Matthew H Bailey, Daniel Cui Zhou, Xianlu L Peng, Mary Goldman, Yongsheng Li, Anil Korkut, Nidhi Sahni, D Neil Hayes, Michael K A Mensah, Ina Felau, Anab Kemal, Samantha Caesar-Johnson, John A Demchok, Liming Yang, Martin L Ferguson, Roy Tarnuzzer, Zhining Wang, Jean C Zenklusen, Paul Spellman, Olivier Elemento

Faculty, Staff and Student Publications

Traditional gene expression deconvolution methods assess a limited number of cell types, therefore do not capture the full complexity of the tumor microenvironment (TME). Here, we integrate nine deconvolution tools to assess 79 TME cell types in 10,592 tumors across 33 different cancer types, creating the most comprehensive analysis of the TME. In total, we found 41 patterns of immune infiltration and stroma profiles, identifying heterogeneous yet unique TME portraits for each cancer and several new findings. Our findings indicate that leukocytes play a major role in distinguishing various tumor types, and that a shared immune-rich TME cluster predicts better …

Cortical Functional Organization In Early Childhood, Jiaxin Tu

Arts & Sciences Graduate Student Theses and Dissertations

The advent of connectivity-based methods, particularly those utilizing spontaneous BOLD signals, has significantly advanced brain mapping and deepened our understanding of the human brain's functional architecture. While prior research has explored functional organization in early childhood, most studies have focused on coarse, group-level distinctions aligned with adult literature, often within narrow age ranges. This dissertation extends these investigations by examining cortical functional organization in greater detail among healthy infants and toddlers aged 1 to 5 years. Chapter 1 employs spontaneous BOLD signals in sleeping infants and toddlers to derive a group-level functional organization at the resolution of areas and networks. …

Chaperone-Usher Pathway Pili Adhesin Conformations And Inhibitors In Urinary Tract Infections, Edward Lopatto

Arts & Sciences Graduate Student Theses and Dissertations

Antibiotic resistant bacteria are becoming increasingly difficult-to-treat resulting in increased morbidity and mortality, especially for common infections such as urinary tract infections (UTIs). Globally, UTIs afflict over 400 million people a year. Numerous different gram-negative and gram-positive bacterial species cause UTIs, including uropathogenic Escherichia coli (UPEC), Klebsiella pneumoniae, and Acinetobacter baumannii. Many of these bacterial species are listed as pathogens of urgent concern by the Center for Disease Control due to the dangerous rise and prevalence of antibiotic resistance necessitating development of new therapeutic measures. Bacteria utilize adhesin factors, such as chaperone-usher pathway (CUP) pili to gain a foothold in …

Blood Flow Occlusion Superimposed On Low-Volume, Low-Intensity Knee Extensions Does Not Evoke Hypoalgesia: A Pilot Study, Sophie-Jayne Morgan, Jenny Zhang, Neil Lemay, Neda Khaledi, Saied J. Aboodarda

Topics in Exercise Science and Kinesiology

Topics in Exercise Science and Kinesiology Volume 6: Issue 1, Article 9, 2025. Exercise-induced hypoalgesia (EIH) is a transient decrease in pain perception that can be observed following various tasks, including low-intensity and high-intensity exercise. The application of blood flow occlusion (BFO) can help enhance exercise adaptations while being able to exercise at a low intensity, which has important implications for clinical and rehabilitative settings. Through descending inhibitory pathways, BFO-induced pain can potentially alleviate exercise-induced pain. This study aimed to assess whether the superimposition of BFO – and its associated augmented perceived responses – during low-intensity, low-volume resistance exercise could …

A Comparison Of Measured Versus Estimated Metabolic Equivalents (Mets) During The Farmer's Carry And Sled Push Exercises On A Commercially Available Step Mill, Colin Miller, Ethan Remotigue, Shane Hammer, J. Jay Dawes, Taylor K. Dinyer-Mcneely

Topics in Exercise Science and Kinesiology

Topics in Exercise Science and Kinesiology Volume 6: Issue 1, Article 8, 2025. The Stairmaster 10G ergometer allows users to perform non-traditional movements such as the sled push and farmer’s carry, which involve substantial upper and lower body contributions. Standard MET calculations for stair stepping do not account for this increase upper-body workload, so there is potential for error when aiming to determine exercise intensity based exclusively on estimated METs. The primary purpose of this study is to compare the metabolic and physiological effects of two training modes on the Stairmaster 10G ergometer, specifically evaluating the accuracy of MET values …

Implementing A Sustainability Approach By Converting Plastic Bottle Waste From A Mischievous Substance To A Beneficial Material By Means Of Zero Residue Level Concept, Younus Mohammed Abed, Fatima Allawi, Shahad Mudhafar Ali, Salem Jawad Alhamd, Thekra Atta Ibrahim, Mohammed Nsaif Abbas

Karbala International Journal of Modern Science

Plastic waste represents a serious environmental and health hazard due to its non-biodegradability and toxic leachates. This study investigates the potential conversion of plastic waste into a sustainable raw material for producing a useful substance. This investigation focuses on repurposing PET beverage bottles—a major contributor to microplastic pollution—into high-value activated carbon (AC) for water treatment, aligning with circular economy principles. The chemical preparation method for AC using phosphoric acid as an activating agent was evaluated. Results demonstrated the successful conversion of 68% of plastic waste into AC under the following conditions: pyrolysis temperature of 700°C, pyrolysis time of 7 hours, …

Correction: Turn-On Fluorescent Glucose Transport Bioprobe Enables Wash-Free Real-Time Monitoring Of Glucose Uptake Activity In Live Cells And Small Organisms, Monica S. Hensley, David Hutchings, Abdelrahman Ismail, Micaela Rayne Geborkoff, Thomas Werner, Marina Tanasova

Michigan Tech Publications

Correction for “Turn-on fluorescent glucose transport bioprobe enables wash-free real-time monitoring of glucose uptake activity in live cells and small organisms” by Monica S. Hensley et al., RSC Chem. Biol., 2025, 6, 987–995, https://doi.org/10.1039/D4CB00239C.

The authors regret that two contributors, Micaela Rayne Geborkoff and Professor Dr Thomas Werner, were inadvertently omitted from the original author list of this article. Both individuals made significant contributions to the research reported.

Micaela Rayne Geborkoff was involved in the design, planning, and execution of the Drosophila experiments, specifically in the growth and treatment of fruit fly larvae. Professor Dr Thomas Werner provided …

Restoring P53 Wild-Type Conformation In Tp53-Y220c-Mutant Acute Myeloid Leukemia, Bing Z Carter, Po Yee Mak, Edward Ayoub, Xiaogang Wu, Baozhen Ke, Yuki Nishida, Andrew Futreal, Lauren B Ostermann, Andrea D Bedoy, Steffen Boettcher, Courtney D Dinardo, Anna Puzio-Kuter, Masha V Poyurovsky, Arnold J Levine, Michael Andreeff

Faculty, Staff and Student Publications

TP53-Y220C is a recurrent hotspot mutation in cancers and leukemias. It is observed predominantly in acute myeloid leukemia (AML)/myelodysplastic syndromes among hematological malignancies and is associated with poor outcome. The mutation creates a structural pocket in the p53 protein. PC14586 (rezatapopt) is a small molecule designed to bind to this pocket and thus restore a p53-wild type (p53-WT) conformation. We demonstrate that PC14586 converts p53-Y220C into a p53-WT conformation and activates p53 transcriptional targets, but surprisingly induces limited/no apoptosis in TP53-Y220C AML. Mechanistically, MDM2 induced by PC14586-activated conformational p53-WT and the nuclear exporter XPO1 reduce the transcriptional activities of p53, …

Genome-Wide Association Study For Lung Cancer In 6531 African Americans Reveals New Susceptibility Loci, Jinyoung Byun, Younghun Han, Jiyeon Choi, Ryan Sun, Vikram R Shaw, Catherine Zhu, Xiangjun Xiao, Christine Lusk, Hoda Badr, Hyun-Sung Lee, Hee-Jin Jang, Yafang Li, Hyeyeun Lim, Erping Long, Yanhong Liu, Linda Kachuri, Kyle M Walsh, John K Wiencke, Demetrius Albanes, Stephen Lam, Adonina Tardon, Marian L Neuhouser, Matt J Barnett, Chu Chen, Stig Bojesen, Hermann Brenner, Maria Teresa Landi, Mattias Johansson, Angela Risch, H-Erich Wichmann, Heike Bickeböller, David C Christiani, Gad Rennert, Susanne Arnold, John K Field, Sanjay Shete, Loic Le Marchand, Geoffrey Liu, Angeline S Andrew, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Fiona Taylor, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Alpa Patel, Xihong Lin, Krista A Zanetti, Curtis C Harris, Stephen Chanock, James Mckay, Ann G Schwartz, Rayjean J Hung, Christopher I Amos

Faculty, Staff and Student Publications

Despite lung cancer affecting all races and ethnicities, disparities are observed in incidence and mortality rates among different ethnic groups in the United States. Non-Hispanic African Americans had a high incidence rate of lung cancer at 55.8 per 100 000 people, as well as the highest death rate at 37.2 per 100 000 people from 2016 to 2020. While previous genome-wide association studies (GWAS) have identified over 45 susceptibility risk loci that influence lung cancer development, few GWAS have investigated the etiology of lung cancer in African Americans. To address this gap in knowledge, we conducted GWAS of lung cancer …

Transcriptomic And Histological Characteristics Of Innate Immune Activation In Brain Parenchyma In A Rat Model Of Neonatal Intraventricular Hemorrhage, Miriam Zamorano, Sanjna Udtha, Aidan M Collier, Erica Underwood, Razan El Sayed, Ankit Agarwal, Devin S Hatchell, Chunfeng Tan, Paul J Nietert, Scott D Olson, Brandon A Miller

Faculty, Staff and Student Publications

Background: Intraventricular hemorrhage (IVH) remains a major complication in preterm infants with lifelong sequelae. There is no effective treatment for IVH other than supportive care and surgery for post-hemorrhagic hydrocephalus. We previously reported that the innate neuroimmune response in an animal model of IVH was dependent on developmental stage, only occurring in older animals.

Methods: This study utilized a lysed-blood injection model of IVH in rats. This model specifically captures the effects of blood products released by IVH on brain parenchyma. We performed RNAseq and differential gene expression analysis on CD11b/c-positive cells in the brain (microglia/macrophages) to define gene expression …

Direct Inhibition Of Ras Reveals The Features Of Oncogenic Signaling Driven By Ras G12 And Q61 Mutations, Michelangelo Marasco, Dinesh Kumar, Santiago Garcia Borrego, Tessa Seale, Giulia Maddalena, Riccardo Mezzadra, Kylie Belanger, Soren Cole, Brayan Perez, Wei Luan, Radha Mukherjee, Ilinca Aricescu, Vladimir Markov, Yuxin Zhu, Sabrina Arena, Alberto Bardelli, Elisa De Stanchina, Scott W Lowe, Richard A Burkhart, Jacquelyn W Zimmerman, Rona Yaeger, Scott E Kopetz, Neal Rosen, Sandra Misale

Faculty, Staff and Student Publications

RAS genes are frequently mutated in cancer, often at codons 12 and 61. With the recent introduction of RAS inhibitors, we can now directly investigate the effects of specific RAS mutations in cancer cells. In this study, we demonstrate that in tumors with RASG12X mutations, mutant RAS can be activated by receptor tyrosine kinases (RTK), and PI3K activation is dependent on mutant RAS. Conversely, RASQ61X mutations activate the MAPK cascade independently of RTKs, and inhibition of RASQ61X impairs MAPK pathway activation but leaves the PI3K pathway unaffected. Our characterization of these distinct features of G12X and Q61X mutations suggests that …

Ptpn11 Mutations Define A Rare But Highly Adverse Subset Of Myelodysplastic Syndromes, Alexandre Bazinet, Alex Bataller, Guillermo Montalban-Bravo, Kelly Chien, Koji Sasaki, Wei Ying Jen, Mahesh Swaminathan, Tapan Kadia, Courtney Dinardo, Farhad Ravandi, Guillermo Garcia-Manero, Hagop Kantarjian

Faculty, Staff and Student Publications

No abstract provided.

A Hedgehog-Foxf Axis Coordinates Dental Follicle-Derived Alveolar Bone Formation, Mizuki Nagata, Gaurav T Gadhvi, Taishi Komori, Yuki Arai, Chiaki Tsutsumi-Arai, Angel Ka Yan Chu, Seth N Nye, Yuntao Yang, Shion Orikasa, Akira Takahashi, Peter Carlsson, W Jim Zheng, Joshua D Welch, Noriaki Ono, Wanida Ono

Faculty, Staff and Student Publications

The alveolar bone is a specialized mineralized structure supporting the lifelong functionality of the tooth in mastication. The alveolar bone develops from the dental follicle (DF) during tooth root formation due to deliberate epithelial-mesenchymal interactions. However, how DF progenitor cell fates are regulated toward alveolar bone osteoblasts remains unknown. We find that Hedgehog signaling activities are transiently activated during the onset of tooth root formation and alveolar bone formation. Parathyroid hormone-related protein (PTHrP)-expressing DF cells are highly responsive to Hedgehog signaling, yet constitutive Hedgehog activation using Pthrp-creER and Ptch1-floxed alleles potently suppresses alveolar osteoblast and ligament differentiation of PTHrP+ DF …

Differential Efficacy Of Bevacizumab And Erlotinib In Preclinical Models Of Renal Medullary Carcinoma And Fumarate Hydratase-Deficient Renal Cell Carcinoma, Niki M Zacharias, Manuel Ozambela, Menuka Karki, Rong He, Pankaj K Chauhan, Pedro I Pesquera, Andres E Hernandez Gonzalez, Oscar Ochoa, Alberto Pieretti, Huiqin Chen, Carolyn De La Cerda, Zhiyuan Yu, Abha Grover, Samantha Hicks-Peña, Natalie W Fowlkes, Lei Wang, Tapati Maity, Priya Rao, Giannicola Genovese, Nizar M Tannir, Jose A Karam, Pavlos Msaouel

Faculty, Staff and Student Publications

Renal medullary carcinoma (RMC) and fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) are rare and highly aggressive cancers. Although the combination of vascular endothelial growth factor (VEGF) inhibition by bevacizumab and epidermal growth factor receptor (EGFR) inhibition by erlotinib is clinically used for both diseases, the differential effect of each component has not been investigated. Transcriptomic profiling revealed that RMC and FH-deficient tumor tissues demonstrate increased EGFR but not VEGF expression compared with adjacent normal kidney. Subsequent in vitro studies revealed that RMC and FH-deficient cell lines are sensitive to erlotinib treatment, whereas clear cell RCC cell lines are resistant. …

Immature Acta2r179c/+ Smooth Muscle Cells Cause Moyamoya-Like Cerebrovascular Lesions In Mice Prevented By Boosting Oxphos, Anita Kaw, Suravi Majumder, Jose E Esparza Pinelo, Ting Wu, Zbigniew Starosolski, Zhen Zhou, Albert J Pedroza, Xueyan Duan, Kaveeta Kaw, Angie D Gonzalez, Ripon Sarkar, Michael P Fischbein, Philip L Lorenzi, Lin Tan, Sara A Martinez, Iqbal Mahmud, Laxman Devkota, L Maximilian Buja, Heinrich Taegtmeyer, Ketan B Ghaghada, Sean P Marrelli, Callie S Kwartler, Dianna M Milewicz

Faculty, Staff and Student Publications

ACTA2 pathogenic variants altering arginine 179 cause childhood-onset strokes due to moyamoya disease (MMD)-like occlusions of the distal internal carotid arteries, but the mechanisms of pathogenesis are unknown and no preventive treatments exist. Here we show that Acta2R179C/+ smooth muscle cells (SMCs) fail to fully differentiate and maintain stem cell-like features, including increased migration and glycolytic flux compared to wildtype (WT) SMCs. Increasing mitochondrial respiration with nicotinamide riboside (NR) drives differentiation and decreases migration of Acta2R179C/+ SMCs. Carotid artery injury of Acta2SMC-R179C/+ mice leads to premature death, intraluminal SMC accumulation leading to MMD-like occlusive lesions, neurologic symptoms, …

Z-Scores Outperform Similar Methods For Analyzing Crispr Paralog Synthetic Lethality Screens, Juihsuan Chou, Nazanin Esmaeili Anvar, Reem Elghaish, Junjie Chen, Traver Hart

Faculty, Staff and Student Publications

Genetic screens offer a promising strategy for identifying tumor-specific therapeutic targets, but single-gene knockout screens often miss functionally redundant paralogs. Multiplex Cas9 and Cas12a CRISPR systems have been deployed to assay genetic interactions, but analysis pipelines vary considerably. Here we evaluate data from four in4mer CRISPR/Cas12a screens in cancer cell lines, using delta log fold change, Z-transformed dLFC, and rescaled dLFC approaches to identify synthetic lethal interactions. Both ZdLFC and RdLFC provide more consistent identification of synthetic lethal pairs across cell lines compared to the unscaled dLFC method, while ZdLFC benefits from not requiring a training set of known interactors.