Medicine and Health Sciences Commons^™

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 …

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 …

Toward Nonparametric Propensity Score Estimation With Guaranteed Covariate Balance, Yan Li

Dissertations and Theses (Open Access)

Establishing clear causality between exposures and outcomes is often complicated by confounders in observational studies, which leads to imbalance in covariate distributions between treatments and biased treatment effect inference. The propensity score (PS) has been widely used to adjust this covariate imbalance in observational data. However, the propensity score analysis methods rely on a correctly specified parametric PS model. When the model is misspecified, the covariate imbalance may occur, which leads to biased estimation of the treatment effect. Therefore, it is necessary to study how to improve the model misspecification in propensity score analysis.

My Ph.D. dissertation consists of three …

Delirium On Admission To The Cicu, Spencer Wittmeyer, Jaime Silva-Gburek, Kelly S. Tieves

Posters

Background: Delirium is increasingly recognized in the pediatric cardiac intensive care unit (CICU) with an incidence up to 67% and is associated with worse outcomes including increased mortality, prolonged hospitalization, and increased rates of intubation and mechanical circulatory support. The Cornell Assessment for Pediatric Delirium (CAPD) is the only validated tool for the diagnosis of delirium in the pediatric population. The CAPD may be limited in children with developmental disabilities as it does not account for baseline ability in scoring. Prior work has identified low specificity for the CAPD in children with developmental disabilities and those requiring mechanical ventilation. This …

Identification Of Critical Illness-Related Corticosteroid Insufficiency After Congenital Heart Surgery With Next Generation Sequencing, Juan S. Farias, Nicholas Diehl, Lori A. Erickson, Jenny Marshall, Nataliya Kibiryeva, Kelly S. Tieves, Jorge Cross-Bu, Jaime Silva-Gburek

Posters

Introduction: Critical illness-related corticosteroid insufficiency (CIRCI) which is characterized by relative inadequate cortisol levels in relation to increased demand during periods of severe stress is common after cardiac surgery and is a cause of hemodynamic instability. The purpose of this study was to identify possible genetic abnormalities related to CIRCI in pediatric patients after congenital heart surgery. Methods: Single-center retrospective study of neonates who underwent cardiac surgery between August 2018 to July 2020. We included patients who had obtained postoperative cortisol levels and next gen DNA-sequencing (NGS) as previous standard of care. Analysis methods are displayed in Figure 1. Results: …

An Unusual Cardiomegaly Culprit: Case Report Of A Hemodynamically Significant Portosystemic Shunt, Zoetta L. Mcloughlin Md, Melanie Kathol, Amanda Mcintosh

Posters

Background: Cardiomegaly discovered in the fetal or neonatal period may be the first sign of cardiac disease. However, the differential diagnosis for cardiomegaly with a structurally and functionally normal heart includes cardiomyopathies as well as non-cardiac etiologies, including extracardiac shunt lesions and vascular malformations, among others. Thus, unexplained cardiomegaly requires further investigation for extracardiac anomalies. In this case, we focus on an unusual etiology of diffuse cardiac dilatation – intrahepatic portosystemic shunt – that was initially misdiagnosed as dilated cardiomyopathy. Case Description: A 9-year-old male with history of learning difficulty and tall stature was seen for follow-up of diffuse cardiomegaly …

Multi-Disciplinary Collaboration And The Use Of Technology In The Reduction Of Cardiac Surgical Site Infections, Kelly Fehlhafer, Tiffany Mullen, Elizabeth Chang, Stacy Reynolds, Shannon Lysaught, Stephanie Doughty, Jessica Nichols

Posters

No abstract provided.

Impacts Of A Duf2207 Family Protein On Streptococcus Mutans Stress Tolerance Responses And Biofilm Formation, Xiaochang Huang, Camile G. Laird, Paul P. Riley, Zezhang Tom Wen

School of Dentistry Faculty Publications

Locus SMU.243 in Streptococcus mutans was annotated as a member of the DUF2207 family proteins highly conserved in all bacteria but with unknown function. To investigate its role in S. mutans physiology, a SMU.243-deficient mutant was constructed using allelic exchange mutagenesis, and the impacts of SMU.243 deletion on bacterial growth, stress tolerance response, and biofilm formation were analyzed. Compared to the wild-type UA159, S. mutans lacking SMU.243 displayed a reduced growth rate and a reduced overnight culture density (p < 0.01) when grown at low pH and in the presence of methyl viologen. Relative to the parent strain, the deficient mutant also had a reduced survival rate following incubation in a buffer of pH 2.8 (p < 0.01) and in a buffer containing hydrogen peroxide at 58 mM after 60 min (p < 0.001) and had a reduced capacity in biofilm formation especially in the presence of sucrose (p < 0.01). To study any ensuing functional/phenotypical links between SMU.243 and uppP, which is located immediately downstream of SMU.243 and encodes an undecaprenyl pyrophosphate phosphatase involved in recycling of carrier lipid undecaprenyl phosphate, a uppP deficient mutant was generated using allelic exchange mutagenesis. Unlike the SMU.243 mutant, deletion of uppP affected cell envelope biogenesis and caused major increases in susceptibility to bacitracin. In addition, two variant morphological mutants, one forming rough colonies and the other forming mucoid, smooth colonies, also emerged following the deletion of uppP. The results suggest that the SMU.243-encoded protein of the DUF2207 family in S. mutans plays an important role in stress tolerance response and biofilm formation, but unlike the downstream uppP, does not seem to be involved in cell envelope biogenesis, although the exact roles in S. mutans’ physiology awaits further investigation.

Investigation Of The Protein Components In A Periplasmic Mechanism Regulating Bacterial Morphology, Alexandra Pulliam

Electronic Theses and Dissertations

Salmonella is a leading bacterial cause of foodborne illness worldwide. During a previous study investigating the enzymes responsible for regulating cyclic-di-GMP concentrations, a mutant in the cyclic-di-GMP-specific phosphodiesterase STM3615 was identified that displayed a phenotype characterized by decreased survival on agar plates and a shorter bacterium length. I was able to determine that the periplasmic domain of STM3615 was responsible for this phenotype, not the enzymatic phosphodiesterase domain. Based upon a bioinformatic analysis of the protein, I then hypothesized that the periplasmic domain of STM3615 was interacting with a periplasmic protein to give rise to this phenotype. To identify this …

Microsporidian Spores And The Integrin Binding Loop Of The Madam Protein Are Important For Integrin Signaling And Attachment To Host Cells, Cindy L. Barrett

Electronic Theses and Dissertations

Microsporidia are a distant fungal pathogen that have severe clinical consequences for the immunocompromised. Previous work identified a microsporidian pathogen protein termed Microsporidian ADAM or MADAM. This protein has close sequence homology to other ADAM proteins (A Disintegrin and Metalloproteinase) in two microsporidian species, Encephalitozoon intestinalis and E. cuniculi. ADAM proteins have a wide range of functions, including binding to integrins and host signaling. It is known that many pathogens manipulate integrins to invade host cells, and it is predicted that microsporidia are also exploiting this host target. Previous work with the MADAM protein demonstrated that this protein has a …

Overdose Prevention Behaviors And The Rural Risk Environment Among People Who Inject Drugs In Rural Appalachia, Jody Teel

Electronic Theses and Dissertations

Introduction: The entire United States has felt the effects of the overdose epidemic, but rural Appalachia has experienced disproportionate overdose deaths. This variation in overdose mortality can be attributed to the risk environment for overdose in rural Appalachia. Overdose prevention behaviors are individual level behaviors that people who inject drugs can implement that may have the potential to reduce their risk of overdose, however limited research exists regarding the utilization of those behaviors. It is important to consider how the risk environment can influence the utilization of overdose prevention behaviors among people who inject drugs. Therefore, the purpose of this …

Prevention Of Intradialytic Hypotension In Hemodialysis Patients: Current Challenges And Future Prospects, Seyed Mehrdad Hamrahian, Salem Vilayet, Johann Herberth, Tibor Fülöp

Division of Nephrology Faculty Papers

Intradialytic hypotension, defined as rapid decrease in systolic blood pressure of greater than or equal to 20 mmHg or in mean arterial pressure of greater than or equal to 10 mmHg that results in end-organ ischemia and requires countermeasures such as ultrafiltration reduction or saline infusion to increase blood pressure to improve patient’s symptoms, is a known complication of hemodialysis and is associated with several potential adverse outcomes. Its pathogenesis is complex and involves both patient-related factors such as age and comorbidities, as well as factors related to the dialysis prescription itself. Key factors include the need for volume removal …

Leveraging Eco-Evolutionary Models For Gene Drive Risk Assessment, Matthew A. Combs, Andrew J. Golnar, Justin M. Overcash, Alun L. Lloyd, Keith R. Hayes, David A. O'Brochta, Kim M. Pepin

United States Department of Agriculture Wildlife Services: Staff Publications

Engineered gene drives create potential for both widespread benefits and irreversible harms to ecosystems. CRISPR-based systems of allelic conversion have rapidly accelerated gene drive research across diverse taxa, putting field trials and their necessary risk assessments on the horizon. Dynamic processbased models provide flexible quantitative platforms to predict gene drive outcomes in the context of system-specific ecological and evolutionary features. Here, we synthesize gene drive dynamic modeling studies to highlight research trends, knowledge gaps, and emergent principles, organized around their genetic, demographic, spatial, environmental, and implementation features. We identify the phenomena that most significantly influence model predictions, discuss limitations of …

Associations Between Cancer Predisposition Mutations And Clonal Hematopoiesis In Patients With Solid Tumors, Sebastià Franch-Expósito, Miika Mehine, Ryan N Ptashkin, Kelly L Bolton, Chaitanya Bandlamudi, Preethi Srinivasan, Linda Zhang, Margaret A Goodell, Erika Gedvilaite, Kamal Menghrajani, Pablo Sánchez-Vela, Diana Mandelker, Elizabeth Comen, Larry Norton, Ryma Benayed, Teng Gao, Elli Papaemmanuil, Barry Taylor, Ross Levine, Kenneth Offit, Zsofia Stadler, Michael F Berger, Ahmet Zehir

Center on Aging Staff Publications

Purpose: Clonal hematopoiesis (CH), the expansion of clones in the hematopoietic system, has been linked to different internal and external features such as aging, genetic ancestry, smoking, and oncologic treatment. However, the interplay between mutations in known cancer predisposition genes and CH has not been thoroughly examined in patients with solid tumors.

Methods: We used prospective tumor-blood paired sequencing data from 46,906 patients who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) testing to interrogate the associations between CH and rare pathogenic or likely pathogenic (P/LP) germline variants.

Results: We observed an enrichment of CH-positive patients among …

Strategies For Advancing Equity In Frontline Clinical Assessment, Chavon M Onumah, Amber T Pincavage, Cindy J Lai, Diane L Levine, Nadia J Ismail, Irene Alexandraki, Nora Y Osman

Faculty and Staff Publications

Educational equity in medicine cannot be achieved without addressing assessment bias. Assessment bias in health professions education is prevalent and has extensive implications for learners and, ultimately, the health care system. Medical schools and educators desire to minimize assessment bias, but there is no current consensus on effective approaches. Frontline teaching faculty have the opportunity to mitigate bias in clinical assessment in real time. Based on their experiences as educators, the authors created a case study about a student to illustrate ways bias affects learner assessment. In this paper, the authors use their case study to provide faculty with evidence-based …