Surgery Commons^™

The Role Of Klotho And Fgf23 In Cardiovascular Outcomes Of Diabetic Patients With Chronic Limb Threatening Ischemia: A Prospective Study, Federico Biscetti, Maria Margherita Rando, Andrea Leonardo Cecchini, Maria Anna Nicolazzi, Enrica Rossini, Flavia Angelini, Roberto Iezzi, Luis H. Eraso, Paul J. Dimuzio, Dario Pitocco, Antonio Gasbarrini, Massimo Massetti, Andrea Flex

Department of Surgery Faculty Papers

Cardiovascular complications after lower extremity revascularization (LER) are common in diabetic patients with peripheral arterial disease (PAD) and chronic limb threatening ischemia (CLTI). The Klotho-fibroblast growth factor 23 (FGF23) axis is associated with endothelial injury and cardiovascular risk. We aimed to analyze the relationship between Klotho and FGF23 serum levels and the incidence of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after LER in diabetic patients with PAD and CLTI. Baseline levels of Klotho and FGF23, and their association with subsequent incidence of MACE and MALE were analyzed in a prospective, non-randomized study in a population …

A Novel 3dna® Nanocarrier Effectively Delivers Payloads To Pancreatic Tumors, Grace A Mccarthy, Aditi Jain, Roberto Di Niro, Christopher W. Schultz, Wei Jiang, Charles Yeo, Jessica Bowers, Jennifer Finan, Kelly Rhodes, Lou Casta, Vivi Hou, Anthony Stefanoni, Samantha Z Brown, Avinoam Nevler, Lebaron C. Agostini, Lori Getts, Robert Getts, Jonathan R Brody

Department of Surgery Faculty Papers

INTRODUCTION: Standard-of-care systemic chemotherapies for pancreatic ductal adenocarcinoma (PDAC) currently have limited clinical benefits, in addition to causing adverse side effects in many patients. One factor known to contribute to the poor chemotherapy response is the poor drug diffusion into PDAC tumors. Novel treatment methods are therefore drastically needed to improve targeted delivery of treatments. Here, we evaluated the efficacy of the 3DNA® Nanocarrier (3DNA) platform to direct delivery of therapeutics to PDAC tumors in vivo.

MATERIALS AND METHODS: A panel of PDAC cell lines and a patient tissue microarray were screened for established tumor-specific proteins to identify targeting moieties …

Peptides That Block Ras-P21 Protein-Induced Cell Transformation, Matthew R Pincus, Bo Lin, Purvi Patel, Elmer Gabutan, Nitzan Zohar, Wilbur Bowne

Department of Surgery Faculty Papers

This is a review of approaches to the design of peptides and small molecules that selectively block the oncogenic RAS-p21 protein in ras-induced cancers. Single amino acid substitutions in this protein, at critical positions such as at Gly 12 and Gln 61, cause the protein to become oncogenic. These mutant proteins cause over 90 percent of pancreatic cancers, 40-50 percent of colon cancers and about one third of non-small cell cancers of the lung (NSCCL). RAS-p21 is a G-protein that becomes activated when it exchanges GDP for GTP. Several promising approaches have been developed that target mutant (oncogenic) RAS-p21 proteins …

Editorial: A Surgeon’S Framework For The Unplanned Intraoperative Consultation, Sunjay Kumar, Talar Tatarian, Francesco Palazzo

Department of Surgery Faculty Papers

Surgeons during their career will likely be called in to assist or offer advice with an unanticipated intraoperative event or finding. Yet, there is no practical framework of how to respond to these consults nor is there any formal training in this area.

Review of the limited literature and expert senior opinion can help explain the ethical components involved but do not address some of the practical aspects that the consulting surgeon may need to confront when responding to an unplanned intraoperative consultation.

In this manuscript we present a selected review of the available literature on the topic, establish some …

Robotically Assisted Mitral Valve Repair—Port-Only Totally Endoscopic Approach, Kellen J. Round, Colin C. Yost, Jake L. Rosen, Jenna L. Mandel, Meagan Wu, Luke C. Olson, Jordan E. Goldhammer, T. Sloane Guy

Department of Surgery Faculty Papers

Robotic mitral valve repair (MVR) is an emerging option to treat degenerative valve disease. Compared to open thoracotomy, robotic mitral valve surgery has been shown to afford decreased postoperative length of stay with comparable rates of mortality and morbidity. Among the variety of techniques for robotic MVR, the totally endoscopic approach remains the least invasive method to date. In this report, we describe our technique for totally endoscopic robotically-assisted MVR. In particular, we seek to highlight the use of several unique techniques in MVR. Percutaneous cannulation with use of the endoballoon is employed for cardiopulmonary bypass (CPB), thus avoiding traditional …

Warren B. Davis And The Birth Of Plastic Surgery In Philadelphia: A Historical Vignette, Sarah F. Wagoner, Charles J. Yeo, Renee M. Tholey, James W. Fox, Steven E. Copit

Department of Surgery Faculty Papers

The field of plastic surgery, formally organized in 1931 with the founding of the American Society of Plastic and Reconstructive Surgery, was shaped in many ways by a small practice of Philadelphia physicians. At the center of the practice was Warren B. Davis, a Philadelphia otolaryngologist and plastics pioneer whose innovations in cleft palate surgery would lead to significant improvements in functional and cosmetic outcomes in his time. In addition to his own innovations, Davis was responsible for the training of John Reese, the inventor of the Reese dermatome that changed the face of burn medicine during World War II. …

Adjuvant Nab-Paclitaxel + Gemcitabine In Resected Pancreatic Ductal Adenocarcinoma: Results From A Randomized, Open-Label, Phase Iii Trial, Margaret A. Tempero, Uwe Pelzer, Eileen M. O'Reilly, Jordan Winter, Do-Youn Oh, Chung-Pin Li, Giampaolo Tortora, Heung-Moon Chang, Charles D. Lopez, Tanios Bekaii-Saab, Andrew H. Ko, Armando Santoro, Joon Oh Park, Marcus S. Noel, Giovanni Luca Frassineti, Yan-Shen Shan, Andrew Dean, Hanno Riess, Eric Van Cutsem, Jordan Berlin, Philip Philip, Malcolm Moore, David Goldstein, Josep Tabernero, Mingyu Li, Stefano Ferrara, Yvan Le Bruchec, George Zhang, Brian Lu, Andrew V. Biankin, Michele Reni

Department of Surgery Faculty Papers

PURPOSE

This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430). METHODS

We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS

Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab …

Pyrvinium Pamoate: Past, Present, And Future As An Anti-Cancer Drug, Christopher W Schultz, Avinoam Nevler

Department of Surgery Faculty Papers

Pyrvinium, a lipophilic cation belonging to the cyanine dye family, has been used in the clinic as a safe and effective anthelminthic for over 70 years. Its structure, similar to some polyaminopyrimidines and mitochondrial-targeting peptoids, has been linked with mitochondrial localization and targeting. Over the past two decades, increasing evidence has emerged showing pyrvinium to be a strong anti-cancer molecule in various human cancers in vitro and in vivo. This efficacy against cancers has been attributed to diverse mechanisms of action, with the weight of evidence supporting the inhibition of mitochondrial function, the WNT pathway, and cancer stem cell renewal. …

Biomarkers In The Development Of Individualized Treatment Regimens For Colorectal Cancer, Madison Crutcher, Scott A Waldman

Department of Surgery Faculty Papers

Introduction: Colorectal cancer (CRC) is the third most common and second most deadly malignancy in the world with an estimated 1. 9 million cases and 0.9 million deaths in 2020. The 5-year overall survival for stage I disease is 92% compared to a dismal 11% in stage IV disease. At initial presentation, up to 35% of patients have metastatic colorectal cancer (mCRC), and 20-50% of stage II and III patients eventually progress to mCRC. These statistics imply both that there is a proportion of early stage patients who are not receiving adequate treatment and that we are not adequately treating …

Systematic Review And Meta-Analysis Of Mid-Term Survival, Reoperation, And Recurrent Mitral Regurgitation For Robotic-Assisted Mitral Valve Repair, Michael L. Williams, Aditya Eranki, Andrew Mamo, Ashley Wilson-Smith, Bridget Hwang, Ramanen Sugunesegran, Tristan Yan, Emiliano Navarra, T. Sloane Guy, Johannes Bonatti

Department of Surgery Faculty Papers

Background: Over the past two decades surgical approaches for mitral valve (MV) disease have evolved with the advent of minimally invasive techniques. Robotic mitral valve repair (RMVr) safety and efficacy has been well documented, however, mid- to long-term data are limited. The aim of this review was to provide a comprehensive analysis of the available mid- to long-term data for RMVr.

Methods: Electronic searches of five databases were performed to identify all relevant studies reporting minimum five-year data on RMVr. Pre-defined primary outcomes of interest were overall survival, freedom from MV reoperation and from moderate or worse mitral regurgitation (MR) …

Serum High Mobility Group Box-1 Levels Associated With Cardiovascular Events After Lower Extremity Revascularization: A Prospective Study Of A Diabetic Population, Maria Margherita Rando, Federico Biscetti, Andrea Leonardo Cecchini, Elisabetta Nardella, Maria Anna Nicolazzi, Flavia Angelini, Roberto Iezzi, Luis H. Eraso, Paul J Dimuzio, Dario Pitocco, Antonio Gasbarrini, Massimo Massetti, Andrea Flex

Department of Surgery Faculty Papers

Background: Peripheral arterial disease (PAD) is one of the most disabling cardiovascular complications of type 2 diabetes mellitus and is indeed associated with a high risk of cardiovascular and limb adverse events. High mobility group box-1 (HMGB-1) is a nuclear protein involved in the inflammatory response that acts as a pro-inflammatory cytokine when released into the extracellular space. HMBG-1 is associated with PAD in diabetic patients. The aim of this study was to evaluate the association between serum HMGB-1 levels and major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after lower-extremity endovascular revascularization (LER) in a group …

External Iliac Vein Aneurysm Treated Via Balloon-Assisted Aneurysmorrhaphy With A Contemporary Review Of The Literature, Kyle W. Prochno, Michael Qaqish, Dawn M. Salvatore, Babak Abai, Paul J. Dimuzio, Michael J. Nooromid

Department of Surgery Faculty Papers

Isolated external iliac vein aneurysm is exceedingly rare, not well-described in the literature, and presents several potential surgical approaches. Herein, we describe the case of a 72-year-old woman who presented with incidentally found 4.3 cm x 3.4 cm x 5.6 cm right external iliac vein aneurysm after undergoing magnetic resonance imaging for orthopedic work-up. She was treated via parallel supra- and infra-inguinal incisions and novel combination of primary aneurysmorrhaphy with intraluminal balloon mandrel-assisted closure. The patient was discharged on postoperative day two, and 6-month follow-up ultrasound showed a normal caliber vessel with normal compressibility, suggesting this technique is safe and …

Large Retroperitoneal Mass, Ryan Lamm, Wilbur B. Bowne

Department of Surgery Faculty Papers

No abstract provided.

Failure Factors For Carpal Tunnel Syndrome Surgical Treatment: When And How To Perform A Revision Carpal Tunnel Decompression Surgery, Carlos Henrique Fernandes, João Baptista Gomes Santos, Francisco Schwartz-Fernandes, A. Lee Ostermann, Flávio Faloppa

Department of Surgery Faculty Papers

Despite being a procedure widely used all over the world with high rates of symptom remission, surgical treatment of carpal tunnel syndrome may present unsatisfactory outcomes. Such outcomes may be manifested clinically by non-remission of symptoms, remission of symptoms with recurrence a time after surgery or appearance of different symptoms after surgery. Different factors are related to this unsuccessful surgical treatment of carpal tunnel syndrome. Prevention can be achieved through a thorough preoperative clinical evaluation of the patient. As such, the surgeon will be able to make differential or concomitant diagnoses, as well as determine factors related to patient dissatisfaction. …

Dietary Risk Factors And Eating Behaviors In Peripheral Arterial Disease (Pad), Andrea Leonardo Cecchini, Federico Biscetti, Maria Margherita Rando, Elisabetta Nardella, Giovanni Pecorini, Luis H. Eraso, Paul J. Dimuzio, Antonio Gasbarrini, Massimo Massetti, Andrea Flex

Department of Surgery Faculty Papers

Dietary risk factors play a fundamental role in the prevention and progression of atherosclerosis and PAD (Peripheral Arterial Disease). The impact of nutrition, however, defined as the process of taking in food and using it for growth, metabolism and repair, remains undefined with regard to PAD. This article describes the interplay between nutrition and the development/progression of PAD. We reviewed 688 articles, including key articles, narrative and systematic reviews, meta-analyses and clinical studies. We analyzed the interaction between nutrition and PAD predictors, and subsequently created four descriptive tables to summarize the relationship between PAD, dietary risk factors and outcomes. We …

Highlights From The 67th Annual Meeting Of The American Society For Artificial Internal Organs In Chicago, Il, Christopher D. Pritting, Alice L. Sweedo, Vakhtang Tchantchaleishvili, Dongfang Wang, Joseph B. Zwischenberger

Department of Surgery Faculty Papers

Dr. Willem J. Kolff founded the American Society for Artificial Internal Organs (ASAIO) in 1955. Each year experts in the fields of renal, pulmonary, pancreatic, cardiac, bioengineering, and orthopedic research congregate to discuss the latest developments in their respective fields. Throughout the conference's history, ASAIO has adapted to promote inquiry, ingenuity, and innovation. The congeniality partnered with the expertise of the conference's attendees has facilitated continuous progress since the conference's inception.

The 2022 ASAIO Annual Conference was held in Chicago, IL in an entirely in-person format, the first since the 65th conference in 2019. This year there were exhibits by …

Robotic Versus Conventional Sternotomy Mitral Valve Surgery: A Systematic Review And Meta-Analysis, Michael L. Williams, Bridget Hwang, Linna Huang, Ashley Wilson-Smith, John Brookes, Aditya Eranki, Tristan D. Yan, T. Sloane Guy, Johannes Bonatti

Department of Surgery Faculty Papers

Background: Robotic-assisted mitral valve surgery (RMVS) is becoming an increasingly performed procedure in cardiac surgery, however, its true safety and efficacy compared to the gold standard conventional sternotomy approach [conventional sternotomy mitral valve surgery (CSMVS)] remains debated. The aim of this meta-analysis was to provide a comprehensive analysis of all available literature comparing RMVS to CSMVS.

Methods: An electronic search of five databases was performed to identify all relevant studies comparing RMVS to CSMVS. Pre-defined primary outcomes of interest included all-cause mortality, cerebrovascular accidents (CVA) and re-operation for bleeding. Secondary outcomes of interest included cross clamp time, cardiopulmonary bypass (CPB) …

Bronchial Artery Revascularization In Lung Transplantation: A Systematic Review And Meta-Analysis., Danial Ahmad, Thomas J O'Malley, Andrew M Jordan, Elizabeth J Maynes, Abhiraj Saxena, Kyle W Prochno, Taufiek K Rajab, Howard T Massey, Richard C Daly, Vakhtang Tchantchaleishvili

Department of Surgery Faculty Papers

Background: Bronchial artery revascularization (BAR) during lung transplantation has been hypothesized to improve early tracheal healing and delay the onset of bronchiolitis obliterans syndrome (BOS). We aimed to assess the outcomes of BAR after lung transplantation.

Methods: Electronic search in Ovid Medline, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Scopus, and Cochrane Controlled Trials Register (CCTR) databases was performed to identify all relevant studies published about lung transplantation with BAR. Studies discussing lung transplantation utilizing BAR were included while those without outcome data such as BOS and survival were excluded. Cohort-level data were extracted and pooled for analysis. …

Editorial: Progress In Understanding The Immunogenetic Basis Of Disease Susceptibility And Outcomes, Tina Bharani, Divyansh Agarwal

Department of Surgery Faculty Papers

No abstract provided.

The Role And Outcomes Of Thoracodistal Bypass, Andrea Mcsweeny, Anthony Feghali, Tuong Nguyen, Michael Nooromid, Dawn Salvatore, Paul Dimuzio, Babak Abai

Department of Surgery Faculty Papers

Objectives

Endovascular procedures for lower extremity revascularization are becoming more commonplace due to low morbidity, mortality, and shorter length of stay. The role of open bypass must be reconsidered. Aortobifemoral bypass is the gold standard for extensive aortoiliac occlusive disease (AIOD); however, thoracodistal bypass holds a niche position. We investigate indications and outcomes of thoracodistal bypass.

Methods

Medical records of five patients who underwent thoracodistal bypass at Thomas Jefferson University Hospital (TJUH) between 2012 and 2019 were reviewed. Contemporary and historical literature was reviewed.

Results

Indications included calcified paravisceral pathology, previous failed or infected bypass grafts, and prior abdominal operations. …

Use Of Autoreactive Antibodies In Blood Of Patients With Pancreatic Intraductal Papillary Mucinous Neoplasms (Ipmn) For Grade Distinction And Detection Of Malignancy, Niall Brindl, Henning Boekhoff, Andrea S Bauer, Matthias M Gaida, Hien Dang, Jörg Kaiser, Jörg D Hoheisel, Klaus Felix

Department of Surgery Faculty Papers

(1) Background: A reliable non-invasive distinction between low- and high-risk pancreatic intraductal papillary mucinous neoplasms (IPMN) is needed to effectively detect IPMN with malignant potential. This would improve preventative care and reduce the risk of developing pancreatic cancer and overtreatment. The present study aimed at exploring the presence of autoreactive antibodies in the blood of patients with IPMN of various grades of dysplasia. (2) Methods: A single-center cohort was studied composed of 378 serum samples from patients with low-grade IPMN (n = 91), high-grade IPMN (n = 66), IPMN with associated invasive cancer (n = 30), pancreatic …

Advanced-Stage Melanoma At Presentation Following The Peak Of The Pandemic: A Covid-19 Cancer Canary In A Coal Mine, Ryan Lamm, Md, Walker Lyons, Md, Winnie So, Rn, Alliric I. Willis, Md, Facs, Msph

Department of Surgery Faculty Papers

Background: For melanoma patients, timely identification and tumor thickness are directly correlated with outcomes. COVID-19 impacted both patients' ability and desire to see physicians. We sought to identify whether the pandemic correlated with changes in melanoma thickness at presentation and subsequent treatment timeline.

Methods: Retrospective chart review was performed on patients who underwent surgery for melanoma in an academic center surgical oncology practice from May 2019 to September 2021. Patients were split into two cohorts: "pre-pandemic" from May 2019 to May 2020 and "pandemic," after May 2020, representing when these patients received their initial diagnostic biopsy. Demographic and melanoma-specific variables …

Reduced Rates Of Post-Transplant Recurrent Hepatocellular Carcinoma In Non-Alcoholic Steatohepatitis: A Propensity Score Matched Analysis, Ryan Lamm, Peter J Altshuler, Keyur Patel, Osama Shaheen, Angel Paulo Amante, Jesse Civan, Warren Maley, Adam Frank, Carlo Ramirez, Jaime Glorioso, Ashesh Shah, Hien Dang, Adam S Bodzin

Department of Surgery Faculty Papers

Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) has become the second leading cause of HCC-related liver transplantation in the United States. This study investigated post-transplant recurrence and survival for patients transplanted for NASH-related HCC compared to non-NASH HCC etiologies. Retrospective review of the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network (OPTN) database identified 7,461 patients with HCC—1,405 with underlying NASH and 6,086 with non-NASH underlying diseases. After propensity score matching (PSM) to account for patient- and tumor-related confounders 1,175 remained in each group. Primary outcomes assessed were recurrence rate and recurrence-free survival. Recurrent malignancy at 5 years …

Socioeconomic Status And Gastric Cancer Surgical Outcomes: A National Cancer Database Study., Ryan Lamm, D Brock Hewitt, Michael Li, Adam C Powell, Adam C Berger

Department of Surgery Faculty Papers

INTRODUCTION: Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Surgical resection is the gold standard of treatment. In the United States, race and socioeconomic status are associated with the diagnosis of GC; however, no studies have examined these as independent risk factors for surgical outcomes. Our study sought to investigate socioeconomic factors and GC surgical outcomes using a national cancer registry.

METHODS: GC patients between 2004 and 2016 were identified using the National Cancer Database. Univariate and multivariate logistic regression was used to analyze associations between socioeconomic factors and 30-d mortality, 90-d mortality, and unplanned readmission …

Popliteal Artery Entrapment Syndrome Treated By A Posterior Approach In A 15-Year-Old Athlete, Lili Sadri, Robert L Myers, Casey Paterson, Quyngdiem Lam, Danielle M Pineda

Department of Surgery Faculty Papers

Popliteal artery entrapment syndrome is a rare source of claudication in young people. We present the case of a 15-year-old male athlete who presented with intermittent numbness of his right foot with exertion. Imaging revealed classic compression from a right type III popliteal artery entrapment. The left popliteal artery was chronically occluded with a large collateral vessel. He underwent release of the accessory bands of the gastrocnemius muscle with significant arteriolysis on the right side via a posterior approach. Chronic popliteal artery entrapment can be treated from a posterior approach, resulting in arterial occlusion and will be asymptomatic if well …

Criminal, Legal, And Ethical Kidney Donation And Transplantation: A Conceptual Framework To Enable Innovation, Alvin E Roth, Ignazio R Marino, Kimberly D Krawiec, Michael A Rees

Department of Surgery Faculty Papers

No abstract provided.

Coil Embolization Of Ruptured Distal Renal Artery Pseudoaneurysm With Gross Hematuria And Hemorrhagic Shock, Andrea Mcsweeney, Anand Tarpara, Dawn Salvatore, Paul J Dimuzio, Michael Nooromid, Babak Abai

Department of Surgery Faculty Papers

Renal artery pseudoaneurysms have been infrequently reported in the literature. In the present report, we have described a case of a ruptured renal artery pseudoaneurysm requiring coil embolization. A 49-year-old man had presented to our institution with a hypertensive emergency. Computed tomography revealed a 3.4-cm right renal artery pseudoaneurysm. Nonemergent coil embolization was planned for the following day. However, he became hypotensive, exsanguinating frank blood from the urethra. An arteriogram showed extravasation of contrast into the pseudoaneurysm sac, renal pelvis, and ureter, consistent with intrarenal pseudoaneurysm rupture. We have demonstrated coil embolization as a method of repairing a ruptured renal …

Toward Zero Prescribed Opioids For Outpatient General Surgery Procedures: A Prospective Cohort Trial, Ryan Lamm, Steven Woodward, Brandon A Creisher, David Nauheim, Lauren Schlegel, Talar Tatarian, Renee Tholey, Courtney Foley, Francesco Palazzo

Department of Surgery Faculty Papers

INTRODUCTION: Achieving satisfactory post-operative pain control for common elective general surgical procedures, while minimizing opioid utilization, remains challenging. Utilizing pre-operative educational strategies, as well as multimodal analgesia, we sought to reduce the post-operative opioid use in elective general surgery cases.

METHODS: Between November 2019 and July 2021, patients undergoing elective inguinal hernia repair or cholecystectomy were enrolled in the study. Patients were divided into three cohorts: Control, opioid sparing (OS), or zero-opioid (ZO). Control patients did not have any intervention; OS patients had an opioid reduction intervention protocol applied (patient education and perioperative multimodal analgesia) and were provided an opioid …

Pnc-27, A Chimeric P53-Penetratin Peptide Binds To Hdm-2 In A P53 Peptide-Like Structure, Induces Selective Membrane-Pore Formation And Leads To Cancer Cell Lysis, Ehsan Sarafraz-Yazdi, Stephen Mumin, Diana Cheung, Daniel Fridman, Brian Lin, Lawrence Wong, Ramon Rosal, Rebecca Rudolph, Matthew Frenkel, Anusha Thadi, William F. Morano, Wilbur B. Bowne, Matthew R. Pincus, Josef Michl

Department of Surgery Faculty Papers

PNC-27, a 32-residue peptide that contains an HDM-2 binding domain and a cell-penetrating peptide (CPP) leader sequence kills cancer, but not normal, cells by binding to HDM-2 associated with the plasma membrane and induces the formation of pores causing tumor cell lysis and necrosis. Conformational energy calculations on the structure of PNC-27 bound to HDM-2 suggest that 1:1 complexes form between PNC-27 and HDM-2 with the leader sequence pointing away from the complex. Immuno-scanning electron microscopy was carried out with cancer cells treated with PNC-27 and decorated with an anti-PNC-27 antibody coupled to 6 nm gold particles and an anti-HDM-2 …

Hur Plays A Role In Double-Strand Break Repair In Pancreatic Cancer Cells And Regulates Functional Brca1-Associated-Ring-Domain-1(Bard1) Isoforms, Aditi Jain, Matthew Mccoy, Carolyn Coats, Samantha Z Brown, Sankar Addya, Carl Pelz, Rosalie C Sears, Charles Yeo, Jonathan R Brody

Department of Surgery Faculty Papers

Human Antigen R (HuR/ELAVL1) is known to regulate stability of mRNAs involved in pancreatic ductal adenocarcinoma (PDAC) cell survival. Although several HuR targets are established, it is likely that many remain currently unknown. Here, we identified BARD1 mRNA as a novel target of HuR. Silencing HuR caused a >70% decrease in homologous recombination repair (HRR) efficiency as measured by the double-strand break repair (pDR-GFP reporter) assay. HuR-bound mRNAs extracted from RNP-immunoprecipitation and probed on a microarray, revealed a subset of HRR genes as putative HuR targets, including the BRCA1-Associated-Ring-Domain-1 (BARD1) (p < 0.005). BARD1 genetic alterations are infrequent in PDAC, and its context-dependent upregulation is poorly understood. Genetic silencing (siRNA and CRISPR knock-out) and pharmacological targeting of HuR inhibited both full length (FL) BARD1 and its functional isoforms (α, δ, Φ). Silencing BARD1 sensitized cells to olaparib and oxaliplatin; caused G2-M cell cycle arrest; and increased DNA-damage while decreasing HRR efficiency in cells. Exogenous overexpression of BARD1 in HuR-deficient cells partially rescued the HRR dysfunction, independent of an HuR pro-oncogenic function. Collectively, our findings demonstrate for the first time that BARD1 is a bona fide HuR target, which serves as an important regulatory point of the transient DNA-repair response in PDAC cells.