Medical Specialties Commons^™

Acetylation-Defective Mutant Of Pparγ Is Associated With Decreased Lipid Synthesis In Breast Cancer Cells., Lifeng Tian, Chenguang Wang, Fred K Hagen, Michael Gormley, Sankar Addya, Raymond Soccio, Mathew C Casimiro, Jie Zhou, Michael J Powell, Ping Xu, Haiteng Deng, Anthony A Sauve, Richard Pestell

Department of Cancer Biology Faculty Papers

In our prior publications we characterized a conserved acetylation motif (K(R)xxKK) of evolutionarily related nuclear receptors. Recent reports showed that peroxisome proliferator activated receptor gamma (PPARγ) deacetylation by SIRT1 is involved in delaying cellular senescence and maintaining the brown remodeling of white adipose tissue. However, it still remains unknown whether lysyl residues 154 and 155 (K154/155) of the conserved acetylation motif (RIHKK) in Pparγ1 are acetylated. Herein, we demonstrate that Pparγ1 is acetylated and regulated by both endogenous TSA-sensitive and NAD-dependent deacetylases. Acetylation of lysine 154 was identified by mass spectrometry (MS) while deacetylation of lysine 155 by SIRT1 was …

Glutathione: A Possible Link To Autophagy In Systemic Lupus Erythematosus, Dilip Shah, Swapan K. Nath

Center for Translational Medicine Faculty Papers

No abstract provided.

Nuclear And Mitochondrial Trna-Lookalikes In The Human Genome., Aristeidis G Telonis, Phillipe Loher, Yohei Kirino, Isidore Rigoutsos

Computational Medicine Center Faculty Papers

We are interested in identifying and characterizing loci of the human genome that harbor sequences resembling known mitochondrial and nuclear tRNAs. To this end, we used the known nuclear and mitochondrial tRNA genes (the "tRNA-Reference" set) to search for "tRNA-lookalikes" and found many such loci at different levels of sequence conservation. We find that the large majority of these tRNA-lookalikes resemble mitochondrial tRNAs and exhibit a skewed over-representation in favor of some mitochondrial anticodons. Our analysis shows that the tRNA-lookalikes have infiltrated specific chromosomes and are preferentially located in close proximity to known nuclear tRNAs (z-score ≤ -2.54, P-value ≤ …

Understanding Patient Options, Utilization Patterns, And Burdens Associated With Breast Cancer Screening., Susan C Harvey, Ashok Vegesna, Sharon Mass, Janice L. Clarke, Alexandria Skoufalos

College of Population Health Faculty Papers

Abstract Despite ongoing awareness, educational campaigns, and advances in technology, breast cancer screening remains a complex topic for women and for the health care system. Lack of consensus among organizations developing screening guidelines has caused confusion for patients and providers. The psychosocial factors related to breast cancer screening are not well understood. The prevailing algorithm for screening results in significant rates of patient recall for further diagnostic imaging or procedures, the majority of which rule out breast cancer rather than confirming it. For women, the consequences of the status quo range from unnecessary stress to additional out-of-pocket expenses to indirect …

Neuroprotective Effect Of Heme Oxygenase-2 Knockout In The Blood Injection Model Of Intracerebral Hemorrhage., Jing Chen-Roetling, Ying Cai, Raymond F Regan

Department of Emergency Medicine Faculty Papers

BACKGROUND: The toxicity of heme breakdown products may contribute to the pathogenesis of intracerebral hemorrhage (ICH). Heme catabolism is catalyzed by the heme oxygenase enzymes. We have previously reported that heme oxygenase-2 (HO-2), the constitutive isoform, protects neurons from hemin in vitro and reduces oxidative stress after striatal blood injection. In order to further evaluate HO-2 as a therapeutic target, we tested the hypothesis that HO-2 gene deletion protects neurons and attenuates behavioral deficits after ICH.

FINDINGS: Injection of 20 μl blood into the right striatum of HO-2 wild-type mice resulted in loss of approximately one third of striatal neurons …

Blau Syndrome, The Prototypic Auto-Inflammatory Granulomatous Disease., Carine H Wouters, Anne Maes, Kevin P Foley, John Bertin, Carlos D Rose

Department of Medicine Faculty Papers

Blau syndrome is a monogenic disease resulting from mutations in the pattern recognition receptor NOD2, and is phenotypically characterized by the triad of granulomatous polyarthritis, dermatitis and uveitis. This paper reviews briefly the classical clinical features of the disease, as well as more recently described extra-triad symptoms. From an ongoing prospective multicenter study, we provide new data on the natural history of Blau syndrome, focusing on functional status and visual outcome. We also present an update of the range of different NOD2 mutations found in Blau syndrome as well as recent data on morphologic and immunohistochemical characteristics of the Blau …

Regulation Of L1 Expression And Retrotransposition By Melatonin And Its Receptor: Implications For Cancer Risk Associated With Light Exposure At Night., Dawn Deharo, Kristine J Kines, Mark Sokolowski, Robert T Dauchy, Vincent A Streva, Steven M Hill, John P Hanifin, George Brainard, David E Blask, Victoria P Belancio

Department of Neurology Faculty Papers

Expression of long interspersed element-1 (L1) is upregulated in many human malignancies. L1 can introduce genomic instability via insertional mutagenesis and DNA double-strand breaks, both of which may promote cancer. Light exposure at night, a recently recognized carcinogen, is associated with an increased risk of cancer in shift workers. We report that melatonin receptor 1 inhibits mobilization of L1 in cultured cells through downregulation of L1 mRNA and ORF1 protein. The addition of melatonin receptor antagonists abolishes the MT1 effect on retrotransposition in a dose-dependent manner. Furthermore, melatonin-rich, but not melatonin-poor, human blood collected at different times during the circadian …

Parp-2 And Parp-3 Are Selectively Activated By 5' Phosphorylated Dna Breaks Through An Allosteric Regulatory Mechanism Shared With Parp-1., Marie-France Langelier, Amanda A Riccio, John M Pascal

Department of Biochemistry and Molecular Biology Faculty Papers

PARP-1, PARP-2 and PARP-3 are DNA-dependent PARPs that localize to DNA damage, synthesize poly(ADP-ribose) (PAR) covalently attached to target proteins including themselves, and thereby recruit repair factors to DNA breaks to increase repair efficiency. PARP-1, PARP-2 and PARP-3 have in common two C-terminal domains-Trp-Gly-Arg (WGR) and catalytic (CAT). In contrast, the N-terminal region (NTR) of PARP-1 is over 500 residues and includes four regulatory domains, whereas PARP-2 and PARP-3 have smaller NTRs (70 and 40 residues, respectively) of unknown structural composition and function. Here, we show that PARP-2 and PARP-3 are preferentially activated by DNA breaks harboring a 5' phosphate …

A Survey Of Expert Opinion Regarding Rotator Cuff Repair., Daniel C Acevedo, E Scott Paxton, Gerald R Williams, Joseph A Abboud

Rothman Institute Papers

Many patients with rotator cuff tears have questions for their surgeons regarding the surgical procedure, perioperative management, restrictions, therapy, and ability to work after a rotator cuff repair. The purpose of our study was to determine common clinical practices among experts regarding rotator cuff repair and to assist them in counseling patients. We surveyed 372 members of the American Shoulder and Elbow Surgeons (ASES) and the Association of Clinical Elbow and Shoulder Surgeons (ACESS); 111 members (29.8%) completed all or part of the survey, and 92.8% of the respondents answered every question. A consensus response (>50% agreement) was achieved …

What's New In Spine Surgery., Keith H Bridwell, Paul A Anderson, Scott D Boden, Han Jo Kim, Alexander Vaccaro, Md, Phd, Jeffrey C Wang

Rothman Institute Papers

No abstract provided.

The Tumor Suppressive Role Of Camk2n1 In Castration-Resistant Prostate Cancer., Tao Wang, Zhuo Liu, Shuiming Guo, Licheng Wu, Mingchao Li, Jun Yang, Ruibao Chen, Hua Xu, Shaoxin Cai, Hui Chen, Weiyong Li, Liang Wang, Zhiquan Hu, Qianyuan Zhuang, Shaohua Xu, Liping Wang, Jihong Liu, Zhangqun Ye, Jun-Yuan Ji, Chenguang Wang, Ke Chen

Department of Cancer Biology Faculty Papers

Prostate cancer at advanced stages including metastatic and castration-resistant cancer remains incurable due to the lack of effective therapies. The CAMK2N1 gene, cloned and characterized as an inhibitor of CaMKII (calcium/calmodulin-dependent protein kinase II), has been shown to affect tumorigenesis and tumor growth. However, it is still unknown whether CAMK2N1 plays a role in prostate cancer development. We first examined the protein and mRNA levels of CAMK2N1 and observed a significant decrease in human prostate cancers comparing to normal prostate tissues. Re-expression of CAMK2N1 in prostate cancer cells reduced cellular proliferation, arrested cells in G0/G1 phases, and induced apoptotic cell …

Multisite Phosphorylation Of The Sum1 Transcriptional Repressor By S-Phase Kinases Controls Exit From Meiotic Prophase In Yeast., Daniel Corbi, Sham Sunder, Michael Weinreich, Aikaterini Skokotas, Erica S Johnson, Edward Winter

Department of Biochemistry and Molecular Biology Faculty Papers

Activation of the meiotic transcription factor Ndt80 is a key regulatory transition in the life cycle of Saccharomyces cerevisiae because it triggers exit from pachytene and entry into meiosis. The NDT80 promoter is held inactive by a complex containing the DNA-binding protein Sum1 and the histone deacetylase Hst1. Meiosis-specific phosphorylation of Sum1 by the protein kinases Cdk1, Ime2, and Cdc7 is required for NDT80 expression. Here, we show that the S-phase-promoting cyclin Clb5 activates Cdk1 to phosphorylate most, and perhaps all, of the 11 minimal cyclin-dependent kinase (CDK) phospho-consensus sites (S/T-P) in Sum1. Nine of these sites can individually promote …

Advances In Neurovascular Treatments., Robert M Starke, Stephen J Monteith, Nohra Chalouhi, Dale Ding, Ricky Medel, David Hasan, Aaron S Dumont

Department of Neurosurgery Faculty Papers

No abstract provided.

Micrornas: The Short Link Between Cancer And Rt-Induced Dna Damage Response., Christopher M Wright, Tu Dan, Adam Dicker Md, Phd, Nicole L Simone

Department of Radiation Oncology Faculty Papers

No abstract provided.

Sphingosine-1-Phosphate Promotes The Differentiation Of Adipose-Derived Stem Cells Into Endothelial Nitric Oxide Synthase (Enos) Expressing Endothelial-Like Cells., Divya Arya, Shaohua Chang, Paul J Dimuzio, Jeffrey Carpenter, Thomas N Tulenko

Department of Surgery Faculty Papers

BACKGROUND: Adipose tissue provides a readily available source of autologous stem cells. Adipose-derived stem cells (ASCs) have been proposed as a source for endothelial cell substitutes for lining the luminal surface of tissue engineered bypass grafts. Endothelial nitric oxide synthase (eNOS) is a key protein in endothelial cell function. Currently, endothelial differentiation from ASCs is limited by poor eNOS expression. The goal of this study was to investigate the role of three molecules, sphingosine-1-phosphate (S1P), bradykinin, and prostaglandin-E1 (PGE1) in ASC endothelial differentiation. Endothelial differentiation markers (CD31, vWF and eNOS) were used to evaluate the level of ASCs differentiation capability. …

Results Of A Phase I Study Of Bendamustine In Combination With Ofatumumab, Carboplatin And Etoposide (Boce) For Refractory Of Relapsed Aggressive B-Cell Non Hodgkin's Lymphomas (Nhl), Sameh Gaballa, Md, Neil D. Palmisiano, Md, Aakanksha Asija, Md, Andrew Chapman, Do, Jennifer K. Cloud, Bs, Joanne Filicko-O'Hara, Md, Lewis Rose, Md, Michael Ramirez, Md, Onder Alpdogan, Md, Neal Flomenberg, Md, Barbara Pro, Md, Elena Gitelson, Md, Phd, Mark Weiss, Md

Department of Medical Oncology Faculty Papers

Introduction:

• There are a number of regimens used to treat relapsed/refractory aggressive lymphomas and little consensus exists on the best salvage treatment.
• No regimen has shown clear superiority but uniformly there was an inferior outcome among patients who had relapsed after a prior rituximab containing regimen.
• Ofatumumab is a fully human IgG1k monoclonal anti-CD20 antibody. It recognizes a distinct epitope on the human CD20 molecule. In vitro studies with ofatumumab have shown more complement dependent cytotoxicity than rituximab.
• Bendamustine has single agent activity in relapsed aggressive lymphomas and has a favorable safety profile.

Objectives:

• We conducted a phase I trial …

Mir-221/222 Promotes S-Phase Entry And Cellular Migration In Control Of Basal-Like Breast Cancer., Yuan Li, Chunli Liang, Haizhong Ma, Qian Zhao, Ying Lu, Zhendong Xiang, Li Li, Jie Qin, Yihan Chen, William C Cho, Richard G Pestell, Li Liang, Zuoren Yu

Department of Cancer Biology Faculty Papers

The miR-221/222 cluster has been demonstrated to function as oncomiR in human cancers. miR-221/222 promotes epithelial-to-mesenchymal transition (EMT) and confers tamoxifen resistance in breast cancer. However, the effects and mechanisms by which miR-221/222 regulates breast cancer aggressiveness remain unclear. Here we detected a much higher expression of miR-221/222 in highly invasive basal-like breast cancer (BLBC) cells than that in non-invasive luminal cells. A microRNA dataset from breast cancer patients indicated an elevated expression of miR-221/222 in BLBC subtype. S-phase entry of the cell cycle was associated with the induction of miR-221/222 expression. miRNA inhibitors specially targeting miR-221 or miR-222 both …

Understanding The Power Of Perinatal Events And Metabolic Status In Childhood., Bonita Falkner, Julie Ingelfinger

Department of Medicine Faculty Papers

No abstract provided.

Azd8931, An Equipotent, Reversible Inhibitor Of Signaling By Epidermal Growth Factor Receptor (Egfr), Her2, And Her3: Preclinical Activity In Her2 Non-Amplified Inflammatory Breast Cancer Models., Zhaomei Mu, Teresa Klinowska, Xiaoshen Dong, Emily Foster, Chris Womack, Sandra V Fernandez, Massimo Cristofanilli

Department of Medical Oncology Faculty Papers

INTRODUCTION: Epidermal growth factor receptor (EGFR) overexpression has been associated with prognostic and predictive value in inflammatory breast cancer (IBC). Epidermal growth factor receptor 2 (HER2) overexpression is observed at a higher rate in IBC compared with noninflammatory breast cancer. Current clinically available anti-HER2 therapies are effective only in patients with HER2 amplified breast cancer, including IBC. AZD8931 is a novel small-molecule equipotent inhibitor of EGFR, HER2, and HER3 signaling. In this study, we investigated the antitumor activity of AZD8931 alone or in combination with paclitaxel using preclinical models of EGFR-overexpressed and HER2 non-amplified IBC cells.

METHODS: Two IBC cell …

The Relative Efficacy Of Antifibrinolytics In Adolescent Idiopathic Scoliosis: A Prospective Randomized Trial., Kushagra Verma, Md, Thomas Errico, Chris Diefenbach, Christian Hoelscher, Austin Peters, Joseph Dryer, Tessa Huncke, Kirstin Boenigk, Baron S Lonner

Department of Orthopaedic Surgery Faculty Papers

BACKGROUND: Antifibrinolytics can reduce intraoperative blood loss. The primary aim of this study was to determine the efficacy of intraoperative tranexamic acid, epsilon-aminocaproic acid, and placebo at reducing perioperative blood loss and the transfusion rate in patients with adolescent idiopathic scoliosis undergoing posterior spinal arthrodesis.

METHODS: This is a prospective, randomized, double-blind comparison of tranexamic acid, epsilon-aminocaproic acid, and placebo used intraoperatively in patients with adolescent idiopathic scoliosis. One hundred and twenty-five patients with adolescent idiopathic scoliosis were randomly assigned to the tranexamic acid, epsilon-aminocaproic acid, or control groups. Parameters recorded included estimated blood loss, hematocrit, blood product usage, drain …

Letter To Alliance For Headache Disorders Advocacy, William B. Young, Md

Department of Jefferson Headache Center Papers and Presentations

Several years ago the Centers for Medicare and Medicare Services (CMS) decided it would not pay for oxygen for the treatment of cluster headache. This is a serious hardship for many people with cluster headache. The American Headache Society and the Alliance for Headache Disorders Advocacy appealed to CMS to reverse this decision but they refused.

In February, we went to Congress, asking them to encourage CMS to reconsider this appeal. As a result of these efforts, Nebraska Senator Johanns and Delaware Senator Coons are circulating a letter for all Senators to sign urging CMS to re-evaluate this situation. To …

The P53-Induced Factor Ei24 Inhibits Nuclear Import Through An Importin Β-Binding-Like Domain., Kim G Lieu, Eun-Hee Shim, Jinling Wang, Ravi K Lokareddy, Tao Tao, Gino Cingolani, Gerard P Zambetti, David A Jans

Department of Biochemistry and Molecular Biology Faculty Papers

The etoposide-induced protein Ei24 was initially identified as a p53-responsive, proapoptotic factor, but no clear function has been described. Here, we use a nonbiased proteomics approach to identify members of the importin (IMP) family of nuclear transporters as interactors of Ei24 and characterize an IMPβ-binding-like (IBBL) domain within Ei24. We show that Ei24 can bind specifically to IMPβ1 and IMPα2, but not other IMPs, and use a mutated IMPβ1 derivative to show that Ei24 binds to the same site on IMPβ1 as the IMPα IBB. Ectopic expression of Ei24 reduced the extent of IMPβ1- or IMPα/β1-dependent nuclear protein import specifically, …

Permeation Redux: Thermodynamics And Kinetics Of Ion Movement Through Potassium Channels., Richard Horn, Benoît Roux, Johan Aqvist

Department of Molecular Physiology and Biophysics Faculty Papers

The fundamental biophysics underlying the selective movement of ions through ion channels was launched by George Eisenman in the 1960s, using glass electrodes. This minireview examines the insights from these early studies and the explosive progress made since then.

Cancer Screening 2014, Richard C. Wender, Md

Department of Family & Community Medicine Presentations and Grand Rounds

Presentation celebrating 40th reunion symposium for the Department of Family and Community Medicine at Thomas Jefferson University Hospital.

Presentation outline includes:

Breast, Colon, Lung and Prostate Cancer

Learning objective: Apply new cancer screening guidelines to primary care physicians

Metformin Inhibits Androgen-Induced Igf-Ir Up-Regulation In Prostate Cancer Cells By Disrupting Membrane-Initiated Androgen Signaling., Roberta Malaguarnera, Antonella Sacco, Alaide Morcavallo, Sebastiano Squatrito, Antimo Migliaccio, Andrea Morrione, Marcello Maggiolini, Antonino Belfiore

Department of Urology Faculty Papers

We have previously demonstrated that, in prostate cancer cells, androgens up-regulate IGF-I receptor (IGF-IR) by inducing cAMP-response element-binding protein (CREB) activation and CREB-dependent IGF-IR gene transcription through androgen receptor (AR)-dependent membrane-initiated effects. This IGF-IR up-regulation is not blocked by classical antiandrogens and sensitizes cells to IGF-I-induced biological effects. Metformin exerts complex antitumoral functions in various models and may inhibit CREB activation in hepatocytes. We, therefore, evaluated whether metformin may affect androgen-dependent IGF-IR up-regulation. In the AR(+) LNCaP prostate cancer cells, we found that metformin inhibits androgen-induced CRE activity and IGF-IR gene transcription. CRE activity requires the formation of a CREB-CREB …

Outcomes Of Older Patients Undergoing 2-Step Approach To Haploidentical And Matched Related Peripheral Blood Hematopoietic Stem Cell Transplantation (Hsct): A Single Institutional Experience, Sameh Gaballa, Md, Seyfettin Onder Alpdogan, Md, Matthew Carabasi, Md, Joanne Filicko-O'Hara, Md, Margaret Kasner, Md, Benjamin E Leiby, Phd, Ubaldo E. Martinez-Outshoorn, Md, Edward C Pequignot, Md, Sarah Rosado, Shannon Rudolph, Ms, John L Wagner, Md, Mark Weiss, Md, Neal Flomenberg, Md, Dolores Grosso, Dnp

Department of Medical Oncology Faculty Papers

Introduction:

HSCT is a curative option for many patients (pts) with hematological malignancies.

Significant advances in supportive care and conditioning regimens over the past decade have allowed the extension of this therapy to older individuals.

Information regarding the outcomes of this older subset of pts undergoing HSCT is limited, especially those undergoing haploidential (HI) HSCT.

Objectives:

To describe the outcomes of patients 60 years of age or older undergoing haploidential and matched related (MR) HSCT using the 2-step approach.

Cell-Mediated Immunity And Vaccines, Jaya Kumari, Senthamil R. Selvan, Stéphane Bécart, Subhasis Chattopadhyay, Roy Ambli Dalmo

Department of Medical Oncology Faculty Papers

No abstract provided.

Anterior Talofibular Ligament Abnormality On Routine Magnetic Resonance Imaging Of The Ankle, Patrick Kane, Md, David Pedowitz, Md, Adam C C. Zoga, Md, Steven M. Raikin, Md

Rothman Institute Conference Posters

The anterior talo­fibular ligament (ATFL) extends from the anteroinferior border of the ­fibula to the talar neck. Primary restraint to ankle inversion in plantar‑exion. Injury (acute or chronic) can be diagnosed with physical exam, stress X-Rays, ultrasound or magnetic resonance imaging (MRI).

Purpose:

MRI abnormalities in asymptomatic individuals known in other areas of orthopaedics (shoulder and spine). Purpose of our study: determine the prevalence of ATFL abnormalities found on MRI in asymptomatic individuals. Asymptomatic individuals - those undergoing MRI for pathology unrelated to lateral ankle trauma, instability, or inversion injuries.

A Clinical Decision Support Tool To Predict The Risk Of Failure In Patients With Femoroacetabular Impingement Undergoing Hip Preservation Surgery, Claudio Diaz-Ledezma, Md, Mitchell Maltenfort, Phd, Lesley Walinchus, Bs, Benjamin Hendy, Bs, Thomas Novack, Bs, Javad Parvizi, Md, Frcs

Rothman Institute Conference Posters

In modern orthopaedics, risk prediction scores can help discriminate between ideal and poor candidates for a specifi­c therapeutic intervention. We consider these tools useful during the process of shared medical decision-making1. To our knowledge, such a strategy has never been explored in the ­field of hip preservation surgery.

The aim of our study is to generate a clinical decision support tool to predict risk of failure after hip preservation surgery among patients with femoroacetabular impingement (FAI).

High Variability In Outcomes Of Two-Stage Exchange To Treat Periprosthetic Joint Infection, Benjamin Zmistowski, Bs, Paul Lichstein, Md, Aaron H Carter, Md, Joshua J. Minori, Do, Javad Parvizi, Md

Rothman Institute Conference Posters

Introduction:

Periprosthetic joint infection (PJI) is a challenging condition to manage with sobering morbidity and mortality.1,2 Treatment options range from simple irrigation and debridement with prosthetic retention to explantation and placement of a temporary cement spacer. Indictations for each option are unclear and non-uniform despite signi­cant efforts to understand the management outcomes. Until recently, a uniform de­nition of success was unavailable, thus clouding the discussion of treatment options. Two-stage exchange is currently considered the “gold-standard” in North America, yet an appropriate understanding of the actual success and ancillary effects of treatment is needed. With the advantage of an expert opinion …