Medical Toxicology Commons^™

Inhibition Of Fatty Acid Synthase Enhances Therapeutic Efficacy And Delays Acquired Resistance To Braf-Targeted Therapy In Colorectal Cancer, Mariah E. Geisen, Elisane W. Tessmann, Courtney O. Kelson, Daheng He, Chi Wang, Abu Saleh Mosa Faisal, Ellen J. Beswick, Yasmine Baca, Stephanie Rock, Jill M. Kolesar, Yekaterina Y. Zaytseva

Toxicology and Cancer Biology Faculty Publications

The presence of BRAF ^V600E mutations is associated with poor prognosis in colorectal cancer (CRC). Although the FDA-approved combination of encorafenib and cetuximab provides clinical benefit in this population, only 22% of patients respond and most eventually develop resistance. This study investigated the mechanisms of resistance to PLX8394, a second-generation BRAF inhibitor. Using primary and established BRAF ^V600E CRC cells, we show that the development of resistance to PLX8394 results in cross-resistance of cells to encorafenib. Moreover, the acquired resistance is associated with increased proliferation, invasion, and upregulation of lipid metabolism, including increased expression of fatty acid synthase (FASN), a …

Investigating The Role Of Traditional Chinese Herbal Medicine For Cancer Symptom Management In Older Adults: A Rapid Review, Isabelle C. Karshner

Honors Undergraduate Theses

Background: Patients with cancer often experience symptoms related to disease, complications, and treatment. One potential method of alleviating these symptoms is traditional Chinese herbal medications (TCHM). This rapid review explores the role of traditional Chinese herbal medications in treating cancer-related symptoms in older adults.

Purpose: The purpose of this rapid review is to gain and provide a better understanding of the effects of TCHM on cancer-symptom management in the older adult population. This review explores the association between TCHM and effects on cancer symptoms in older adults, including interactions, toxicity, and signs/symptoms of TCHM use that may be useful information …

Artesunate Enhances The Efficacy Of Enzalutamide In Advanced Prostate Cancer, Xinyi Wang, Jinghui Liu, Fengyi Mao, Yifan Kong, Qiongsi Zhang, Chaohao Li, Daheng He, Chi Wang, Yanquan Zhang, Ruixin Wang, Sally R. Ellingson, Qiou Wei, Zhiguo Li, Xiaoqi Liu

Toxicology and Cancer Biology Faculty Publications

Prostate cancer (PCa) is one of the leading causes of death among men worldwide. Treatments targeting the androgen receptor pathway remain the standard therapy for PCa patients. Enzalutamide (ENZ), a second-generation androgen receptor inhibitor, was developed to treat castration-resistant prostate cancer. However, while patients initially respond to ENZ, drug resistance typically develops within a few months. Artesunate (ART), a semisynthetic derivative of the Artemisinin plant, is approved for antimalaria treatment. In this study, we conducted an FDA-approved drug screening and identified ART as a potential candidate for overcoming ENZ resistance in PCa. Mechanistically, ART induces the degradation of c-Myc, enhancing …

Facilitation Of Chemotherapy Efficacy Through Targeted Drug Delivery In Lung Cancer Cells Via Ultrasound And Implications On Health Interventions, Ibrahim Nasim

Honors Undergraduate Theses

Lung Cancer (small cell and non-small cell) is the leading cause of cancer death in the US, accounting for about 20% of all cancer deaths. Paclitaxel (PTX) is a chemotherapeutic agent commonly used to treat lung cancer. It works by slowing and stopping cancer growth by stiffening microtubules within cells, promoting mitotic halt and cell death. Carboplatin (CP) is another agent given to lung cancer patients containing platinum and works via direct damage of oncolytic DNA. The exact mechanism of how PTX and CP cause cell death is still an under-studied area. This thesis aims to provide insight into how …

Enolase Inhibitors As Therapeutic Leads For Naegleria Fowleri Infection, Jillian E Milanes, Victoria C Yan, Cong-Dat Pham, Florian Muller, Samuel Kwain, Kerrick C Rees, Brian N Dominy, Daniel C Whitehead, Steven W Millward, Madison Bolejack, Roger Shek, Logan Tillery, Isabelle Q Phan, Bart Staker, E Ashley Moseman, Xiang Zhang, Xipeng Ma, Audriy Jebet, Xinmin Yin, James C Morris

Faculty, Staff and Student Publications

Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amoebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used …

Comparative Toxicological Assessment Of 2 Bisphenols Using A Systems Approach: Evaluation Of The Behavioral And Transcriptomic Responses Of Danio Rerio To Bisphenol A And Tetrabromobisphenol A, Michael G Morash, Morgan W Kirzinger, John C Achenbach, Ananda B Venkatachalam, Jessica Nixon, Susanne Penny, Joëlle Pinsonnault Cooper, Deborah E Ratzlaff, Cindy L A Woodland, Lee D Ellis

Faculty, Staff and Student Publications

The zebrafish (Danio rerio) is becoming a critical component of new approach methods (NAMs) in chemical risk assessment. As a whole organism in vitro NAM, the zebrafish model offers significant advantages over individual cell-line testing, including toxicokinetic and toxicodynamic competencies. A transcriptomic approach not only allows for insight into mechanism of action for both apical endpoints and unobservable adverse outcomes, but also changes in gene expression induced by lower, environmentally relevant concentrations. In this study, we used a larval zebrafish model to assess the behavioral and transcriptomic alterations caused by subphenotypic concentrations of 2 chemicals with the same structural backbone, …

A Dynamic Model Of Inorganic Arsenic-Induced Carcinogenesis Reveals An Epigenetic Mechanism For Epithelial–Mesenchymal Plasticity, Matthew Rea, Greg Kimmerer, Shania Mittendorf, Xiaopeng Xiong, Megan Green, Darrell Chandler, Wesley Saintilnord, Jessica S. Blackburn, Tianyan Gao, Yvonne N. Fondufe-Mittendorf

Markey Cancer Center Faculty Publications

Inorganic arsenic (iAs) causes cancer by initiating dynamic transitions between epithelial and mesenchymal cell phenotypes. These transitions transform normal cells into cancerous cells, and cancerous cells into metastatic cells. Most in vitro models assume that transitions between states are binary and complete, and do not consider the possibility that intermediate, stable cellular states might exist. In this paper, we describe a new, two-hit in vitro model of iAs-induced carcinogenesis that extends to 28 weeks of iAs exposure. Through week 17, the model faithfully recapitulates known and expected phenotypic, genetic, and epigenetic characteristics of iAs-induced carcinogenesis. By 28 weeks, however, exposed …

Chronic Wasting Disease: State Of The Science, Jason C Bartz, Rebeca Benavente, Byron Caughey, Sonja Christensen, Allen Herbst, Edward A Hoover, Candace K Mathiason, Debbie Mckenzie, Rodrigo Morales, Marc D Schwabenlander, Daniel P Walsh, The Nc North American Interdisciplinary Chronic Wasting Disease Research Consortium Members

Faculty, Staff and Student Publications

Chronic wasting disease (CWD) is a prion disease affecting cervid species, both free-ranging and captive populations. As the geographic range continues to expand and disease prevalence continues to increase, CWD will have an impact on cervid populations, local economies, and ecosystem health. Mitigation of this "wicked" disease will require input from many different stakeholders including hunters, landowners, research biologists, wildlife managers, and others, working together. The NC1209 (North American interdisciplinary chronic wasting disease research consortium) is composed of scientists from different disciplines involved with investigating and managing CWD. Leveraging this broad breadth of expertise, the Consortium has created a state-of-the-science …

Avaren-Fc, A Novel Immunotherapeutic, Recruits Nk Cells In B16f10 Melanoma Tumor Tissue, Sreevatsa Vemuri, Katarina Mayer, Nobuyuki Matoba

Posters-at-the-Capitol

Melanoma is the fifth most common cancer in the US, with limited effective immunotherapeutic options available for patients. Avaren-Fc (AvFc) is a novel experimental immunotherapeutic agent with a unique “lectibody” property. It is capable of targeting cancer cells through the selective recognition of high mannose glycans, which are aberrantly overrepresented on the surface of malignant cells. AvFc can interact with circulating effector immune cells equipped with Fc receptors, such as natural killer (NK) cells to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and kill cancer cells. Previous work has shown that AvFc effectively induces ADCC activity against B16F10 cancer cells in vitro …

Insights Into The Assembly And Regulation Of The Bacterial Divisome, Todd A Cameron, William Margolin

Faculty, Staff and Student Publications

The ability to split one cell into two is fundamental to all life, and many bacteria can accomplish this feat several times per hour with high accuracy. Most bacteria call on an ancient homologue of tubulin, called FtsZ, to localize and organize the cell division machinery, the divisome, into a ring-like structure at the cell midpoint. The divisome includes numerous other proteins, often including an actin homologue (FtsA), that interact with each other at the cytoplasmic membrane. Once assembled, the protein complexes that comprise the dynamic divisome coordinate membrane constriction with synthesis of a division septum, but only after overcoming …

Enolase Inhibitors As Early Lead Therapeutics Against Trypanosoma Brucei, Colm P Roster, Danielle Lavigne, Jillian E Milanes, Emily Knight, Heidi D Anderson, Sabrina Pizarro, Elijah M Harding, Meredith T Morris, Victoria C Yan, Cong-Dat Pham, Florian Muller, Samuel Kwain, Kerrick C Rees, Brian Dominy, Daniel C Whitehead, Md Nasir Uddin, Steven W Millward, James C Morris

Faculty, Staff and Student Publications

Glucose metabolism is critical for the African trypanosome, Trypanosoma brucei, serving as the lone source of ATP production for the bloodstream form (BSF) parasite in the glucose-rich environment of the host blood. Recently, phosphonate inhibitors of human enolase (ENO), the enzyme responsible for the interconversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis or PEP to 2-PG in gluconeogenesis, have been developed for the treatment of glioblastoma multiforme (GBM). Here, we have tested these agents against T. brucei ENO (TbENO) and found the compounds to be potent enzyme inhibitors and trypanocides. For example, (1-hydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (deoxy-SF2312) …

Social Vulnerability Of The People Exposed To Wildfires In Us West Coast States, Arash Modaresi Rad, John T Abatzoglou, Erica Fleishman, Miranda H Mockrin, Volker C Radeloff, Yavar Pourmohamad, Megan Cattau, J Michael Johnson, Philip Higuera, Nicholas J Nauslar, Mojtaba Sadegh

Faculty, Staff and Student Publications

Understanding of the vulnerability of populations exposed to wildfires is limited. We used an index from the U.S. Centers for Disease Control and Prevention to assess the social vulnerability of populations exposed to wildfire from 2000-2021 in California, Oregon, and Washington, which accounted for 90% of exposures in the western United States. The number of people exposed to fire from 2000-2010 to 2011-2021 increased substantially, with the largest increase, nearly 250%, for people with high social vulnerability. In Oregon and Washington, a higher percentage of exposed people were highly vulnerable (>40%) than in California (~8%). Increased social vulnerability of …

Aspergillus Flavus And Fusarium Verticillioides And Their Main Mycotoxins: Global Distribution And Scenarios Of Interactions In Maize, Xiangrong Chen, Mohamed F Abdallah, Sofie Landschoot, Kris Audenaert, Sarah De Saeger, Xiangfeng Chen, Andreja Rajkovic

Faculty, Staff and Student Publications

Maize is frequently contaminated with multiple mycotoxins, especially those produced by Aspergillus flavus and Fusarium verticillioides. As mycotoxin contamination is a critical factor that destabilizes global food safety, the current review provides an updated overview of the (co-)occurrence of A. flavus and F. verticillioides and (co-)contamination of aflatoxin B1 (AFB1) and fumonisin B1 (FB1) in maize. Furthermore, it summarizes their interactions in maize. The gathered data predict the (co-)occurrence and virulence of A. flavus and F. verticillioides would increase worldwide, especially in European cold climate countries. Studies on the interaction of both fungi regarding their growth mainly showed antagonistic …

Brief Report: Clinical Response, Toxicity, And Resistance Mechanisms To Osimertinib Plus Met Inhibitors In Patients With Egfr-Mutant Met-Amplified Nsclc, Kaiwen Wang, Robyn Du, Sinchita Roy-Chowdhuri, Ziping T Li, Lingzhi Hong, Natalie Vokes, Yasir Y Elamin, Celyne Bueno Hume, Ferdinandos Skoulidis, Carl M Gay, George Blumenschein, Frank V Fossella, Anne Tsao, Jianjun Zhang, Niki Karachaliou, Aurora O'Brate, Claudia-Nanette Gann, Jeff Lewis, Waree Rinsurongkawong, J Jack Lee, Don Lynn Gibbons, Ara A Vaporciyan, John V Heymach, Mehmet Altan, Xiuning Le

Faculty, Staff and Student Publications

INTRODUCTION:MET amplification is a known resistance mechanism to EGFR tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant NSCLC. Dual EGFR-MET inhibition has been reported with success in overcoming such resistance and inducing clinical benefit. Resistance mechanisms to dual EGFR-MET inhibition require further investigation and characterization.

METHODS: Patients with NSCLC with both MET amplification and EGFR mutation who have received crizotinib, capmatinib, savolitinib, or tepotinib plus osimertinib (OSI) after progression on OSI at MD Anderson Cancer Center were included in this study. Molecular profiling was completed by means of fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). Radiological response …

Clustering Of Pediatric Brain Tumors In Texas, 2000-2017, Thanh T Hoang, Omar Rosales, Elyse Burgess, Philip J Lupo, Michael E Scheurer, Abiodun O Oluyomi

Faculty, Staff and Students Publications

Risk factors for pediatric brain tumors are largely unknown. Identifying spatial clusters of these rare tumors on the basis of residential address may provide insights into childhood socio-environmental factors that increase susceptibility. From 2000-2017, the Texas Cancer Registry recorded 4305 primary brain tumors diagnosed among children (≤19 years old). We performed a spatial analysis in SaTScan to identify neighborhoods (census tracts) where the observed number of pediatric brain tumors was higher than expected. Within each census tract, the number of pediatric brain tumors was summed on the basis of residential address at diagnosis. The population estimate from the 2007-2011 American …

The In Vitro Activity Of Delafloxacin And Comparator Agents Against Bacterial Pathogens Isolated From Patients With Cancer, Bahgat Gerges, Kenneth Rolston, Samuel A Shelburne, Joel Rosenblatt, Randall Prince, Issam Raad

Faculty, Staff and Student Publications

BACKGROUND: Fluoroquinolones are used for infection prevention in high-risk patients with haematological malignancies. Fluoroquinolones are active against many Gram-negative bacilli (GNB) but are less active against Gram-positive organisms. We evaluated the

METHODS: Antimicrobial susceptibility testing and time-kill studies were performed using CLSI-approved methodology and interpretive criteria for 350 Gram-positive organisms and 210 GNB that had been recently isolated from patients with cancer.

RESULTS: Delafloxacin was more active than ciprofloxacin and levofloxacin against

CONCLUSIONS: Delafloxacin is more active than ciprofloxacin and levofloxacin against

Microbiome Influencers Of Checkpoint Blockade-Associated Toxicity, Yinghong Wang, Robert R Jenq, Jennifer A Wargo, Stephanie S Watowich

Faculty, Staff and Student Publications

Immunotherapy has greatly improved cancer outcomes, yet variability in response and off-target tissue damage can occur with these treatments, including immune checkpoint inhibitors (ICIs). Multiple lines of evidence indicate the host microbiome influences ICI response and risk of immune-related adverse events (irAEs). As the microbiome is modifiable, these advances indicate the potential to manipulate microbiome components to increase ICI success. We discuss microbiome features associated with ICI response, with focus on bacterial taxa and potential immune mechanisms involved in irAEs, and the overall goal of driving novel approaches to manipulate the microbiome to improve ICI efficacy while avoiding irAE risk.

Long And Short Duration Exposures To The Selective Serotonin Reuptake Inhibitors (Ssris) Fluoxetine, Paroxetine And Sertraline At Environmentally Relevant Concentrations Lead To Adverse Effects On Zebrafish Behaviour And Reproduction, Ananda Baskaran Venkatachalam, Bailey Levesque, John C Achenbach, Jane J Pappas, Lee D Ellis

Faculty, Staff and Student Publications

Selective serotonin reuptake inhibitors (SSRIs) are currently the most prescribed class of psychotropic medications. Their increased global manufacture and use have become growing concerns for aquatic toxicologists and environmental biologists, who assess both the direct and indirect effects of substances on the environment and on human health. In order to assess the potential impact of environmentally relevant levels of SSRIs on fish development, behaviour and reproduction, we exposed juvenile and adult zebrafish to a select group of SSRIs using two separate exposure paradigms. In the first paradigm, juvenile zebrafish were exposed to Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft) or a …

Monitoring And Modulating Diet And Gut Microbes To Enhance Response And Reduce Toxicity To Cancer Treatment, Anne Knisely, Yongwoo David Seo, Jennifer A Wargo, Manoj Chelvanambi

Faculty, Staff and Student Publications

The gut microbiome comprises a diverse array of microbial species that have been shown to dynamically modulate host immunity both locally and systemically, as well as contribute to tumorigenesis. In this review, we discuss the scientific evidence on the role that gut microbes and diet play in response and toxicity to cancer treatment. We highlight studies across multiple cancer cohorts that have shown an association between particular gut microbiome signatures and an improved response to immune checkpoint blockade, chemotherapy, and adoptive cell therapies, as well as the role of particular microbes in driving treatment-related toxicity and how the microbiome can …

Germline Variants Associated With Toxicity To Immune Checkpoint Blockade, Stefan Groha, Sarah Abou Alaiwi, Wenxin Xu, Vivek Naranbhai, Amin H Nassar, Ziad Bakouny, Talal El Zarif, Renee Maria Saliby, Guihong Wan, Ahmad Rajeh, Elio Adib, Pier V Nuzzo, Andrew L Schmidt, Chris Labaki, Biagio Ricciuti, Joao Victor Alessi, David A Braun, Sachet A Shukla, Tanya E Keenan, Eliezer Van Allen, Mark M Awad, Michael Manos, Osama Rahma, Leyre Zubiri, Alexandra-Chloe Villani, Benjamin Fairfax, Christian Hammer, Zia Khan, Kerry Reynolds, Yevgeniy Semenov, Deborah Schrag, Kenneth L Kehl, Matthew L Freedman, Toni K Choueiri, Alexander Gusev

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10-8) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10-11; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10-8; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10-8, HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival.

Recent Advances In Rapid Detection Techniques For Pesticide Residue: A Review, Lingyuan Xu, A M Abd El-Aty, Jong-Bang Eun, Jae-Han Shim, Jing Zhao, Xingmei Lei, Song Gao, Yongxin She, Fen Jin, Jing Wang, Maojun Jin, Bruce D Hammock

Faculty, Staff and Student Publications

As an important chemical pollutant affecting the safety of agricultural products, the on-site and efficient detection of pesticide residues has become a global trend and hotspot in research. These methodologies were developed for simplicity, high sensitivity, and multiresidue detection. This review introduces the currently available technologies based on electrochemistry, optical analysis, biotechnology, and some innovative and novel technologies for the rapid detection of pesticide residues, focusing on the characteristics, research status, and application of the most innovative and novel technologies in the past 10 years, and analyzes challenges and future development prospects. The current review could be a good reference …

Daphnia As A Sentinel Species For Environmental Health Protection: A Perspective On Biomonitoring And Bioremediation Of Chemical Pollution, Muhammad Abdullahi, Xiaojing Li, Mohamed Abou-Elwafa Abdallah, William Stubbings, Norman Yan, Marianne Barnard, Liang-Hong Guo, John K Colbourne, Luisa Orsini

Faculty, Staff and Student Publications

Despite available technology and the knowledge that chemical pollution damages human and ecosystem health, chemical pollution remains rampant, ineffectively monitored, rarely prevented, and only occasionally mitigated. We present a framework that helps address current major challenges in the monitoring and assessment of chemical pollution by broadening the use of the sentinel species Daphnia as a diagnostic agent of water pollution. And where prevention has failed, we propose the application of Daphnia as a bioremediation agent to help reduce hazards from chemical mixtures in the environment. By applying “omics” technologies to Daphnia exposed to real-world ambient chemical mixtures, we show improvements …

Public Health Burden Of Secondhand Smoking: Case Reports Of Lung Cancer And A Literature Review, Ladislav Štěpánek, Jarmila Ševčíková, Dagmar Horáková, Mihir Sanjay Patel, Radka Durďáková

Faculty, Staff and Student Publications

Secondhand smoke (SHS), composed of mainstream and sidestream smoke, is a known human carcinogen. It contains a variety of harmful substances at even higher concentrations than mainstream smoke itself, which is inhaled during firsthand smoking. Exposure to SHS, affecting more than a third of the worldwide population, increases the likelihood of lung cancer by roughly 30%, with specific contributions depending on the histological type of cancer. This study aimed to present the harmful potential of SHS through case reports and describe the burden of SHS via a literature review. From a collection of lung cancer case reports occurring in never …

Epigenetic Dysregulations In Arsenic-Induced Carcinogenesis, Ranakul Islam, Lei Zhao, Yifang Wang, Grace Lu-Yao, Ling-Zhi Liu

Department of Medical Oncology Faculty Papers

Arsenic is a crucial environmental metalloid whose high toxicity levels negatively impact human health. It poses significant health concerns to millions of people in developed and developing countries such as the USA, Canada, Bangladesh, India, China, and Mexico by enhancing sensitivity to various types of diseases, including cancers. However, how arsenic causes changes in gene expression that results in heinous conditions remains elusive. One of the proposed essential mechanisms that still has seen limited research with regard to causing disease upon arsenic exposure is the dysregulation of epigenetic components. In this review, we have extensively summarized current discoveries in arsenic-induced …

Radioresistance In Prostate Cancer: Focus On The Interplay Between Nf-Κb And Sod, Sameera Kumar, Daret St. Clair

Toxicology and Cancer Biology Faculty Publications

Prostate cancer occurs frequently in men and can often lead to death. Many cancers, including prostate cancer, can be initiated by oxidative insult caused by free radicals and reactive oxygen species. The superoxide dismutase family removes the oxygen-derived reactive oxygen species, and increased superoxide dismutase activity can often be protective against prostate cancer. Prostate cancer can be treated in a variety of ways, including surgery, androgen deprivation therapy, radiation therapy, and chemotherapy. The clinical trajectory of prostate cancer varies from patient to patient, but more aggressive tumors often tend to be radioresistant. This is often due to the free-radical and …

Untargeted Lipidomics Of Non-Small Cell Lung Carcinoma Demonstrates Differentially Abundant Lipid Classes In Cancer Vs. Non-Cancer Tissue, Joshua M. Mitchell, Robert M. Flight, Hunter N. B. Moseley

Molecular and Cellular Biochemistry Faculty Publications

Lung cancer remains the leading cause of cancer death worldwide and non-small cell lung carcinoma (NSCLC) represents 85% of newly diagnosed lung cancers. In this study, we utilized our untargeted assignment tool Small Molecule Isotope Resolved Formula Enumerator (SMIRFE) and ultra-high-resolution Fourier transform mass spectrometry to examine lipid profile differences between paired cancerous and non-cancerous lung tissue samples from 86 patients with suspected stage I or IIA primary NSCLC. Correlation and co-occurrence analysis revealed significant lipid profile differences between cancer and non-cancer samples. Further analysis of machine-learned lipid categories for the differentially abundant molecular formulas identified a high abundance sterol, …

Rorα Suppresses Cancer-Associated Inflammation By Repressing Respiratory Complex I-Dependent Ros Generation, Wei Mao, Gaofeng Xiong, Yuanyuan Wu, Chi Wang, Daret St. Clair, Jai-Da Li, Ren Xu

Markey Cancer Center Faculty Publications

Breast cancer development is associated with macrophage infiltration and differentiation in the tumor microenvironment. Our previous study highlights the crucial function of reactive oxygen species (ROS) in enhancing macrophage infiltration during the disruption of mammary tissue polarity. However, the regulation of ROS and ROS-associated macrophage infiltration in breast cancer has not been fully determined. Previous studies identified retinoid orphan nuclear receptor alpha (RORα) as a potential tumor suppressor in human breast cancer. In the present study, we showed that retinoid orphan nuclear receptor alpha (RORα) significantly decreased ROS levels and inhibited ROS-mediated cytokine expression in breast cancer cells. RORα expression …

Co-Targeting Plk1 And Dnmt3a In Advanced Prostate Cancer, Zhuangzhuang Zhang, Lijun Cheng, Qiongsi Zhang, Yifan Kong, Daheng He, Kunyu Li, Matthew Rea, Jianlin Wang, Ruixin Wang, Jinghui Liu, Zhiguo Li, Chongli Yuan, Enze Liu, Yvonne N. Fondufe-Mittendorf, Lang Li, Tao Han, Chi Wang, Xiaoqi Liu

Toxicology and Cancer Biology Faculty Publications

Because there is no effective treatment for late-stage prostate cancer (PCa) at this moment, identifying novel targets for therapy of advanced PCa is urgently needed. A new network-based systems biology approach, XDeath, is developed to detect crosstalk of signaling pathways associated with PCa progression. This unique integrated network merges gene causal regulation networks and protein-protein interactions to identify novel co-targets for PCa treatment. The results show that polo-like kinase 1 (Plk1) and DNA methyltransferase 3A (DNMT3a)-related signaling pathways are robustly enhanced during PCa progression and together they regulate autophagy as a common death mode. Mechanistically, it is shown that Plk1 …

Pi3k/Mtor Dual Inhibitor Pf-04691502 Is A Schedule-Dependent Radiosensitizer For Gastroenteropancreatic Neuroendocrine Tumors, Zeta Chow, Jeremy Johnson, Aman Chauhan, Tadahide Izumi, Michael Cavnar, Heidi L. Weiss, Courtney M. Townsend Jr., Lowell B. Anthony, Carrigan Wasilchenko, Matthew L. Melton, Jörg Schrader, B. Mark Evers, Piotr G. Rychahou

Markey Cancer Center Faculty Publications

Patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have a poor overall prognosis despite chemotherapy and radiotherapy (e.g., peptide receptor radionuclide therapy (PRRT)). Better treatment options are needed to improve disease regression and patient survival. The purpose of this study was to examine a new treatment strategy by combining PI3K/mTOR dual inhibition and radiotherapy. First, we assessed the efficacy of two PI3K/mTOR dual inhibitors, PF-04691502 and PKI-402, to inhibit pAkt and increase apoptosis in NET cell lines (BON and QGP-1) and patient-derived tumor spheroids as single agents or combined with radiotherapy (XRT). Treatment with PF-04691502 decreased pAkt (Ser473) expression for up …

Role Of Ampk And Akt In Triple Negative Breast Cancer Lung Colonization, Jeremy Johnson, Zeta Chow, Eun Young Lee, Heidi L. Weiss, B. Mark Evers, Piotr G. Rychahou

Pathology and Laboratory Medicine Faculty Publications

Triple negative breast cancer (TNBC) is an aggressive disease with a 5-y relative survival rate of 11% after distant metastasis. To survive the metastatic cascade, tumor cells remodel their signaling pathways by regulating energy production and upregulating survival pathways. AMP-activated protein kinase (AMPK) and Akt regulate energy homeostasis and survival, however, the individual or synergistic role of AMPK and Akt isoforms during lung colonization by TNBC cells is unknown. The purpose of this study was to establish whether targeting Akt, AMPKα or both Akt and AMPKα isoforms in circulating cancer cells can suppress TNBC lung colonization. Transient silencing of Akt1 …