Medicine and Health Sciences Commons^™

Inhibition Of Bruton Tyrosine Kinase Reduces Neuroimmune Cascade And Promotes Recovery After Spinal Cord Injury, Chen Guang Yu, Vimala Bondada, Hina Iqbal, Kate L. Moore, John C. Gensel, Subbarao Bondada, James W. Geddes

Physiology Faculty Publications

Microglia/astrocyte and B cell neuroimmune responses are major contributors to the neurological deficits after traumatic spinal cord injury (SCI). Bruton tyrosine kinase (BTK) activation mechanistically links these neuroimmune mechanisms. Our objective is to use Ibrutinib, an FDA-approved BTK inhibitor, to inhibit the neuroimmune cascade thereby improving locomotor recovery after SCI. Rat models of contusive SCI, Western blot, immunofluorescence staining imaging, flow cytometry analysis, histological staining, and behavioral assessment were used to evaluate BTK activity, neuroimmune cascades, and functional outcomes. Both BTK expression and phosphorylation were increased at the lesion site at 2, 7, 14, and 28 days after SCI. Ibrutinib …

Mitochondrial Phenotypes In Purified Human Immune Cell Subtypes And Cell Mixtures, Shannon Rausser, Caroline Trumpff, Marlon A. Mcgill, Alex Junker, Wei Wang, Siu-Hong Ho, Anika Mitchell, Kalpita R. Karan, Catherine Monk, Suzanne C. Segerstrom, Rebecca G. Reed, Martin Picard

Psychology Faculty Publications

Using a high-throughput mitochondrial phenotyping platform to quantify multiple mitochondrial features among molecularly defined immune cell subtypes, we quantify the natural variation in mitochondrial DNA copy number (mtDNAcn), citrate synthase, and respiratory chain enzymatic activities in human neutrophils, monocytes, B cells, and naïve and memory T lymphocyte subtypes. In mixed peripheral blood mononuclear cells (PBMCs) from the same individuals, we show to what extent mitochondrial measures are confounded by both cell type distributions and contaminating platelets. Cell subtype-specific measures among women and men spanning four decades of life indicate potential age- and sex-related differences, including an age-related elevation in mtDNAcn, …

Long-Term Survival Of Older Patients Hospitalized For Covid-19. Do Clinical Characteristics Upon Admission Matter?, Michał Chojnicki, Agnieszka Neumann-Podczaska, Mikołaj Seostianin, Zofia Tomczak, Hamza Tariq, Jerzy Chudek, Sławomir Tobis, Iwona Mozer-Lisewska, Aleksandra Suwalska, Andrzej Tykarski, Piotr Merks, Sylwia Kropińska, Małgorzata Sobieszczańska, Frank Romanelli, Katarzyna Wieczorowska-Tobis

Pharmacy Practice and Science Faculty Publications

Older adults are particularly susceptible to COVID-19 in terms of both disease severity and risk of death. To compare clinical differences between older COVID-19 hospitalized survivors and non-survivors, we investigated variables influencing mortality in all older adults with COVID-19 hospitalized in Poznań, Poland, through the end of June 2020 (n = 322). In-hospital, post-discharge, and overall 180-day mortality were analyzed. Functional capacity prior to COVID-19 diagnosis was also documented. The mean age of subjects was 77.5 ± 10.0 years; among them, 191 were females. Ninety-five (29.5%) died during their hospitalization and an additional 30 (9.3%) during the post-discharge period …

Bias Of The Immune Response To Pneumocystis Murina Does Not Alter The Ability Of Neonatal Mice To Clear The Infection, Cathryn J. Kurkjian, Melissa L. Hollifield, David J. Feola, Beth A. Garvy

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Newborn mice are unable to clear Pneumocystis (PC) infection with the same efficiency as adults due, in part, to their inability to develop a robust immune response to infection until three weeks of age. It is known that infants tend develop a Th2 skewed response to antigen so we sought to determine whether a biased cytokine response altered the clearance of PC infection in neonatal mice. P. murina infection in neonatal mice resulted in increased IL-4 expression by CD4 T cells and myeloid cells, augmented IL-13 secretion within the airways and increased arginase activity in the airways, indicative of Th2-type …

Apobec Mutagenesis Is Concordant Between Tumor And Viral Genomes In Hpv-Positive Head And Neck Squamous Cell Carcinoma, Daniel L. Faden, Krystle A. Lang Kuhs, Maoxuan Lin, Adam Langenbucher, Maisa Pinheiro, Meredith Yeager, Michael Cullen, Joseph F. Boland, Mia Steinberg, Sara Bass, James S. Lewis, Michael S. Lawrence, Robert L. Ferris, Lisa Mirabello

Epidemiology and Environmental Health Faculty Publications

APOBEC is a mutagenic source in human papillomavirus (HPV)-mediated malignancies, including HPV+ oropharyngeal squamous cell carcinoma (HPV + OPSCC), and in HPV genomes. It is unknown why APOBEC mutations predominate in HPV + OPSCC, or if the APOBEC-induced mutations observed in both human cancers and HPV genomes are directly linked. We performed sequencing of host somatic exomes, transcriptomes, and HPV16 genomes from 79 HPV + OPSCC samples, quantifying APOBEC mutational burden and activity in both host and virus. APOBEC was the dominant mutational signature in somatic exomes. In viral genomes, there was a mean of five (range 0–29) mutations per …

Targeted Oral Delivery Of Paclitaxel Using Colostrum-Derived Exosomes, Raghuram Kandimalla, Farrukh Aqil, Sara S. Alhakeem, Jeyaprakash Jeyabalan, Neha Tyagi, Ashish Agrawal, Jun Yan, Wendy Spencer, Subbarao Bondada, Ramesh C. Gupta

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) is the most common type accounting for 84% of all lung cancers. Paclitaxel (PAC) is a widely used drug in the treatment of a broad spectrum of human cancers, including lung. While efficacious, PAC generally is not well tolerated and its limitations include low aqueous solubility, and significant toxicity. To overcome the dose-related toxicity of solvent-based PAC, we utilized bovine colostrum-derived exosomes as a delivery vehicle for PAC for the treatment of lung cancer. Colostrum provided higher yield of exosomes and could be loaded with higher …

Report Of The Pathogenesis And Pathophysiology Of Lyme Disease Subcommittee Of The Hhs Tick Borne Disease Working Group, Sam T. Donta, Leith J. States, Wendy A. Adams, Troy Bankhead, Nicole Baumgarth, Monica E. Embers, Robert B. Lochhead, Brian Stevenson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

An understanding of the pathogenesis and pathophysiology of Lyme disease is key to the ultimate care of patients with Lyme disease. To better understand the various mechanisms underlying the infection caused by Borrelia burgdorferi, the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee was formed to review what is currently known about the pathogenesis and pathophysiology of Lyme disease, from its inception, but also especially about its ability to persist in the host. To that end, the authors of this report were assembled to update our knowledge about the infectious process, identify the gaps that exist in our understanding of …

The Effects Of Myelin On Macrophage Activation Are Phenotypic Specific Via Cpla2 In The Context Of Spinal Cord Injury Inflammation, Timothy J. Kopper, Bei Zhang, William M. Bailey, Kara E. Bethel, John C. Gensel

Physiology Faculty Publications

Spinal cord injury (SCI) produces chronic, pro-inflammatory macrophage activation that impairs recovery. The mechanisms driving this chronic inflammation are not well understood. Here, we detail the effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-dependent role for cytosolic phospholipase-A2 (cPLA₂) in myelin-mediated potentiation of pro-inflammatory macrophage activation. We hypothesized that cPLA₂ and myelin debris are key mediators of persistent pro-inflammatory macrophage responses after SCI. To test this, we examined spinal cord tissue 28-days after thoracic contusion SCI in 3-month-old female mice and observed both cPLA₂ activation and intracellular accumulation of lipid-rich myelin …

Laboratory Markers Predictive Of Fulminant Clostridioides Difficile Infection Refractory To Fluid Resuscitation, Omar Ahmad, Timothy N. Crawford, Vaneet Arora, Mitu Karki Maskey

Internal Medicine Faculty Publications

Background

Old age, leucocytosis, hypoalbuminemia, and elevated creatinine have been identified as risk factors for fulminant Clostridioides difficile infection (CDI). High ATLAS scores have also been linked to fatal disease. The affiliated studies, however, involved patients prescribed metronidazole - a regimen no longer standard of care. The variables were thus reassessed in patients prescribed optimal therapy.

Methods

Adults hospitalized with CDI at University of Kentucky Medical Center were retrospectively reviewed. Enrolled subjects were separated according to disease classification i.e. non-severe/severe versus fulminant CDI. Fulminant patients were further subdivided into hypotensive persons responsive to fluid resuscitation, and those with sequent shock, …

Immunomodulatory Effects Of Azithromycin Revisited: Potential Applications To Covid-19, Vincent J. Venditto, Dalia Haydar, Ahmed K. Abdel-Latif, John C. Gensel, Michael I. Anstead, Michelle G. Pitts, Jarrod W. Creameans, Timothy J. Kopper, Chi Peng, David J. Feola

Pharmaceutical Sciences Faculty Publications

The rapid advancement of the COVID-19 pandemic has prompted an accelerated pursuit to identify effective therapeutics. Stages of the disease course have been defined by viral burden, lung pathology, and progression through phases of the immune response. Immunological factors including inflammatory cell infiltration and cytokine storm have been associated with severe disease and death. Many immunomodulatory therapies for COVID-19 are currently being investigated, and preliminary results support the premise of targeting the immune response. However, because suppressing immune mechanisms could also impact the clearance of the virus in the early stages of infection, therapeutic success is likely to depend on …

S. Gordonii-Produced Hydrogen Peroxide Modulates Mir-663a And Ccl20 Expression In Oral Epithelial Cells, Marshall Houston Maynard

Theses and Dissertations--Medical Sciences

The mechanisms through which a persistent recognition of commensal bacteria by oral epithelial cells (OECs) mitigates an uncontrolled inflammatory response of the oral mucosa remain unknown. CCL20 secretion by OECs in response to pathogenic bacteria is regulated by S. gordonii (Sg)-induced miR-663a; nevertheless, the mechanisms involved in these Sg-modulated responses remain to be elucidated. Since Sg is a hydrogen peroxide (H₂O₂) producer, and H₂O₂ has been shown to stimulate miRNA expression, we hypothesized that H₂O₂ could be involved in Sg-induced miR663a and CCL20 responses. Expression of miR663a …

Immunostimulatory Membrane Proteins Potentiate H. Pylori-Induced Carcinogenesis By Enabling Caga Translocation, Matthew G. Varga, Cecily R. Wood, Julia Butt, Mackenzie E. Ryan, Wei-Cheng You, Kaifeng Pan, Tim Waterboer, Meira Epplein, Carrie L. Shaffer

Veterinary Science Faculty Publications

Infection with Helicobacter pylori is the single greatest risk factor for developing gastric adenocarcinoma. In prospective, population-based studies, seropositivity to the uncharacterized H. pylori proteins Hp0305 and Hp1564 was significantly associated with cancer risk in East Asia. However, the mechanism underlying this observation has not been elucidated. Here, we show that Hp0305 and Hp1564 act in concert with previously ascribed H. pylori virulence mechanisms to orchestrate cellular alterations that promote gastric carcinogenesis. In samples from 546 patients exhibiting premalignant gastric lesions, seropositivity to Hp0305 and Hp1564 was significantly associated with increased gastric atrophy across all stomach conditions. In vitro, …