Medical Specialties Commons^™

Dense Granule Protein 3 Of Toxoplasma Gondii Plays A Crucial Role In The Capability Of The Tissue Cysts Of The Parasite To Persist In The Presence Of Anti-Cyst Cd8+ T Cells During The Chronic Stage Of Infection, Rajesh Mani, Mohamed H. Abdelaziz, Eri Ochiai, Qila Sa, Barbara A. Fox, David J. Bzik, Yasuhiro Suzuki

Markey Cancer Center Faculty Publications

Toxoplasma gondii establishes chronic infection by forming tissue cysts, and this chronic infection is one of the most common parasitic infections in humans. Our recent studies revealed that whereas CD8 + T cells of genetically resistant BALB/c mice have the capability to remove the tissue cysts of the parasite through their perforin-mediated activities, small portions of the cysts are capable of persisting in the presence of the anti-cyst CD8+ T cells. It is currently unknown how those small portions of the cysts resist or escape the T-cell immunity and persist in the hosts. In the present study, we discovered that …

Distinct Camp Signaling Microdomains Differentially Regulate Melanosomal Ph And Pigmentation, Maftuna Yusupova, Dalee Zhou, Jaewon You, Jeydi Gonzalez-Guzman, Megha B. Ghanta, Hong Pu, Zalfa Abdel-Malek, Qiuying Chen, Steven S. Gross, John August D'Orazio, Shosuke Ito, Kazumasa Wakamatsu, Melissa L. Harris, Jonathan H. Zippin

Markey Cancer Center Faculty Publications

cAMP signaling is a well-established regulator of melanin synthesis. Two distinct cAMP signaling pathways—the transmembrane adenylyl cyclase pathway, activated primarily by the MC1R, and the soluble adenylyl cyclase (sAC) pathway—affect melanin synthesis. The sAC pathway affects melanin synthesis by regulating melanosomal pH, and the MC1R pathway affects melanin synthesis by regulating gene expression and post-translational modifications. However, whether MC1R genotype affects melanosomal pH is poorly understood. We now report that loss of function MC1R does not affect melanosomal pH. Thus, sAC signaling appears to be the only cAMP signaling pathway that regulates melanosomal pH. We also addressed whether MC1R genotype …

Effects Of Interfraction Dose Variations Of Target And Organs At Risk On Clinical Outcomes In High Dose Rate Brachytherapy For Cervical Cancer, Brien Washington, Dennis C. Cheek, Denise Fabian, Mahesh R. Kudrimoti, Damodar Pokhrel, Chi Wang, Cameron Thayer-Freeman, Wei Luo

Markey Cancer Center Faculty Publications

Meeting dose prescription is critical to control tumors in radiation therapy. Interfraction dose variations (IDVs) from the prescribed dose in high dose rate brachytherapy (HDR) would cause the target dose to deviate from the prescription but their clinical effect has not been widely discussed in the literature. Our previous study found that IDVs followed a left-skewed distribution. The clinical effect of the IDVs in 100 cervical cancer HDR patients will be addressed in this paper. An in-house Monte Carlo (MC) program was used to simulate clinical outcomes by convolving published tumor dose response curves with IDV distributions. The optimal dose …

Elongation Of Very Long Chain Fatty Acids-3 (Elovl3) Is Activated By Zhx2 And Is A Regulator Of Cell Cycle Progression, Kate Townsend Creasy, Hui Ren, Jieyun Jiang, Martha L. Peterson, Brett T. Spear

Markey Cancer Center Faculty Publications

Zinc fingers and homeoboxes 2 (Zhx2) are transcriptional regulators of liver gene expression with key functions in embryonic development as well as tissue regeneration in response to damage and disease, presumably through its control of target genes. Previous microarray data suggested that elongation of very long chain fatty acids-3 (Elovl3), a member of the ELOVL family of enzymes that synthesize very long chain fatty acids (VLCFAs), is a putative Zhx2 target gene. VLCFAs are core component of ceramides and other bioactive sphingolipids that are often dysregulated in diseases and regulate key cellular processes including proliferation. Since several previously identified Zhx2 …

Inhibition Of Mitochondrial Fission Activates Glycogen Synthesis To Support Cell Survival In Colon Cancer, Sumati Raj Hasani, Lyndsay E. A. Young, Warren Van Nort, Moumita Banerjee, Dylan R. Rivas, Jinhwan Kim, Xiaopeng Xiong, Ramon C. Sun, Matthew S. Gentry, Hiromi Sesaki, Tianyan Gao

Markey Cancer Center Faculty Publications

Metabolic reprogramming has been recognized as one of the major mechanisms that fuel tumor initiation and progression. Our previous studies demonstrate that activation of Drp1 promotes fatty acid oxidation and downstream Wnt signaling. Here we investigate the role of Drp1 in regulating glycogen metabolism in colon cancer. Knockdown of Drp1 decreases mitochondrial respiration without increasing glycolysis. Analysis of cellular metabolites reveals that the levels of glucose-6-phosphate, a precursor for glycogenesis, are significantly elevated whereas pyruvate and other TCA cycle metabolites remain unchanged in Drp1 knockdown cells. Additionally, silencing Drp1 activates AMPK to stimulate the expression glycogen synthase 1 (GYS1) mRNA …

Phosphatidic Acid Binding To Patched Contributes To The Inhibition Of Smoothened And Hedgehog Signaling In Drosophila Wing Development, Jie Zhang, Yajuan Liu, Chi Wang, Craig W. Vander Kooi, Jianhang Jia

Markey Cancer Center Faculty Publications

Hedgehog (Hh) signaling controls growth and patterning during embryonic development and homeostasis in adult tissues. Hh binding to the receptor Patched (Ptc) elicits intracellular signaling by relieving Ptc-mediated inhibition of the transmembrane protein Smoothened (Smo). We uncovered a role for the lipid phosphatidic acid (PA) in the regulation of the Hh pathway in Drosophila melanogaster. Deleting the Ptc C-terminal tail or mutating the predicted PA-binding sites within it prevented Ptc from inhibiting Smo in wing discs and in cultured cells. The C-terminal tail of Ptc directly interacted with PA in vitro, an association that was reduced by Hh, and increased …

Proteasome Inhibition Protects Blood–Brain Barrier P-Glycoprotein And Lowers Aβ Brain Levels In An Alzheimer’S Disease Model, Milica Vulin, Yu Zhong, Bryan J. Maloney, Björn Bauer, Anika M. S. Hartz

Markey Cancer Center Faculty Publications

Background Loss of P-glycoprotein (P-gp) at the blood–brain barrier contributes to amyloid-β (Aβ) brain accumulation in Alzheimer’s disease (AD). Using transgenic human amyloid precursor protein (hAPP)-overexpressing mice (Tg2576), we previously showed that Aβ triggers P-gp loss by activating the ubiquitin–proteasome pathway, which leads to P-gp degradation. Furthermore, we showed that inhibiting the ubiquitin-activating enzyme (E1) prevents P-gp loss and lowers Aβ accumulation in the brain of hAPP mice. Based on these data, we hypothesized that repurposing the FDA-approved proteasome inhibitor, bortezomib (Velcade®; BTZ), protects blood–brain barrier P-gp from degradation in hAPP mice in vivo.

Methods We treated hAPP mice with …

Regulated Translocation Of Neutral Sphingomyelinase-2 To The Plasma Membrane Drives Insulin Resistance In Steatotic Hepatocytes, Salim S. El-Amouri, Alexander A. Karakashian, Erhard Bieberich, Mariana N. Nikolova‑Karakashian

Markey Cancer Center Faculty Publications

Abstract Obesity-associated diabetes is linked to the accumulation of ceramide in various organs, including the liver. The exact mechanisms by which ceramide contributes to diabetic pathology are unclear, but one proposed scenario is that ceramide accumulation may inhibit insulin signaling pathways. It is unknown however whether the excess ceramide is generated proximal to the insulin receptor, that is, at the plasma membrane (PM), where it could affect the insulin signaling pathway directly, or the onset of insulin resistance is due to ceramide- induced mitochondrial dysfunction and/or lipotoxicity. Using hepatic cell lines and primary cultures, gain- and loss- of function approach, …

Rit1 Regulation Of Cns Lipids Rit1 Deficiency Alters Cerebral Lipid Metabolism And Reduces White Matter Tract Oligodendrocytes And Conduction Velocities, Lei Wu, Fang Wang, Carole L. Moncman, Mritunjay Pandey, Harrison A. Clarke, Hilaree N. Frazier, Lyndsay E. A. Young, Matthew S. Gentry, Weikang Cai, Olivier Thibault, Ramon C. Sun, Douglas A. Andres

Markey Cancer Center Faculty Publications

Oligodendrocytes (OLs) generate lipid-rich myelin membranes that wrap axons to enable efficient transmission of electrical impulses. Using a RIT1 knockout mouse model and in situ high- resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) coupled with MS-based lipidomic analysis to determine the contribution of RIT1 to lipid homeostasis. Here, we report that RIT1 loss is associated with altered lipid levels in the central nervous system (CNS), including myelin-associated lipids within the corpus callosum (CC). Perturbed lipid metabolism was correlated with reduced numbers of OLs, but increased numbers of GFAP+ glia, in the CC, but not in grey matter. This was …

Stat3 Modulates Cd4+ T Mitochondrial Dynamics And Function In Aging, Emelia Zukowski, Marco Sannella, Jack Donato Rockhold, Gabriella Kalantar, Jingting Yu, Sara Santacruz-Calvo, Madison K. Kuhn, Nasun Hah, Ling Ouyang, Tzu-Wen Wang, Lyanne Murphy, Heather Marszalkowski, Kaleigh Gibney, Micah J. Drummond, Elizabeth A. Proctor, Hatice Hasturk, Barbara S. Nikolajczyk, Leena P. Bharath

Markey Cancer Center Faculty Publications

Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and T-cell cytokine production. Mechanistically, mitoSTAT3 increased the activity of aging T-cell mitochondria by increasing complex II. Limiting mitoSTAT3 using a mitochondria-targeted STAT3 inhibitor, Mtcur-1 lowered complex II activity, prevented age-induced changes in mitochondrial dynamics and function, and reduced Th17 inflammation. Exogenous expression of a constitutively phosphorylated form of STAT3 in T cells from young adults mimicked changes in mitochondrial dynamics and …

Non-Contact Optical Spectroscopy For Tumor-Sensitive Diffuse Reflectance And Fluorescence Measurements On Murine Subcutaneous Tissue Models: Monte Carlo Modeling And Experimental Validations, Zahid Hasan, Pranto Soumik Saha, Madison O. Korfhage, Caigang Zhu

Markey Cancer Center Faculty Publications

Fiber-optic probes are commonly used in biomedical optical spectroscopy platforms for light delivery and collection. At the same time, it was reported that the inconsistent probe- sample contact could induce significant distortions in measured optical signals, which consequently cause large analysis errors. To address this challenge, non-contact optical spectroscopy has been explored for tissue characterizations. However, existing non-contact optical spectroscopy platforms primarily focused on diffuse reflectance measurements and may still use a fiber probe in which the probe was imaged onto the tissue surface using a lens, which serves as a non-contact probe for the measurements. Here, we report a …

A Lamprey Neural Cell Type Atlas Illuminates The Origins Of The Vertebrate Brain, Francesco Lamanna, Francisca Hervas-Sotomayor, A. Phillip Oel, David Jandzik, Daniel Sobrido-Cameán, Gabriel N. Santos-Durán, Megan L. Martik, Jan Stundl, Stephen A. Green, Thoomke Brüning, Katharina Mößinger, Julia Schmidt, Celine Schneider, Mari Sepp, Florent Murat, Jeramiah J. Smith, Marianne E. Bronner, María Celina Rodicio, Antón Barreiro-Iglesias, Daniel M. Medeiros, Detlev Arendt, Henrik Kaessmann

Markey Cancer Center Faculty Publications

The vertebrate brain emerged more than ~500 million years ago in common evolutionary ancestors. To systematically trace its cellular and molecular origins, we established a spatially resolved cell type atlas of the entire brain of the sea lamprey—a jawless species whose phylogenetic position affords the reconstruction of ancestral vertebrate traits—based on extensive single-cell RNA-seq and in situ sequencing data. Comparisons of this atlas to neural data from the mouse and other jawed vertebrates unveiled various shared features that enabled the reconstruction of cell types, tissue structures and gene expression programs of the ancestral vertebrate brain. However, our analyses also revealed …

Bacteroides Fragilis In The Gut Microbiomes Of Alzheimer’S Disease Activates Microglia And Triggers Pathogenesis In Neuronal C/Ebpβ Transgenic Mice, Yiyuan Xia, Yifan Xiao, Zi-Hao Wang, Ashfaqul M. Alam, John P. Haran, Beth A. Mccormick, Xiji Shu, Xiaochuan Wang, Keqiang Ye

Markey Cancer Center Faculty Publications

Gut dysbiosis contributes to Alzheimer’s disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPβ transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPβ/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors’ fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing …

New Insights On The Differential Interaction Of Sulfiredoxin With Members Of The Peroxiredoxin Family Revealed By Protein-Protein Docking And Experimental Studies, Murli Mishra, Hong Jiang, Qiou Wei

Markey Cancer Center Faculty Publications

Sulfiredoxin (Srx) is the enzyme that restores the peroxidase activity of peroxiredoxins (Prxs) through catalyzing the reduction of hyperoxidized Prxs back to their active forms. This process involves protein-protein interaction in an enzyme-substrate binding manner. The integrity of the Srx-Prx axis contributes to the pathogenesis of various oxidative stress related human disorders including cancer, inflammation, cardiovascular and neurological diseases. The purpose of this study is to understand the structural and molecular biology of the Srx-Prx interaction, which may be of significance for prediction of target site for the novel drug-discovery. Homology modeling and protein-protein docking approaches were applied to examine …

Syne1 Mutation Is Associated With Increased Tumor Mutation Burden And Immune Cell Infiltration In Ovarian Cancer, Laura M. Harbin, Nan Lin, Frederick R. Ueland, Jill M. Kolesar

Markey Cancer Center Faculty Publications

SYNE1, a nuclear envelope protein critical for cellular structure and signaling, is downregulated in numerous malignancies. SYNE1 alterations are found in 10% of gynecologic malignancies and 5% of epithelial ovarian cancers. Previous studies demonstrated an association between SYNE1 mutation, increased tumor mutation burden (TMB), and immunotherapy response. This study evaluates the SYNE1 mutation frequency, association with TMB, and downstream effects of SYNE1 mutation in ovarian cancer. Genetic information, including whole-exome sequencing, RNA analysis, and somatic tumor testing, was obtained for consenting ovarian cancer patients at an academic medical center. Mutation frequencies were compared between the institutional cohort and The Cancer …

Interferon-Stimulated Gene Tdrd7 Interacts With Ampk And Inhibits Its Activation To Suppress Viral Replication And Pathogenesis, Sukanya Chakravarty, Gayatri Subramanian, Sonam Popli, Manoj Veleeparambil, Shumin Fan, Ritu Chakravarti, Saurabh Chattopadhyay

Markey Cancer Center Faculty Publications

Many viruses activate cellular autophagy in infected cells to facilitate their replication. Recently, we identified an interferon (IFN)-stimulated gene (ISG) Tudor domain containing 7 (TDRD7), which inhibits viral replication by blocking autophagy pathway. Here, we present a molecular mechanism for TDRD7 action and its relative contribution to protection against viral pathogenesis. TDRD7 inhibited the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a kinase required for initiating autophagy. Mechanistically, TDRD7 interacted directly with AMPK in the cytosolic compartment. Domain-mapping analyses revealed C-terminal Tudor domain of TDRD7 interacted with auto-inhibitory domain of AMPK. Deletion of Tudor domains abolished anti-AMPK and antiviral …

Unleashing The Potential Of 1,3-Diketone Analogues As Selective Lh2 Inhibitors, Juhoon Lee, Hou-Fu Guo, Shike Wang, Yazdan Maghsoud, Erik Antonio Vázquez-Montelongo, Zhifeng Jing, Rae M. Sammons, Eun Jeong Cho, Pengyu Ren, G. Andrés Cisneros, Jonathan M. Kurie, Kevin N. Dalby

Markey Cancer Center Faculty Publications

Lysyl hydroxylase 2 (LH2) catalyzes the formation of highly stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs), thus promoting lung cancer metastasis through its capacity to modulate specific types of collagen cross-links within the tumor stroma. Using 1 and 2 from our previous high-throughput screening (HTS) as lead probes, we prepared a series of 1,3-diketone analogues, 1−18, and identified 12 and 13 that inhibit LH2 with IC50’s of approximately 300 and 500 nM, respectively. Compounds 12 and 13 demonstrate selectivity for LH2 over LH1 and LH3. Quantum mechanics/molecular mechanics (QM/MM) modeling indicates that the selectivity of 12 and 13 may stem from …

Asparagine Restriction Enhances Cd8+ T Cell Metabolic Fitness And Antitumoral Functionality Through An Nrf2-Dependent Stress Response, J. N. Rashida Gnanaprakasam, Bhavana Kushwaha, Lingling Liu, Xuyong Chen, Siwen Kang, Tingting Wang, Teresa A. Cassel, Christopher M. Adams, Richard M. Higashi, David A. Scott, Gang Xin, Zihai Li, Jun Yang, Andrew N. Lane, Teresa Whei-Mei Fan, Ji Zhang, Ruoning Wang

Markey Cancer Center Faculty Publications

Robust and effective T cell immune surveillance and cancer immunotherapy require proper allocation of metabolic resources to sustain energetically costly processes, including growth and cytokine production. Here, we show that asparagine (Asn) restriction on CD8+ T cells exerted opposing effects during activation (early phase) and differentiation (late phase) following T cell activation. Asn restriction suppressed activation and cell cycle entry in the early phase while rapidly engaging the nuclear factor erythroid 2-related factor 2 (NRF2)-dependent stress response, conferring robust proliferation and effector function on CD8+ T cells during differentiation. Mechanistically, NRF2 activation in CD8+ T cells conferred by Asn restriction …

Chemokine Receptor Cxcr7 Activates Aurora Kinase A And Promotes Neuroendocrine Prostate Cancer Growth, Galina Gritsina, Ka-Wing Fong, Xiaodong Lu, Zhuoyuan Lin, Wanqing Xie, Shivani Agarwal, Dong Lin, Gary E. Schiltz, Himisha Beltran, Eva Corey, Colm Morrissey, Yuzhuo Wang, Jonathan C. Zhao, Maha Hussain, Jindan Yu

Markey Cancer Center Faculty Publications

CXCR7 is an atypical chemokine receptor that recruits β-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here, we report that CXCR7 was elevated in the majority of prostate cancer (PCa) cases with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle gene expression. Mechanistically, we identified Aurora Kinase A (AURKA), a key regulator of mitosis, as a novel target that was bound and activated by the CXCR7-ARRB2 complex. CXCR7 interacted with proteins associated with microtubules and golgi, and, as such, the CXCR7-ARRB2-containing vesicles trafficked …

Chronic Nsmase Inhibition Suppresses Neuronal Exosome Spreading And Sex-Specifically Attenuates Amyloid Pathology In App Knock-In Alzheimer's Disease Mice, Francesca E. Mowry, Francisco Espejo-Porras, Shijie Jin, Zainuddin Quadri, Limin Wu, Marcela Bertolio, Rachel Jarvis, Caroline Reynolds, Rashed Alananzeh, Erhard Bieberich, Yongjie Yang

Markey Cancer Center Faculty Publications

Female biased pathology and cognitive decline in Alzheimer’s disease (AD) have been consistently observed with unclear underlying mechanisms. Although brain sphingolipid ceramide is elevated in AD patients, whether and how ceramide may contribute to sex-specific differences in amyloid pathology is unknown. Here we investigated the sex-specific impact of chronic pharmacological inhibition of neutral sphingomyelinase (nSMase), a key enzyme responsible for ceramide metabolism, on in vivo neuron-derived exosome dynamics, Aβ plaque load, and cognitive function in the APPNL-F/NL-F knock-in (APP NL-F) AD mouse model. Our results found sex-specific increase of cortical C20:0 ceramide and brain exosome levels only in APP NL-F …

Co-Targeting Nucleus Accumbens Associate 1 And Nf-Κb Signaling Synergistically Inhibits Melanoma Growth, Lixiang Gu, Xingcong Ren, Chrispus Ngule, Xiaofang Xiong, Jianxun Song, Zhiguo Li, Jin-Ming Yang

Markey Cancer Center Faculty Publications

Nucleus-accumbens-associated protein-1 (NAC1) is a cancer-related transcriptional factor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and has been appreciated as one of the top potential cancer driver genes. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. Here, we show that NAC1 is a negative regulator of NF-κB signaling, and NAC1 depletion enhances the level of the nuclear NF-κB in human melanoma. Furthermore, the inhibition of NF-κB signaling significantly potentiates the antineoplastic activity of the NAC1 inhibition in both the cultured melanoma cells and xenograft tumors. This study …

Identification Of Immunodominant T Cell Epitopes Induced By Natural Zika Virus Infection, Christopher S. Eickhoff, Krystal A. Meza, Frances E. Terry, Chase G. Colbert, Azra Blazevic, Andres H. Gutiérrez, E. Taylor Stone, James D. Brien, Amelia K. Pinto, Hana M. El Sahly, Mark J. Mulligan, Nadine Rouphael, Maria L. Alcaide, Kay M. Tomashek, Chris Focht, William D. Martin, Leonard Moise, Anne S. De Groot, Daniel F. Hoft

Markey Cancer Center Faculty Publications

Zika virus (ZIKV) is a flavivirus primarily transmitted by Aedes species mosquitoes, first discovered in Africa in 1947, that disseminated through Southeast Asia and the Pacific Islands in the 2000s. The first ZIKV infections in the Americas were identified in 2014, and infections exploded through populations in Brazil and other countries in 2015/16. ZIKV infection during pregnancy can cause severe brain and eye defects in offspring, and infection in adults has been associated with higher risks of Guillain-Barré syndrome. We initiated a study to describe the natural history of Zika (the disease) and the immune response to infection, for which …

Identification Of Monotonically Expressed Long Non-Coding Rna Signatures For Breast Cancer Using Variational Autoencoders, Dongjiao Wang, Ling Gao, Xinliang Gao, Chi Wang, Suyan Tian

Markey Cancer Center Faculty Publications

As breast cancer is a multistage progression disease resulting from a genetic sequence of mutations, understanding the genes whose expression values increase or decrease monotonically across pathologic stages can provide insightful clues about how breast cancer initiates and advances. Utilizing variational autoencoder (VAE) networks in conjunction with traditional statistical testing, we successfully ascertain long non-coding RNAs (lncRNAs) that exhibit monotonically differential expression values in breast cancer. Subsequently, we validate that the identified lncRNAs really present monotonically changed patterns. The proposed procedure identified 248 monotonically decreasing expressed and 115 increasing expressed lncRNAs. They correspond to a total of 65 and 33 …

Impact Of A Cancer Education Curriculum On Appalachian Kentucky Middle And High School Students, Lauren Hudson‑Rose, L. Todd Weiss, Nathan L. Vanderford

Markey Cancer Center Faculty Publications

Appalachian Kentucky is disproportionately affected by elevated cancer incidence and mortality rates. This disparity is driven by inequities in health behaviors and social determinants of health including decreased education attainment levels that cause lower health literacy. To increase cancer literacy in the region, a three-part cancer education curriculum was designed for Appalachian Kentucky middle and high school students. This study was designed to evaluate the effect the curriculum had on students’ cancer literacy. The curriculum lessons were disseminated to Appalachian Kentucky middle and high school teachers who engaged 223 students with the material. For each lesson, students filled out a …

Inhibition Of Acid Sphingomyelinase Reduces Reactive Astrocyte Secretion Of Mitotoxic Extracellular Vesicles And Improves Alzheimer’S Disease Pathology In The 5xfad Mouse, Simone M. Crivelli, Zainuddin Quadri, Hemendra J. Vekaria, Zhihui Zhu, Priyanka Tripathi, Ahmed Elsherbini, Liping Zhang, Patrick G. Sullivan, Erhard Bieberich

Markey Cancer Center Faculty Publications

In Alzheimer’s disease (AD), reactive astrocytes produce extracellular vesicles (EVs) that affect mitochondria in neurons. Here, we show that Aβ-induced generation of the sphingolipid ceramide by acid sphingomyelinase (A-SMase) triggered proinflammatory cytokine (C1q, TNF-α, IL-1α) release by microglia, which induced the reactive astrocytes phenotype and secretion of EVs enriched with ceramide. These EVs impeded the capacity of neurons to respond to energy demand. Inhibition of A-SMase with Arc39 and Imipramine reduced the secretion of cytokines from microglia, prompting us to test the effect of Imipramine on EV secretion and AD pathology in the 5xFAD mouse model. Brain derived-EVs from 5xFAD …

Liver Transplantation For Biliary Cysts: Perioperative And Long-Term Outcomes, Gabriel Orozco, Malay B. Shah, Meera Gupta, Francesc Marti, Xiaonan Mei, Alexandre Ancheta, Siddharth Desai, Michael Cavnar, B. Mark Evers, Joseph B. Zwischenberger, Roberto Gedaly

Markey Cancer Center Faculty Publications

Background: Biliary cysts (BC) is a rare indication for orthotopic liver transplantation (OLT).

Methods: We queried the UNOS dataset to identify patients who underwent OLT for Caroli’s disease (CD) and choledochal cysts (CC). All patients with BC (CD + CC) were compared to a cohort of patients transplanted for other indications. Patients with CC were also compared to those with CD. Cox proportional hazard model was performed to assess predictors of graft and patient survival.

Results: 261 patients underwent OLT for BC. Patients with BC had better pre-operative liver function compared to those transplanted for other indications. 5-year graft and …

Metabolic Disruption Induced By Mtor Signaling Pathway Inhibition In Regulatory T-Cell Expansion For Clinical Application, Roberto Gedaly, Gabriel Orozco, Alexandre P. Ancheta, Mackenzie Donoho, Siddharth Desai, Fanny Chapelin, Aman Khurana, Lillie J. Lewis, Cuiping Zhang, Francesc Marti

Markey Cancer Center Faculty Publications

Background: Regulatory T cell (Treg) therapy is considered an alternative approach to induce tolerance in transplantation. If successful, this therapy may have implications on immunosuppression minimization/withdrawal to reduce drug-induced toxicity in patients. The aim of this study was to assess the efficacy of the mTORC1/C2 inhibitor, AZD8055, in the manufacturing of clinically competent Treg cells and compare the effects with those induced by rapamycin (RAPA), another mTOR inhibitor commonly used in Treg expansion protocols.

Methods: Primary human Treg cells were isolated from leukapheresis product. Cell viability, expansion rates, suppressive function, autophagy, mitochondrial unfolded protein response (mitoUPR), and cell metabolic profile …

Pcb126 Exposure During Pregnancy Alters Maternal And Fetal Gene Expression, Cetewayo S. Rashid, Joshua D. Preston, Sara Y. Ngo Tenlep, Marissa K. Cook, Eric M. Blalock, Changcheng Zhou, Hollie I. Swanson, Kevin J. Pearson

Markey Cancer Center Faculty Publications

Polychlorinated biphenyls (PCBs) are organic pollutants that can have lasting impacts on offspring health. Here, we sought to examine maternal and fetal gene expression differences of aryl hydrocarbon receptor (AHR)- regulated genes in a mouse model of prenatal PCB126 exposure. Female mice were bred and gavaged with 1 μmole/kg bodyweight PCB126 or vehicle control on embryonic days 0 and 14, and maternal and fetal tissues were collected on embryonic day 18.5. Total RNAs were isolated, and gene expression levels were analyzed in both maternal and fetal tissues using the NanoString nCounter system. Interestingly, we found that the expression levels of …

Phosphatase And Pseudo-Phosphatase Functions Of Phosphatase Of Regenerating Liver 3 (Prl-3) Are Insensitive To Divalent Metals In Vitro, Jeffery T. Jolly, Ty C. Cheatham, Jessica S. Blackburn

Markey Cancer Center Faculty Publications

Phosphatase of regenerating liver 3 (PRL-3) is associated with cancer metastasis and has been shown to interact with the cyclin and CBS domain divalent metal cation transport mediator (CNNM) family of proteins to regulate the intracellular concentration of magnesium and other divalent metals. Despite PRL-3’s importance in cancer, factors that regulate PRL-3’s phosphatase activity and its interactions with CNNM proteins remain unknown. Here, we show that divalent metal ions, including magnesium, calcium, and manganese, have no impact on PRL-3’s structure, stability, phosphatase activity, or CNNM binding capacity, indicating that PRL-3 does not act as a metal sensor, despite its interaction …

Portable Optical Spectroscopic Assay For Non-Destructive Measurement Of Key Metabolic Parameters On In Vitro Cancer Cells And Organotypic Fresh Tumor Slices, Jing Yan, Carlos Frederico Lima Goncalves, Madison O. Korfhage, Zahid Hasan, Teresa Whei-Mei Fan, Xiaoqin Wang, Caigang Zhu

Markey Cancer Center Faculty Publications

To enable non-destructive metabolic characterizations on in vitro cancer cells and organotypic tumor models for therapeutic studies in an easy-to-access way, we report a highly portable optical spectroscopic assay for simultaneous measurement of glucose uptake and mitochondrial function on various cancer models with high sensitivity. Well-established breast cancer cell lines (MCF-7 and MDA-MB-231) were used to validate the optical spectroscopic assay for metabolic characterizations, while fresh tumor samples harvested from both animals and human cancer patients were used to test the feasibility of our optical metabolic assay for non-destructive measurement of key metabolic parameters on organotypic tumor slices. Our optical …