Medicine and Health Sciences Commons^™

Phosphorylation Meets Nuclear Import: A Review., Jonathan D Nardozzi, Kaylen Lott, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

Phosphorylation is the most common and pleiotropic modification in biology, which plays a vital role in regulating and finely tuning a multitude of biological pathways. Transport across the nuclear envelope is also an essential cellular function and is intimately linked to many degeneration processes that lead to disease. It is therefore not surprising that phosphorylation of cargos trafficking between the cytoplasm and nucleus is emerging as an important step to regulate nuclear availability, which directly affects gene expression, cell growth and proliferation. However, the literature on phosphorylation of nucleocytoplasmic trafficking cargos is often confusing. Phosphorylation, and its mirror process dephosphorylation, …

Finding High Quality Hospitals In Philadelphia., Robert D. Lieberthal, Phd

College of Population Health Lectures, Presentations, Workshops

Guest lecture for PBH609 GIS Mapping. Fall, 2010 session. Philadelphia, PA.

15 PowerPoint slides.

Acetate Causes Alcohol Hangover Headache In Rats., Christina R Maxwell, Rebecca Jay Spangenberg, Jan B Hoek, Stephen D Silberstein, Michael L Oshinsky

Department of Neurology Faculty Papers

BACKGROUND: The mechanism of veisalgia cephalgia or hangover headache is unknown. Despite a lack of mechanistic studies, there are a number of theories positing congeners, dehydration, or the ethanol metabolite acetaldehyde as causes of hangover headache.

METHODS: We used a chronic headache model to examine how pure ethanol produces increased sensitivity for nociceptive behaviors in normally hydrated rats.

RESULTS: Ethanol initially decreased sensitivity to mechanical stimuli on the face (analgesia), followed 4 to 6 hours later by inflammatory pain. Inhibiting alcohol dehydrogenase extended the analgesia whereas inhibiting aldehyde dehydrogenase decreased analgesia. Neither treatment had nociceptive effects. Direct administration of acetate …

Biological Rationale For The Use Of Dna Methyltransferase Inhibitors As New Strategy For Modulation Of Tumor Response To Chemotherapy And Radiation., Giovanni L Gravina, Claudio Festuccia, Francesco Marampon, Vladimir M Popov, Richard G Pestell, Bianca M Zani, Vincenzo Tombolini

Kimmel Cancer Center Faculty Papers

Epigenetic modifications play a key role in the patho-physiology of many tumors and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. DNA methyltransferase (DNMT) inhibitors represent a promising class of epigenetic modulators. Research performed yielded promising anti-tumorigenic activity for these agents in vitro and in vivo against a variety of hematologic and solid tumors. These epigenetic modulators cause cell cycle and growth arrest, differentiation and apoptosis. Rationale for combining these agents with cytotoxic therapy or radiation is straightforward since the use of DNMT inhibitor offers greatly improved access for cytotoxic …

Subglottic Secretion Aspiration In The Prevention Of Ventilator-Associated Pneumonia: A Review Of The Literature., Rachel Scherzer

Jefferson Hospital Staff Papers and Presentations

Ventilator-associated pneumonia is a common nosocomial infection that results in both negative patient outcomes and increased health care costs. Recently, many efforts have been targeted at ventilator-associated pneumonia prevention, including the practice of subglottic secretion aspiration. Six randomized control studies examining the effectiveness of subglottic secretion aspiration in the prevention of ventilator-associated pneumonia were reviewed for this article. Results consistently show that subglottic secretion aspiration significantly reduces the incidence of ventilator-associated pneumonia in a variety of patient populations. Despite these findings, this practice is limited in clinical settings. This clinical practice should be implemented in individuals requiring mechanical ventilation to …

Pp32 (Anp32a) Expression Inhibits Pancreatic Cancer Cell Growth And Induces Gemcitabine Resistance By Disrupting Hur Binding To Mrnas., Timothy K Williams, Christina L Costantino, Nikolai A Bildzukewicz, Nathan G Richards, David W Rittenhouse, Lisa Einstein, Joseph A Cozzitorto, Judith C Keen, Abhijit Dasgupta, Myriam Gorospe, Gregory E Gonye, Charles J Yeo, Agnieszka K Witkiewicz, Jonathan R Brody

Department of Surgery Faculty Papers

The expression of protein phosphatase 32 (PP32, ANP32A) is low in poorly differentiated pancreatic cancers and is linked to the levels of HuR (ELAV1), a predictive marker for gemcitabine response. In pancreatic cancer cells, exogenous overexpression of pp32 inhibited cell growth, supporting its long-recognized role as a tumor suppressor in pancreatic cancer. In chemotherapeutic sensitivity screening assays, cells overexpressing pp32 were selectively resistant to the nucleoside analogs gemcitabine and cytarabine (ARA-C), but were sensitized to 5-fluorouracil; conversely, silencing pp32 in pancreatic cancer cells enhanced gemcitabine sensitivity. The cytoplasmic levels of pp32 increased after cancer cells are treated with certain stressors, …

Ms4a4b, A Cd20 Homologue In T Cells, Inhibits T Cell Propagation By Modulation Of Cell Cycle., Hui Xu, Yaping Yan, Mark S Williams, Gregory B Carey, Jingxian Yang, Hongmei Li, Guang-Xian Zhang, Abdolmohamad Rostami

Department of Neurology Faculty Papers

MS4a4B, a CD20 homologue in T cells, is a novel member of the MS4A gene family in mice. The MS4A family includes CD20, FcεRIβ, HTm4 and at least 26 novel members that are characterized by their structural features: with four membrane-spanning domains, two extracellular domains and two cytoplasmic regions. CD20, FcεRIβ and HTm4 have been found to function in B cells, mast cells and hematopoietic cells respectively. However, little is known about the function of MS4a4B in T cell regulation. We demonstrate here that MS4a4B negatively regulates mouse T cell proliferation. MS4a4B is highly expressed in primary T cells, natural …

A New Frontier For Headache., Stephen Silberstein

Department of Jefferson Headache Center papers and presentations

No abstract provided.

Differential Regulation Of P53 Function By The N-Terminal Δnp53 And Δ113p53 Isoforms In Zebrafish Embryos., William R Davidson, Csaba Kari, Qing Ren, Borbala Daroczi, Adam P Dicker, Ulrich Rodeck

Department of Radiation Oncology Faculty Papers

BACKGROUND: The p53 protein family coordinates stress responses of cells and organisms. Alternative promoter usage and/or splicing of p53 mRNA gives rise to at least nine mammalian p53 proteins with distinct N- and C-termini which are differentially expressed in normal and malignant cells. The human N-terminal p53 variants contain either the full-length (FL), or a truncated (ΔN/Δ40) or no transactivation domain (Δ133) altogether. The functional consequences of coexpression of the different p53 isoforms are poorly defined. Here we investigated functional aspects of the zebrafish ΔNp53 ortholog in the context of FLp53 and the zebrafish Δ133p53 ortholog (Δ113p53) coexpressed in the …

High Inspired Co2 Capnograph Reading Due To Misplaced End Tidal Co2 Sampling Port, Andrew Ng, Md, Elia Elia, Md, Lisa Luyun, Md

Department of Anesthesiology Faculty Papers

In conclusion, if abnormal capnography is seen where the baseline inspiratory CO2 is higher than usual, inspect the circuit for rebreathing and consider examining the position of ETCO2 sampling port. We recommend confirming ETCO2 sampling port is connected immediately distal to Y-piece before starting a case for accurate CO2 measurement.

A Clincial Outcomes Commentary On "A Longitudinal Study Of Outcome Measures For Children Receiving Early Intervention Services", Marcia Levinson, Pt, Phd, Mft, Rosaleen Creedon Gnoffo, Pt, Ms, Dpt, Pcs

Department of Physical Therapy Faculty Papers

Pediatric physical therapy, especially in early intervention (EI), focuses on children’s function in natural environments and within daily routines. Valid and reliable tests measuring the ICF participation component are important to consider if we are to align our treatment focus and goals to our measures of progress. This article demonstrates that the Pediatric Evaluation of Disability Inventory (PEDI) Functional Skill scaled scores are sensitive to change in children receiving EI with and without motor involvement.

Clinical And Diagnostic Features Of Patients With Compound Heterozygous A467t/W748s Polg1 Mutations: A Case Report And Review Of Previous Cases, David Roshal, D.O., Andro Zangaladze, Md, Phd

Department of Neurology Faculty Papers

Introduction

Mutations in the POLG1 gene are considered to be the most common gene defect identified in autosomal recessive mitochondrial DNA depletion disorders. POLG1 is a gene encoding the 195kDa catalytic (alpha) subunit of the mitochondrial (gamma) DNA polymerase, located on chromosome 15q25 and is responsible for mtDNA replication. Mutations in POLG1 are associated with chronic progressive external ophthalmoplegia (CPEO). Other genes that have been implicated in causing syndromic and non-syndromic mitochondrial disorders have been found on both mtDNA (3243A>G, 8344A>G, 8993T>G, and 11778A>G) and nDNA (SURF1, POLG1, TWINKLE, and ANT1).

We report a patient with …

Factors Influencing The One- And Two-Year Growth Response In Children Treated With Growth Hormone: Analysis From An Observational Study., Judith Ross, Peter A Lee, Robert Gut, John Germak

Department of Pediatrics Faculty Papers

To assess gender-, pubertal-, age-related differences in change from baseline height standard deviation score (ΔHSDS), data from 5,797 growth hormone (GH) naïve pediatric patients (<18 >years) with growth hormone deficiency (GHD), multiple pituitary hormone deficiency (MPHD), Turner syndrome (TS), small for gestational age (SGA), Noonan syndrome (NS), and idiopathic short stature (ISS) were obtained from the ANSWER (American Norditropin Studies: Web-enabled Research) Program registry. For patients with SGA, ΔHSDS at year 1 was significantly greater for males versus females (P = .016), but no other gender differences were observed. For patients with GHD, ΔHSDS was greater in prepubertal than in …

Using Hospital Discharge Abstract Data To Identify Incident Breast Cancer Cases And Assess Quality Of Care, Elaine J. Yuen, Daniel Z. Louis, Carol Rabinowitz, Vittorio Maio, L. Cisbani, R. Depalma, R. Grilli

College of Population Health Faculty Papers

No abstract provided.

One Year Survival With Poorly Differentiated Metastatic Pancreatic Carcinoma Following Chemoembolization With Gemcitabine And Cisplatin., Daniel B Brown, Carin F Gonsalves, Charles J Yeo, Agnes K Witkiewicz, Brian I Carr

Department of Radiology Faculty Papers

While hepatic arterial chemoembolization is efficacious for a number of malignancies, there is scant data regarding treatment of pancreatic adenocarcinoma. We report a complete radiographic response at one year from diagnosis of metastatic pancreatic carcinoma. Gemcitabine/cisplatin based chemoembolization may be of potential benefit for patients with liver-dominant metastases from pancreatic carcinoma. Given the typical survival of 6 months or less in this patient group with standard therapies, further research is warranted.

Identification Of Thioaptamer Ligand Against E-Selectin: Potential Application For Inflamed Vasculature Targeting., Aman P Mann, Anoma Somasunderam, René Nieves-Alicea, Xin Li, Austin Hu, Anil K Sood, Mauro Ferrari, David G Gorenstein, Takemi Tanaka

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Active targeting of a drug carrier to a specific target site is crucial to provide a safe and efficient delivery of therapeutics and imaging contrast agents. E-selectin expression is induced on the endothelial cell surface of vessels in response to inflammatory stimuli but is absent in the normal vessels. Thus, E-selectin is an attractive molecular target, and high affinity ligands for E-selectin could be powerful tools for the delivery of therapeutics and/or imaging agents to inflamed vessels. In this study, we identified a thiophosphate modified aptamer (thioaptamer, TA) against E-selectin (ESTA-1) by employing a two-step selection strategy: a recombinant protein-based …

Relationship Between Maternal Methadone Dose At Delivery And Neonatal Abstinence Syndrome., Neil S., Seligman, Christopher V. Almario, Edward J. Hayes, Kevin C. Dysart, Vincenzo Berghella, Jason K. Baxter

Department of Obstetrics and Gynecology Faculty Papers

OBJECTIVE: To estimate the relationship between maternal methadone dose and the incidence of neonatal abstinence syndrome (NAS).

STUDY DESIGN: We performed a retrospective cohort study of pregnant women treated with methadone for opiate addiction who delivered live-born neonates between 1996 and 2006. Four dose groups, on the basis of total daily methadone dose, were compared (160 mg/d). The primary outcome was treatment for NAS. Symptoms of NAS were objectively measured with the Finnegan scoring system, and treatment was initiated for a score>24 during the prior 24 hours.

RESULTS: A total of 330 women treated with methadone and their 388 …

A Role For The Histone Deacetylase Hdac4 In The Life-Cycle Of Hiv-1-Based Vectors., Johanna A Smith, Jennifer Yeung, Gary D Kao, René Daniel

Department of Medicine Faculty Papers

HIV-1 integration is mediated by the HIV-1 integrase protein, which joins 3'-ends of viral DNA to host cell DNA. To complete the integration process, HIV-1 DNA has to be joined to host cell DNA also at the 5'-ends. This process is called post-integration repair (PIR). Integration and PIR involve a number of cellular co-factors. These proteins exhibit different degrees of involvement in integration and/or PIR. Some are required for efficient integration or PIR. On the other hand, some reduce the efficiency of integration. Finally, some are involved in integration site selection. We have studied the role of the histone deacetylase …

Pediatric Ophthalmology And Strabismus: Something For Everyone., Alex V. Levin

Wills Eye Hospital Papers

This issue of Current Opinion in Ophthalmology highlights the uniquely broad range of pediatric ophthalmology and strabismus. Perhaps, unlike any other area of ophthalmology, our specialty covers virtually every part of the eye and a multitude of systemic disorders. Pediatric ophthalmology offers the practitioner the opportunity to impact a patient’s visual life for many decades giving them a lifetime of good vision. This issue of the journal highlights the many ways that this is so.

Survival Associated Pathway Identification With Group Lp Penalized Global Auc Maximization., Zhenqiu Liu, Laurence S Magder, Terry Hyslop, Li Mao

Department of Pharmacology and Experimental Therapeutics Faculty Papers

It has been demonstrated that genes in a cell do not act independently. They interact with one another to complete certain biological processes or to implement certain molecular functions. How to incorporate biological pathways or functional groups into the model and identify survival associated gene pathways is still a challenging problem. In this paper, we propose a novel iterative gradient based method for survival analysis with group Lp penalized global AUC summary maximization. Unlike LASSO, Lp (p < 1) (with its special implementation entitled adaptive LASSO) is asymptotic unbiased and has oracle properties 1. We first extend Lp for individual gene identification to group Lp penalty for pathway selection, and then develop a novel iterative gradient algorithm for penalized global AUC summary maximization (IGGAUCS). This method incorporates the genetic pathways into global AUC summary maximization and identifies survival associated pathways instead of individual genes. The tuning parameters are determined using 10-fold cross validation with training data only. The prediction performance is evaluated using test data. We apply the proposed method to survival outcome analysis with gene expression profile and identify multiple pathways simultaneously. Experimental results with simulation and gene expression data demonstrate that the proposed procedures can be used for identifying important biological pathways that are related to survival phenotype and for building a parsimonious model for predicting the survival times.

Dopaminergic Neurons Derived From Human Induced Pluripotent Stem Cells Survive And Integrate Into 6-Ohda-Lesioned Rats., Jingli Cai, Ming Yang, Elizabeth Poremsky, Sarah Kidd, Jay S Schneider, Lorraine Iacovitti

Farber Institute for Neuroscience Faculty Papers

Cell replacement therapy could be an important treatment strategy for Parkinson's disease (PD), which is caused by the degeneration of dopamine neurons in the midbrain (mDA). The success of this approach greatly relies on the discovery of an abundant source of cells capable of mDAergic function in the brain. With the paucity of available human fetal tissue, efforts have increasingly focused on renewable stem cells. Human induced pluripotent stem (hiPS) cells offer great promise in this regard. If hiPS cells can be differentiated into authentic mDA neuron, hiPS could provide a potential autologous source of transplant tissue when generated from …

Rabies Virus Infection Induces Type I Interferon Production In An Ips-1 Dependent Manner While Dendritic Cell Activation Relies On Ifnar Signaling., Elizabeth J Faul, Celestine N Wanjalla, Mehul S Suthar, Michael Gale, Christoph Wirblich, Matthias J Schnell

Department of Microbiology and Immunology Faculty Papers

As with many viruses, rabies virus (RABV) infection induces type I interferon (IFN) production within the infected host cells. However, RABV has evolved mechanisms by which to inhibit IFN production in order to sustain infection. Here we show that RABV infection of dendritic cells (DC) induces potent type I IFN production and DC activation. Although DCs are infected by RABV, the viral replication is highly suppressed in DCs, rendering the infection non-productive. We exploited this finding in bone marrow derived DCs (BMDC) in order to differentiate which pattern recognition receptor(s) (PRR) is responsible for inducing type I IFN following infection …

Gsk-3alpha Directly Regulates Beta-Adrenergic Signaling And The Response Of The Heart To Hemodynamic Stress In Mice., Jibin Zhou, Hind Lal, Xiongwen Chen, Xiying Shang, Jianliang Song, Yingxin Li, Risto Kerkela, Bradley W Doble, Katrina Macaulay, Morgan Decaul, Walter J Koch, John Farber, James Woodgett, Erhe Gao, Thomas Force

Center for Translational Medicine Faculty Papers

The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, alpha and beta. Although GSK-3beta has an important role in cardiac development, much remains unknown about the function of either GSK-3 isoform in the postnatal heart. Herein, we present what we believe to be the first studies defining the role of GSK-3alpha in the mouse heart using gene targeting. Gsk3a(-/-) mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile dysfunction. Following thoracic aortic constriction in young mice, we observed enhanced hypertrophy that rapidly transitioned to ventricular dilatation and contractile dysfunction. …

Physiologically Based Pharmacokinetics Of Molecular Imaging Nanoparticles For Mrna Detection Determined In Tumor-Bearing Mice., Armin W Opitz, Eric Wickstrom, Mathew L Thakur, Norman J Wagner

Kimmel Cancer Center Faculty Papers

Disease detection and management might benefit from external imaging of disease gene mRNAs. Previously we designed molecular imaging nanoparticles (MINs) based on peptide nucleic acids complementary to cancer gene mRNAs. The MINs included contrast agents and analogs of insulin-like growth factor 1 (IGF-1). Analysis of MIN tumor uptake data showed stronger binding in tumors than in surrounding tissues. We hypothesized that MINs with an IGF-1 analog stay in circulation by binding to IGF-binding proteins. To test that hypothesis, we fit the tissue distribution results of several MINs in xenograft-bearing mice to a physiological pharmacokinetics model. Fitting experimental tissue distribution data …

Assessment Of Epidermal Growth Factor Receptor (Egfr) Expression In Human Meningioma., A Gabriella Wernicke, Adam P Dicker, Michal Whiton, Jana Ivanidze, Terry Hyslop, Elizabeth H Hammond, Arie Perry, David W Andrews, Lawrence Kenyon

Kimmel Cancer Center Faculty Papers

PURPOSE: This study explores whether meningioma expresses epidermal growth factor receptor (EGFR) and determines if there is a correlation between the WHO grade of this tumor and the degree of EGFR expression.

METHODS: Following institutional review board approval, 113 meningioma specimens from 89 patients were chosen. Of these, 85 were used for final analysis. After a blinded review, immunohistochemical stains for EGFR were performed. Staining intensity (SI) was scored on a scale 0-3 (from no staining to strong staining). Staining percentage of immunoreactive cells (SP) was scored 1-5 (from the least to the maximum percent of the specimen staining). Immunohistochemical …

Workshop Enhances Clinical Faculty Development, Joseph F. Lipscomb, Crna, Ms

College of Nursing Faculty Papers & Presentations

Enhanced clinical faculty teaching strategies and skills. Consistent approaches to clinical education. Increased faculty and student satisfaction. Positive student outcomes. Strengthened alliance with clinical affiliates.

Enhanced Psychosocial Well-Being Following Participation In A Mindfulness-Based Stress Reduction Program Is Associated With Increased Natural Killer Cell Activity., Carolyn Y Fang, Diane K Reibel, Margaret L Longacre, Steven Rosenzweig, Donald E Campbell, Steven D Douglas

Marcus Institute of Integrative Health Faculty Papers

BACKGROUND: Mindfulness-based stress reduction (MBSR) programs have consistently been shown to enhance the psychosocial well-being of participants. Given the well-established association between psychosocial factors and immunologic functioning, it has been hypothesized that enhanced psychosocial well-being among MBSR participants would be associated with corresponding changes in markers of immune activity.

OBJECTIVES: The objectives of this study were to examine changes in psychosocial and immunologic measures in a heterogeneous patient sample following participation in a MBSR program.

DESIGN: A single-group, pretest/post-test design was utilized.

SETTING: The intervention was conducted at an academic health center.

SUBJECTS: This pilot study involved 24 participants (aged …

Ask A Different Question, Get A Different Answer: Why Living Wills Are Poor Guides To Care Preferences At The End Of Life., Laraine Winter, Susan M Parks, James J Diamond

Center for Applied Research on Aging and Health Research Papers

CONTEXT: Living wills have a poor record of directing care at the end of life, as a copious literature attests. Some speculation centers on the questionable correspondence between the scenario described in living wills versus the real-life circumstances that typically arise at the end of life.

OBJECTIVE: To assess the strength of association between responses to a standard living will question and preferences for treatments in six end-of-life scenarios.

DESIGN: Cross-sectional.

SETTING: Telephone interviews.

PARTICIPANTS: Two hundred two community-dwelling men and women 70 years of age or older in the greater Philadelphia area.

MAIN OUTCOME MEASURES: Strength of preferences for …

Pregnancy Outcomes In Female Liver Recipients Transplanted Under The Age Of 21, Carlo B. Ramirez, Warren R. Maley, Cataldo Doria, Lisa A. Coscia, Michael J. Moritz, Vincent T. Armenti

Department of Surgery Faculty Papers

Conclusions: Liver recipients transplanted under the age of 21 are able to maintain pregnancy with 75% resulting in a livebirth. Pregnancy, potential risks for mother and newborn, and long-term maternal survival should be discussed with the recipient and the parents of the recipient. Transplant centers are encouraged to report pregnancy outcomes in these recipients to the NTPR.

Preoperative Drainage In Pancreatic Cancer., Eugene P Kennedy, Ernest L Rosato, Charles J Yeo

Department of Surgery Faculty Papers

Van der Gaag et al. conclude that preoperative biliary drainage in patients undergoing surgery for cancer of the head of the pancreas increases complications. Previous studies have shown that stenting is associated with a doubling in the risk of wound infection and an overall slightly increased risk of any complication.