Medicine and Health Sciences Commons^™

Acute Neurological Toxicity (Nt) And Long-Term Outcomes In High-Grade Glioma Rtog Trials, Y. R. Lawrence, M. Wang, A. P. Dicker, D. W. Andrews, W. J. Curran, J. M. Michalski, L. Souhami, W. A. Yung, M. Mehta

Bodine Journal

Background: Treatment of high-grade glioma consists of fractionated radiation therapy (RT) ± chemotherapy. The incidence/significance of neurological toxicity (NT) in this disease is not known. We evaluated the relationship between acute and chronic NT, and ultimate outcome, as well as risk factors for NT from the RTOG database.

American Society of Clinical Oncology (ASCO) 46th Annual Meeting June 4-8, Chicago, IL.

Potential For Thermal Enhancement By Quercetin Mediated Mechanisms Targeting P53 Antagonists In Human Melanoma Cells, T. Thangasamy, K. Limesand, D. B. Leeper, R. Burd

Bodine Journal

Introduction: Recently Temozolomide (TMZ) has become the more commonly used analog of DTIC-related oral agents. Although the response rates achieved by TMZ alone are less than satisfactory, there is great interest in identifying compounds that could be used in combination therapy. We have previously demonstrated that the bioflavonoid quercetin (Qct) promotes a p53-mediated response in melanoma and sensitizes melanoma to DTIC. Here we demonstrate that Qct also sensitizes cells to TMZ by a mechanism that involves the modulation of a truncated p53 family member, ΔNp73.

Society for Thermal Medicine Annual Meeting April 23-26, Clearwater Beach, FL.

Control Of Glycolytic Flux By Ampk And P53-Mediated Signaling Pathways In Tumor Cells Adapted To Grow At Low Ph, E. E. Mendoza, J. Caro, D. B. Leeper, R. Burd

Bodine Journal

Introduction: Tumor cells grow in nutrient and oxygen deprived microenvironments and adapt to the suboptimal growth conditions by altering metabolic pathways. This adaptation process characteristically results in a tumor phenotype that displays anaerobic glycolysis, chronic acidification and aggressive tumor characteristics. Understanding the tumor cell reaction to the microenvironment is a critical factor in predicting the tumor response to hyperthermia. The glucose regulatory molecule, 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase Isoform-3 (PFKFB3), is a bifunctional enzyme central to glycolytic flux and downstream of the metabolic stress sensor AMP-activated protein kinase (AMPK), which has been shown to activate an isoform of Phosphofructokinase (PFK-2).

Society for Thermal Medicine …

Functional Antagonism Between Vorinostat And Temozolomide When Combined With Ionizing Radiation (Ir) In Glioblastoma, Y. R. Lawrence, Y. Liu, B. Andersen, X. Xia, A. P. Dicker, P. Wachsberger

Bodine Journal

Background: Glioblastoma is the most common primary adult brain tumor. Surgery followed by radiation therapy in combination with temozolomide (Tmz) produces a median survival of 14.6 months. Tmz is a DNA akylating agent that leads to the mispairing of guanine residues with thymine. An intact mismatch-repair mechanism (MMR) converts the mispaired thymine into a lethal double-strand DNA break. Vorinostat (SAHA), an HDAC inhibitor, has been shown to act as a radiosensitizer, possibly through inhibition of DNA repair. SAHA has successfully been combined with a number of cytotoxic agents. We hypothesized that SAHA would further potentiate the radiosensitizing properties of Tmz …

Effects Of Egfr Expression On Anti-Tumor Efficacy Of Vandetanib Or Cediranib Combined With Radiotherapy (Rt) In U87 Human Glioblastoma (Gbm) Xenografts, P. Wachsberger, Y. R. Lawrence, Y. Liu, A. P. Dicker

Bodine Journal

Introduction: Vandetanib is a receptor tyrosine kinase inhibitor (RTKI) with activity against vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR). Cediranib is a highly potent VEGF RTKI that inhibits all three VEGF receptors. In this study we investigated the effect of exogenous overexpression of EGFR on sensitivity of human GBM U87 xenografts to vandetanib or cediranib, alone or in combination with RT.

American Association for Cancer Research (AACR) 101st Annual Meeting April 17-21, Washington, DC.

Bodine Journal, Table Of Contents, Volume 3, Issue 1, Fall 2010

Bodine Journal

Table of Contents for Fall 2010 issue of Bodine Journal.

C-Jun Inhibits Mammary Apoptosis In Vivo., Sanjay Katiyar, Mathew C Casimiro, Luis Dettin, Xiaoming Ju, Erwin F Wagner, Hirokazu Tanaka, Richard Pestell

Department of Cancer Biology Faculty Papers

c-jun, which is overexpressed in a number of human cancers encodes a critical component of the AP-1 complex. c-jun has been shown to either induce or inhibit cellular apoptosis. Germ line deletion of both c-jun alleles is embryonically lethal. To determine the role of the endogenous c-jun gene in apoptosis, we performed mammary epithelial cell-targeted somatic deletion using floxed c-jun (c-jun(f/f)) conditional knockout mice. Laser capture microdissection demonstrated endogenous c-jun inhibits expression of apoptosis inducing genes and reactive oxygen species (ROS)-reducing genes (MnSOD, catalase). ROS have been implicated in apoptosis and undergo enzymatic elimination via MnSOD and CuZnSOD with further …

Is The Quality Of Neurosurgical Literature Improving?, James Harrop, Md, Mitchell Maltenfort, Phd

JHN Journal

Introduction:

The advent of evidence-based medicine has resulted in higher quality journal manuscripts in numerous medical disciplines. However, the impact in the neurosurgical literature has not been reported.

Objective:

To quantify the impact of evidence-based medicine on the quality of articles published in the Neurosurgery literature.

Methods:

Articles published in the journal Neurosurgery (founded in 1977) were reviewed for 1978, 1988, 1998, and 2008. Each decade’s sample was classified as therapeutic, diagnostic and prognostic based on a published system for determining level of evidence.

Results:

438 articles were reviewed. Articles not considered included any published under the heading “Case Report” …

Vigabatrin-Induced Peripheral Visual Field Defects In Patients With Refractory Partial Epilepsy, Robert C. Sergott, Richard M. Bittman, Erin M. Christen, Stephen M. Sagar

Wills Eye Hospital Papers

Purpose:

Vigabatrin can cause retinopathy, resulting in bilateral visual field constriction. Previous analyses of results from a prospective, observational study assessing vigabatrin-induced visual field constriction (described below) employed a partially subjective interpretation of static perimetery. In an effort to affirm these previous findings through more objective, quantitative methodology, we now report data from a subset analysis of refractory partial epilepsy patients in the study who underwent Goldmann kinetic perimetry.

Methods:

Patients aged ≥8 years with refractory partial seizures were enrolled and grouped: those receiving vigabatrin for ≥6 months (Group I); those who had received vigabatrin for ≥6 months and then …

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 …

Mechanism Of N-Methylation By The Trna M1g37 Methyltransferase Trm5., Thomas Christian, Georges Lahoud, Cuiping Liu, Katherine Hoffmann, John J Perona, Ya-Ming Hou

Department of Biochemistry and Molecular Biology Faculty Papers

Trm5 is a eukaryal and archaeal tRNA methyltransferase that catalyzes methyl transfer from S-adenosylmethionine (AdoMet) to the N(1) position of G37 directly 3' to the anticodon. While the biological role of m(1)G37 in enhancing translational fidelity is well established, the catalytic mechanism of Trm5 has remained obscure. To address the mechanism of Trm5 and more broadly the mechanism of N-methylation to nucleobases, we examined the pH-activity profile of an archaeal Trm5 enzyme, and performed structure-guided mutational analysis. The data reveal a marked dependence of enzyme-catalyzed methyl transfer on hydrogen ion equilibria: the single-turnover rate constant for methylation increases by one …

Hydroxyurea And Acute Painful Crises In Sickle Cell Anemia: Effects On Hospital Length Of Stay And Opioid Utilization During Hospitalization, Outpatient Acute Care Contacts, And At Home, Samir K. Ballas, Md, Facp, Robert L. Bauserman, Phd, William F. Mccarthy, Phd, Oswaldo L. Castro, Md, Wally R. Smith, Md, Myron A. Waclawiw, Phd

Department of Medicine Faculty Papers

Recurrent acute sickle cell painful crises are the hallmark of sickle cell anemia. These events may be mild, moderate or severe in nature and often require treatment at home, in acute care facilities as outpatients, and in the hospital with oral and/or parenteral opioids. The type, dose, route & frequency of administration of opioids, as well as the length of hospital stay (LOS), are not well known for adults with sickle cell anemia (SS). We analyzed these aspects in the 299 patients enrolled in the Multicenter Study of Hydroxyurea (MSH) in SS. For these patients there were 16818 home diaries, …

Incidence Of, Predictors For, And Mortality Associated With Malignant Ventricular Arrhythmias In Non-St Elevation Myocardial Infarction Patients., Shuchita Gupta, Md, Gregg S. Pressman, Vincent M. Figueredo, M.D.

Division of Cardiology Faculty Papers

BACKGROUND: The incidence of non-ST elevation myocardial infarction (NSTEMI) is increasing. Although life-threatening ventricular arrhythmias have been well-documented in patients with ST elevation MI (STEMI), their incidence and importance in NSTEMI have not been examined in similar detail. We examined the incidence, predictors, and mortality rates of ventricular arrhythmias in a cohort of NSTEMI patients undergoing an early invasive strategy.

METHODS: Consecutive patients admitted with NSTEMI who underwent cardiac catheterization within 48 h of admission were identified by chart review. Presence and type of ventricular arrhythmias and 30-day mortality were recorded. Malignant arrhythmias were defined as sustained ventricular tachycardia (VT, …

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 …

Self-Protecting Bactericidal Titanium Alloy Surface Formed By Covalent Bonding Of Daptomycin Bisphosphonates., Chang-Po Chen, Eric Wickstrom

Department of Biochemistry and Molecular Biology Faculty Papers

Infections are a devastating complication of titanium alloy orthopedic implants. Current therapy includes antibiotic-impregnated bone cement and antibiotic-containing coatings. We hypothesized that daptomycin, a Gram-positive peptide antibiotic, could prevent bacterial colonization on titanium alloy surfaces if covalently bonded via a flexible, hydrophilic spacer. We designed and synthesized a series of daptomycin conjugates for bonding to the surface of 1.0 cm² Ti6Al4V foils through bisphosphonate groups, reaching a maximum yield of 180 pmol/cm². Daptomycin-bonded foils killed 53 ± 5% of a high challenge dose of 3 × 10⁵ cfu Staphylococcus aureus ATCC 29213.

Effects Of High Intraoperative Inspired Oxygen On Postoperative Nausea And Vomiting In Gynecologic Laparoscopic Surgery, Tatjana Šimurina, Md, Msc, Boris Mraović, Md, Simon Mikulandra, Md, Msc, Zdenko Sonicki, Md, Phd, Nina Sulen, Md, Branko Dukić, Md, Tong J. Gan, M.D

Department of Anesthesiology Faculty Papers

Study objective: To assess the efficacy of intraoperative different inspired oxygen fractions (FIO2) of 0.8 and 0.5 when compared with standard FIO2 0.3 in prevention of postoperative nausea and vomiting (PONV).

Design: A prospective, controlled, randomized, double-blind study.

Setting: General hospital, postanesthesia care unit (PACU) and gynecologic floor room. Patients: 120 ASA physical status I and II women, aged 21 to 76 y, undergoing elective gynecologic laparoscopic surgery.

Interventions: Patients were randomized to receive gas mixture of 30% oxygen in air (FI O2=0.3, group G30), 50% oxygen in air (FIO2=0.5, group G50) or 80% oxygen in air (FIO2=0.8, group G80), …

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 …

What's Going On Here? Deconstructing The Interactive Encounter., Janice P Burke

Department of Occupational Therapy Faculty Papers

Eleanor Clarke Sagle Lecture

Knowledge, Attitudes, And Practice Behaviors Of Oncology Advanced Practice Nurses Regarding Advanced Care Planning For Patients With Cancer., Guiyun Zhou, Dnp, Crnp, Aocns, Jill C Stoltzfus, Phd, Arlene D Houldin, Phd, Pmhcns-Bc, Susan M Parks, Md, Beth Ann Swan, Phd, Crnp, Faan

College of Nursing Faculty Papers & Presentations

Purpose/Objectives: To establish initial reliability and validity of a Web-based survey focused on oncology advanced practice nurses' (APNs') knowledge, attitudes, and practice behaviors regarding advanced care planning, and to obtain preliminary understanding of APNs' knowledge, attitudes, and practice behaviors and perceived barriers to advanced care planning.

Design: Descriptive, cross-sectional, pilot survey study.

Setting: The eastern United States.Sample: 300 oncology APNs.Methods: Guided by the Theory of Planned Behavior, a knowledge, attitudes, and practice behaviors survey was developed and reviewed for content validity. The survey was distributed to 300 APNs via e-mail and sent again to the 89 APNs who responded to …

Nfκb Activation And Stimulation Of Chemokine Production In Normal Human Macrophages By The Gadolinium-Based Magnetic Resonance Contrast Agent Omniscan: Possible Role In The Pathogenesis Of Nephrogenic Systemic Fibrosis., Francesco Del Galdo, Peter J Wermuth, Sankar Addya, Paolo Fortina, Sergio A Jimenez

Jefferson Institute of Molecular Medicine Papers and Presentations

OBJECTIVE: Nephrogenic systemic fibrosis (NSF) is a generalised fibrotic disorder occurring in certain individuals with renal insufficiency exposed to gadolinium-based contrast agents (GdBCA) for MRI. Histopathological examination of affected tissues shows increased numbers of activated macrophages. To elucidate the mechanisms responsible for macrophage activation, the effects of the GdBCA Omniscan on normal human macrophage global gene expression, chemokine production and nuclear factor κB (NFκB) activation was examined.

METHODS: Normal human monocyte-derived macrophages were incubated with Omniscan (50 mM) and their gene expression analysed by microarrays and real-time PCR. Macrophage chemokine production was assayed by multiplex ELISA. NFκB activation was assessed …

Wild-Type And Mutant Sod1 Share An Aberrant Conformation And A Common Pathogenic Pathway In Als., Daryl A Bosco, Gerardo Morfini, N Murat Karabacak, Yuyu Song, Francois Gros-Louis, Piera Pasinelli, Holly Goolsby, Benjamin A Fontaine, Nathan Lemay, Diane Mckenna-Yasek, Matthew P Frosch, Jeffrey N Agar, Jean-Pierre Julien, Scott T Brady, Robert H Brown

Farber Institute for Neuroscience Faculty Papers

Many mutations confer one or more toxic function(s) on copper/zinc superoxide dismutase 1 (SOD1) that impair motor neuron viability and cause familial amyotrophic lateral sclerosis (FALS). Using a conformation-specific antibody that detects misfolded SOD1 (C4F6), we found that oxidized wild-type SOD1 and mutant SOD1 share a conformational epitope that is not present in normal wild-type SOD1. In a subset of human sporadic ALS (SALS) cases, motor neurons in the lumbosacral spinal cord were markedly C4F6 immunoreactive, indicating that an aberrant wild-type SOD1 species was present. Recombinant, oxidized wild-type SOD1 and wild-type SOD1 immunopurified from SALS tissues inhibited kinesin-based fast axonal …

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, …

Obstructive Sleep Apnea And Ocular Disorders., Deepak P. Grover

Wills Eye Hospital Papers

PURPOSE OF REVIEW: Obstructive sleep apnea is a diagnosis that ophthalmologists can screen for when a patient presents with certain risk factors. Recent literature provides strong data for associations between sleep apnea and ocular disorders.

RECENT FINDINGS: A potentially serious disorder, sleep apnea can lead to many systemic and ocular complications. Recent findings provide data on the prevalence of sleep apnea with various disorders. Adequate treatment of sleep apnea has also shown to reverse both systemic and eye-related complications.

SUMMARY: Early diagnosis and management of sleep apnea is critical for reducing the risk of devastating systemic complications and preserving ocular …

J. Graham Smith Jr, Md (November 22, 1926-May 18, 2010)., Lawrence Charles Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

With the passing of J. Graham Smith, Jr. on May 18, 2010, following a short illness, dermatology lost one of its most distinguished envoys. (Figure 1) Skee*, as he was known by his many friends, held the important offices in American dermatology for which he made many significant contributions.

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 …

The Addition Of Rituximab To Fludarabine And Cyclophosphamide Improves Progression-Free Survival In Patients With Previously Treated Chronic Lymphocytic Leukemia., Amit Mahipal, Mark Weiss

Department of Medical Oncology Faculty Papers

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States. There has been considerable progress in understanding the biology and treatment of CLL in last 20 years. The introduction of purine analogs (pentostatin, fludarabine, and cladribine) dramatically increased the response rates compared to alkylating agents. Combination chemoimmunotherapy has further improved the overall frequency of response to over 80% in treatment-naïve and over 60% in relapsed/ refractory disease, respectively.

Role Of Growth Factors In The Pathogenesis Of Tissue Fibrosis In Systemic Sclerosis., Sergio A. Jimenez, Susan V. Castro, Sonsoles Piera-Velazquez

Department of Medicine Faculty Papers

The most severe clinical and pathologic manifestations of systemic sclerosis (SSc) are the result of a fibrotic process characterized by the excessive and often progressive deposition of collagen and other connective tissue macromolecules in skin and numerous internal organs. The mechanisms involved in the initiation and progression of the remarkable fibrotic process in SSc remain largely unknown. Extensive recent studies have indicated that a variety of polypeptide growth factors play a crucial role in this process. The most commonly implicated growth factors include transforming growth factor beta (TGF-β), connective tissue growth factor (CTGF), platelet derived growth factor (PDGF), and vascular …

Sepsis-Induced Cardiomyopathy: A Review Of Pathophysiologic Mechanisms., Anthony Flynn, Bhalaghuru Chokkalingam Mani, Paul J Mather

Department of Medicine Faculty Papers

Cardiac dysfunction is a well-recognized complication of severe sepsis and septic shock. Cardiac dysfunction in sepsis is characterized by ventricular dilatation, reduction in ejection fraction and reduced contractility. Initially, cardiac dysfunction was considered to occur only during the "hypodynamic" phase of shock. But we now know that it occurs very early in sepsis even during the "hyperdynamic" phase of septic shock. Circulating blood-borne factors were suspected to be involved in the evolution of sepsis induced cardiomyopathy, but it is not until recently that the cellular and molecular events are being targeted by researchers in a quest to understand this enigmatic …

Biosynthesis: A New (Old) Way Of Hijacking Trna., Georges Lahoud, Ya-Ming Hou

Department of Biochemistry and Molecular Biology Faculty Papers

Aminoacylation of tRNA is the cellular process for providing aminoacyl donors for the ribosome synthesis of polypeptides. New research highlights an unexpected structural overlap between enzymes involved in this process and those involved in the biosynthesis of cyclodipeptides, an important class of bioactive molecules.

Chart Rounds In The Digital Age: A Survey Of North American Institutions, M. A. Whiton, A. P. Dicker, E. J. Wuthrick, L. Doyle, A. S. Harrison, Y. R. Lawrence

Department of Radiation Oncology Faculty Papers

Purpose:

Recent reports of medical errors in radiaKon treatment delivery have emphasized the importance of quality assurance (QA) pracKces. Strict guidelines exist for medical physics QA, but not for QA procedures as applied to clinicians. We sought to document how clinical quality assurance (QA) meeKngs or “chart rounds” are performed across academic North American RadiaKon Oncology departments.