Medical Specialties Commons^™

Protein Oxidation In Aging And Alzheimer’S Disease Brain, Rukhsana Sultana, D. Allan Butterfield

Markey Cancer Center Faculty Publications

Proteins are essential molecules that play crucial roles in maintaining cellular homeostasis and carrying out biological functions such as catalyzing biochemical reactions, structural proteins, immune response, etc. However, proteins also are highly susceptible to damage by reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this review, we summarize the role of protein oxidation in normal aging and Alzheimer’s disease (AD). The major emphasis of this review article is on the carbonylation and nitration of proteins in AD and mild cognitive impairment (MCI). The oxidatively modified proteins showed a strong correlation with the reported changes in brain structure, carbohydrate …

Predicting The Pathway Involvement Of Metabolites Based On Combined Metabolite And Pathway Features, Erik D. Huckvale, Hunter N. B. Moseley

Markey Cancer Center Faculty Publications

A major limitation of most metabolomics datasets is the sparsity of pathway annotations for detected metabolites. It is common for less than half of the identified metabolites in these datasets to have a known metabolic pathway involvement. Trying to address this limitation, machine learning models have been developed to predict the association of a metabolite with a “pathway category”, as defined by a metabolic knowledge base like KEGG. Past models were implemented as a single binary classifier specific to a single pathway category, requiring a set of binary classifiers for generating the predictions for multiple pathway categories. This past approach …

Regulation Of Rorα Stability Through Prmt5-Dependent Symmetric Dimethylation, Gaofeng Xiong, Brynne Obringer, Austen Jones, Elise Horton, Ren Xu

Markey Cancer Center Faculty Publications

Retinoic acid receptor-related orphan receptor alpha (RORα), a candidate tumor suppressor, is prevalently downregulated or lost in malignant breast cancer cells. However, the mechanisms of how RORα expression is regulated in breast epithelial cells remain incompletely understood. Protein arginine N-methyltransferase 5 (PRMT5), a type II methyltransferase catalyzing the symmetric methylation of the amino acid arginine in target proteins, was reported to regulate protein stability. To study whether and how PRMT5 regulates RORα, we examined the direct interaction between RORα and PRMT5 by immunoprecipitation and GST pull-down assays. The results showed that PRMT5 directly bound to RORα, and PRMT5 mainly symmetrically …

A Cautionary Tale About Properly Vetting Datasets Used In Supervised Learning Predicting Metabolic Pathway Involvement, Erik D. Huckvale, Hunter N. B. Moseley

Markey Cancer Center Faculty Publications

The mapping of metabolite-specific data to pathways within cellular metabolism is a major data analysis step needed for biochemical interpretation. A variety of machine learning approaches, particularly deep learning approaches, have been used to predict these metabolite-to-pathway mappings, utilizing a training dataset of known metabolite-to-pathway mappings. A few such training datasets have been derived from the Kyoto Encyclopedia of Genes and Genomes (KEGG). However, several prior published machine learning approaches utilized an erroneous KEGG-derived training dataset that used SMILES molecular representations strings (KEGG-SMILES dataset) and contained a sizable proportion (~26%) duplicate entries. The presence of so many duplicates taint the …

Overexpression Of Fatty Acid Synthase Upregulates Glutamine–Fructose-6-Phosphate Transaminase 1 And O-Linked N-Acetylglucosamine Transferase To Increase O-Glcnac Protein Glycosylation And Promote Colorectal Cancer Growth, James Drury, Mariah E. Geisen, Josiane Weber Tessmann, Piotr G. Rychahou, Courtney O. Kelson

Markey Cancer Center Faculty Publications

Fatty acid synthesis has been extensively investigated as a therapeutic target in cancers, including colorectal cancer (CRC). Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated in CRC, and therapeutic approaches of targeting this enzyme are currently being tested in multiple clinical trials. However, the mechanisms behind the pro- oncogenic action of FASN are still not completely understood. Here, for the first time, we show that overexpression of FASN increases the expression of glutamine–fructose-6-phosphate transaminase 1 (GFPT1) and O-linked N-acetylglucosamine transferase (OGT), enzymes involved in hexosamine metabolism, and the level of O-GlcNAcylation in vitro …

Chromosomal 3q Amplicon Encodes Essential Regulators Of Secretory Vesicles That Drive Secretory Addiction In Cancer, Xiaochao Tan, Shike Wang, Guan-Yu Xiao, Chao Wu, Xin Liu, Biyao Zhou, Yu Jiang, Dzifa Y. Duose, Yuanxin Xi, Jing Wang, Kunika Gupta, Apar Pataer, Jack A. Roth, Michael P. Kim, Fengju Chen, Chad J. Creighton, William K. Russell, Jonathan M. Kurie

Markey Cancer Center Faculty Publications

Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identified a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase secretory pathway Ca2+ transporting 1 (ATP2C1). We show that GOLIM4 recruited ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate Ca2+ -dependent cargo loading, Golgi membrane bending, and vesicle scission. GOLIM4 depletion disrupted the protein complex, resulting in a secretory blockade that inhibited the progression of 3q-amplified malignancies. In addition to its role …

Shared Genomic Segments Analysis Identifies Mhc Class I And Class Iii Molecules As Genetic Risk Factors For Juvenile Idiopathic Arthritis, Cecile N. Avery, Nicole D. Russell, Cody J. Steely, Aimee O. Hersh, John F. Bohnsack, Sampath Prahalad, Lynn B. Jorde

Markey Cancer Center Faculty Publications

Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease encompassing several clinically defined subtypes of varying severity. The etiology of JIA remains largely unknown, but genome-wide association studies (GWASs) have identified up to 22 genes associated with JIA susceptibility, including a well-established association with HLA-DRB1. Continued investigation of heritable risk factors has been hindered by disease heterogeneity and low disease prevalence. In this study, we utilized shared genomic segments (SGS) analysis on whole-genome sequencing of 40 cases from 12 multi-generational pedigrees significantly enriched for JIA. Subsets of cases are connected by a common ancestor in large extended pedigrees, increasing the …

Inhibition Of Carbohydrate Metabolism Potentiated By The Therapeutic Effects Of Oxidative Phosphorylation Inhibitors In Colon Cancer Cells, Lichao Guo, Baochen Zhang, Wen Zhang, Yanqi Xie, Xi Chen, Xueke Sun, David S. Watt, Chunming Liu, H. Peter Spielmann, Xifu Liu

Markey Cancer Center Faculty Publications

Cancer cells undergo a significant level of “metabolic reprogramming” or “remodeling” to ensure an adequate supply of ATP and “building blocks” for cell survival and to facilitate accelerated proliferation. Cancer cells preferentially use glycolysis for ATP production (the Warburg effect); however, cancer cells, including colorectal cancer (CRC) cells, also depend on oxidative phospho- rylation (OXPHOS) for ATP production, a finding that suggests that both glycolysis and OXPHOS play significant roles in facilitating cancer progression and proliferation. Our prior studies identified a semisynthetic isoflavonoid, DBI-1, that served as an AMPK activator targeting mitochondrial com- plex I. Furthermore, DBI-1 and a glucose …

Relative Adrenal Insufficiency Is A Risk Factor For Pediatric Sepsis: A Proof-Of-Concept Study, Dan Hao, Ling Guo, Qian Wang, Misa Ito, Bin Huang, Chieko Mineo, Philip W. Shaul, Xiang-An Li

Markey Cancer Center Faculty Publications

Glucocorticoid (GC) therapy had been strongly recommended for pediatric sepsis (grade 1A). However, the recommendation was changed to grade 2C in 2020 due to weak evidence. About 32.8% of patients with pediatric septic develop relative adrenal insufficiency (RAI). But whether GC therapy should be determined by RAI status is controversial. This study utilized 21-day- old SF1CreSRBIfl/fl mice as the first pediatric RAI mouse model to assess the pathogenesis of RAI and evaluate GC therapy. RAI mice exhibited a substantially higher mortality rate in cecal ligation and puncture and cecal slurry–induced sepsis. These mice featured persistent inflammatory responses and were effectively …

The Nonvesicular Sterol Transporter Aster-C Plays A Minor Role In Whole Body Cholesterol Balance, Ranjan Banerjee, Rachel C. Hohe, Shijie Cao, Bryan M. Jung, Anthony J. Horak, Iyappan Ramachandiran, William J. Massey, Venkateshwari Varadharajan, Natalie I. Zajczenko, Amy C. Burrows, Sumita Dutta, Maryam Goudarzi, Kala Mahen, Abigail Carter, Robert N. Helsley, Scott M. Gordon, Richard E. Morton, Christopher Strauch, Belinda Willard, Camelia Baleanu Gogonea, Valentin Gogonea, Matteo Pedrelli, Paolo Parini, J. Mark Brown

Markey Cancer Center Faculty Publications

Introduction: The Aster-C protein (encoded by the Gramd1c gene) is an endoplasmic reticulum (ER) resident protein that has been reported to transport cholesterol from the plasma membrane to the ER. Although there is a clear role for the closely-related Aster-B protein in cholesterol transport and downstream esterification in the adrenal gland, the specific role for Aster-C in cholesterol homeostasis is not well understood. Here, we have examined whole body cholesterol balance in mice globally lacking Aster-C under low or high dietary cholesterol conditions.

Method: Age-matched Gramd1c^+/+ and Gramd1c^−/− mice were fed either low (0.02%, wt/wt) or high (0.2%, …

Patient Experience Of Head And Neck Surgery With Free Flap Reconstruction., Lillian W. Dattilo, Trinity I. Russell, Chloe B. Warinner, Heather Starmer, Donald J. Annino, Laura A. Goguen, Rosh K. V. Sethi, Ravindra Uppaluri, Melina Windon, Regan W. Bergmark, Eleni M. Rettig

Markey Cancer Center Faculty Publications

IMPORTANCE: Major head and neck surgery with microvascular free tissue transfer reconstruction is complex, with considerable risk of morbidity. Little is known about patients' experiences, including decision-making prior to, and regret following, free flap surgery.

OBJECTIVE: To characterize patient experiences and decision regret of patients undergoing head and neck reconstructive free flap surgery.

DESIGN, SETTING, AND PARTICIPANTS: This mixed-methods cohort study comprising semistructured interviews was conducted June to August 2021 at a single tertiary academic cancer center. Participants underwent head and neck reconstructive surgery with microvascular free tissue transfer (flap) more than 3 months before recruitment (range, 3 months to …

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 …

A Single Hydrogen Bond That Tunes Flavin Redox Reactivity And Activates It For Modification, Debarati Das, Anne-Frances Miller

Markey Cancer Center Faculty Publications

Electron bifurcation produces high-energy products based on less energetic reagents. This feat enables biological systems to exploit abundant mediocre fuel to drive vital but demanding reactions, including nitrogen fixation and CO₂ capture. Thus, there is great interest in understanding principles that can be portable to man-made devices. Bifurcating electron transfer flavoproteins (Bf ETFs) employ two flavins with contrasting reactivities to acquire pairs of electrons from a modest reductant, NADH. The bifurcating flavin then dispatches the electrons individually to a high and a low reduction midpoint potential (E°) acceptor, the latter of which captures most of the energy. Maximum efficiency …

Myeloid-Derived Suppressor Cell Mitochondrial Fitness Governs Chemotherapeutic Efficacy In Hematologic Malignancies, Saeed Daneshmandi, Jee Eun Choi, Qi Yan, Cameron R. Macdonald, Manu Pandey, Mounika Goruganthu, Nathan Roberts, Prashant K. Singh, Richard M. Higashi, Andrew N. Lane, Teresa W-M Fan, Jianmin Wang, Philip L. Mccarthy, Elizabeth A. Repasky, Hemn Mohammadpour

Markey Cancer Center Faculty Publications

Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprogram- ing, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of …

Colorectal Cancer Survival Disparities In The Five Regions Of Georgia, Meng-Han Tsai, Daramola N. Cabral, Caitlyn Grunert, Justin X. Moore

Markey Cancer Center Faculty Publications

Background/objective

The objective of this study was to examine 5-year colorectal cancer survival rates. We also determined whether demographics, tumor characteristics, and treatment modality were associated with 5-year CRC survival in the Clayton, West Central, East Central, Southeast, and Northeast Georgia regions because the significant higher CRC mortality rates in these regions in comparison to the overall rates in the State of Georgia.

Methods

We conducted a retrospective cohort analysis using data from the 1975–2016 Surveillance, Epidemiology, and End Results program aggregated CRC patients to these five regions. Five-year CRC survival was calculated and stratified by the five regions of …

The Hagfish Genome And The Evolution Of Vertebrates, Ferdinand Marlétaz, Nataliya Timoshevskaya, Vladimir A. Timoshevskiy, Elise Parey, Oleg Simakov, Daria Gavriouchkina, Masakazu Suzuki, Kaoru Kubokawa, Sydney Brenner, Jeramiah James Smith, Daniel S. Rokhsar

Markey Cancer Center Faculty Publications

As the only surviving lineages of jawless fishes, hagfishes and lampreys provide a crucial window into early vertebrate evolution1–3 . Here we investigate the complex history, timing and functional role of genome-wide duplications4–7 and programmed DNA elimination8,9 in vertebrates in the light of a chromosome-scale genome sequence for the brown hagfish Eptatretus atami. Combining evidence from syntenic and phylogenetic analyses, we establish a comprehensive picture of vertebrate genome evolution, including an auto-tetraploidization (1RV) that predates the early Cambrian cyclostome–gnathostome split, followed by a mid–late Cambrian allo-tetraploidization (2RJV) in gnathostomes and a prolonged Cambrian–Ordovician hexaploidization (2RCY) in cyclostomes. Subsequently, hagfishes underwent …

Altered Lipid Metabolism In Apc-Driven Colorectal Cancer: The Potential For Therapeutic Intervention, Courtney O. Kelson, Yekaterina Y. Zaytseva

Markey Cancer Center Faculty Publications

Altered lipid metabolism is a well-recognized feature of solid cancers, including colorectal cancer. In colorectal cancer, upregulation of lipid metabolism contributes to initiation, progression, and metastasis; thus, aberrant lipid metabolism contributes to a poor patient outcome. The inactivating mutation of APC, a vital tumor suppressor in the Wnt signaling pathway, is a key event that occurs early in the majority of colorectal cancer cases. The potential crosstalk between lipid metabolism and APC-driven colorectal cancer is poorly understood. This review collectively highlights and summarizes the limited understanding between mutations in APC and the upregulation of Wnt/beta- catenin signaling and lipid metabolism. …

Interferons In Viral Infections, Pracheta Sengupta, Saurabh Chattopadhyay

Markey Cancer Center Faculty Publications

No abstract provided.

Integration Of Pan-Omics Technologies And Three-Dimensional In Vitro Tumor Models: An Approach Toward Drug Discovery And Precision Medicine., Anmi Jose, Pallavi Kulkarni, Jaya Thilakan, Murali Munisamy, Anvita Gupta Malhotra, Jitendra Singh, Ashok Kumar, Vivek M. Rangnekar, Neha Arya, Mahadev Rao

Markey Cancer Center Faculty Publications

Despite advancements in treatment protocols, cancer is one of the leading cause of deaths worldwide. Therefore, there is a need to identify newer and personalized therapeutic targets along with screening technologies to combat cancer. With the advent of pan-omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, and lipidomics, the scientific community has witnessed an improved molecular and metabolomic understanding of various diseases, including cancer. In addition, three-dimensional (3-D) disease models have been efficiently utilized for understanding disease pathophysiology and as screening tools in drug discovery. An integrated approach utilizing pan-omics technologies and 3-D in vitro tumor models has led to …

Financial-Legal Navigation Reduces Financial Toxicity Of Pediatric, Adolescent, And Young Adult Cancers, Jean Edward, Kimberly D. Northrip, Mary Kay Rayens, Andrea Welker, Rachel O'Farrel, Jennifer Knuf, Haafsah Fariduddin, Julia Costich, John A. D'Orazio

Markey Cancer Center Faculty Publications

Background: Pediatric, adolescent, and young adult patients with cancer and their caregivers are at high risk of financial toxicity, and few evidence-based oncology financial and legal navigation programs exist to address it. We tested the feasibility, acceptability, and preliminary effectiveness of Financial and Insurance Navigation Assistance, a novel interdisciplinary financial and legal naviga- tion intervention for pediatric, adolescent and young adult patients and their caregivers.

Methods: We used a single-arm feasibility and acceptability trial design in a pediatric hematology and oncology clinic and collected preintervention and postintervention surveys to assess changes in financial toxicity (3 domains: psychological response/ Comprehensive Score …

Staphylococcus Aureus Oleate Hydratase Produces Ligands That Activate Host Ppara, Christopher D. Radka, Matthew W. Frank, Tyler S. Simmons, Cydney N. Johnson, Jason W. Rosch, Charles O. Rock

Markey Cancer Center Faculty Publications

Commensal gut bacteria use oleate hydratase to release a spectrum of hydroxylated fatty acids using host-derived unsaturated fatty acids. These compounds are thought to attenuate the immune response, but the underlying signaling mechanism(s) remain to be established. The pathogen Staphylococcus aureus also expresses an oleate hydratase and 10- hydroxyoctadecanoic acid (h18:0) is the most abundant oleate hydratase metabolite found at Staphylococcal skin infection sites. Here, we show h18:0 stimulates the transcription of a set of lipid metabolism genes associated with the activation of peroxisome proliferator activated receptor (PPAR) in the RAW 264.7 macrophage cell line and mouse primary bone marrow-derived …

Cold-Inducible Rna Binding Protein Impedes Breast Tumor Growth In The Pymt Murine Model For Breast Cancer, Daniel A. Lujan, Joey L. Ochoa, Ellen J. Beswick, Tamara A. Howard, Helen J. Hathaway, Nora I. Perrone-Bizzozero, Rebecca S. Hartley

Markey Cancer Center Faculty Publications

RNA binding proteins (RBPs) post-transcriptionally regulate gene expression by associating with regulatory sequences in the untranslated regions of mRNAs. Cold-inducible RBP (CIRP) is a stress-induced RBP that was recently shown to modulate inflammation in response to cellular stress, where it increases or decreases pro-tumorigenic (proinflammatory) cytokines in different contexts. CIRP expression is altered in several cancers, including breast cancer, but the effects of CIRP on inflammation in breast cancer is not known. Here, we investigate if CIRP alters growth and the inflammatory profile of breast tumors. Transgenic mice overexpressing CIRP in the mammary epithelium were crossed with the PyMT mouse …

Association Between Circulating Inflammatory Markers And Adult Cancer Risk: A Mendelian Randomization Analysis., James Yarmolinsky, Jamie W. Robinson, Daniela Mariosa, Ville Karhunen, Jian Huang, Niki Dimou, Neil Murphy, Kimberley Burrows, Emmanouil Bouras, Karl Smith-Byrne, Sarah J. Lewis, Tessel E. Galesloot, Lambertus A. Kiemeney, Sita Vermeulen, Paul Martin, Demetrius Albanes, Lifang Hou, Polly A. Newcomb, Emily White, Alicja Wolk, Anna H. Wu, Loïc Le Marchand, Amanda I. Phipps, Daniel D. Buchanan, The International Lung Cancer Consortium, The Practical Consortium, Sizheng Steven Zhao, Dipender Gill, Stephen J. Chanock, Mark P. Purdue, George Davey Smith, Paul Brennan, Karl-Heinz Herzig, Marjo-Riitta Järvelin, Chris I. Amos, Rayjean J. Hung, Abbas Dehghan, Mattias Johansson, Marc J. Gunter, Kostas K. Tsilidis, Richard M. Martin

Markey Cancer Center Faculty Publications

BACKGROUND: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear.

METHODS: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were …

Feasibility And Clinical Utility Of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified In Research Germline Sequencing: A Prospective Interventional Study, Megan L. Hutchcraft, Shulin Zhang, Nan Lin, Justine C. Pickarski, Elizabeth Belcher, Sainan Wei, Therese J. Bocklage, Rachel W. Miller, John L. Villano, Michael J. Cavnar, Joseph Kim, Susanne M. Arnold, Frederick R. Ueland, Jill M. Kolesar

Markey Cancer Center Faculty Publications

PURPOSE

Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant sec- ondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician.

METHODS

This prospective, interventional cohort study enrolled Total Cancer Care par- ticipants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic anal- ysis in a Clinical Laboratory Improvement Amendments–certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College …

Effect Of Zwitterionic Additives On Solvation And Transport Of Sodium And Potassium Cations In (Ethylene Oxide)10: A Molecular Dynamics Simulation Study, Manh Tien Nguyen, Yuhua Duan, Qing Shao

Markey Cancer Center Faculty Publications

Sodium- (Na+) and potassium- (K+) ion batteries are cost-effective alternatives to lithium- ion (Li+) batteries due to the abundant sodium and potassium resources. Solid polymer electrolytes (SPEs) are essential for safer and more efficient Na+ and K+ batteries because they often exhibit low ionic conductivity at room temperature. While zwitterionic (ZW) materials enhance Li+ battery conductivity, their potential for Na+ and K+ transport in batteries remains unexplored. In this study, we investigated the effect of three ZW molecules (ChoPO4, i.e., 2-methacryloyloxyethyl phosphoryl- choline, ImSO3, i.e., sulfobetaine ethylimidazole, and ImCO2, i.e., carboxybetaine ethylimidazole) on the dissociation of Na+ and K+ coordination …

Cancer Survivorship Care In The United States At Facilities Accredited By The Commission On Cancer, Julia Stal, Kimberly A. Miller, Timothy W. Mullett, Judy C. Boughey, Amanda B. Francescatti, Elizabeth Funk, Heidi Nelson, David R. Freyer

Markey Cancer Center Faculty Publications

IMPORTANCE Since 2021, American College of Surgeons Commission on Cancer (CoC) accreditation standards require providing a survivorship program for patients with adult-onset cancer treated with curative intent. Since more than 70% of all patients with cancer in the US are treated at CoC-accredited facilities, this presents an opportunity for a landscape analysis of survivorship care availability.

OBJECTIVE To determine the prevalence, types, and outcomes of cancer survivorship services at CoC-accredited facilities.

DESIGN, SETTING, AND PARTICIPANTS This survey study used an anonymous, online, cross-sectional survey conducted from May 4 to 25, 2023. Participants were CoC-accredited facilities in the US representing diverse …

Nalfurafine Promotes Myelination In Vitro And Facilitates Recovery From Cuprizone + Rapamycin-Induced Demyelination In Mice, Ross Van De Wetering, Rabia Bibi, Andy Biggerstaff, Sheein Hong, Bria Pengelly, Thomas E. Prisinzano, Anne C. La Flamme, Bronwyn M. Kivell

Markey Cancer Center Faculty Publications

The kappa opioid receptor has been identified as a promising therapeutic target for promoting remyelination. In the current study, we evaluated the ability of nalfurafine to promote oligodendrocyte progenitor cell (OPC) differentiation and myelination in vitro, and its efficacy in an extended, cuprizone-induced demyelination model. Primary mouse (C57BL/6J) OPC-containing cultures were treated with nalfurafine (0.6–200 nM), clemastine (0.01–100 μM), T3 (30 ng/mL), or vehicle for 5 days. Using immunocytochemistry and confocal microscopy, we found that nalfurafine treatment increased OPC differentiation, oligodendrocyte (OL) morphological complexity, and myelination of nanofibers in vitro. Adult male mice (C57BL/6J) were given a diet con- taining …

The Potential Beneficial Role Of Anti-Platelet/Anti-Coagulant Medications On Diabetic Retinopathy: A Scoping Review Protocol, Sarah Draud, Qingjun Wang, Lauren E. Robinson

Markey Cancer Center Faculty Publications

Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes mellitus (DM, both types 1 and 2), affecting millions of individuals worldwide. DM is known to induce changes in platelet function and hemostasis, thereby elevating the risk of thrombotic incidents. The hyperglycemic environment in DM can trigger platelet hyperactivity, potentially exacerbating the onset and progression of DR. Despite the intricate pathophysiology of DR, which involves oxidative stress, inflammation, retinal neovascularization, and the disruption of the blood-retina barrier, the specific mechanisms underlying platelet hyperactivity in the microvasculature of DM patients remain inadequately explored. Antiplatelet and anticoagulation medications have proven beneficial in …

Ezh2 Inhibition Promotes Tumor Immunogenicity In Lung Squamous Cell Carcinomas, Tanner Ducote, Xiulong Song, Kassandra J. Naughton, Fan Chen, Daniel Plaugher, Avery R. Childress, Abigail R. Gellert, Erika M. Skaggs, Xufeng Qu, Jinze Liu, Jinpeng Liu, Fei Li, Kwok-Kin Wong, Christine F. Brainson

Markey Cancer Center Faculty Publications

Two important factors that contribute to resistance to immune checkpoint inhibitors (ICI) are an immune-suppressive microenvironment and limited antigen presentation by tumor cells. In this study, we examine whether in- hibition of the methyltransferase enhancer of zeste homolog 2 (EZH2) can increase ICI response in lung squamous cell carcinomas (LSCC). Our in vitro experiments using two-dimensional human cancer cell lines as well as three-dimensional murine and patient-derived organoids treated with two inhibitors of the EZH2 plus IFNγ showed that EZH2 inhibition leads to expression of both MHC class I and II (MHCI/II) expression at both the mRNA and protein levels. …

Zebrafish Drug Screening Identifies Erlotinib As An Inhibitor Of Wnt/ Β-Catenin Signaling And Self-Renewal In T-Cell Acute Lymphoblastic Leukemia, Majd A. Al-Hamaly, Anna H. Cox, Meghan G. Haney, Wen Zhang, Emma C. Arvin, Shilpa Sampathi, Mary Wimsett, Chunming Liu, Jessica S. Blackburn

Markey Cancer Center Faculty Publications

The Wnt/β-catenin pathway’s significance in cancer initiation, progression, and stem cell biology underscores its therapeutic potential. However, the clinical application of Wnt inhibitors remains limited due to challenges posed by off-target effects and complex cross-talk of Wnt signaling with other pathways. In this study, we leveraged a zebrafish model to perform a robust and rapid drug screening of 773 FDA-approved compounds to identify Wnt/β-catenin inhibitors with minimal toxicity. Utilizing zebrafish expressing a Wnt reporter, we identified several drugs that suppressed Wnt signaling without compromising zebrafish development. The effi- cacy of the top hit, Erlotinib, extended to human cells, where it …