Digital Commons Network^™

Ultrastructure For The Diagnosis Of Primary Ciliary Dyskinesia In South Africa, A Resource-Limited Setting, Monica Birkhead, Samuel Otido, Theodore Mabaso, Keketso Mopeli, Dorcas Tlhapi, Charl Verwey, Ziyaad Dangor

Paediatrics and Child Health, East Africa

Introduction: International guidelines recommend a multi-faceted approach for successful diagnoses of primary ciliary dyskinesia (PCD). In the absence of a gold standard test, a combination of genetic testing/microscopic analysis of structure and function/nasal nitric oxide measurement is used. In resourcelimited settings, often none of the above tests are available, and in South Africa, only transmission electron microscopy (TEM) is available in central anatomical pathology departments. The aim of this study was to describe the clinical and ultrastructural findings of suspected PCD cases managed by pediatric pulmonologists at a tertiary-level state funded hospital in Johannesburg.

Methods: Nasal brushings were …

Superficial Thrombophlebitis In Ipsilateral Breast After Covid-19 Vaccination, Zhichao Zhou, Patricia Q Tran, Alyssa M Adams, Kristopher Kieft, John A Breier, Caroline S Fortunato, Cody S Sheik, Julie A Huber, Meng Li, Gregory J Dick, Karthik Anantharaman

Faculty, Staff and Student Publications

In globally distributed deep-sea hydrothermal vent plumes, microbiomes are shaped by the redox energy landscapes created by reduced hydrothermal vent fluids mixing with oxidized seawater. Plumes can disperse over thousands of kilometers and their characteristics are determined by geochemical sources from vents, e.g., hydrothermal inputs, nutrients, and trace metals. However, the impacts of plume biogeochemistry on the oceans are poorly constrained due to a lack of integrated understanding of microbiomes, population genetics, and geochemistry. Here, we use microbial genomes to understand links between biogeography, evolution, and metabolic connectivity, and elucidate their impacts on biogeochemical cycling in the deep sea. Using …

Role Of Hospital Leadership In Pandemic Preparedness: Experience At A Tertiary Hospital In Kenya During The Covid-19 Pandemic, Lucy Mwangi, William Macharia, Benjamin Wachira, Jemimah Kimeu, Boniface Mativa, Lukoye Atwoli

Paediatrics and Child Health, East Africa

Introduction: Pandemic preparedness refers to being ready for, responding to and recovering from public health crises, and is integral for health security. Hospital leadership is a critical building block of an effective healthcare system, providing policy, accountability and stewardship in a health crisis.

Objectives and methods: We aimed to describe the leadership and governance structures put in place at the Aga Khan University Hospital, Nairobi, a private not-forprofit tertiary healthcare facility, following the COVID-19 pandemic. We reviewed over 200 hospital documents archived in the COVID-19 repository including those received from the Kenya Ministry of Health, emails, memos, bulletins, meeting minutes, …

Apheresis Collection Of Mononuclear Cells For Chimeric-Antigen Receptor Therapies, Robert W. Maitta

Faculty Scholarship

Collections of lymphocytes to be genetically modified to treat hematologic malignancies have seen a dramatic increase over the last few years as commercial products have been approved. Reports of new products in development that can possibly treat solid organ malignancies represent a massive change in the field. Apheresis is at the center of the collection of cells for the manufacture of these chimeric-antigen receptor therapy products. The expansion of these collections represents one of the areas of apheresis procedures growth. This review will summarize concepts important to this type of collection and variables that need to be optimized to obtain …

Demodex Blepharitis: A Comprehensive Review Of The Disease, Current Management, And Emerging Therapies, Michelle K. Rhee, Elizabeth Yeu, Melissa Barnett, Christopher J. Rapuano, Deepinder K Dhaliwal, Kelly K. Nichols, Paul Karpecki, Francis S. Mah, Arthur Chan, James Mun, Ian Benjamin Gaddie

Wills Eye Hospital Papers

Demodex blepharitis is a common disease of the eyelid, affecting approximately 25 million Americans. This article reviews what is known about the mechanisms and impact of Demodex blepharitis, risk factors, signs and symptoms, diagnostic techniques, current management options, and emerging treatments. Demodex mites contribute to blepharitis in several ways: direct mechanical damage, as a vector for bacteria, and by inducing hypersensitivity and inflammation. Risk factors for Demodex blepharitis include increasing age, rosacea, and diabetes. The costs, symptom burden, and psychosocial effects of Demodex blepharitis are considerable. The presence of collarettes is pathognomonic for Demodex blepharitis. Redness, dryness, discomfort, foreign body …

Functional Exploration Of Conserved Sequences In The Distal Face Of Angiotensinogen - Brief Report, Naofumi Amioka, Chia-Hua Wu, Hisashi Sawada, Sohei Ito, Alex C. Pettey, Congqing Wu, Jessica J. Moorleghen, Deborah A. Howatt, Gregory A. Graf, Craig W. Vander Kooi, Alan Daugherty, Hong S. Lu

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND: Angiotensinogen (AGT) is an essential component in the renin-angiotensin system. AGT has highly conserved sequences in the loop and β-sheet regions among species; however, their functions have not been studied.

METHODS: Adeno-associated viral vector (AAV) serotype 2/8 encoding mouse AGT with mutations of conserved sequences in the loop (AAV.loop-Mut), β-sheet (AAV.βsheet-Mut), or both regions (AAV.loop/βsheet-Mut) was injected into male hepatocyte-specific AGT-deficient (hepAGT−/− ) mice in an LDL (low-density lipoprotein) receptor–deficient background. AAV containing mouse wild-type AGT (AAV.mAGT) or a null vector (AAV.null) were used as controls. Two weeks after AAV administration, all mice were fed a western diet for …

A Spatially Resolved Single-Cell Genomic Atlas Of The Adult Human Breast, Tapsi Kumar, Kevin Nee, Runmin Wei, Siyuan He, Quy H Nguyen, Shanshan Bai, Kerrigan Blake, Maren Pein, Yanwen Gong, Emi Sei, Min Hu, Anna K Casasent, Aatish Thennavan, Jianzhuo Li, Tuan Tran, Ken Chen, Benedikt Nilges, Nachiket Kashikar, Oliver Braubach, Bassem Ben Cheikh, Nadya Nikulina, Hui Chen, Mediget Teshome, Brian Menegaz, Huma Javaid, Chandandeep Nagi, Jessica Montalvan, Tatyana Lev, Sharmila Mallya, Delia F Tifrea, Robert Edwards, Erin Lin, Ritesh Parajuli, Summer Hanson, Sebastian Winocour, Alastair Thompson, Bora Lim, Devon A Lawson, Kai Kessenbrock, Nicholas Navin

Faculty, Staff and Student Publications

The adult human breast is comprised of an intricate network of epithelial ducts and lobules that are embedded in connective and adipose tissue1-3. Although most previous studies have focused on the breast epithelial system4-6, many of the non-epithelial cell types remain understudied. Here we constructed the comprehensive Human Breast Cell Atlas (HBCA) at single-cell and spatial resolution. Our single-cell transcriptomics study profiled 714,331 cells from 126 women, and 117,346 nuclei from 20 women, identifying 12 major cell types and 58 biological cell states. These data reveal abundant perivascular, endothelial and immune cell populations, and highly diverse luminal epithelial cell states. …

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 …

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 …

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 …

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 …

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 …

Factors Associated With Choice Of Behavioural Weight Loss Program By Adults With Obesity, Yasaman Jamshidi-Naeini, Susan B Roberts, Stephanie Dickinson, Arthur Owora, Jon Agley, Roger S Zoh, Xiwei Chen, David B Allison

Children’s Nutrition Research Center Staff Publications

We assessed the preference for two behavioural weight loss programs, Diabetes Prevention Program (DPP) and Healthy Weight for Living (HWL) in adults with obesity. A cross-sectional survey was fielded on the Amazon Mechanical Turk. Eligibility criteria included reporting BMI ≥30 and at least two chronic health conditions. Participants read about the programs, selected their preferred program, and answered follow-up questions. The estimated probability of choosing either program was not significantly different from .5 (N = 1005, 50.8% DPP and 49.2% HWL, p = .61). Participants' expectations about adherence, weight loss magnitude, and dropout likelihood were associated with their choice (p <  .0001). Non-White participants (p = .040) and those with monthly income greater than $4999 (p = .002) were less likely to choose DPP. Participants who had postgraduate education (p = .007), did not report high serum cholesterol (p = .028), and reported not having tried losing weight before (p = .025) were more likely to choose DPP. Those who chose HWL were marginally more likely to report that being offered two different programs rather than one would likely affect their decision to enrol in one of the two (p = .052). The enrolment into DPP and HWL was balanced, but race, educational attainment, income, previous attempt to lose weight, and serum cholesterol levels had significant associations with the choice of weight loss program.

T-Cell Receptor Beta Variable Gene Polymorphism Predicts Immune-Related Adverse Events During Checkpoint Blockade Immunotherapy, Bettzy Stephen, Joud Hajjar, Shrutii Sarda, Dzifa Yawa Duose, Jeffrey M Conroy, Carl Morrison, Anas Alshawa, Mingxuan Xu, Abdulrazzak Zarifa, Sapna P Patel, Ying Yuan, Evan Kwiatkowski, Linghua Wang, Jordi Rodon Ahnert, Siqing Fu, Funda Meric-Bernstam, Geoffrey M Lowman, Timothy Looney, Aung Naing

Faculty, Staff and Student Publications

BACKGROUND: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the …

Uncertainty In The Physical Basis Of Estimates Of Relative Biological Effectiveness In Carbon Radiotherapy, Shannon Hartzell, Shannon Hartzell Ph.D.

Dissertations and Theses (Open Access)

Carbon ion radiotherapy is a novel modality used for the treatment of tumors that are unresectable, close to critical structures, or resistant to standard radiotherapy. A unique benefit of this therapy is the relative biological effectiveness (RBE) of the beam (i.e., how biologically potent carbon ions are as compared to x-rays), which is significantly elevated. This RBE also varies as a function of many parameters, and there are currently several models implemented in clinical and research-based treatment planning systems with which to predict RBE. These algorithms are computationally expensive and there are currently no means of validating their implementation within …

Integrative Prognostic Machine Learning Models In Mantle Cell Lymphoma, Holly A Hill, Preetesh Jain, Chi Young Ok, Koji Sasaki, Han Chen, Michael L Wang, Ken Chen

Faculty, Staff and Student Publications

Patients with mantle cell lymphoma (MCL), an incurable B-cell malignancy, benefit from accurate pretreatment disease stratification. We curated an extensive database of 862 patients diagnosed between 2014 and 2022. A machine learning (ML) gradient-boosted model incorporated baseline features from clinicopathologic, cytogenetic, and genomic data with high predictive power discriminating between patients with indolent or responsive MCL and those with aggressive disease (AUC ROC = 0.83). In addition, we utilized the gradient-boosted framework as a robust feature selection method for multivariate logistic and survival modeling. The best ML models incorporated features from clinical and genomic data types highlighting the need for …

Upregulation Of Epac1 Promotes Pericyte Loss By Inducing Mitochondrial Fission, Reactive Oxygen Species Production, And Apoptosis, Wenli Yang, Fan Xia, Fang Mei, Shuizhen Shi, William G Robichaux, Wei Lin, Wenbo Zhang, Hua Liu, Xiaodong Cheng

The Brown Foundation: Institute of Molecular Medicine

PURPOSE: The pathogenic mechanisms behind the development of ischemic retinopathy are complex and poorly understood. This study investigates the involvement of exchange protein directly activated by cAMP (Epac)1 signaling in pericyte injury during ischemic retinopathy, including diabetic retinopathy, a disease that threatens vision.

METHODS: Mouse models of retinal ischemia-reperfusion injury and type 1 diabetes induced by streptozotocin were used to investigate the pathogenesis of these diseases. The roles of Epac1 signaling in the pathogenesis of ischemic retinopathy were determined by an Epac1 knockout mouse model. The cellular and molecular mechanisms of Epac1-mediated pericyte dysfunction in response to high glucose were …

Whole Blood Resuscitation And Association With Survival In Injured Patients With An Elevated Probability Of Mortality, Jason L Sperry, Bryan A Cotton, James F Luther, Jeremy W Cannon, Martin A Schreiber, Ernest E Moore, Nicholas Namias, Joseph P Minei, Stephen R Wisniewski, Frank X Guyette, Shock, Whole Blood, And Assessment Of Traumatic Brain Injury (Swat) Study Group

Faculty, Staff and Student Publications

BACKGROUND: Low-titer group O whole blood (LTOWB) resuscitation is becoming common in both military and civilian settings and may represent the ideal resuscitation intervention. We sought to characterize the safety and efficacy of LTOWB resuscitation relative to blood component resuscitation.

STUDY DESIGN: A prospective, multicenter, observational cohort study was performed using 7 trauma centers. Injured patients at risk of massive transfusion who required both blood transfusion and hemorrhage control procedures were enrolled. The primary outcome was 4-hour mortality. Secondary outcomes included 24-hour and 28-day mortality, achievement of hemostasis, death from exsanguination, and the incidence of unexpected survivors.

RESULTS: A total …

The Hylefm Gene In Phylefm Of Enterococcus Faecium Is Not Required In Pathogenesis Of Murine Peritonitis, Victoria H Wu, Bryan S Yung, Farhoud Faraji, Robert Saddawi-Konefka, Zhiyong Wang, Alexander T Wenzel, Miranda J Song, Meghana S Pagadala, Lauren M Clubb, Joshua Chiou, Sanju Sinha, Marin Matic, Francesco Raimondi, Thomas S Hoang, Rebecca Berdeaux, Dario A A Vignali, Ramiro Iglesias-Bartolome, Hannah Carter, Eytan Ruppin, Jill P Mesirov, J Silvio Gutkind

Faculty, Staff and Student Publications

Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable responses. G-protein-coupled receptors (GPCRs) are the most intensively studied drug targets but are underexplored in immuno-oncology. Here, we cross-integrated large singe-cell RNA-sequencing datasets from CD8+ T cells covering 19 distinct cancer types and identified an enrichment of Gαs-coupled GPCRs on exhausted CD8+ T cells. These include EP2, EP4, A2AR, β1AR and β2AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gαs–DREADD to activate …

Accelerated Epigenetic Aging In Older Adults With Hiv Disease: Associations With Serostatus, Hiv Clinical Factors, And Health Literacy, Steven Paul Woods, Antonio L Teixeira, Lais B Martins, Gabriel R Fries, Gabriela D Colpo, Natalia P Rocha

Faculty, Staff and Student Publications

The prevalence of older persons with HIV (PWH) disease has increased considerably in the last 20 years, but our understanding of biological factors of aging and their clinical correlates among PWH remains limited. Study participants were 149 persons aged 50 and older, including 107 PWH and 42 seronegatives. All participants completed a blood draw, research medical evaluation, structured psychiatric interview, neurocognitive assessment, questionnaires, and measures of health literacy. Four epigenetic clocks were generated from stored blood samples using standardized laboratory methods. In regression models adjusting for sex and smoking status, PWH had significantly higher epigenetic aging acceleration values than seronegatives …

Hernia Prevention Using Biologic Mesh And/Or Small Bites: A Multispecialty 2 × 2 Factorial Randomized Controlled Trial, Rainna Coelho, Naila H Dhanani, Nicole B Lyons, Karla Bernardi, Erik P Askenasy, Stefanos Millas, Julie L Holihan, Zuhair Ali, Mike K Liang

Faculty, Staff and Student Publications

BACKGROUND: Ventral incisional hernias are the most common complication after abdominal operation. Randomized trials have shown efficacy of prophylactic synthetic mesh and small bites. Adoption of these practices has been limited due to concerns with placement of synthetic mesh in contaminated cases and small bites in an overweight population. We sought to assess the efficacy of prophylactic biologic mesh and small bites to prevent postoperative major complications: ventral incisional hernias, surgical site infection, reoperation, and death.

STUDY DESIGN: High-risk patients (overweight/obese, current smoker) undergoing abdominal operation with a midline incision (5 cm or greater) were randomized (2 × 2 factorial …

Biologic Versus Synthetic Mesh In Ventral Hernia Repair: Participant-Level Analysis Of Two Randomized Controlled Trials At Twenty-Four To Thirty-Six Months, Naila H Dhanani, Kyung Hyun Lee, Oscar A Olavarria, Charlotte Young, Frank Primus, Julie L Holihan, Mike K Liang, Hobart W Harris

Faculty, Staff and Student Publications

Background: Biologic mesh has been used increasingly in complex ventral hernia repair despite limited evidence at low risk of bias supporting its use. Patients and

Methods: We performed a participant-level analysis of published randomized controlled trials (RCTs) comparing biologic to synthetic mesh with complex ventral hernia repair at 24 to 36 months. Primary outcome was major complication (composite of mesh infection, recurrence, reoperation, or death) at 24 to 36 months post-operative. Secondary outcomes included length of index hospital stay, surgical site occurrence, surgical site infection, and death. Outcomes were assessed using both frequentist and Bayesian generalized linear regression models.

Results: …

Eosinophils Promote Effector Functions Of Lung Group 2 Innate Lymphoid Cells In Allergic Airway Inflammation In Mice, William E Lesuer, Melanie Kienzl, Sergei I Ochkur, Rudolf Schicho, Alfred D Doyle, Benjamin L Wright, Matthew A Rank, Alexander S Krupnick, Hirohito Kita, Elizabeth A Jacobsen

Faculty, Staff and Student Publications

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are critical mediators of type 2 respiratory inflammation, releasing IL-5 and IL-13 and promoting the pulmonary eosinophilia associated with allergen provocation. Although ILC2s have been shown to promote eosinophil activities, the role of eosinophils in group 2 innate lymphoid cell (ILC2) responses is less well defined.

OBJECTIVE: We sought to investigate the role of eosinophils in activation of ILC2s in models of allergic asthma and in vitro.

METHODS: Inducible eosinophil-deficient mice were exposed to allergic respiratory inflammation models of asthma, such as ovalbumin or house dust mite challenge, or to innate models of …