Medical Specialties Commons^™

Gdp-Mannose 4,6-Dehydratase Is A Key Driver Of Mycn-Amplified Neuroblastoma Core Fucosylation And Tumorigenesis, Beibei Zhu, Michelle G. Pitts, Michael D. Buoncristiani, Lindsay T. Bryant, Oscar Lopez-Nunez, Juan P. Gurria, Cameron Shedlock, Roberto Ribas, Shannon Keohane, Jinpeng Liu, Chi Wang, Matthew S. Gentry, Nathan R. Shelman, Derek B. Allison, B. Mark Evers, Ramon C. Sun, Eric J. Rellinger

Markey Cancer Center Faculty Publications

MYCN-amplification is a genetic hallmark of ~40% of high-risk neuroblastomas (NBs). Altered glycosylation is a common feature of adult cancer progression, but little is known about how genetic signatures such as MYCN-amplification alter glycosylation profiles. Herein, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) revealed increased core fucosylated glycan abundance within neuroblast-rich regions of human MYCN-amplified NB tumors. GDP-mannose 4,6-dehydratase (GMDS) is responsible for the first-committed and rate-limiting step of de novo GDP-fucose synthesis. High GMDS expression was found to be associated with poor patient survival, advanced stage disease, and MYCN-amplification in human NB tumors. Chromatin immunoprecipitation and promoter reporter assays …

A Microrna-Regulated Transcriptional State Defines Intratumoral Cd8+ T Cells That Respond To Immunotherapy, William W. Tang, Ben Battistone, Kaylyn M. Bauer, Allison M. Weis, Cindy Barba, Muhammad Zaki Hidayatullah Fadlullah, Arevik Ghazaryan, Van B. Tran, Soh-Hyun Lee, Z. Busra Agir, Morgan C. Nelson, Emmanuel Stephen Victor, Amber Thibeaux, Colton Hernandez, Jacob Tantalla, Aik C. Tan, Dinesh Rao, Matthew Williams, Micah J. Drummond, Ellen J. Beswick, June L. Round, H. Atakan Ekiz, Warren P/ Voth, Ryan M. O’Connell

Markey Cancer Center Faculty Publications

The rising incidence of advanced-stage colorectal cancer (CRC) and poor survival outcomes necessitate new and effective therapies. Immune checkpoint inhibitors (ICIs), specifically anti-PD-1 therapy, show promise, yet clinical determinants of a positive response are suboptimal. Here, we identify microRNA-155 (miR-155) as necessary for CD8 + T cell-infiltrated tumors through an unbiased in vivo CRISPR-Cas9 screen identifying functional tumor antigen-specific CD8+ T cell-expressed microRNAs. T cell miR-155 is required for anti-PD-1 responses and for a vital intratumor CD8 + T cell differentiation cascade by repressing Ship-1, inhibiting Tcf-1 and stemness, and subsequently enhancing Cxcr6 expression, anti-tumor immunity, and effector functions. Based …

Staying Sane In The Membrane: Neutral Sphingomyelinase 2 As A Master Regulator Of Plasma Membrane Ceramide, Zainuddin Quadri, Erhard Bieberich

Markey Cancer Center Faculty Publications

Ceramide, a key signaling sphingolipid in the plasma membrane, plays a pivotal role in fundamental cellular processes such as adhesion, polarity, and programmed cell death. The generation of plasma membrane ceramide is largely attributed to the activity of two types of sphingomyelinases: neutral sphingomyelinase 2 (nSMase2, Smpd3) and acid sphingomyelinase (aSMase, Smpd1). While many studies have explored ceramide generation following experimental activation of these enzymes, the mechanisms governing basal or steady- state ceramide levels have remained poorly understood. Using an innovative mass spectrometry approach developed in the Canals’ lab, the team has quantified the distinct contributions of nSMase2 and aSMase …

Bilirubin Bioconversion To Urobilin In The Gut-Liver-Kidney Axis: A Biomarker For Insulin Resistance In The Cardiovascular-Kidney-Metabolic (Ckm) Syndrome, Zachary A. Kipp, Olufunto O. Badmus, David E. Stec, Brantley Hall, Terry D. Hinds Jr.

Markey Cancer Center Faculty Publications

The rising rates of obesity worldwide have increased the incidence of cardiovascular disease (CVD), making it the number one cause of death. Higher plasma bilirubin levels have been shown to prevent metabolic dysfunction and CVD. However, reducing levels leads to deleterious outcomes, possibly due to reduced bilirubin half-life that escalates the production of its catabolized product, urobilinogen, produced by gut bacteria and naturally oxidized to urobilin. Recent findings suggest that the involvement of the microbiome catabolism of bilirubin to urobilin and its absorption via the hepatic portal vein contributes to CVD, suggesting a liver-gut axis involvement. We discuss the studies …

Ddo-Adjuvanted Influenza A Virus Nucleoprotein Mrna Vaccine Induces Robust Humoral And Cellular Type 1 Immune Responses And Protects Mice From Challenge, Victoria Gnazzo, Hanaa Saleh, Ítalo A. Castro, Adrianus C. M. Boon, Amelia K. Pinto, James D. Brien, Carolina B. López

Markey Cancer Center Faculty Publications

A challenge in viral vaccine development is to produce vaccines that generate both neutralizing antibodies to prevent infection and cytotoxic CD8+ T-cells that target conserved viral proteins and can eliminate infected cells to control virus spread. mRNA technology offers an opportunity to design vaccines based on conserved CD8-targeting epitopes, but achieving robust antigen-specific CD8+ T-cells remains a challenge. Here, we tested the viral-derived oligonucleotide DDO268 as an adjuvant in the context of a model influenza A virus (IAV) nucleoprotein (NP) mRNA vaccine in C57BL/6 mice. DDO268 when co-packaged with mRNA in lipid nanoparticles is sensed by RIG I-like receptors and …

The Mitochondria As An Emerging Target Of Self- Renewal In T-Cell Acute Lymphoblastic Leukemia, Majd Al-Hamaly, Evelyn Winter, Jessica S. Blackburn

Markey Cancer Center Faculty Publications

Acute lymphocytic leukemia (ALL) is the most common leukemia in children, with the T-cell subtype (T- ALL) accounting for 15% of those cases. Despite advancements in the treatment of T-ALL, patients still face a dismal prognosis following their first relapse. Relapse can be attributed to the inability of chemotherapy agents to eradicate leukemia stem cells (LSC), which possess self-renewal capabilities and are responsible for the long-term maintenance of the disease. Mitochondria have been recognized as a therapeutic vulnerability for cancer stem cells, including LSCs. Mitocans have shown promise in T-ALL both in vitro and in vivo, with some currently in …

Gdp-Mannose 4,6-Dehydratase Is A Key Driver Of Mycn- Amplified Neuroblastoma Core Fucosylation And Tumorigenesis, Beibei Zhu, Michelle G. Pitts, Michael D. Buoncristiani, Lindsay T. Bryant, Oscar Lopez-Nunez, Juan P. Gurria, Cameron Shedlock, Roberto Ribas, Shannon Keohane, Jinpeng Liu, Chi Wang, Matthew S. Gentry, Nathan R. Shelman, Derek B. Allison, B. Mark Evers, Ramon C. Sun, Eric J. Rellinger

Markey Cancer Center Faculty Publications

MYCN-amplification is a genetic hallmark of ~40% of high-risk neuroblastomas (NBs). Altered glycosylation is a common feature of adult cancer progression, but little is known about how genetic signatures such as MYCN-amplification alter glycosylation profiles. Herein, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) revealed increased core fucosylated glycan abundance within neuroblast-rich regions of human MYCN-amplified NB tumors. GDP-mannose 4,6-dehydratase (GMDS) is responsible for the first-committed and rate-limiting step of de novo GDP-fucose synthesis. High GMDS expression was found to be associated with poor patient survival, advanced stage disease, and MYCN-amplification in human NB tumors. Chromatin immunoprecipitation and promoter reporter assays …

Metformin In Overcoming Enzalutamide Resistance In Castration-Resistant Prostate Cancer, Kendall Simpson, Derek B. Allison, Daheng He, Jinpeng Liu, Chi Wang, Xiaoqi Liu

Markey Cancer Center Faculty Publications

Androgen deprivation is the standard treatment for patients with prostate cancer. However, the disease eventually progresses as castration-resistant prostate cancer (CRPC). Enzalutamide, an androgen receptor inhibitor, is a typical drug for treating CRPC and with continuous reliance on the drug, can lead to enzalutamide resistance. This highlights the necessity for developing novel therapeutic targets to combat the gain of resistance. Metformin has been recently investigated for its potential antitumorigenic effects in many cancer types. In this study, we used enzalutamide and metformin in combination to explore the possible rescued efficacy of enzalutamide in the treatment of enzalutamide-resistant CRPC. We first …

Portable Multi-Parametric Microscopy For Noninvasive Metabolic And Vascular Imaging Of Orthotopic Tongue Cancer Models In Vivo, Pranto Soumik Saha, Jing Yan, Caigang Zhu

Markey Cancer Center Faculty Publications

Significance: Precise imaging of tumor metabolism with its vascular microenvironment becomes emerging critical for cancer research because increasing evidence shows that the key attribute that allows a tumor to survive therapies is metabolic and vascular reprogramming. However, there are surprisingly few imaging techniques available to provide a systems-level view of tumor metabolism and vasculature in vivo on small animals for cancer discoveries.

Aim: We aim to develop a new multi-parametric microscope that can faithfully recapitulate in vivo metabolic and vascular changes with a wide field of view and microscope-level resolution to advance cancer-related investigations. To maximize the ease and accessibility …

Dihydropyrimidine Enzyme Activity And Its Effect On Chemotherapy Toxicity: Importance Of Genetic Testing, Alexia Shamaei Zadeh, Danielle Roberts, Abby Williams, Deepali Pandey, John L. Villano

Markey Cancer Center Faculty Publications

Purpose

Patients with partial or complete DPD deficiency have decreased capacity to degrade fluorouracil and are at risk of developing toxicity, which can be even life-threatening.

Case

A 43-year-old man with moderately differentiated rectal adenocarcinoma on capecitabine presented to the emergency department with complaints of nausea, vomiting, diarrhea, weakness, and lower abdominal pain for several days. Laboratory findings include grade 4 neutropenia (ANC 10) and thrombocytopenia (platelets 36,000). Capecitabine is used as a component of first-line adjuvant therapy by approximately 2 million patients worldwide each year. Capecitabine is metabolized to fluorouracil via the enzyme dihydropyrimidine dehydrogenase (DPD). With worsening pancytopenia …

Tam Receptors Mediate The Fpr2-Driven Pain Resolution And Fibrinolysis After Nerve Injury, Beate Hartmannsberger, Adel Ben‑Kraiem, Sofia Kramer, Carolina Guidolin, Ida Kazerani, Kathrin Doppler, Dominique Thomas, Robert Gurke, Marco Sisignano, Pranav P. Kalelkar, Andrés J. García, Paula V. Monje, Michael Sammeth, Asma Nusrat, Alexander Brack, Susanne M. Krug, Claudia Sommer, Heike L. Rittner

Markey Cancer Center Faculty Publications

Nerve injury causes neuropathic pain and multilevel nerve barrier disruption. Nerve barriers consist of perineurial, endothe- lial and myelin barriers. So far, it is unclear whether resealing nerve barriers fosters pain resolution and recovery. To this end, we analysed the nerve barrier property portfolio, pain behaviour battery and lipidomics for precursors of specialized pro-resolving meditators (SPMs) and their receptors in chronic constriction injury of the rat sciatic nerve to identify tar- gets for pain resolution by resealing the selected nerve barriers. Of the three nerve barriers—perineurium, capillaries and myelin—only capillary tightness specifically against larger molecules, such as fibrinogen, recuperated with …

Extracellular Vesicles Released By All Patients Contain Hne-Adducted Proteins: Implications Of Collateral Damage, Jenni Ho, Suriyan Sukati, Tamara Taylor, Sherry Carter, Brittany Fuller, Amy Marmo, Caryn Sorge, John A. D'Orazio, D. Allan Butterfield, Subbarao Bondada, Heidi Weiss, Daret K. St. Clair, Luksana Chaiswing

Markey Cancer Center Faculty Publications

Off-target neuronal injury is a serious side-effect observed in cancer survivors. It has previously been shown that pediatric acute lymphoblastic leukemia (ALL) survivors have a decline in neurocognition compared to healthy age-matched counterparts. Elevated oxidative stress has been documented to be a mediator in off- target tissue damage in cancer survivors. Early detection of oxidative stress markers may provide an opportunity to prevent off-target tissue damage. Extracellular vesicles (EVs) have surfaced as a potential diagnostic tool due to molecular cargo they contain. We investigated the potential for EVs to be a sensitive indicator of oxidative stress and off-target tissue damage …

Engaging Nurses In Effective Cost Of Care Conversations To Address Cancer-Related Financial Toxicity: Results From An Exploratory Survey, Jean Edward, Amanda T. Wiggins, Louis G. Baser, Haafsah Fariduddin, Joanna F. Doran, Monica F. Bryant, John August D'Orazio, Kimberly D. Northrip

Markey Cancer Center Faculty Publications

Few evidence-based trainings exist on how to equip healthcare providers, particularly nurses, with the skills to engage in cost of care conversations with patients/caregivers to mitigate the impact of cancer-related financial toxicity. This study evaluated a pilot training developed in collaboration with Triage Cancer® to prepare oncology nurses to identify and assist patients/caregivers facing financial and/or legal barriers to care. Ten pediatric oncology nurses completed the training and pre/post-surveys on behaviors related to financial and legal need screening, frequency and comfort level of answering questions, knowledge, and behavior changes, along with training evaluation questions. At baseline, six nurses reported never …

Pharmacological Or Genetic Inhibition Of Ltcc Promotes Cardiomyocyte Proliferation Through Inhibition Of Calcineurin Activity, Lynn A. C. Devilée, Abou Bakr M. Salama, Jessica M. Miller, Janice D. Reid, Qinghui Ou, Nourhan M. Baraka, Kamal Abou Farraj, Madiha Jamal, Yibing Nong, Todd K. Rosengart, Douglas A. Andres, Jonathan Satin, Tamer M. A. Mohamed, James E. Hudson, Riham R. E. Abouleisa

Markey Cancer Center Faculty Publications

Cardiomyocytes (CMs) lost during ischemic cardiac injury cannot be replaced due to their limited proliferative capacity. Calcium is an important signal transducer that regulates key cellular processes, but its role in regulating CM proliferation is incompletely understood. Here we show a robust pathway for new calcium signaling-based cardiac regenerative strategies. A drug screen targeting proteins involved in CM calcium cycling in human embryonic stem cell-derived cardiac organoids (hCOs) revealed that only the inhibition of L-Type Calcium Channel (LTCC) induced the CM cell cycle. Furthermore, overexpression of Ras-related associated with Diabetes (RRAD), an endogenous inhibitor of LTCC, induced CM cell cycle …

The Adiponectin-Pparγ Axis In Hepatic Stellate Cells Regulates Liver Fibrosis, Shangang Zhao, Qingzhang Zhu, Wang-Hsin Lee, Jan-Bernd Funcke, Zhuzhen Zhang, May-Yun Wang, Qian Lin, Bianca Field, Xue-Nan Sun, Guannan Li, Mbolle Ekane, Toshiharu Onodera, Na Li, Yi Zhu, Christine M. Kusminski, Terry D. Hinds Jr., Philipp E. Scherer

Markey Cancer Center Faculty Publications

Hepatic stellate cells (HSCs) are key drivers of local fibrosis. Adiponectin, conventionally thought of as an adipokine, is also expressed in quiescent HSCs. However, the impact of its local expression on the progression of liver fibrosis remains unclear. We recently generated a transgenic mouse line (Lrat-rtTA) that expresses the doxycycline-responsive transcriptional activator rtTA under the control of the HSC-specific lecithin retinol acyltransferase (Lrat) promoter, which enables us to specifically and inducibly overexpress or eliminate genes in these cells. The inducible elimination of HSCs protects mice from methionine/choline-deficient (MCD) diet-induced liver fibrosis, confirming their causal involvement in fibrosis development. We generated …

Urobilin Derived From Bilirubin Bioconversion Binds Albumin And May Interfere With Bilirubin Interacting With Albumin: Implications For Disease Pathology, Kevin I. Williams, Priyanka Suryadevara, Chang-Guo Zhan, Terry D. Hinds Jr., Zachary A. Kipp

Markey Cancer Center Faculty Publications

Background/Objectives: Bilirubin is a hydrophobic molecule that binds the carrier protein albumin for transport through systemic circulation. Bilirubin is cleared from the body through the liver and excreted into the intestines, where the microbiota modifies the chemical structure, forming urobilin, which can be reabsorbed into circulation by the hepatic portal vein. Urobilin has no known function. It is also unknown whether urobilin binds albumin for transport in circulation. We hypothesized that because of the likeness of their chemical structures, urobilin would also bind albumin like bilirubin does. Methods: First, we used in silico docking to predict if urobilin would bind …

Heme Oxygenase, Biliverdin Reductase, And Bilirubin Pathways Regulate Oxidative Stress And Insulin Resistance: A Focus On Diabetes And Therapeutics, Wang-Hsin Lee, Zachary A. Kipp, Sally Pauss, Genesee J. Martinez, Evelyn A. Bates, Olufunto O. Badmus, David E. Stec, Terry D. Hinds Jr.

Markey Cancer Center Faculty Publications

Metabolic and insulin-resistant diseases, such as type 2 diabetes mellitus (T2DM), have become major health issues worldwide. The prevalence of insulin resistance in the general population ranges from 15.5% to 44.6%. Shockingly, the global T2DM population is anticipated to double by 2050 compared with 2021. Prior studies indicate that oxidative stress and inflammation are instrumental in causing insulin resistance and instigating metabolic diseases. Numerous methods and drugs have been designed to combat insulin resistance, including metformin, thiazolidinediones (TZDs), sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA), and dipeptidyl peptidase 4 inhibitors (DPP4i). Bilirubin is an antioxidant with …

Dissecting The Biophysical Mechanisms Of Oleate Hydratase Association With Membranes, William A. Lathram, Robert J. Neff, Ashley N. Zalla, James D. Brien, Vivekanandan Subramanian, Christopher D. Radka

Markey Cancer Center Faculty Publications

This study investigates the dynamics of oleate hydratase (OhyA), a bacterial flavoenzyme from Staphylococcus aureus, and its interactions with lipid membranes, focusing on the factors influencing membrane binding and oligomerization. OhyA catalyzes the hydration of unsaturated fatty acids, playing a key role in bacterial pathogenesis by neutralizing host antimicrobial fatty acids. OhyA binds the membrane bilayer to access membrane-embedded substrates for catalysis, and structural studies have revealed that OhyA forms oligomers on membrane surfaces, stabilized by both protein-protein and protein-lipid interactions. Using fluorescence correlation spectroscopy (FCS), we examined the effects of membrane curvature and lipid availability on OhyA binding to …

Advances In Magnetic Nanoparticles For Molecular Medicine, Xiaoyue Yang, Sarah E. Kubican, Zhongchao Yi, Sheng Tong

Markey Cancer Center Faculty Publications

Magnetic nanoparticles (MNPs) are highly versatile nanomaterials in nanomedicine, owing to their diverse magnetic properties, which can be tailored through variations in size, shape, composition, and exposure to inductive magnetic fields. Over four decades of research have led to the clinical approval or ongoing trials of several MNP formulations, fueling continued innovation. Beyond traditional applications in drug delivery, imaging, and cancer hyperthermia, MNPs have increasingly advanced into molecular medicine. Under external magnetic fields, MNPs can generate mechano- or thermal stimuli to modulate individual molecules or cells deep within tissue, offering precise, remote control of biological processes at cellular and molecular …

Mir-27a-3p Regulates Intestinal Cell Proliferation And Differentiation Through Wnt/Β-Catenin Signalling, Chang Li, Yuning Zhou, Yinping Jiang, Zhijie Yin, Heidi L. Weiss, Qingding Wang, B. Mark Evers

Markey Cancer Center Faculty Publications

Intestinal stem cells differentiate into absorptive enterocytes, characterised by increased brush border enzymes such as intestinal alkaline phosphatase (IAP), making up the majority (95%) of the terminally differentiated cells in the villus. Loss of integrity of the intestinal epithelium plays a key role in inflammatory diseases and gastrointestinal infection. Here, we show that the intestinal microRNA (miR)-27a-3p is an important regulator of intestinal epithelial cell proliferation and enterocyte differentiation. Repression of endogenous miR-27a-3p leads to increased enterocyte differentiation and decreased intestinal epithelial cell proliferation in mouse and human small intestinal organoids. Mechanistically, miR-27a-3p regulates intestinal cell differentiation and proliferation at …

Engaging Nurses In Effective Cost Of Care Conversations To Address Cancer-Related Financial Toxicity: Results From An Exploratory Survey, Jean Edward, Abigail Wiggins, Louis G. Baser, Haafsah Fariduddin, Joanna F. Doran, Monica F. Bryant, John A. D'Orazio, Kimberly D. Northrip

Markey Cancer Center Faculty Publications

Few evidence-based trainings exist on how to equip healthcare providers, particularly nurses, with the skills to engage in cost of care conversations with patients/caregivers to mitigate the impact of cancer-related financial toxicity. This study evaluated a pilot training developed in collaboration with Triage Cancer® to prepare oncology nurses to identify and assist patients/caregivers facing financial and/or legal barriers to care. Ten pediatric oncology nurses completed the training and pre/post-surveys on behaviors related to financial and legal need screening, frequency and comfort level of answering questions, knowledge, and behavior changes, along with training evaluation questions. At baseline, six nurses reported never …

Association Between Education And Allostatic Load With Risk Of Cancer Mortality Among Hispanic Women, Melissa Lopez-Pentecost, Cynthia Li, Marlo Vernon, Sydney P. Howard, Jessica Amezcua, Justin Xavier Moore

Markey Cancer Center Faculty Publications

Purpose: Cancer remains the leading cause of death among Hispanics in the US. While social determinants of health, such as educational attainment, have been linked to negative health outcomes, their biological mechanisms remain poorly understood. We evaluated the association between educational attainment and allostatic load (AL), a measure of chronic physiologic stress, with risk of cancer mortality in Hispanic women from the National Health and Nutrition Examination Survey (NHANES).

Methods: We performed a retrospective analysis among 5637 Hispanic women in NHANES from 1988 to 2010 with follow-up data through 2019. Educational attainment was categorized into a two-level variable: less than …

Functional Assessment Of Migration And Adhesion To Quantify Cancer Cell Aggression, Lauren E. Mehanna, James D. Boyd, Chloe G. Walker, Adrianna R. Osborne, Martha E. Grady, Brad J. Berron

Markey Cancer Center Faculty Publications

During epithelial-to-mesenchymal transition (EMT), cancer cells lose their cell–cell adhesion junctions as they become more metastatic, altering cell motility and focal adhesion disassembly associated with increased detachment from the primary tumor and a migratory response into nearby tissue and vasculature. Current in vitro strategies characterizing a cell’s metastatic potential heavily favor quantifying the presence of cell adhesion biomarkers through biochemical analysis; however, mechanical cues such as adhesion and motility directly relate to cell metastatic potential without needing to first identify a cell specific biomarker for a particular type of cancer. This paper presents a comprehensive comparison of two functional metrics …

Inclusion Of Surgery In Multimodality Treatment Is Predictive Of Better Survival In Stage Iiia Non-Small Cell Lung Cancer: An Inverse Probability Treatment-Weighting Analysis, Feitong Lei, Janeesh Sekkath-Veedu, Bin Huang, Quan Chen, Mansi Shah-Jadeja, Thomas E. Stinchcombe, Zhonglin Hao

Markey Cancer Center Faculty Publications

Introduction: Stage IIIA non-small cell lung cancers (NSCLC) are treated with surgery-based multimodality approach or definitive chemoradiation therapy plus durvalumab consolidation. It is not clear whether surgery-based multimodality therapy has any survival advantage over definitive chemoradiation plus immunotherapy consolidation.

Method: National Cancer Database (NCDB) was used to identify NSCLC patients at stage IIIA (AJCC8, T3N1/T4N0-1 or T1N2/T2N2) who are treated with surgery-based multimodality approach or definitive chemoradiation plus durvalumab. Survival between groups were compared using inverse probability treatment weighting (IPTW)-adjusted Kaplan Meier curves and Cox proportional hazards regression analysis. Results were independently confirmed by Landmark Inverse and Clone Censor Weight …

M1 Macrophage‑Engineered Vesicles Have Anti‑Cancer Activity In Ovarian Cancer, Connie D. Cao, J. Robert Mccorkle, Derek B. Allison, Donglin Yan, Kristen S. Hill, Lan Li, Rani Jayswal, David Schweer, Charles S. Dietrich Iii, Frederick R. Ueland, Christopher I. Richards, Jill M. Kolesar

Markey Cancer Center Faculty Publications

Background: Ovarian cancer typically presents at an advanced stage, has a poor prognosis, and is a leading cause of cancer-related deaths in women. Extracellular vesicles (EVs) are cell membrane-derived nanoparticles that function in specific cell- to-cell communication and are under development as novel drug delivery vehicles and modulators of the tumor microenvironment. Artificial cell-derived vesicles (ACDVs) from M1 macrophages are able to repolarize macrophages from a M2 to a M1 phenotype and target tumor cells in in vitro studies.

Results: In this study, we generated engineered EVs (EEVs) by membrane disruption of M1 macrophages (MEVs) with and without cisplatin to …

Measuring The Impact Of A Catchment Area Surveillance Tool On Cancer Center Adopters, Todd Burus, Caree R. Mcafee, Natalie P. Wilhite, Pamela C. Hull

Markey Cancer Center Faculty Publications

Background: The University of Kentucky Markey Cancer Center developed the data gathering and visualization platform Cancer InFocus (CIF) as a solution for cancer center catchment area surveillance. CIF was released in June 2022 and made available for use to other institutions through a no‐cost licensing agreement. The purpose of this study was to evaluate the impact CIF has had on cancer centers since its release.

Methods: The authors adapted an existing management evaluation framework to assess the impact of CIF across three spheres—idea dissemination, product engagement, and adopter satisfaction. This assessment included an online survey administered between the dates of …

Tracking Community Outreach And Engagement Activities Among National Cancer Institute-Designated Cancer Centers, Todd Burus, Caree R. Mcafee, Pamela C. Hull, Amy E. Leader, Christopher Mcnair

Markey Cancer Center Faculty Publications

The National Cancer Institute’s (NCI) Cancer Center Support Grant mandates that NCI-designated cancer centers establish a Community Outreach and Engagement (COE) component to help direct efforts at reducing cancer burden within their catchment areas. Despite the critical role of COE offices, little is known about how they track and evaluate outreach activities and outcomes. We gathered information on current practices from representatives of 40 out of 65 COE offices using an online survey. Although nearly all responding centers (97.5%) tracked COE activities, no consensus existed on resources used, and satisfaction with current solutions was mixed (51.0% not satisfied). Respondents expressed …

Biparental Inheritance Of Germline-Specific Chromosomes In The Sea Lamprey And Their Roles In Oocytes, Vladimir A. Timoshevskiy, Nataliya Timoshevskaya, Kaan İ. Eşkut, Kasturi Rajandran, Jeramiah J. Smith

Markey Cancer Center Faculty Publications

Many eukaryotic species undergo programmed elimination of specific chromosomes during embryogenesis, typically retaining these chromosomes only in their germ cells. In some species, programmatic elimination of GRCs, or sex chromosomes, also occurs in a sex-specific manner, with specific chromosomes being transmitted or eliminated by only one sex. As such, these chromosomes provide a unique perspective on the evolution of gene functions that are advantageous to the germline and genetic tradeoffs between somatic vs germline or oocyte vs sperm biology. While GRCs have been extensively characterized in male sea lampreys (Petromyzon marinus), the status of GRCs in females has not yet …

Cryptic To Conventional Cytogenetics: Philadelphia- Like All Presenting With Hypereosinophilia, Zena Chahine, Leonard Yenwong Fai, Sainan Wei, Ayman Qasrawi

Markey Cancer Center Faculty Publications

BCR::ABL1-like B-lymphoblastic leukaemia (B-ALL) neoplasms lack the BCR::ABL1 translocation but have a gene expression profile like BCR::ABL1 positive B-ALL. This includes alterations in cytokine receptors and signalling genes, such as CRLF2, ABL1, ABL2, JAK2, PDGFRB and EPOR. Cases with CRLF2 rearrangements account for approximately 50% of cases of Philadelphia-like acute lymphoblastic leukaemia (Ph-like ALL), and the frequency of specific genomic lesions varies with ethnicity such that IGH::CRLF2 translocations are more common in Hispanics and Native Americans. We report two cases of BCR::ABL1-like ALL, with significant eosinophilia. A Hispanic man in his early 20s and a Hispanic woman in her 50s …

Cabozantinib Selectively Induces Proteasomal Degradation Of P53 Somatic Mutant Y220c And Impedes Tumor Growth, Fang Lin Lv, Lu Zhang, Cheng Ji, Lei Peng, Mingxian Zhu, Shumin Yang, Shunli Dong, Mingxuan Zhou, Fanfan Guo, Zhenyun Li, Fang Wang, Youguo Chen, Jinhua Zhou, Xingcong Ren, Genhai Shen, Jin-Ming Yang, Bin Li, Yi Zhang

Markey Cancer Center Faculty Publications

Inactivation of p53 by mutations commonly occurs in human cancer. The mutated p53 proteins may escape proteolytic degradation and exhibit high expression in tumors and acquire gain-of-function activity that promotes tumor progression and chemo-resistance. Therefore, selectively targeting of the gain-of-function p53 mutants may serve as a promising therapeutic strategy for cancer prevention and treatment. In this study, we identified cabozantinib, a multikinase inhibitor currently used in the clinical treatment of several types of cancer, as a selective inducer of proteasomal degradation of the p53-Y220C mutant. We demonstrate that cabozantinib disrupts the interaction between p53Y220C and USP7, a deubiquitylating enzyme, resulting …