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Proton-Pump Inhibitor Treatment In Eosinophilic Esophagitis Is Associated With Decreased Eosinophil Degranulation, J. Levine, Y. Lu, C. Carreon, M. Edelman

Journal Articles

No abstract provided.

Tat-Hsp70 Attenuates Experimental Lung Injury, M. M. Lyons, N. N. Raj, J. L. Chittams, L. Kilpatrick, C. S. Deutschman

Journal Articles

Sepsis, a poorly understood syndrome of disordered inflammation, is the leading cause of death in critically ill patients. Lung injury, in the form of acute respiratory distress syndrome (ARDS), is the most common form of organ injury in sepsis. The heat shock response, during which heat shock proteins (HSPs) are expressed, is an endogenous mechanism to protect cells from injury. We have found that the abundance of pulmonary HSP70 is not increased after cecal ligation and double puncture (CLP) in a rat model of sepsis-induced ARDS. Using the HIV-1 trans-activator of transcription (TAT) cell-penetrating protein, we enhanced HSP70 protein abundance …

Addition Of Interleukin-21 For Expansion Of T-Cells For Adoptive Immunotherapy Of Murine Melanoma, Christine Kathryn Zoon, Wen Wan, Laura Graham, Harry D. Bear

Surgery Publications

We previously demonstrated that interleukin (IL)-7/15 was superior to IL-2 for expansion of T cells in vitro for adoptive immunotherapy. We sought to ascertain whether IL-21 would further improve yield and therapeutic efficacy of T cells in culture. Naïve T cell receptor (TcR) transgenic splenocytes or antigen-sensitized lymph node cells were harvested from PMEL-1 mice and exposed to bryostatin-1 and ionomycin (B/I) for 18 h. Cells were then cultured in IL-2, IL-21, IL-7/15 or IL-7/15/21 for six days. Harvested cells were analyzed by flow cytometry and used to treat C57Bl/6 mice injected intravenously with B16 melanoma. Lungs were harvested and …

Cancer Stem Cells In The Screening Of Anticancer Drugs For Central Nervous System Tumors, Sarah Elizabeth Daron-Mathis

Theses, Dissertations and Capstones

There is a growing need (in the medical field) to design personalized therapy for cancer patients. Decades of cancer research have found no silver bullet that can cure all or even most patients. This study evaluated four patients affected by central nervous system (CNS) tumors (Ependymoma and Glioblastoma), and found that tumors with the same histology had unique responses to treatment. Each sample presented different levels of heterogeneity in expressed biomarkers and responded to drugs at varying levels.

Oncologists conventionally treat cancer patients with drugs tested in large clinical trials. However, often patients do not experience positive outcomes following treatments …

Investigation Of Ultrasound Targeted Microbubbles As A Therapeutic Gene Delivery System For Prostate Cancer, Rounak Paramjeet Nande

Theses, Dissertations and Capstones

A major challenge for effective gene therapy is systemic delivery of viruses carrying therapeutic genes into affected tissue. The immunogenic nature of human adenoviruses (Ads) limits their use for intratumoral (IT) injection in gene therapy. Ads transfection is further hampered by the fluctuating presence of Coxsackie and Adenovirus Receptor (CAR) and integrins on the cells’ surface. To circumvent these limitations we developed a novel approach wherein Ads are encapsulated inside the shell of lyophilized, lipid-encapsulated, perfluorocarbon microbubbles (MBs)/ultrasound (US) contrast agents, which act as delivery vehicles for a sitespecific gene transfer system.

We performed infection studies with Ad.GFP (Green Fluorescent …

Type I Diabetes In Children And Vitamin D, Ashley B. Litchfield, Rebecca M. Hayes, Franklin D. Shuler Md, Phd, Susan L. Flesher Md

MIIR Faculty Research

Vitamin D deficiency is associated with multiple childhood diseases including type 1 diabetes mellitus (T1DM). T1DM in children is becoming more prevalent, with a 23% increase nationally from 2001 to 2009. Similarly, West Virginia has had an 8.1% increase in children with type 1Diabetes from 2008/2009 to 2010/2011. This article highlights the association between vitamin D and type 1 diabetes and discusses vitamin D’s potential role in the reduction and management of T1DM in children.

Percutaneous Mr Guided Direct Left Atrial Access To Deliver Large Interventional Devices, Toby Rogers, William Schenke, Jonathan R. Mazal, Merdim Sonmez, Ozgur Kocaturk, Kanishka Ratnayaka, Michael Hansen, Anthony Z. Faranesh, Robert J. Lederman

Pediatrics Faculty Publications

No abstract provided.

Differential Expression Of The Nrf2-Linked Genes In Pediatric Septic Shock., Jocelyn R Grunwell, Scott L Weiss, Natalie Z Cvijanovich, Geoffrey L Allen, Neal J Thomas, Robert J. Freishtat, +10 Additional Authors

Pediatrics Faculty Publications

INTRODUCTION: Experimental data from animal models of sepsis support a role for a transcription factor, nuclear erythroid-related factor 2 p45-related factor 2 (Nrf2), as a master regulator of antioxidant and detoxifying genes and intermediary metabolism during stress. Prior analysis of a pediatric septic shock transcriptomic database showed that the Nrf2 response is a top 5 upregulated signaling pathway in early pediatric septic shock.

METHODS: We conducted a focused analysis of 267 Nrf2-linked genes using a multicenter, genome-wide expression database of 180 children with septic shock 10 years of age or younger and 53 healthy controls. The analysis involved RNA isolated …

Intracellular Cd24 Disrupts The Arf-Npm Interaction And Enables Mutational And Viral Oncogene-Mediated P53 Inactivation., Lizhong Wang, Runhua Liu, Peiying Ye, Chunshu Wong, Guo-Yun Chen, Penghui Zhou, +11 Additional Authors

Pediatrics Faculty Publications

CD24 is overexpressed in nearly 70% human cancers, whereas TP53 is the most frequently mutated tumour-suppressor gene that functions in a context-dependent manner. Here we show that both targeted mutation and short hairpin RNA (shRNA) silencing of CD24 retard the growth, progression and metastasis of prostate cancer. CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A. CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen. In support of the …

Genetic And Informatic Analyses Implicate Kif12 As A Candidate Gene Within The Mpkd2 Locus That Modulates Renal Cystic Disease Severity In The Cys1cpk Mouse., Michal Mrug, Juling Zhou, Chaozhe Yang, Bruce J Aronow, Xiangqin Cui, Trenton R Schoeb, Gene P Siegal, Bradley K Yoder, Lisa M. Guay-Woodford

Pediatrics Faculty Publications

We have previously mapped the interval on Chromosome 4 for a major polycystic kidney disease modifier (Mpkd) of the B6(Cg)-Cys1cpk/J mouse model of recessive polycystic kidney disease (PKD). Informatic analyses predicted that this interval contains at least three individual renal cystic disease severity-modulating loci (Mpkd1-3). In the current study, we provide further validation of these predicted effects using a congenic mouse line carrying the entire CAST/EiJ (CAST)-derived Mpkd1-3 interval on the C57BL/6J background. We have also generated a derivative congenic line with a refined CAST-derived Mpkd1-2 interval and demonstrated its dominantly-acting disease-modulating effects (e.g., 4.2-fold increase in total cyst area; …

Extraordinary Diversity Of Immune Response Proteins Among Sea Urchins: Nickel-Isolated Sp185/333 Proteins Show Broad Variations In Size And Charge., Lauren S. Sherman, Catherine S. Schrankel, Kristy J. Brown, L. Courtney Smith

Pediatrics Faculty Publications

Effective protection against pathogens requires the host to produce a wide range of immune effector proteins. The Sp185/333 gene family, which is expressed by the California purple sea urchin Strongylocentrotus purpuratus in response to bacterial infection, encodes a highly diverse repertoire of anti-pathogen proteins. A subset of these proteins can be isolated by affinity to metal ions based on multiple histidines, resulting in one to four bands of unique molecular weight on standard Western blots, which vary depending on the individual sea urchin. Two dimensional gel electrophoresis (2DE) of nickel-isolated protein samples followed by Western blot was employed to detect …

Serum Amyloid A Stimulates Pkr Expression And Hmgb1 Release Possibly Through Tlr4/Rage Receptors, W. Li, S. Zhu, J. Li, J. D'Amore, J. D'Angelo, H. Yang, P. Wang, K. J. Tracey, H. Wang

Journal Articles

Serum amyloid A proteins (SAAs) have been suggested as surrogate markers of sepsis, but their pathogenic roles remain poorly elucidated. Here we provide evidence to support a possible role of SAA as a pathogenic mediator of lethal sepsis. In a subset of septic patients whose serum HMGB1 levels paralleled with the clinical scores, some anti-HMGB1 antibodies detected a 12 kDa protein belonging to the SAA family. In contrast to the most abundant SAA1, human SAA induced PKR expression and HMGB1 release in the wild-type, but not TLR4/RAGE-deficient, macrophages. Pharmacological inhibition of PKR phosphorylation blocked SAA-induced HMGB1 release, suggesting an important …

Cannabinoid Cb2 Receptors In A Mouse Model Of A Beta Amyloidosis: Immunohistochemical Analysis And Suitability As A Pet Biomarker Of Neuroinflammation, A. V. Savonenko, T. Melnikova, Y. C. Wang, H. Ravert, Y. J. Gao, J. Koppel, D. Lee, P. Davies, M. G. Pomper, A. G. Horti, +6 Additional Authors

Journal Articles

In Alzheimer's disease (AD), one of the early responses to A beta amyloidosis is recruitment of microglia to areas of new plaque. Microglial receptors such as cannabinoid receptor 2 (CB2) might be a suitable target for development of PET radiotracers that could serve as imaging biomarkers of A beta-induced neuroinflammation. Mouse models of amyloidosis (J20APPswe/ind and APPswe/PS1 Delta E9) were used to investigate the cellular distribution of CB2 receptors. Specificity of CB2 antibody (H60) was confirmed using J20APPswe/ind mice lacking CB2 receptors. APPswe/PS1 Delta E9 mice were used in small animal PET with a CB2-targeting radiotracer, [C-11]A836339. These studies revealed …

Novel Mechanisms Of Herbal Therapies For Inhibiting Hmgb1 Secretion Or Action, A. H. Wu, L. He, W. Long, Q. Zhou, S. Zhu, P. Wang, S. Fan, H. Wang

Journal Articles

High mobility group box 1 (HMGB1) is an evolutionarily conserved protein and is constitutively expressed in virtually all types of cells. In response to microbial infections, HMGB1 is secreted from activated immune cells to orchestrate rigorous inflammatory responses. Here we review the distinct mechanisms by which several herbal components inhibit HMGB1 action or secretion, such as by modulating inflammasome activation, autophagic degradation, or endocytic uptake. In light of the reciprocal interactions between these cellular processes, it is possible to develop more effective combinational herbal therapies for the clinical management of inflammatory diseases.

Editorial Comment: Symposium: Biologics And Tissue Healing In Orthopaedics, A. Bedi, J. Dines

Journal Articles

No abstract provided.

Platelet-Rich Plasma And Other Cellular Strategies In Orthopedic Surgery, P. N. Williams, G. Moran, J. P. Bradley, N. S. Elattrache, J. S. Dines

Journal Articles

The use of biologics in the treatment of musculoskeletal disease has become increasingly more common as research studies continue to provide further elucidation of their mechanisms in healing. Platelet-rich plasma, patches, growth factors, and stem cells are among the many biologics under active investigation and have varying levels of success in augmenting surgical or nonoperative interventions. However, the limitations of these treatments exist, and clear guidelines for their indications and application have yet to be established. Well-designed clinical trials will help determine the appropriate future use of biologics to ensure consistent outcomes.

Integrating Biodegradable 3-Dimensional-Printing Into Tracheal Reconstruction, T. Goldstein, L. Smith, B. Smith, D. Grande, D. Zeltsman

Journal Articles

No abstract provided.

Comorbid Profile Rather Than Age Determines Hip Fracture Mortality In A Nonagenarian Population, A. Graver, S. Merwin, L. Collins, N. Kohn, A. Goldman

Journal Articles

BACKGROUND: In light of poor outcomes with nonoperative management of hip fractures, orthopedic surgeons are faced with difficult decisions about which patients are too ill or too old for surgical treatment. QUESTIONS/PURPOSES: This study sought to investigate if patients over 90 years had different preoperative laboratory, clinical, and injury characteristics than younger patients with the same injury. We compared our cohort with previously published data. We wished to identify if there were pre-injury risk factors associated with 30-day mortality, which could be modified to enhance postoperative outcomes. METHODS: This is a retrospective review of 198 operatively managed hip fractures in …

Age Influences Inflammatory Responses, Hemodynamics, And Cardiac Proteasome Activation During Acute Lung Injury, H. M. Linge, J. Y. Lee, K. Ochani, K. Koga, N. Kohn, K. Ojamaa, S. R. Powell, E. J. Miller

Journal Articles

Background: Acute lung injury (ALI) is a significant source of morbidity and mortality in critically ill patients. Age is a major determinant of clinical outcome in ALI. The increased ALI-associated mortality in the older population suggests that there are age-dependent alterations in the responses to pulmonary challenge. The objective of this observational study was to evaluate age-dependent differences in the acute (within 6 hours) immunological and physiological responses of the heart and lung, to pulmonary challenge, that could result in increased severity. Methods: Male C57Bl/6 mice (young: 2-3 months, old: 18-20 months) were challenged intratracheally with cell wall components from …

Approaching The Next Revolution? Evolutionary Integration Of Neural And Immune Pathogen Sensing And Response, K. J. Tracey

Journal Articles

Mammalian immunity evolved by the process of natural selection that produced differential survival and reproduction advantages through combinations of hereditary traits underlying the response to pathogens. Primitive animals sense the presence of microbial pathogens through recognition of pathogen-derived molecules in their rudimentary immune and nervous systems. No molecular biological mechanism assigns primacy of pathogen sensing mechanisms to immune cells over neurons. Rather, in animals as diverse as Caenorhabditis elegans to mammals, neural reflexes are activated by the presence of pathogens and transduce neural mechanisms that control the development of immunity. A coming revolution in immunological thinking will require immunologists to …

Hmgb1 Mediates Anemia Of Inflammation In Murine Sepsis Survivors, S. I. Valdes-Ferrer, J. Papoin, M. E. Dancho, L. P. S. Olofsson, J. Li, J. M. Lipton, P. Avancena, H. Yang, Y. R. Zou, S. S. Chavan, B. T. Volpe, S. Rivella, B. Diamond, B. M. Steinberg, L. Blanc, K. J. Tracey, +2 Additional Authors

Journal Articles

Patients surviving sepsis develop anemia but the molecular mechanism is unknown. Here we observed that mice surviving polymicrobial Gram-negative sepsis develop hypochromic, microcytic anemia with reticulocytosis. The bone marrow of sepsis survivors accumulates polychromatophilic and orthochromatic erythroblasts. Compensatory extramedullary erythropoiesis in the spleen is defective during terminal differentiation. Circulating TNF and IL-6 are elevated for five days after the onset of sepsis, and serum HMGB1 levels are increased from day seven until at least day 28. Administration of recombinant HMGB1 to healthy mice mediates anemia with extramedullary erythropoiesis and significantly elevated reticulocyte counts. Moreover, administration of anti-HMGB1 monoclonal antibodies after …

Stress Induces The Danger-Associated Molecular Pattern Hmgb-1 In The Hippocampus Of Male Sprague Dawley Rats: A Priming Stimulus Of Microglia And The Nlrp3 Inflammasome, M. D. Weber, M. G. Frank, K. J. Tracey, L. R. Watkins, S. F. Maier

Journal Articles

Exposure to acute and chronic stressors sensitizes the proinflammatory response of microglia to a subsequent immune challenge. However, the proximal signal by which stressors prime microglia remains unclear. Here, high mobility group box-1 (HMGB-1) protein was explored as a potential mediator of stress-induced microglial priming and whether HMGB-1 does so via the nucleotide-binding domain, leucine-rich repeat, pyrin domain containing protein 3 (NLRP3) inflammasome. Exposure to 100 inescapable tail shocks (ISs) increased HMGB-1 and NLRP3 protein in the hippocampus and led isolated microglia to release HMGB-1 ex vivo. To determine whether HMGB-1 signaling is necessary for stress-induced sensitization of microglia, the …

Competence Acquisition For Single-Incision Laparoscopic Cholecystectomy, G. B. Deutsch, S. A. Sathyanarayana, M. Giangola, M. Akerman, G., 3rd Denoto, J. D. Klein, H. Zemon, E. Rubach

Journal Articles

BACKGROUND AND OBJECTIVES: Within the past few years, there has been a push for an even more minimally invasive approach to biliary disease with the adoption of single-incision laparoscopic cholecystectomy. We sought to compare 4 individual surgeon experiences to define whether there exists a learning curve for performing single-incision laparoscopic cholecystectomy. METHODS: We performed a retrospective review 290 single-incision laparoscopic cholecystectomies performed by a group of general surgeons, with varying levels of experience and training, at 3 institutions between May 2008 and September 2010. The procedure times were recorded for each single-incision laparoscopic cholecystectomy, ordered chronologically for each surgeon, and …

Growth Arrest-Specific Protein 6 Protects Against Renal Ischemia-Reperfusion Injury, M. D. Giangola, W. L. Yang, S. R. Rajayer, M. Kuncewitch, E. Molmenti, J. Nicastro, G. F. Coppa, P. Wang

Journal Articles

BACKGROUND: Renal injury caused by ischemia-reperfusion (I/R) often occurs after shock or transplantation. Growth arrest-specific protein 6 (Gas6) is a secreted protein that binds to the TAM-Tyro3, Axl, Mer-family tyrosine kinase receptors, which modulate the inflammatory response and activate cell survival pathways. We hypothesized that Gas6 could have a protective role in attenuating the severity of renal injury after I/R. MATERIALS AND METHODS: Adult mice were subjected to 45 min of bilateral renal ischemia. Recombinant mouse Gas6 (rmGas6, 5 mug per mouse) or normal saline (vehicle) was administered intraperitoneally 1 h before ischemia and all subjects were sacrificed at 23 …

The Role Of B-1 Cells In Inflammation, M. Aziz, N. E. Holodick, T. L. Rothstein, P. Wang

Journal Articles

B-1 lymphocytes exhibit unique phenotypic, ontogenic, and functional characteristics that differ from the conventional B-2 cells. B-1 cells spontaneously secrete germline-like, repertoire-skewed polyreactive natural antibody, which acts as a first line of defense by neutralizing a wide range of pathogens before launching of the adaptive immune response. Immunomodulatory molecules such as interleukin-10, adenosine, granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-35 are also produced by B-1 cells in the presence or absence of stimulation, which regulate acute and chronic inflammatory diseases. Considerable progress has been made during the past three decades since the discovery of B-1 cells, which has improved not only …

Post Splenectomy Related Pulmonary Hypertension, A.V. Palkar, A. Agrawal, S. Verma, A. Iftikhar, E.J. Miller, A. Talwar

Journal Articles

No abstract provided.

Mfg-E8 Inhibits Neutrophil Migration Through Alpha(V)Beta(3)-Integrin-Dependent Map Kinase Activation, M. Aziz, W. L. Yang, L. M. Corbo, W. W. Chaung, S. Matsuo, P. Wang

Journal Articles

We have previously demonstrated the involvement of milk fat globule-epidermal growth factor-factor 8 (MFG-E8) in reducing neutrophil infiltration in a murine model of acute lung injury (ALI). In the present study, we aimed to delineate the mechanisms through which MFG-E8 attenuates neutrophil migration. Recombinant human MFG-E8 (rhMFG-E8) was expressed and purified in our facility. The human differentiated neutrophil cell line, dHL-60, was treated with rhMFG-E8 and cell migration assay was performed in a Boyden chamber using recombinant interleukin-8 (IL-8) as the chemoattractant. Surface CXCR2 and intracellular G protein-coupled receptor kinase 2 (GRK2) levels were evaluated by flow cytometry or western …

Milk Fat Globule-Egf Factor Viii Attenuates Cns Injury By Promoting Neural Stem Cell Proliferation And Migration After Cerebral Ischemia, C. Cheyuo, M. Aziz, W. L. Yang, A. Jacob, M. Zhou, P. Wang

Journal Articles

The mediators in activating neural stem cells during the regenerative process of neurogenesis following stroke have not been fully identified. Milk fat globule-EGF Factor VIII (MFGE8), a secreted glycoprotein serves several cellular functions by binding to its receptor, alpha(v)beta(3)-integrin. However, its role in regulating neural stem cells after stroke has not been determined yet. We therefore, aim to reveal whether MFG-E8 promotes neural stem cell proliferation and migration during stroke. Stroke was induced in wild-type (Wt) and MFG-E8-deficinet (Mfge8(-/-)) mice by transient middle cerebral artery occlusion (tMCAO). Commercially available recombinant mouse MFG-E8 (rmMFG-E8) was used for mechanistic assays in neural …

Blocking Cold-Inducible Rna-Binding Protein Protects Liver From Ischemia-Reperfusion Injury, A. Godwin, W. L. Yang, A. Sharma, A. Khader, Z. Wang, F. Zhang, J. Nicastro, G.F. Coppa, P. Wang

Journal Articles

Cold-inducible RNA-binding protein (CIRP) is a nuclear protein that has been recently identified as a novel inflammatory mediator in hemorrhagic shock and sepsis. We hypothesized that CIRP acts as a potent inflammatory mediator in hepatic ischemia-reperfusion (I/R), and thus blocking CIRP protects against I/R-induced liver injury. Male C57BL/6 mice were subjected to 70% hepatic ischemia by microvascular clamping of the hilum of the left and median liver lobes for 60 min, followed by reperfusion. Anti-CIRP antibody (1 mg/kg body weight) or vehicle (normal saline) in 0.2 mL was injected via the internal jugular vein at the beginning of the reperfusion. …

Neutralization Of Osteopontin Attenuates Neutrophil Migration In Sepsis-Induced Acute Lung Injury, Y. Hirano, M. Aziz, W.L. Yang, Z. Wang, M. Zhou, M. Ochani, A. Khader, P. Wang

Journal Articles

INTRODUCTION: Sepsis refers to severe systemic inflammation leading to acute lung injury (ALI) and death. Introducing novel therapies can reduce the mortality in ALI. Osteopontin (OPN), a secretory glycoprotein produced by immune reactive cells, plays a deleterious role in various inflammatory diseases. However, its role in ALI caused by sepsis remains unexplored. We hypothesize that treatment with an OPN-neutralizing antibody (anti-OPN Ab) protects mice against ALI during sepsis. METHODS: Sepsis was induced in 8-week-old male C57BL/6 mice by cecal ligation and puncture (CLP). Anti-OPN Ab or non-immunized IgG as control, at a dose of 50 mug/mouse, was intravenously injected at …