Medical Specialties Commons^™

Structures Of The Insecticidal Toxin Complex Subunit Xpta2 Highlight Roles For Flexible Domains, Cole L. Martin, David W. Chester, Christopher D. Radka, Lurong Pan, Zhengrong Yang, Rachel C. Hart, Elad M. Binshtein, Zhao Wang, Lisa Nagy, Lawrence J. Delucas, Stephen G. Aller

Markey Cancer Center Faculty Publications

The Toxin Complex (Tc) superfamily consists of toxin translocases that contribute to the targeting, delivery, and cytotoxicity of certain pathogenic Gram-negative bacteria. Membrane receptor targeting is driven by the A-subunit (TcA), which comprises IgG-like receptor binding domains (RBDs) at the surface. To better understand XptA2, an insect specific TcA secreted by the symbiont X. nematophilus from the intestine of entomopathogenic nematodes, we determined structures by X-ray crystallography and cryo-EM. Contrary to a previous report, XptA2 is pentameric. RBD-B exhibits an indentation from crystal packing that indicates loose association with the shell and a hotspot for possible receptor binding or a …

Using Artificial Intelligence To Identify Tumor Microenvironment Heterogeneity In Non–Small Cell Lung Cancers, Tanner Ducote, Kassandra J. Naughton, Erika M. Skaggs, Therese J. Bocklage, Derek B. Allison, Christine Fillmore Brainson

Markey Cancer Center Faculty Publications

Lung cancer heterogeneity is a major barrier to effective treatments and encompasses not only the malignant epithelial cell phenotypes and genetics but also the diverse tumor-associated cell types. Current techniques used to investigate the tumor microenvironment can be time-consuming, expensive, complicated to interpret, and often involves destruction of the sample. Here we use standard hematoxylin and eosinestained tumor sections and the HALO AI nuclear phenotyping software to characterize 6 distinct cell types (epithelial, mesenchymal, macrophage, neutrophil, lymphocyte, and plasma cells) in both murine lung cancer models and human lung cancer samples. CD3 immunohistochemistry and lymph node sections were used to …

The Role Of Vaccination Route With An Adenovirus-Vectored Vaccine In Protection, Viral Control, And Transmission In The Sars-Cov-2/K18-Hace2 Mouse Infection Model, Alexandria Dickson, Elizabeth Geerling, E. Taylor Stone, Mariah Hassert, Tara L. Steffen, Taneesh Makkena, Madeleine Smither, Katherine E. Schwetye, Jianfeng Zhang, Bertrand Georges, M. Scot Roberts, John J. Suschak, Amelia K. Pinto, James D. Brien

Markey Cancer Center Faculty Publications

Introduction: Vaccination is the most effective mechanism to prevent severe COVID-19. However, breakthrough infections and subsequent transmission of SARS-CoV-2 remain a significant problem. Intranasal vaccination has the potential to be more effective in preventing disease and limiting transmission between individuals as it induces potent responses at mucosal sites.

Methods: Utilizing a replication-deficient adenovirus serotype 5-vectored vaccine expressing the SARS-CoV-2 RBD (AdCOVID) in homozygous and heterozygous transgenic K18-hACE2, we investigated the impact of the route of administration on vaccine immunogenicity, SARS-CoV-2 transmission, and survival.

Results: Mice vaccinated with AdCOVID via the intramuscular or intranasal route and subsequently challenged with SARS-CoV-2 showed …

The S1p Receptor 1 Antagonist Ponesimod Reduces Tlr4-Induced Neuroinflammation And Increases Aβ Clearance In 5xfad Mice, Zhihui Zhu, Liping Zhang, Ahmed Elsherbini, Simone M. Crivelli, Priyanka Tripathi, Carmen Harper, Zainuddin Quadri, Stefka D. Spassieva, Erhard Bieberich

Markey Cancer Center Faculty Publications

Background Previously, we showed that the sphingosine-1-phosphate (S1P) transporter spinster 2 (Spns2) mediates activation of microglia in response to amyloid β peptide (Aβ). Here, we investigated if Ponesimod, a functional S1P receptor 1 (S1PR1) antagonist, prevents Aβ-induced activation of glial cells and Alzheimer’s disease (AD) pathology.

Methods We used primary cultures of glial cells and the 5XFAD mouse model to determine the effect of Aβ and Ponesimod on glial activation, Aβ phagocytosis, cytokine levels and pro-inflammatory signaling pathways, AD pathology, and cognitive performance.

Findings Aβ42 increased the levels of TLR4 and S1PR1, leading to their complex formation. Ponesimod prevented the …

Weighted Mean Difference Statistics For Paired Data In The Presence Of Missing Values, Yuntong Li, Brent J. Shelton, William St Clair, Heidi L. Weiss, John L. Villano, Arnold Stromberg, Chi Wang, Li Chen

Markey Cancer Center Faculty Publications

Missing data is a common issue in many biomedical studies. Under a paired design, some subjects may have missing values in either one or both of the conditions due to loss of follow-up, insufficient biological samples, etc. Such partially paired data complicate statistical comparison of the distribution of the variable of interest between the two conditions. In this article, we propose a general class of test statistics based on the difference in weighted sample means without imposing any distributional or model assumption. An optimal weight is derived from this class of tests. Simulation studies show that our proposed test with …

A Comparative Effectiveness Study On Opioid Use Disorder Prediction Using Artificial Intelligence And Existing Risk Models, Sajjad Fouladvand, Jeffery Talbert, Linda Phyliss Dwoskin, Heather M. Bush, Amy L. Meadows, Lars E. Peterson, Yash R. Mishra, Steven K. Roggenkamp, Fei Wang, Ramakanth Kavuluru, Jin Chen

Markey Cancer Center Faculty Publications

Opioid use disorder (OUD) is a leading cause of death in the United States placing a tremendous burden on patients, their families, and health care systems. Artificial intelligence (AI) can be harnessed with available healthcare data to produce automated OUD prediction tools. In this retrospective study, we developed AI based models for OUD prediction and showed that AI can predict OUD more effectively than existing clinical tools including the unweighted opioid risk tool (ORT). Data include 474,208 patients’ data over 10 years; 269,748 were females with an average age of 56.78 years. Cases are prescription opioid users with at least …

Emt Activates Exocytotic Rabs To Coordinate Invasion And Immunosuppression In Lung Cancer, Guan-Yu Xiao, Xiaochao Tan, Bertha L. Rodriguez, Don L. Gibbons, Shike Wang, Chao Wu, Xin Liu, Jiang Yu, Mayra E. Vasquez, Hai T. Tran, Jun Xu, William K. Russell, Cara Haymaker, Younghee Lee, Jianjun Zhang, Luisa Solis, Ignacio I. Wistuba, Jonathan M. Kurie

Markey Cancer Center Faculty Publications

Epithelial-to- mesenchymal transition (EMT) underlies immunosuppression, drug resistance, and metastasis in epithelial malignancies. However, the way in which EMT orchestrates disparate biological processes remains unclear. Here, we identify an EMT- activated vesicular trafficking network that coordinates promigratory focal adhesion dynamics with an immunosuppressive secretory program in lung adenocarcinoma (LUAD). The EMT-activating transcription factor ZEB1 drives exocytotic vesicular trafficking by relieving Rab6A, Rab8A, and guanine nucleotide exchange factors from miR-148a-dependent silencing, thereby facilitating MMP14-dependent focal adhesion turnover in LUAD cells and autotaxin-mediated CD8+ T cell exhaustion, indicating that cell- intrinsic and extrinsic processes are linked through a microRNA that coordinates vesicular …

Enhanced Bypass Of Pd-L1 Translation Reduces The Therapeutic Response To Mtor Kinase Inhibitors, Yanan Cao, Qing Ye, Murong Ma, Qing-Bai She

Markey Cancer Center Faculty Publications

Increased PD-L1 expression in cancer cells is known to enhance immunosuppression, but the mechanism underlying PD-L1 upregulation is incompletely characterized. We show that PD-L1 expression is upregulated through internal ribosomal entry site (IRES)-mediated translation upon mTORC1 inhibition. We identify an IRES element in the PD-L1 50-UTR that permits cap-independent translation and promotes continuous production of PD-L1 protein despite effective inhibition of mTORC1. eIF4A is found to be a key PD-L1 IRES-binding protein that enhances PD-L1 IRES activity and protein production in tumor cells treated with mTOR kinase inhibitors (mTORkis). Notably, treatment with mTORkis in vivo elevates PD-L1 levels and reduces …

Integrative Analysis Of Mendelian Randomization And Gene Expression Profiles Reveals A Null Causal Relationship Between Adiponectin And Diabetic Retinopathy, Ao Zhang, Hui Wu, Chi Wang, Suyan Tian

Markey Cancer Center Faculty Publications

Observational studies have been conducted to investigate the correlation between adiponectin and diabetic retinopathy (DR), but no consistent relationship has been established. In this study, we employed an integrative analysis that combined Mendelian randomization (MR) and bioinformatics analyses to comprehensively explore the association between DR and adiponectin, aiming to provide a unified answer of their relationship. Using the inverse-variance weighted (IVW) method, the odd ratio (OR) of developing DR per 1 mg/dL increment in genetically predicted log- transformed adiponectin concentration was estimated to be 0.949 (P = 0.557). Other robust MR methods produced consistent results, confirming the absence of a …

Lung And Colorectal Cancer Disparities In Appalachian Kentucky: Spatial Analysis On The Influence Of Education And Literacy, Nicole Robertson Mph, Todd Burus, Lauren Hudson, Pamela C. Hull, Lee Park, Nathan L. Vanderford

Markey Cancer Center Faculty Publications

Low educational attainment and high cancer incidence and mortality rates have long been a challenge in Appalachian Kentucky. Prior studies have reported disparities in cancer incidence and mortality between Appalachian and non-Appalachian populations, but the influence of education on this disparity has not been extensively studied. Herein, all cancers and two cancer sites with available screenings (colorectal and lung) were joined with education indicators (educational attainment and literacy) and one geographic indicator across all 120 Kentucky counties. This dataset was used to build choropleth maps and perform simple linear and spatial regression to assess statistical significance and to measure the …

Messes: Software For Transforming Messy Research Datasets Into Clean Submissions To Metabolomics Workbench For Public Sharing, P. Travis Thompson, Hunter N. B. Moseley

Markey Cancer Center Faculty Publications

In recent years, the FAIR guiding principles and the broader concept of open science has grown in importance in academic research, especially as funding entities have aggressively promoted public sharing of research products. Key to public research sharing is deposition of datasets into online data repositories, but it can be a chore to transform messy unstructured data into the forms required by these repositories. To help generate Metabolomics Workbench depositions, we have developed the MESSES (Metadata from Experimental SpreadSheets Extraction System) software package, implemented in the Python 3 programming language and supported on Linux, Windows, and Mac operating systems. MESSES …

Nac1 Confines Virus‐Specific Memory Formation Of Cd4+ T Cells Through The Rock1‐Mediated Pathway, Liqing Wang, Hao-Yun Peng, Jugal Kishore Das, Anil Kumar, Yijie Ren, Darby J. Ballard, Xiaofang Xiong, Wen Yang, Xingcong Ren, Paul De Figueiredo, Jin-Ming Yang, Jianxun Song

Markey Cancer Center Faculty Publications

Nucleus accumbens‐associated protein 1 (NAC1), a transcriptional cofactor, has been found to play important roles in regulating regulatory T cells, CD8 + T cells, and antitumor immunity, but little is known about its effects on T‐cell memory. In this study, we found that NAC1 expression restricts memory formation of CD4 + T cells during viral infection. Analysis of CD4 + T cells from wild‐type (WT) and NAC1‐ deficient (−/−) mice showed that NAC1 is essential for T‐cell metabolism, including glycolysis and oxidative phosphorylation, and supports CD4 + T‐cell survival in vitro. We further demonstrated that a deficiency of NAC1 downregulates …

The Metabolomics Workbench File Status Website: A Metadata Repository Promoting Fair Principles Of Metabolomics Data, Christian D. Powell, Hunter N. B. Moseley

Markey Cancer Center Faculty Publications

Background: An updated version of the mwtab Python package for programmatic access to the Metabolomics Workbench (MetabolomicsWB) data repository was released at the beginning of 2021. Along with updating the package to match the changes to MetabolomicsWB’s ‘mwTab’ file format specification and enhancing the package’s functionality, the included validation facilities were used to detect and catalog file inconsistencies and errors across all publicly available datasets in MetabolomicsWB.

Results: The MetabolomicsWB File Status website was developed to provide continuous validation of MetabolomicsWB data files and a useful interface to all found inconsistencies and errors. This list of detectable issues/errors include format …

Maternal Polychlorinated Biphenyl 126 (Pcb 126) Exposure Modulates Offspring Gut Microbiota Irrespective Of Diet And Exercise, Manisha Agarwal, Jessie Hoffman, Sara Y. Ngo Tenlep, Sara Santarossa, Kevin J. Pearson, Alexandra R. Sitarik, Andrea E. Cassidy-Bushrow, Michael C. Petriello

Markey Cancer Center Faculty Publications

The gut microbiota plays an important role throughout the lifespan in maintaining host health, and several factors can modulate microbiota composition including diet, exercise, and environmental exposures. Maternal microbiota is transferred to offspring during early life; thus, environmental exposures before gestation may also modulate offspring microbiota. Here we aimed to investigate the effects of maternal exposure to dioxin-like polychlorinated biphenyls (PCBs) on the microbiota of aged offspring and to determine if lifestyle factors, including maternal exercise or offspring high-fat feeding alter these associations. To test this, dams were exposed to PCB 126 (0.5 μmole/kg body weight) or vehicle oil by …

A Case For Accelerating Standards To Achieve The Fair Principles Of Environmental Health Research Experimental Data, Rance Nault, Matthew C. Cave, Gabriele Ludewig, Hunter N. B. Moseley, Kelly G. Pennell, Tim Zacharewski

Markey Cancer Center Faculty Publications

BACKGROUND: Funding agencies, publishers, and other stakeholders are pushing environmental health science investigators to improve data sharing; to promote the findable, accessible, interoperable, and reusable (FAIR) principles; and to increase the rigor and reproducibility of the data collected. Accomplishing these goals will require significant cultural shifts surrounding data management and strategies to develop robust and reliable resources that bridge the technical challenges and gaps in expertise.

OBJECTIVE : In this commentary, we examine the current state of managing data and metadata—referred to collectively as (meta)data—in the experimental environmental health sciences. We introduce new tools and resources based on in vivo …

A Proposed Fair Approach For Disseminating Geospatial Information System Maps, P. Travis Thompson, Sweta Ojha, Christian D. Powell, Kelly G. Pennell, Hunter N. B. Moseley

Markey Cancer Center Faculty Publications

We present a draft Minimum Information about Geospatial Information System (MIaGIS) standard for facilitating public deposition of geospatial information system (GIS) datasets that follows the FaIR (Findable, accessible, Interoperable and Reusable) principles. the draft MIaGIS standard includes a deposition directory structure and a minimum javascript object notation (JSON) metadata formatted file that is designed to capture critical metadata describing GIS layers and maps as well as their sources of data and methods of generation. the associated miagis Python package facilitates the creation of this MIAGIS metadata file and directly supports metadata extraction from both Esri JSON and GEOJSON GIS data …

Creation Of Egd-Derived Gastric Cancer Organoids To Predict Treatment Responses, Hannah Mcdonald, Megan Harper, Kristen S. Hill, Anqi Gao, Angelica L. Solomon, Charles J. Bailey, Miranda Lin, Mautin Barry-Hundeyin, Michael Cavnar, Samuel H. Mardini, Prakash Pandalai, Reema A. Patel, Jill M. Kolesar, Justin A. Rueckert, Lawrence Hookey, Mark Ropeleski, Shaila J. Merchant, Joseph Kim, Mei Gao

Markey Cancer Center Faculty Publications

Gastric adenocarcinoma (GAd) is the third leading cause of cancer-related deaths worldwide. Most patients require perioperative chemotherapy, yet methods to accurately predict responses to therapy are lacking. Thus, patients may be unnecessarily exposed to considerable toxicities. Here, we present a novel methodology using patient-derived organoids (PDOs) that rapidly and accurately predicts the chemotherapy efficacy for GAd patients.

Methods: Endoscopic GAd biopsies were obtained from 19 patients, shipped overnight, and PDOs were developed within 24 h. Drug sensitivity testing was performed on PDO single-cells with current standard-of-care systemic GAd regimens and cell viability was measured. Whole exome sequencing was used to …

Differential Inhibition Of Anaplerotic Pyruvate Carboxylation And Glutaminolysis-Fueled Anabolism Underlies Distinct Toxicity Of Selenium Agents In Human Lung Cancer, Teresa W-M Fan, Jason Winnike, Ahmad Al-Attar, Alex C. Belshoff, Pawel Lorkiewicz, Jin Lian Tan, Min Wu, Richard M. Higashi, Andrew N. Lane

Markey Cancer Center Faculty Publications

Past chemopreventive human trials on dietary selenium supplements produced controversial outcomes. They largely employed selenomethionine (SeM)-based diets. SeM was less toxic than selenite or methylseleninic acid (MSeA) to lung cancer cells. We thus investigated the toxic action of these Se agents in two non-small cell lung cancer (NSCLC) cell lines and ex vivo organotypic cultures (OTC) of NSCLC patient lung tissues. Stable isotope-resolved metabolomics (SIRM) using 13C6-glucose and 13C5,15N2-glutamine tracers with gene knockdowns were employed to examine metabolic dysregulations associated with cell type- and treatment-dependent phenotypic changes. Inhibition of key anaplerotic processes, pyruvate carboxylation (PyC) and glutaminolysis were elicited by …

Green Solvent Mediated Extraction Of Micro- And Nano-Plastic Particles From Water, Jameson R. Hunter, Qi Qiao, Yuxuan Zhang, Qing Shao, Czarena L. Crofcheck, Jian Shi

Markey Cancer Center Faculty Publications

The production of plastic and the amount of waste plastic that enters the ecosystem increases every year. Synthetic plastics gradually break down into particles on the micro‑ and nano‑scale in the environment. The micro‑ and nano‑plastics pose a significant ecological threat by transporting toxic chemicals and causing inflammation and cellular damage when ingested; however, removal of those particles from water is challenging using conventional separation methods. Deep eutectic solvents (DES), a new class of solvents composed of hydrogen bond donors and acceptors, have been proposed as a cheaper alternative to ionic liquids. Hydrophobic DES derived from natural compounds (NADES) show …

Identifying And Sharing Per-And Polyfluoroalkyl Substances Hot-Spot Areas And Exposures In Drinking Water, Sweta Ojha, P. Travis Thompson, Christian D. Powell, Hunter N. B. Moseley, Kelly G. Pennell

Markey Cancer Center Faculty Publications

Exposure to per- and polyfluoroalkyl substances (PFAS) in drinking water is widely recognized as a public health concern. Decision-makers who are responsible for managing PFAS drinking water risks lack the tools to acquire the information they need. In response to this need, we provide a detailed description of a Kentucky dataset that allows decision-makers to visualize potential hot-spot areas and evaluate drinking water systems that may be susceptible to PFAS contamination. The dataset includes information extracted from publicly available sources to create five different maps in ArcGIS Online and highlights potential sources of PFAS contamination in the environment in relation …

Noncovalent Interactions That Tune The Reactivities Of The Flavins In Bifurcating Electron Transferring Flavoprotein, María González-Viegas, Rajiv K. Kar, Anne-Frances Miller, Maria-Andrea Mroginski

Markey Cancer Center Faculty Publications

Bifurcating electron transferring flavoproteins (Bf-ETFs) tune chemically identical flavins to two contrasting roles. To understand how, we used hybrid quantum mechanical molecular mechanical calculations to characterize noncovalent interactions applied to each flavin by the protein. Our computations replicated the differences between the reactivities of the flavins: the electron transferring flavin ( ETflavin) was calculated to stabilize anionic semiquinone (ASQ) as needed to execute its single-electron transfers, whereas the Bf flavin (Bfflavin) was found to disfavor the ASQ state more than does free flavin and to be less susceptible to reduction. The stability of ETflavin ASQ was attributed in part to …

Novel Isolation Method Reveals Sex-Specific Composition And Neurotoxicity Of Small Extracellular Vesicles In A Mouse Model Of Alzheimer’S Disease, Ahmed Elsherbini, Zhihui Zhu, Zainuddin Quadri, Simone M. Crivelli, Xiaojia Ren, Hemendra J. Vekaria, Priyanka Tripathi, Liping Zhang, Wenbo Zhi, Erhard Bieberich

Markey Cancer Center Faculty Publications

We developed a new method to isolate small extracellular vesicles (sEVs) from male and female wild-type and 5xFAD mouse brains to investigate the sex-specific functions of sEVs in Alzheimer’s disease (AD). A mass spectrometric analysis revealed that sEVs contained proteins critical for EV formation and Aβ. ExoView analysis showed that female mice contained more GFAP and Aβ-labeled sEVs, suggesting that a larger proportion of sEVs from the female brain is derived from astrocytes and/or more likely to bind to Aβ. Moreover, sEVs from female brains had more acid sphingomyelinase (ASM) and ceramide, an enzyme and its sphingolipid product important for …

The Kappa Opioid Receptor Agonist 16-Bromo Salvinorin A Has Anti-Cocaine Effects Without Significant Effects On Locomotion, Food Reward, Learning And Memory, Or Anxiety And Depressive-Like Behaviors, Ross Van De Wetering, Amy Ewald, Susan Welsh, Lindsay Kornberger, Samuel E. Williamson, Bryan D. Mcelroy, Eduardo R. Butelman, Thomas E. Prisinzano, Bronwyn M. Kivell

Markey Cancer Center Faculty Publications

Kappa opioid receptor (KOR) agonists have preclinical antipsychostimulant effects; however, adverse side effects have limited their therapeutic development. In this preclinical study, conducted in Sprague Dawley rats, B6-SJL mice, and non-human primates (NHPs), we evaluated the G-protein-biased analogue of salvinorin A (SalA), 16-bromo salvinorin A (16-BrSalA), for its anticocaine effects, side effects, and activation of cellular signaling pathways. 16-BrSalA dose-dependently decreased the cocaine-primed reinstatement of drug-seeking behavior in a KOR-dependent manner. It also decreased cocaine-induced hyperactivity, but had no effect on responding for cocaine on a progressive ratio schedule. Compared to SalA, 16-BrSalA had an improved side effect profile, with …

Combination Therapy With Trastuzumab And Niraparib: Quantifying Early Proliferative Alterations In Her2+ Breast Cancer Models, Ameer Mansur, Patrick N. Song, Yun Lu, Andrew C. Burns, Luke Sligh, Eddy S. Yang, Anna G. Sorace

Markey Cancer Center Faculty Publications

HER2–targeted treatments have improved survival rates in HER2+ breast cancer patients, yet poor responsiveness remains a major clinical obstacle. Recently, HER2+ breast cancer cells, both resistant and responsive to HER2–targeted therapies, have demonstrated sensitivity to poly–(ADP– ribose) polymerase (PARP) inhibition, independent of DNA repair deficiencies. This study seeks to describe biological factors that precede cell viability changes in response to the combination of trastuzumab and PARP inhibition. Treatment response was evaluated in HER2+ and HER2– breast cancer cells. Further, we evaluated the utility of 3′–Deoxy–3′–[18F]–fluorothymidine positron emission tomography ([18F]FLT–PET) imaging for early response assessment in a HER2+ patient derived xenograft …

Artificial Intelligence In Continuous Kidney Replacement Therapy, Lucas J. Liu, Tomonori Takeuchi, Jin Chen, Javier A. Neyra

Markey Cancer Center Faculty Publications

Over the past decade, artificial intelligence (AI) through machine learning (ML) has been increasingly used in health care applications. The use of AI/ML to enhance the provision of continuous kidney replacement therapy (CKRT) is an area of active investigation because of the growing clinical needs of critically ill patients and the abundance of multimodal data from the electronic health records (EHRs) and the CKRT machine itself. Importantly, best clinical practices of CKRT have not been sufficiently standardized, so there is considerable heterogeneity in utilization and deliverables. In this context, AI/ML-based tools could facilitate informed decisions to enhance CKRT goal-oriented deliver- …

Development And Characterization Of Nanobodies That Specifically Target The Oncogenic Phosphatase Of Regenerating Liver-3 (Prl-3) And Impact Its Interaction With A Known Binding Partner, Cnnm3, Caroline N. Smith, Kyle Kihn, Zachary A. Williamson, K. Martin Chow, Louis B. Hersh, Konstantin V. Korotkov, Daniel Deredge, Jessica S. Blackburn

Markey Cancer Center Faculty Publications

Phosphatase of Regenerating Liver-3 (PRL-3) is associated with cancer progression and metastasis. The mechanisms that drive PRL-3’s oncogenic functions are not well under- stood, partly due to a lack of research tools available to study this protein. We have begun to address these issues by developing alpaca-derived single domain antibodies, or nanobo- dies, targeting PRL-3 with a KD of 30–300 nM and no activity towards highly homologous family members PRL-1 and PRL-2. We found that longer and charged N-terminal tags on PRL-3, such as GFP and FLAG, changed PRL-3 localization compared to untagged protein, indicating that the nanobodies may provide …

Icam-1-Supar-Cd11b Axis Is A Novel Therapeutic Target For Metastatic Triple-Negative Breast Cancer, Dong Li, Hami Hemati, Younhee Park, Rokana Taftaf, Youbin Zhang, Jinpeng Liu, Massimo Cristofanilli, Xia Liu

Markey Cancer Center Faculty Publications

Accumulating evidence demonstrates that circulating tumor cell (CTC) clusters have higher metastatic ability than single CTCs and negatively correlate with cancer patient outcomes. Along with homotypic CTC clusters, heterotypic CTC clusters (such as neutrophil–CTC clusters), which have been identified in both cancer mouse models and cancer patients, lead to more efficient metastasis formation and worse patient outcomes. However, the mechanism by which neutrophils bind to CTCs remains elusive. In this study, we found that intercellular adhesion molecule-1 (ICAM-1) on triple- negative breast cancer (TNBC) cells and CD11b on neutrophils mediate tumor cell–neutrophil binding. Consequently, CD11b deficiency inhibited tumor cell–neutrophil binding …

Life Stressors And Immune Aging: Protective Effects Of Cognitive Reappraisal, Rebecca G. Reed, Steven R. Presnell, Ahmad Al-Attar, Charles T. Lutz, Suzanne C. Segerstrom

Markey Cancer Center Faculty Publications

Stressful life events may accelerate aspects of immune aging, but habitual use of an adaptive emotion regulation strategy, cognitive reappraisal, may attenuate these effects. This study examined whether cognitive reappraisal moderates the associations between life stressor frequency and stressor desirability on aspects of immune aging, including late-differentiated CD8+ T and natural killer (NK) cells and inflammatory markers (IL-6, TNF-α, and CRP), both between and within people in a longitudinal sample of 149 older adults (mean age = 77.8, range: 64–92 years). Participants reported stressful life events, use of cognitive reappraisal, and provided blood semiannually for up to 5 years to …

Single Fraction And Hypofractionated Radiation Cause Cochlear Damage, Hearing Loss, And Reduced Viability Of Merlin-Deficient Schwann Cells, Christine T. Dinh, Si Chen, Aida Nourbakhsh, Kyle Padgett, Perry Johnson, Stefania Goncalves, Olena Bracho, Esperanza Bas, Jorge Bohorquez, Paula V. Monje, Cristina Fernandez-Valle, Nagy Elsayyad, Xuezhong Liu, Scott M. Welford, Fred Telischi

Markey Cancer Center Faculty Publications

Background: Vestibular schwannomas (VS) are benign intracranial tumors caused by loss of function of the merlin tumor suppressor. We tested three hypotheses related to radiation, hearing loss (HL), and VS cell survival: (1) radiation causes HL by injuring auditory hair cells (AHC), (2) fractionation reduces radiation-induced HL, and (3) single fraction and equivalent appropriately dosed multi-fractions are equally effective at controlling VS growth. We investigated the effects of single fraction and hypofractionated radiation on hearing thresholds in rats, cell death pathways in rat cochleae, and viability of human merlin-deficient Schwann cells (MD-SC). Methods: Adult rats received cochlear irradiation with single …

The Plod2/Succinate Axis Regulates The Epithelial–Mesenchymal Plasticity And Cancer Cell Stemness, Yuxin Tong, Yifei Qi, Gaofeng Xiong, Junyan Li, Timothy L. Scott, Jie Chen, Daheng He, Linzhang Li, Chi Wang, Andrew N. Lane, Ren Xu

Markey Cancer Center Faculty Publications

Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate …