Digital Commons Network^™

Recurrent Gain Of Function Mutation In Calcium Channel Cacna1h Causes Early-Onset Hypertension With Primary Aldosteronism, U. I. Scholl, G. Stolting, C. Nelson-Williams, A. A. Vichot, M. Choi, E. Loring, M. L. Prasad, G. Goh, C. B. Sethna, R. P. Lifton, +11 Additional Authors

Journal Articles

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1H(M1549V) mutation. Two mutations were demonstrated to be de novo events, and all mutations …

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 …

Tell Me A Story: The Relationship Between Identity And Life Stories Following Brain Injury, Sara Henson

Theses, Dissertations and Capstones

Following brain injury, people can demonstrate cognitive-linguistic deficits as well as a shift in their identities. Clinicians use assessment and treatment methods that focus on cognitive-linguistic deficits with this population; however, they rarely (if ever) consider identity as a viable and necessary target for intervention efforts. For individuals with brain injury, life narratives can be used to assess and treat the cognitive-linguistic skills and discourse at a macro-systemic level, build relationships through the use of a client-centered approach, develop a strong sense of self-identity that aids in goal setting, establish life purpose that motivates greater participation and effort in rehabilitation, …

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.

Oncology Section Edge Task Force On Prostate Cancer Outcomes: A Systematic Review Of Clinical Measures Of Strength And Muscular Endurance, Mary Insana Fisher, Claire Davies, Genevieve Colon, Hannah Geyer, Lucinda Pfalzer

Physical Therapy Faculty Publications

Background: Strength deficits are a common morbidity following treatment for prostate cancer. Accurate assessment of strength and muscular endurance following prostate cancer treatments is essential to identify deficits and plan rehabilitation.

Purpose: To identify strength and muscular endurance outcome measures that possess strong psychometric properties and are clinically useful for examination of men treated for prostate cancer.

Methods: Multiple electronic databases were searched for articles published after 1995. Studies of tools used to assess strength and muscular endurance were included if they reported psychometric properties, were clinically feasible methods, performed on adults, and published in the English language. Each outcome …

Improving Anatomical Knowledge Through Interactive Modules On The Ob/Gyn Clinical Clerkship, Artin Galoosian, Jill A. Krapf, Kirsten Brown, Gisela Butera, Ellen F. Goldman, Rosalyn A. Jurjus

Anatomy and Regenerative Biology Faculty Posters and Presentations

The goal of this study is to evaluate the impact of a newly designed interactive method of teaching clinically relevant anatomy to medical students on the OB/GYN clerkship. A 20-question multiple-choice exam was administered to 143 consenting third-year medical students at the beginning and end of each OB/GYN rotation. Students participated in a skills lab with preparatory e-modules that linked anatomy to clinical applications during each rotation. Topics included perineal muscle anatomy (laceration), anterior abdominal wall anatomy (cesarean section), vulvovaginal and uterine anatomy (IUD), and pelvic organ, vasculature, and neural anatomy (hysterectomy). Mean scores improved significantly after the nesting of …

Temporal Order Of Rnase Iiib And Loss-Of-Function Mutations During Development Determines Phenotype In Dicer1 Syndrome: A Unique Variant Of The Two-Hit Tumor Suppression Model [V1; Ref Status: Approved With Reservations 1, Http://F1000r.Es/5l9], Mark Brenneman, Amanda Field, Jiandong Yang, Gretchen Williams, Leslie A. Doros, Christopher T. Rossi, Heather A. Gordish-Dressman, D. Ashley Hill, Et Al.

Pediatrics Faculty Publications

Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing DICER1 mutations and sought correlations with clinical phenotypes. Over …

Beyond Cd19: Opportunities For Future Development Of Targeted Immunotherapy In Pediatric Relapsed-Refractory Acute Leukemia., Haneen Shalabi, Anne Angiolillo, Terry J Fry

Pediatrics Faculty Publications

Chimeric antigen receptor (CAR) T cell therapy has been used as a targeted approach in cancer therapy. Relapsed and refractory acute leukemia in pediatrics has been difficult to treat with conventional therapy due to dose-limiting toxicities. With the recent success of CD 19 CAR in pediatric patients with B cell acute lymphoblastic leukemia (ALL), this mode of therapy has become a very attractive option for these patients with high-risk disease. In this review, we will discuss current treatment paradigms of pediatric acute leukemia and potential therapeutic targets for additional high-risk populations, including T cell ALL, AML, and infant ALL.

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 …

Mllt1 Yeats Domain Mutations In Clinically Distinctive Favourable Histology Wilms Tumours., Elizabeth J Perlman, Samantha Gadd, Stefan T Arold, Anand Radhakrishnan, Daniela S Gerhard, Jeffrey S. Dome, +19 Additional Authors

Pediatrics Faculty Publications

Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1-mutant tumours present at a younger age and have a high prevalence of precursor intralobar …

Liver Sinusoid On A Chip: Long-Term Layered Co-Culture Of Primary Rat Hepatocytes And Endothelial Cells In Microfluidic Platforms, Young Bok (Abraham) Kang, Temitope R. Sodunke, Jason Lamontagne, Joseph Cirillo, Caroline Rajiv, Michael J. Bouchard, Moses Noh

Faculty Publications - Biomedical, Mechanical, and Civil Engineering

We describe the generation of microfluidic platforms for the co-culture of primary hepatocytes and endothelial cells; these platforms mimic the architecture of a liver sinusoid. This paper describes a progressional study of creating such a liver sinusoid on a chip system. Primary rat hepatocytes (PRHs) were co-cultured with primary or established endothelial cells in layers in single and dual microchannel configurations with or without continuous perfusion. Cell viability and maintenance of hepatocyte functions were monitored and compared for diverse experimental conditions. When primary rat hepatocytes were co-cultured with immortalized bovine aortic endothelial cells (BAECs) in a dual microchannel with continuous …

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 …

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 …

Similarities Between Interstitial Cystitis/Bladder Pain Syndrome And Vulvodynia: Implications For Patient Management, J. Y. Fariello, R. M. Moldwin

Journal Articles

Interstitial cystitis/bladder pain syndrome (IC/BPS) and vulvodynia are chronic pain syndromes that appear to be intertwined from the perspectives of embryology, pathology and epidemiology. These associations may account for similar responses to various therapies.

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 …

Long-Term (60-Month) Results For The Implantable Miniature Telescope: Efficacy And Safety Outcomes Stratified By Age In Patients With End-Stage Age-Related Macular Degeneration, D. Boyer, K. B. Freund, C. Regillo, M. H. Levy, S. Garg

Journal Articles

BACKGROUND: The purpose of this study was to evaluate the long-term results of an implantable miniature telescope (IMT) in patients with bilateral, end-stage, age-related macular degeneration (AMD). METHODS: A prospective, open-label, multicenter clinical trial with fellow eye controls enrolled 217 patients (mean age 76 years) with AMD and moderate-to-profound bilateral central visual acuity loss (20/80-20/800) resulting from untreatable geographic atrophy, disciform scars, or both. A subgroup analysis was performed with stratification for age (patient age 65 to[group 1; n=70] and patient age >/=75 years [group 2; n=127]), with a comparative evaluation of change in best-corrected distance visual acuity (BCDVA), quality …

Comparative Review Of The Treatment Methodologies Of Carotid Stenosis, C. Bae, M. Szuchmacher, J. B. Chang

Journal Articles

The treatment of carotid stenosis entails three methodologies, namely, medical management, carotid angioplasty and stenting (CAS), as well as carotid endarterectomy (CEA). The North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST) have shown that symptomatic carotid stenosis greater than 70% is best treated with CEA. In asymptomatic patients with carotid stenosis greater than 60%, CEA was more beneficial than treatment with aspirin alone according to the Asymptomatic Carotid Atherosclerosis (ACAS) and Asymptomatic Carotid Stenosis Trial (ACST) trials. When CAS is compared with CEA, the CREST resulted in similar rates of ipsilateral stroke and death rates …

Weight Trends In United States Living Kidney Donors: Analysis Of The Unos Database, M. Sachdeva, L. M. Rosen, J. Varghese, S. Fishbane, E. P. Molmenti

Journal Articles

AIM: To analyze the national trends associated with body mass index (BMI) and living kidney donation. METHODS: Forty-seven thousand seven hundred and five adult living kidney donors as reported to the Organ Procurement and Transplantation Network from 1999 to 2011 were analyzed using their pre-donation BMI. Predictor variables of interest included age, gender, ethnicity, relationship, education status, and transplant region. RESULTS: Sixteen thousand nine hundred and seventy-one of the living kidney donors were normal weight (35.6%); 19337 were overweight (40.5%); 9007 were mildly obese (18.9%); 1992 were moderate to morbidly obese (4.2%). Overweight and mildly obese kidney donors have increased …

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 …