Medicine and Health Sciences Commons^™

A Neuronal Network Of Mitochondrial Dynamics Regulates Metastasis., M. Cecilia Caino, Jae Ho Seo, Angeline Aguinaldo, Eric Wait, Kelly G. Bryant, Andrew V. Kossenkov, James E. Hayden, Valentina Vaira, Annamaria Morotti, Stefano Ferrero, Silvano Bosari, Dmitry I. Gabrilovich, Lucia R. Languino, Andrew R. Cohen, Dario C. Altieri

Department of Cancer Biology Faculty Papers

The role of mitochondria in cancer is controversial. Using a genome-wide shRNA screen, we now show that tumours reprogram a network of mitochondrial dynamics operative in neurons, including syntaphilin (SNPH), kinesin KIF5B and GTPase Miro1/2 to localize mitochondria to the cortical cytoskeleton and power the membrane machinery of cell movements. When expressed in tumours, SNPH inhibits the speed and distance travelled by individual mitochondria, suppresses organelle dynamics, and blocks chemotaxis and metastasis, in vivo. Tumour progression in humans is associated with downregulation or loss of SNPH, which correlates with shortened patient survival, increased mitochondrial trafficking to the cortical cytoskeleton, greater …

Ido1 Is An Integral Mediator Of Inflammatory Neovascularization., Arpita Mondal, Courtney Smith, James B. Duhadaway, Erika Sutanto-Ward, George C. Prendergast, Arturo Bravo-Nuevo, Alexander J. Muller

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

The immune tolerogenic effects of IDO1 (indoleamine 2,3-dioxygenase 1) have been well documented and genetic studies in mice have clearly established the significance of IDO1 in tumor promotion. Dichotomously, the primary inducer of IDO1, the inflammatory cytokine IFNγ (interferon-γ), is a key mediator of immune-based tumor suppression. One means by which IFNγ can exert an anti-cancer effect is by decreasing tumor neovascularization. We speculated that IDO1 might contribute to cancer promotion by countering this anti-neovascular effect of IFNγ, possibly through IDO1-potentiated elevation of the pro-tumorigenic inflammatory cytokine IL6 (interleukin-6). In this study, we investigated how genetic loss of IDO1 affects …

The Potential Roles Of Long Noncoding Rnas (Lncrna) In Glioblastoma Development, Shuang Liu, Ramkrishna Mitra, Ming-Ming Zhao, Wenhong Fan, Christine M. Eischen, Feng Yin, Zhongming Zhao

Department of Cancer Biology Faculty Papers

Long noncoding RNA (lncRNA) may contribute to the initiation and progression of tumor. In this study, we first systematically compared lncRNA and mRNA expression between glioblastoma and paired normal brain tissues using microarray data. We found 27 lncRNA and 82 mRNA significantly upregulated in glioblastoma, as well as 198 lncRNA and 285 mRNA significantly downregulated in glioblastoma. We identified 138 coexpressed lncRNA–mRNA pairs from these differentially expressed lncRNA and genes. Subsequent pathway analysis of the lncRNA-paired genes indicated that EphrinB–EPHB, p75-mediated signaling, TNFα/NF-κB, and ErbB2/ErbB3 signaling pathways might be altered in glioblastoma. Specifically, lncRNA RAMP2-AS1 had significant decrease of expression …

V-Src Oncogene Induces Trop2 Proteolytic Activation Via Cyclin D1., Xiaoming Ju, Xuanmao Jiao, Adam Ertel, Mathew C. Casimiro, Gabriele Disante, Shengqiong Deng, Zhiping Li, Agnese Di Rocco, Tingting Zhan, Adam Hawkins, Tanya Stoyanova, Sebastiano Andò, Alessandro Fatatis, Michael P. Lisanti, Leonard G. Gomella, Lucia R. Languino, Richard G. Pestell

Department of Cancer Biology Faculty Papers

Proteomic analysis of castration-resistant prostate cancer demonstrated the enrichment of Src tyrosine kinase activity in approximately 90% of patients. Src is known to induce cyclin D1, and a cyclin D1-regulated gene expression module predicts poor outcome in human prostate cancer. The tumor-associated calcium signal transducer 2 (TACSTD2/Trop2/M1S1) is enriched in the prostate, promoting prostate stem cell self-renewal upon proteolytic activation via a γ-secretase cleavage complex (PS1, PS2) and TACE (ADAM17), which releases the Trop2 intracellular domain (Trop2 ICD). Herein, v-Src transformation of primary murine prostate epithelial cells increased the proportion of prostate cancer stem cells as characterized by gene expression, …

Intrahepatic Cholangiocarcinoma Presenting As Li-Rads 5 "Hcc", Raja K. Dhanekula, Md, Donald Mitchell, Md, John Farber, Md, Ashwin R. Sama, Md, Jesse M. Civan, Md

Division of Gastroenterology and Hepatology Posters

Background

• Hepatocellular Carcinoma (HCC), if within Milan Criteria, is an indication for liver transplantation.

• In contrast, intrahepatic cholangiocarcinoma (IHCC) is a contra-indication to liver transplantation due to high rates of recurrence.

• LI-RADS 5 classification (synonymous with OPTN-5) carries a near 100% positive predictive value for HCC, allowing prioritization of patients for liver transplantation without histological confirmation.

• The “LI-RADS M” classification indicates the presence of malignancy not meeting diagnostic criteria for HCC. In theory, IHCC lesions should be identified as LI-RADS M and not LI-RADS 5.

Download Entire Bodine Journal Volume 1, Issue 1, 2008

Bodine Journal

No abstract provided.

Factors Associated With Severe Late Toxicity After Concurrent Chemoradiation For Locally Advanced Head And Neck Cancer: An Rtog Analysis, Mitchell Machtay, Md, Jennifer Moughan, Ms, Andrew Trotti, Md, Adam S. Garden, Md, Randal S. Weber, Md, Jay S. Cooper, Md, Arlene Forastiere, Md, K. Kian Ang, Md

Bodine Journal

Purpose

Concurrent chemoradiotherapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases both local tumor control and toxicity. This study evaluates clinical factors that are associated with and might predict severe late toxicity after CCRT.

Methods

Patients were analyzed from a subset of three previously reported RTOG trials of concurrent chemoradiotherapy for locally advanced SCCHN (RTOG 91-11; 97-03; and 99-14). Severe late toxicity was defined in this secondary analysis as chronic Grade 3-4 pharyngeal/laryngeal toxicity (RTOG/EORTC late toxicity scoring system) and/or requirement for a feeding tube ≥2 years after registration and/or potential treatment-related death (e.g. pneumonia) within …

Increasing Tumor Volume Is Predictive Of Poor Overall And Progression-Free Survival: Secondary Analysis Of The Radiation Therapy Oncology Group 93-11 Phase I-Ii Radiation Dose-Escalation Study In Patients With Inoperable Non-Small-Cell Lung Cancer, Maria Werner-Wasik, R. Suzanne Swann, Phd, Jeffrey Bradley, Md, Mary Graham, Md, Bahman Emani, Md, James Purdy, Phd, William Sause, Md

Bodine Journal

Purpose

Patients with non–small-cell lung cancer (NSCLC) in the Radiation Therapy Oncology Group (RTOG) 93-11 trial received radiation doses of 70.9, 77.4, 83.8, or 90.3 Gy. The locoregional control and survival rates were similar among the various dose levels.We investigated the effect of the gross tumor volume (GTV) on the outcome.

Methods and Materials

The GTV was defined as the sum of the volumes of the primary tumor and involved lymph nodes. The tumor response, median survival time (MST), and progression-free survival (PFS) were analyzed separately for smaller (≤45 cm3) vs. larger (>45 cm3) tumors.

Results

The distribution of …

Inhibition Of P73 Function By Pifithrin-Α As Revealed By Studies In Zebrafish Embryos, William R Davidson, Qing Ren, Gabor Kari, Ori Kashi, Adam Dicker Md, Phd, Ulrich Rodeck

Bodine Journal

The p53 family of proteins contains two members that have been implicated in sensitization of cells and organisms to genotoxic stress, i.e., p53 itself and p73. In vitro, lack of either p53 or p73 can protect certain cell types in the adult organism against death upon exposure to DNA damaging agents. The present study was designed to assess the relative contribution of p53 to radiation resistance of an emerging vertebrate model organism, i.e., zebrafish embryos. Consistent with previous reports, suppressing p53 protein expression using antisense morpholino oligonucleotides (MOs) increased survival and reduced gross morphological alterations in zebrafish embryos exposed to …

Vegf Trap In Combination With Radiotherapy Improves Tumor Control In U87 Glioblastoma, Phyllis Wachsberger, Phd, Randy Burd, Phd, Chris Cardi, Ms, Mathew L. Thakur, Constantine Daskalakis, Jocelyn Holash, Phd, George D. Yancopoulos, Phd, Adam Dicker Md, Phd

Bodine Journal

Purpose

To determine the effect of vascular endothelial growth factor VEGF Trap (Regeneron Pharmaceuticals, Tarrytown, NY), a humanized soluble vascular endothelial growth factor (VEGF) receptor protein, and radiation (RT) on tumor growth in U87 glioblastoma xenografts in nude mice.

Methods and Materials

U87 cell suspensions were implanted subcutaneously into hind limbs of nude mice. VEGF Trap (2.5–25 mg/kg) was administered every 3 days for 3 weeks alone or in combination with a single dose of 10 Gy or fractionated RT (3 x 5 Gy). In addition, three scheduling protocols for VEGF Trap plus fractionated RT were examined.

Results

Improved tumor …

A Cone Beam Ct-Based Study For Clinical Target Definition Using Pelvic Anatomy During Post-Prostatectomy Radiotherapy, Timothy Showalter Md, A. Omer Nawaz, Ma, Ying Xiao, James Galvin Phd, Richard K. Valicenti, Md

Bodine Journal

Introduction:

Radiation therapy (RT) is delivered after radical prostatectomy (RP) either as salvage treatment for an elevated prostate-specific antigen (PSA) level1-6 or as adjuvant therapy for patients with highrisk pathologic features7-8. Recent prospective data demonstrated a disease-free survival benefit of adjuvant RT for pathologic T3N0 prostate cancer9-10. Despite literature supporting the delivery of post-RP RT to the prostatic fossa (PF), no clear target definition guidelines exist for intensity modulated radiation therapy (IMRT) or image-guided RT (IGRT)11.

Visualization of the PF is limited on standard CT images, with significant interobserver variability and uncertainty in CTV definition12. Efforts to incorporate complementary imaging …

Toxicity Of Radiotherapy In Patients With Collagen Vascular Disease, Alexander Lin, Md, Eyad Abu-Isa, Md, Kent A. Griffith, Mph, Ms, Edgar Ben-Josef, Md

Bodine Journal

Background

A diagnosis of collagen vascular disease (CVD) may predispose to radiotherapy (RT) toxicity. The objective of the current study was to identify factors that influence RT toxicity in the setting of CVD.

Methods

A total of 86 RT courses for 73 patients with CVD were delivered between 1985 and 2005. CVD subtypes include rheumatoid arthritis (RA; 33 patients), systemic lupus erythematosus (SLE; 13 patients), scleroderma (9 patients), dermatomyositis/polymyositis (5 patients), ankylosing spondylitis (4 patients), polymyalgia rheumatica/temporal arteritis (4 patients), Wegener granulomatosis (3 patients), and mixed connective tissue disorders (MCTD)/other (2 patients). Each patient with CVD was matched to 1 …

Table Of Contents: Bodine Journal Volume 1, Issue 1, Fall 2008

Bodine Journal

No abstract provided.

Download Entire Bodine Journal Volume 2, Issue 1, 2009

Bodine Journal

No abstract provided.

Flexible Needle-Tissue Interaction Modeling With Depth-Varying Mean Parameter: Preliminary Study, Kai Guo Yan, Tarun Podder, Yan Yu, Tien-I Liu, Christopher W.S. Cheng, Wan Sing Ng

Bodine Journal

Flexible needle steering has aroused a lot of research interest in recent years. It has the potential to correct targeting errors, which may be caused by needle bending, tissue deformation, or error in insertion angle. In addition, control and planning based on a steering model can guide the needle to some areas that are currently not amenable to needles because of obstacles, such as bone or sensitive tissues. Thus, there is a clear motivation for needle steering. In this paper, a spring–beam– damper model is proposed to describe the dynamics during the needle–tissue contact procedure. Considering tissue inhomogeneity, depth-varying mean …

Does Intraoperative Radiation Therapy Improve Local Tumor Control In Patients Undergoing Pancreaticoduodenectomy For Pancreatic Adenocarcinoma? A Propensity Score Analysis, Timothy Showalter Md, Atul Rao, Rani Anne Md, Francis E. Rosato, Ernest L Rosato, Jocelyn Andrel, Terry Hyslop, Xia Xu, Adam C. Berger

Bodine Journal

Background:

Locoregional recurrence (LRR) is an important factor after pancreaticoduodenectomy (PD) for pancreatic cancer. IORT administered to the resection bed may improve local tumor control.

Methods:

We performed a retrospective analysis of patients who underwent PD at Thomas Jefferson University Hospital (TJUH) between 1995 and 2005 to identify patients who underwent resection with and without intraoperative radiation therapy (IORT). Data collected included age, gender, complications, margin status, stage, survival, and recurrence. Unadjusted analyses of the IORT and non-IORT groups were performed using Fisher’s chi-square method for discrete variables and Wilcoxon Rank Sum test for continuous variables. To account for biases …

Combination Of Vandetanib, Radiotherapy, And Irinotecan In The Lovo Human Colorectal Cancer Xenograft Model, Phyllis Wachsberger, Phd, Randy Burd, Phd, Anderson Ryan, Phd, Constantine Daskalakis, Phd, Adam Dicker Md, Phd

Bodine Journal

Purpose:

The tumor growth kinetics of the human LoVo colorectal xenograft model was assessed in response to vandetanib, an orally available receptor tyrosine kinase inhibitor, radiotherapy (RT), or irinotecan (CPT-11), as single therapies and in combination.

Methods and Materials:

LoVo cells were injected subcutaneously into the right hind limb (5x106 cells in 100μL phosphate-buffered saline) of athymic NCR NUM mice and tumors were grown to a volume of 200–300mm3 before treatment. Vandetanib was administered at 50 mg/kg daily orally for 14 days starting on Day 1. RT was given as three fractions (3x3 Gy) on Days 1, 2, and 3. …

Nuclear Factor Κb Inhibitors Alleviate And The Proteasome Inhibitor Ps-341 Exacerbates Radiation Toxicity In Zebrafish Embryos, Borbala Daroczi, Gabor Kari, Qing Ren, Adam Dicker Md, Phd, Ulrich Rodeck

Bodine Journal

Inflammatory changes are a major component of the normal tissue response to ionizing radiation, and increased nuclear factor κB (NF-κB) activity is an important mediator of inflammatory responses. Here, we used zebrafish embryos to assess the capacity of two different classes of pharmacologic agents known to target NF-κB to modify radiation toxicity in the vertebrate organism. These were proteasome inhibitors, including lactacystin, MG132, and PS-341 (Bortezomib/VELCADE), and direct inhibitors of NF-κB activity, including ethyl pyruvate (EP) and the synthetic triterpenoid CDDO-TFEA (RTA401), among others. The proteasome inhibitors either did not significantly affect radiation sensitivity of zebrafish embryos (MG132, lactacystin) or …

Bodine Journal, Table Of Contents, Volume 2, Issue 1, Fall 2009

Bodine Journal

No abstract provided.

Numerical Investigation Of Novel Microwave Applicators Based On Zero-Order Mode Resonance For Hyperthermia Treatment Of Cancer, David Vrba, Jan Vrba, Dario B. Rodrigues, Paul R. Stauffer

Department of Radiation Oncology Faculty Papers

This paper characterizes three novel microwave applicators based on zero-order mode resonators for use in hyperthermia treatment of cancer. The radiation patterns are studied with numerical simulations in muscle tissue-equivalent model at 434 MHz. The relative performance of the applicators is compared in terms of reflection coefficient, current distribution, power deposition (SAR) pattern, effective field size in 2D and 3D tissue volumes, and penetration depth. One particular configuration generated the most uniform SAR pattern, with 25% SAR covering 84 % of the treatment volume extending to 1 cm depth under the aperture, while remaining above 58% coverage as deep as …

Celecoxib Inhibits Proliferation And Survival Of Chronic Myelogeous Leukemia (Cml) Cells Via Ampk-Dependent Regulation Of Β-Catenin And Mtorc1/2., Beatrice Riva, Marco De Dominici, Ilaria Gnemmi, Samanta A. Mariani, Alberto Minassi, Valentina Minieri, Paolo Salomoni, Pier Luigi Canonico, Armando A Genazzani, Bruno Calabretta, Fabrizio Condorelli

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

CML is effectively treated with tyrosine kinase inhibitors (TKIs). However, the efficacy of these drugs is confined to the chronic phase of the disease and development of resistance to TKIs remains a pressing issue. The anti-inflammatory COX2 inhibitor celecoxib has been utilized as anti-tumour drug due to its anti-proliferative activity. However, its effects in hematological malignancies, in particular CML, have not been investigated yet. Thus, we tested biological effects and mechanisms of action of celecoxib in Philadelphia-positive (Ph+) CML and ALL cells.We show here that celecoxib suppresses the growth of Ph+ cell lines by increasing G1-phase and apoptotic cells and …

Cd99 Triggering Induces Methuosis Of Ewing Sarcoma Cells Through Igf-1r/Ras/Rac1 Signaling., Maria Cristina Manara, Mario Terracciano, Caterina Mancarella, Marika Sciandra, Clara Guerzoni, Michela Pasello, Andrea Grilli, Nicoletta Zini, Piero Picci, Mario P. Colombo, Andrea Morrione, Katia Scotlandi

Department of Urology Faculty Papers

CD99 is a cell surface molecule that has emerged as a novel target for Ewing sarcoma (EWS), an aggressive pediatric bone cancer. This report provides the first evidence of methuosis in EWS, a non-apoptotic form of cell death induced by an antibody directed against the CD99 molecule. Upon mAb triggering, CD99 induces an IGF-1R/RAS/Rac1 complex, which is internalized into RAB5-positive endocytic vacuoles. This complex is then dissociated, with the IGF-1R recycling to the cell membrane while CD99 and RAS/Rac1 are sorted into immature LAMP-1-positive vacuoles, whose excessive accumulation provokes methuosis. This process, which is not detected in CD99-expressing normal mesenchymal …

Exosome-Mediated Transfer Of Αvβ3 Integrin From Tumorigenic To Nontumorigenic Cells Promotes A Migratory Phenotype., Amrita Singh, Carmine Fedele, Huimin Lu, Marja T. Nevalainen, James H. Keen, Lucia R. Languino

Department of Cancer Biology Faculty Papers

The αvβ3 integrin is known to be highly upregulated during cancer progression and promotes a migratory and metastatic phenotype in many types of tumors. We hypothesized that the αvβ3 integrin is transferred through exosomes and, upon transfer, has the ability to support functional aberrations in recipient cells. Here, for the first time, it is demonstrated that αvβ3 is present in exosomes released from metastatic PC3 and CWR22Pc prostate cancer cells. Exosomal β3 is transferred as a protein from donor to nontumorigenic and tumorigenic cells as β3 protein or mRNA levels remain unaffected upon transcription or translation inhibition in recipient cells. …

Symptom Clusters., Andrea M. Barsevick

Department of Medical Oncology Faculty Papers

No abstract provided.

Haploinsufficiency Of The Myc Regulator Mtbp Extends Survival And Delays Tumor Development In Aging Mice., Brian C. Grieb, Kelli Boyd, Ramkrishna Mitra, Christine M. Eischen

Department of Cancer Biology Faculty Papers

Alterations of specific genes can modulate aging. Myc, a transcription factor that regulates the expression of many genes involved in critical cellular functions was shown to have a role in controlling longevity. Decreased expression of Myc inhibited many of the deleterious effects of aging and increased lifespan in mice. Without altering Myc expression, reduced levels of Mtbp, a recently identified regulator of Myc, limit Myc transcriptional activity and proliferation, while increased levels promote Myc-mediated effects. To determine the contribution of Mtbp to the effects of Myc on aging, we studied a large cohort of Mtbp heterozygous mice and littermate matched …

A Survey Of Physician Receptivity To Molecular Diagnostic Testing And Readiness To Act On Results For Early-Stage Colon Cancer Patients., Ronald E. Myers, Thomas Wolf, Phillip Shwae, Sarah E. Hegarty, Stephen C. Peiper, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: We sought to assess physician interest in molecular prognosic testing for patients with early stage colon cancer, and identify factors associated with the likelihood of test adoption.

METHODS: We identified physicians who care for patients with early-stage (pN0) colon cancer patients, mailed them a survey, and analyzed survey responses to assess clinician receptivity to the use of a new molecular test (GUCY2C) that identifies patients at risk for recurrence, and clinician readiness to act on abnormal test results.

RESULTS: Of 104 eligible potential respondents, 41 completed and returned the survey. Among responding physicians, 56 % were receptive to using …

An Approach Using Psa Levels Of 1.5 Ng/Ml As The Cutoff For Prostate Cancer Screening In Primary Care., E. David Crawford, Matt T. Rosenberg, Alan W. Partin, Matthew R. Cooperberg, Michael Maccini, Stacy Loeb, Curtis A. Pettaway, Neal D. Shore, Paul Arangua, John Hoenemeyer, Mike Leveridge, Michael Leapman, Peter Pinto, Ian M. Thompson, Peter Carroll, James Eastham, Leonard G. Gomella, Eric A. Klein

Department of Urology Faculty Papers

No abstract provided.

Post-Transplant Outcomes In High-Risk Compared With Non-High-Risk Multiple Myeloma: A Cibmtr Analysis., Emma C. Scott, Parameswaran Hari, Manish Sharma, Jennifer Le-Rademacher, Jiaxing Huang, Dan Vogl, Muneer Abidi, Amer Beitinjaneh, Henry Fung, Siddhartha Ganguly, Gerhard Hildebrandt, Leona Holmberg, Matt Kalaycio, Shaji Kumar, Robert Kyle, Hillard Lazarus, Cindy Lee, Richard T. Maziarz, Kenneth Meehan, Joseph Mikhael, Taiga Nishihori, Muthalagu Ramanathan, Saad Usmani, Jason Tay, David Vesole, Baldeep Wirk, Jean Yared, Bipin N. Savani, Cristina Gasparetto, Amrita Krishnan, Tomer Mark, Yago Nieto, Anita D'Souza

Department of Medical Oncology Faculty Papers

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (-Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher …

Detection And Characterization Of Circulating Tumor Associated Cells In Metastatic Breast Cancer., Zhaomei Mu, Naoual Benali-Furet, Georges Uzan, Anaëlle Znaty, Zhong Ye, Carmela Paolillo, Chun Wang, Laura Austin, Giovanna Rossi, Paolo Fortina, Hushan Yang, Massimo Cristofanilli

Department of Medical Oncology Faculty Papers

The availability of blood-based diagnostic testing using a non-invasive technique holds promise for real-time monitoring of disease progression and treatment selection. Circulating tumor cells (CTCs) have been used as a prognostic biomarker for the metastatic breast cancer (MBC). The molecular characterization of CTCs is fundamental to the phenotypic identification of malignant cells and description of the relevant genetic alterations that may change according to disease progression and therapy resistance. However, the molecular characterization of CTCs remains a challenge because of the rarity and heterogeneity of CTCs and technological difficulties in the enrichment, isolation and molecular characterization of CTCs. In this …

The Clock Is Ticking: Countdown To Metastases., Linda D. Siracusa, Karen M. Bussard

Department of Microbiology and Immunology Faculty Papers

No abstract provided.