Medicine and Health Sciences Commons^™

Sumo-Mediated Regulation Of Nlrp3 Modulates Inflammasome Activity., Rachael Barry, Sidonie Wicky John, Gianmaria Liccardi, Tencho Tenev, Isabel Jaco, Chih-Hong Chen, Justin Choi, Paulina Kasperkiewicz, Teresa Fernandes-Alnemri, Emad S Alnemri, Marcin Drag, Yuan Chen, Pascal Meier

Department of Biochemistry and Molecular Biology Faculty Papers

The NLRP3 inflammasome responds to infection and tissue damage, and rapidly escalates the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. How the NLRP3 inflammasome is negatively regulated is poorly understood. Here we show that NLRP3 inflammasome activation is suppressed by sumoylation. NLRP3 is sumoylated by the SUMO E3-ligase MAPL, and stimulation-dependent NLRP3 desumoylation by the SUMO-specific proteases SENP6 and SENP7 promotes NLRP3 activation. Defective NLRP3 sumoylation, either by NLRP3 mutation of SUMO acceptor lysines or depletion of MAPL, results in enhanced caspase-1 activation and IL-1β release. Conversely, depletion of SENP7 suppresses NLRP3-dependent ASC oligomerisation, …

Trna 3'-Amino-Tailing For Stable Amino Acid Attachment., Howard Gamper, Ya-Ming Hou

Department of Biochemistry and Molecular Biology Faculty Papers

Amino acids are attached to the tRNA 3'-end as a prerequisite for entering the ribosome for protein synthesis. Amino acid attachment also gives tRNA access to nonribosomal cellular activities. However, the normal attachment is via an ester linkage between the carboxylic group of the amino acid and the 3'-hydroxyl of the terminal A76 ribose in tRNA. The instability of this ester linkage has severely hampered studies of aminoacyl-tRNAs. Although the use of 3'-amino-3'-deoxy A76 in a 3'-amino-tailed tRNA provides stable aminoacyl attachment via an amide linkage, there are multiple tailing protocols and the efficiency of each relative to the others …

Dna Methylation-Based Age Prediction And Telomere Length In White Blood Cells And Cumulus Cells Of Infertile Women With Normal Or Poor Response To Ovarian Stimulation., Scott J. Morin, Xin Tao, Diego Marin, Yiping Zhan, Jessica Landis, Jenna Bedard, Richard T. Scott, Emre Seli

Department of Biochemistry and Molecular Biology Faculty Papers

An algorithm assessing the methylation levels of 353 informative CpG sites in the human genome permits accurate prediction of the chronologic age of a subject. Interestingly, when there is discrepancy between the predicted age and chronologic age (age acceleration or "AgeAccel"), patients are at risk for morbidity and mortality. Identification of infertile patients at risk for accelerated reproductive senescence may permit preventative action. This study aimed to assess the accuracy of the "epigenetic clock" concept in reproductive age women undergoing fertility treatment by applying the age prediction algorithm in peripheral (white blood cells [WBCs]) and follicular somatic cells (cumulus cells …

A Learning Community Approach To Identifying Interventions In Health Systems To Reduce Colorectal Cancer Screening Disparities., Lillian C. Man, Melissa Dicarlo, Emily Lambert, Randa Sifri, Martha Romney, Linda Fleisher, Ronald Myers

Department of Medical Oncology Faculty Papers

Although colorectal cancer (CRC) screening in the United States has been increasing, screening rates are not optimal, and there are persistent disparities in CRC screening and mortality, particularly among minority patients. As most CRC screening takes place in primary care, health systems are well-positioned to address this important population health problem. However, most health systems have not actively engaged in identifying and implementing effective evidence-based intervention strategies that can raise CRC screening rates and reduce disparities. Drawing on the Collective Impact Model and the Interactive Systems Framework for Dissemination and Implementation, our project team applied a learning community strategy to …

The Genomic Landscape Of Cutaneous Scc Reveals Drivers And A Novel Azathioprine Associated Mutational Signature., Gareth J. Inman, Jun Wang, Ai Nagano, Ludmil B. Alexandrov, Karin J. Purdie, Richard G. Taylor, Victoria Sherwood, Jason Thomson, Sarah Hogan, Lindsay C. Spender, Andrew P. South, Michael Stratton, Claude Chelala, Catherine A. Harwood, Charlotte M. Proby, Irene M. Leigh

Department of Dermatology and Cutaneous Biology Faculty Papers

Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients and integrate this analysis with independent gene expression studies. We identify commonly mutated genes, copy number changes and altered pathways and processes. Comparisons with tumour differentiation status suggest events which may drive disease progression. Mutational signature analysis reveals the presence of a novel signature (signature 32), whose incidence correlates with chronic exposure …

The Dermatologist And Color, Andrzej Grzybowski, Lawrence Charles Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

The idea for an issue on color and the skin was initiated by the 2017 exhibit “Breathing Color” that had been created by the new Design Museum in London, England. While variations in color may play a significant role in diagnosing a skin disease, little attention has been directed towards the influence that color may be used to identify a dermatologic disease and even monitor a therapeutic agent. The reader need only to recall how early dermatology atlases were hand colored to provide a more realistic picture of a disease.

Presentation And Outcomes After Medical And Surgical Treatment Versus Medical Treatment Alone Of Spontaneous Infectious Spondylodiscitis: A Systematic Literature Review And Meta-Analysis., Davis G Taylor, Avery L Buchholz, Durga R Sure, Thomas J Buell, James H Nguyen, Ching-Jen Chen, Joshua M Diamond, Perry A Washburn, James Harrop, Christopher I Shaffrey, Justin S Smith

Department of Medicine Faculty Papers

Study Design: Systematic literature review.

Objectives: The aims of this study were to (1) describe the clinical features, disabilities, and incidence of neurologic deficits of pyogenic spondylodiscitis prior to treatment and (2) compare the functional outcomes between patients who underwent medical treatment alone or in combination with surgery for pyogenic spondylodiscitis.

Methods: A systematic literature review was performed using PubMed according to PRISMA guidelines. No year restriction was put in place. Statistical analysis of pooled data, when documented in the original report (ie, number of patients with desired variable and number of patients evaluated), was conducted to determine the most …

Spinal Infections: From Prevention To Cure, James Harrop

Department of Neurosurgery Faculty Papers

AOSpine North America (AOSNA) is honored to have the ability to present this focused issue on spinal infections. As we are all aware, spinal infections are a prevalent part of our daily treatment regimen as spine surgeons—whether these infections are in our elective practice or emergencies.

Loss-Of-Function Mutations In Atp6ap1 And Atp6ap2 In Granular Cell Tumors., Fresia Pareja, Alissa H. Brandes, Thais Basili, Pier Selenica, Felipe C. Geyer, Dan Fan, Arnaud Da Cruz Paula, Rahul Kumar, David N. Brown, Rodrigo Gularte-Mérida, Barbara Alemar, Rui Bi, Raymond S. Lim, Ino De Bruijn, Sho Fujisawa, Rui Gardner, Elvin Feng, Anqi Li, Edaise M. Da Silva, John R. Lozada, Pedro Blecua, Leona Cohen-Gould, Achim A. Jungbluth, Emad A. Rakha, Ian O. Ellis, Maria I.A. Edelweiss, Juan P. Palazzo, Larry Norton, Travis Hollmann, Marcia Edelweiss, Brian P. Rubin, Britta Weigelt, Jorge S. Reis-Filho

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Granular cell tumors (GCTs) are rare tumors that can arise in multiple anatomical locations, and are characterized by abundant intracytoplasmic granules. The genetic drivers of GCTs are currently unknown. Here, we apply whole-exome sequencing and targeted sequencing analysis to reveal mutually exclusive, clonal, inactivating somatic mutations in the endosomal pH regulators ATP6AP1 or ATP6AP2 in 72% of GCTs. Silencing of these genes in vitro results in impaired vesicle acidification, redistribution of endosomal compartments, and accumulation of intracytoplasmic granules, recapitulating the cardinal phenotypic characteristics of GCTs and providing a novel genotypic-phenotypic correlation. In addition, depletion of ATP6AP1 or ATP6AP2 results in …

Use Or Consequences: Probing The Cognitive Difference Between Two Measures Of Divergent Thinking, Richard W. Hass, Roger E. Beaty

College of Humanities and Sciences Faculty Papers

Recent studies have highlighted both similarities and differences between the cognitive processing that underpins memory retrieval and that which underpins creative thinking. To date, studies have focused more heavily on the Alternative Uses task, but fewer studies have investigated the processing underpinning other idea generation tasks. This study examines both Alternative Uses and Consequences idea generation with a methods pulled from cognitive psychology, and a novel method for evaluating the creativity of such responses. Participants were recruited from Amazon Mechanical Turk using a custom interface allowing for requisite experimental control. Results showed that both Alternative Uses and Consequences generation are …

Feasibility Of Using A Commercial Fitness Tracker As An Adjunct To Family-Based Weight Management Treatment: Pilot Randomized Trial., Thao-Ly Tam Phan, Nadia Barnini, Sherlly Xie, Angelica Martinez, Lauren Falini, Atiera Abatemarco, Maura Waldron, Jane M. Benton, Steve Frankenberry, Cassandra Coleman, Linhda Nguyen, Cindy Bo, George A. Datto, Lloyd N. Werk

Department of Pediatrics Faculty Papers

BACKGROUND: Fitness trackers can engage users through automated self-monitoring of physical activity. Studies evaluating the utility of fitness trackers are limited among adolescents, who are often difficult to engage in weight management treatment and are heavy technology users.

OBJECTIVE: We conducted a pilot randomized trial to describe the impact of providing adolescents and caregivers with fitness trackers as an adjunct to treatment in a tertiary care weight management clinic on adolescent fitness tracker satisfaction, fitness tracker utilization patterns, and physical activity levels.

METHODS: Adolescents were randomized to 1 of 2 groups (adolescent or dyad) at their initial weight management clinic …

Comparison Of Germline Versus Somatic Bap1 Mutations For Risk Of Metastasis In Uveal Melanoma., K. G. Ewens, E. Lalonde, J. Richards-Yutz, C. L. Shields, A. Ganguly

Wills Eye Hospital Papers

BACKGROUND: Germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma. Alternatively, somatic mutations in BAP1 in UM have been associated with high risk for metastasis. In this study, we compare the risk of metastasis in UM that carry germline versus somatic BAP1 mutations and mutation-negative tumors.

METHODS: DNA extracted from 142 UM and matched blood samples was sequenced using Sanger or next generation sequencing to identify BAP1 gene mutations.

RESULTS: Eleven of 142 UM (8%) carried …

Pigmented Villonodular Synovitis Does Not Influence The Outcome Following Cementless Total Hip Arthroplasty Using Ceramic-On-Ceramic Articulation: A Case-Control Study With Middle-Term Follow-Up., Chi Xu, Heng Guo, Kerri L. Bell, Feng-Chih Kuo, Ji-Ying Chen

Rothman Institute Papers

BACKGROUND: Pigmented villonodular synovitis (PVNS) is a relatively rare, locally aggressive, and potentially recurrent synovial disease of large joints. The purpose of this study was to investigate (1) the disease recurrence rate and (2) the treatment outcomes including Harris hip scores, complications, and revision following cementless total hip arthroplasty (THA) with ceramic-on-ceramic (CoC) articulation in patients with PVNS.

METHODS: Twenty-two patients (14 females and 8 males) with histologically confirmed PVNS underwent cementless THA using CoC bearings between 2000 and 2013. Three patients with less than 5-year follow-up were excluded. The mean age was 35.2 years (range, 22-58 years) with a …

Semaphorin 5a Drives Melanoma Progression: Role Of Bcl-2, Mir-204 And C-Myb., Simona D'Aguanno, Elisabetta Valentini, Maria Grazia Tupone, Marianna Desideri, Marta Di Martile, Manuela Spagnuolo, Simonetta Buglioni, Cristiana Ercolani, Italia Falcone, Marco De Dominici, Michele Milella, Maria Giulia Rizzo, Bruno Calabretta, Carlo Cota, Andrea Anichini, Daniela Trisciuoglio, Donatella Del Bufalo

Department of Cancer Biology Faculty Papers

BACKGROUND: Melanoma, the most aggressive form of skin cancer, is characterized by high rates of metastasis, drug resistance and mortality. Here we investigated the role of Semaphorin 5A (Sema5A) on the properties associated with melanoma progression and the factors involved in Sema5A regulation.

METHODS: Western blotting, qRT-PCR, Chromatin immunoprecipitation (ChIP) assay, immunohistochemistry of melanoma patient specimens and xenograft tissues, in vitro Transwell assay for cell migration and invasion evaluation, in vitro capillary-like structure formation analysis.

RESULTS: A significant correlation of Sema5A mRNA expression and melanoma progression was observed by analyzing GEO profile dataset. Endogenous Sema5A protein was detected in 95% …

Optimizing Psychosocial Care Of Older Adults With Cancer: An Early Assessment And Intervention Model, Lora Rhodes, Lcsw, Andrew Chapman, Do, Facp

Department of Medical Oncology Posters

Background

Jefferson Multidisciplinary Senior Adult Oncology Center

History

• Established September 2010
• First multidisciplinary geriatric oncology evaluation center in the tristate area

Demographics

• 890 patients evaluated to date
• All tumor types
• Age 70 and above & Pre-transplant (Bone Marrow) evaluation age 65 and above

Format

• Consultative service
• Two sessions weekly
• Average evaluation time: two hours

Multidisciplinary Team

• Navigator, Medical Oncologist, Geriatrician, Pharmacist, Nutritionist, Social Worker
• As needed: Psychiatry, Rehab Medicine, Radiation Oncology, Surgery

Micu1 Interacts With The D-Ring Of The Mcu Pore To Control Its Ca2+ Flux And Sensitivity To Ru360, Melanie Paillard, György Csordás, Kai-Ting Huang, Peter Várnai, Suresh K. Joseph, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Proper control of the mitochondrial Ca²⁺ uniporter’s pore (MCU) is required to allow Ca²⁺ dependent activation of oxidative metabolism and to avoid mitochondrial Ca²⁺ overload and cell death. The MCU’s gatekeeping and cooperative activation is mediated by the Ca²⁺ sensing MICU1 protein, which has been proposed to form dimeric complexes anchored to the EMRE scaffold of MCU. We unexpectedly find that MICU1 suppresses inhibition of MCU by ruthenium red/Ru360, which bind to MCU’s DIME motif, the selectivity filter. This led us to recognize in MICU1’s sequence, a putative DIME Interacting Domain (DID) which is required for …

Identifying And Addressing Hepatitis C Linkage Barriers Through An Institutional Screening Process, Madalene Zale, Mph, Priya Mammen, Md, Mph

Department of Emergency Medicine Posters

Aim

This study evaluates the impact of Act 87 on HCV screening in an urban, academic hospital system with particular attention to disparate care and barriers to linkage to specialty treatment

Distinct Role Of Il-27 In Immature And Lps-Induced Mature Dendritic Cell-Mediated Development Of Cd4, Fang Zhou, Guang-Xian Zhang, A. M. Rostami

Department of Neurology Faculty Papers

Interleukin-27 (IL-27) plays an important role in regulation of anti-inflammatory responses and autoimmunity; however, the molecular mechanisms of IL-27 in modulation of immune tolerance and autoimmunity have not been fully elucidated. Dendritic cells (DCs) play a central role in regulating immune responses mediated by innate and adaptive immune systems, but regulatory mechanisms of DCs in CD4⁺ T cell-mediated immune responses have not yet been elucidated. Here we show that IL-27 treated mature DCs induced by LPS inhibit immune tolerance mediated by LPS-stimulated DCs. IL-27 treatment facilitates development of the CD4⁺ CD127⁺3G11⁺ regulatory T cell subset …

Survivorship And The Skcc Cancer Support And Welcome Center, Shawnna Cannaday, Rn, Msn, Fnp-Bc, Gregory Garber, Msw, Lcsw, Rebecca Cammy, Msw, Lcsw, Lisa Capparella, Mss, Lcsw, Osw-C

Pancreatic Cancer & Related Diseases Patient Symposium

No abstract provided.

Scientific Collaborations In Pancreatic Cancer And What's On The Horizon For Research/Clinical Trials, Jonathan R. Brody, Phd, Elda Grabocka, Phd, Michael J. Pishvaian, Md, Phd, James A. Poser, Iii, Md

Pancreatic Cancer & Related Diseases Patient Symposium

No abstract provided.

Anti-Aging Therapy: Can We Age Cancer Cells So They Stop Growing?, Jonathan R. Brody, Phd

Pancreatic Cancer & Related Diseases Patient Symposium

No abstract provided.

Update On Multimodal Therapy For Pancreatic Cancer, Harish Lavu, Md

Pancreatic Cancer & Related Diseases Patient Symposium

No abstract provided.

Precious Data: 2018 Interim Report From The Jefferson Pancreas Tumor Registry, Theresa Yeo, Phd, Mph, Msn, Aocnp

Pancreatic Cancer & Related Diseases Patient Symposium

No abstract provided.

An Update On Personalized Therapy For Pancreatic Cancer, Michael J. Pishvaian, Md, Phd

Pancreatic Cancer & Related Diseases Patient Symposium

No abstract provided.

Advances In Genetic Testing For Pancreatic Cancer, Colette Hyatt, Ms, Lcgc

Pancreatic Cancer & Related Diseases Patient Symposium

Overview

• Background on genetics
• Hereditary risk for pancreatic cancer
• Why do genetic testing?
• How to schedule a clinical genetics appointment at Jefferson

What To Expect From Your Oncology Care Team, Eleanor Vanderklok, Crnp, Aocnp

Pancreatic Cancer & Related Diseases Patient Symposium

No abstract provided.

Welcome And Program Overview, Charles J. Yeo, Md

Pancreatic Cancer & Related Diseases Patient Symposium

No abstract provided.

Breakfast With The Experts, Tbd

Pancreatic Cancer & Related Diseases Patient Symposium

Continental Breakfast, Informational Tables & Scientific Poster Presentations

Redox Regulation Of Type-I Inositol Trisphosphate Receptors In Intact Mammalian Cells., Suresh K. Joseph, Michael P. Young, Kamil Alzayady, David I. Yule, Mehboob Ali, David M. Booth, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

A sensitization of inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ release is associated with oxidative stress in multiple cell types. These effects are thought to be mediated by alterations in the redox state of critical thiols in the IP3R, but this has not been directly demonstrated in intact cells. Here, we utilized a combination of gel-shift assays with MPEG-maleimides and LC-MS/MS to monitor the redox state of recombinant IP3R1 expressed in HEK293 cells. We found that under basal conditions, ∼5 of the 60 cysteines are oxidized in IP3R1. Cell treatment with 50 μm thimerosal altered gel shifts, indicating oxidation of ∼20 cysteines. …

Mutant Ubqln2p497h In Motor Neurons Leads To Als-Like Phenotypes And Defective Autophagy In Rats, Tianhong Chen, Bo Huang, Xinglong Shi, Limo Gao, Cao Huang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mutations in ubiquilin2 (UBQLN2) have been linked to abnormal protein aggregation in amyotrophic lateral sclerosis (ALS). The mechanisms underlying UBQLN2-related neurodegenerative diseases remain unclear. Using a tetracycline-regulated gene expression system, the ALS-linked UBQLN2P497H mutant was selectively expressed in either the spinal motor neurons or astrocytes in rats. We found that selectively expressing mutant UBQLN2P497H in the spinal motor neurons caused several core features of ALS, including the progressive degeneration of motor neurons, the denervation atrophy of skeletal muscles, and the abnormal protein accumulation. Furthermore, mutant UBQLN2P497H accumulation was associated with an age-dependent decrease in several core autophagy-related proteins. ALS-like phenotypes …