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Translational Oncology

Alexander Quaas, Carina Heydt, Florian Gebauer, Hakan Alakus, Heike Loeser, Reinhard Buettner, Axel Hillmer, Christiane Bruns, Sabine Merkelbach-Bruse, Thomas Zander, Peter Frommolt
No abstract text is available yet for this article.
October 11, 2018: Translational Oncology
Kais Zakharia, Katsuyuki Miyabe, Yu Wang, Dehai Wu, Catherine D Moser, Mitesh J Borad, Lewis R Roberts
PURPOSE: We investigated the antitumor effect of the casein kinase II (CK2) inhibitor CX-4945 on cholangiocarcinoma (CCA). METHODS: We assessed the effect of CX-4945 alone and/or in combination with gemcitabine and cisplatin on cell viability, colony formation, and apoptosis of CCA cell lines and on in vivo growth of HuCCT1 xenografts. RESULTS: CX-4945 dose-dependently decreased viability of HuCCT1, EGI-1, and Liv27 and decreased phospho-AKT/total AKT and phospho-PTEN/total PTEN ratios...
October 10, 2018: Translational Oncology
Samantha L Jumbe, Sean R Porazinski, Sebastian Oltean, Jason P Mansell, Bahareh Vahabi, Ian D Wilson, Michael R Ladomery
The oncogene ERG encodes an ETS family transcription factor and is implicated in blood, vascular, and bone development and in prostate, blood, and bone cancer. The ERG gene is alternatively spliced; of particular interest is its cassette exon 7b which adds 24 amino acids, in frame, to the transcriptional activation domain. Higher exon 7b inclusion rates are associated with increased cell proliferation and advanced prostate cancer. The 24 amino acids encoded by exon 7b show evolutionary conservation from humans to echinoderms, highlighting their functional importance...
October 5, 2018: Translational Oncology
Saritha Tantravedi, Farhad Vesuna, Paul T Winnard, Allison Martin, Michael Lim, Charles G Eberhart, Cynthia Berlinicke, Eric Raabe, Paul J van Diest, Venu Raman
Medulloblastoma is the most common malignant tumor that arises from the cerebellum of the central nervous system. Clinically, medulloblastomas are treated by surgery, radiation, and chemotherapy, all of which result in toxicity and morbidity. Recent reports have identified that DDX3, a member of the RNA helicase family, is mutated in medulloblastoma. In this study, we demonstrate the role of DDX3 in driving medulloblastoma. With the use of a small molecule inhibitor of DDX3, RK-33, we could inhibit growth and promote cell death in two medulloblastoma cell lines, DAOY and UW228, with IC50 values of 2...
October 3, 2018: Translational Oncology
Artem Fayzullin, Cecilie J Sandberg, Matthew Spreadbury, Birthe Mikkelsen Saberniak, Zanina Grieg, Erlend Skaga, Iver A Langmoen, Einar O Vik-Mo
BACKGROUND: Tumor cell invasion is a hallmark of glioblastoma (GBM) and a major contributing factor for treatment failure, tumor recurrence, and the poor prognosis of GBM. Despite this, our understanding of the molecular machinery that drives invasion is limited. METHODS: Time-lapse imaging of patient-derived GBM cell invasion in a 3D collagen gel matrix, analysis of both the cellular invasive phenotype and single cell invasion pattern with microarray expression profiling...
October 3, 2018: Translational Oncology
Ho-Hyung Woo, Sang C Lee, Jha'nae B Stoffer, Demaretta Rush, Setsuko K Chambers
Vigilin, a nucleocytoplasmic shuttling protein, post-transcriptionally suppresses proto-oncogene c-fms expression (encoding CSF-1R) in breast cancer by binding to a 69 nt cis-acting 3-UTR element in CSF-1R mRNA. CSF-1R is an important mediator of breast cancer development, metastasis, and survival. We confirm that vigilin decreases in vitro reporter luciferase activity as well as the translation rate of target mRNAs. We further explore the mechanism of suppression of CSF-1R. We show that the 69 nt binding element has profound effects on translation efficiency of CSF-1R mRNA, not seen in the presence of mutation of the element...
October 3, 2018: Translational Oncology
Karim Rihawi, Roberta Alfieri, Michelangelo Fiorentino, Francesca Fontana, Elisa Capizzi, Andrea Cavazzoni, Mario Terracciano, Silvia La Monica, Alberto Ferrarini, Genny Buson, Pier Giorgio Petronini, Andrea Ardizzoni
INTRODUCTION: Translocations of the anaplastic lymphoma kinase (ALK) can be effectively targeted in advanced non-small cell lung cancer by ALK-TKI inhibitors including Crizotinib. However, the development of acquired resistance often limits the duration of these therapies. While several mechanisms of secondary resistance have been already identified, little is known about molecular determinants of primary resistance. In our brief report we investigated the tumor molecular profile of a patient who failed to respond to Crizotinib...
October 2, 2018: Translational Oncology
Adele P Williams, Evan F Garner, Alicia M Waters, Laura L Stafman, Jamie M Aye, Hooper Markert, Jerry E Stewart, Elizabeth A Beierle
High-risk neuroblastoma continues to carry a poor prognosis. Nearly 50% of these tumors relapse following extensive treatment regimens. Protein phosphatase 2A (PP2A), a tumor suppressor, has been shown to be downregulated in many human cancers via multiple mechanisms including upregulation of its endogenous inhibitors, I2PP2A or CIP2A. We hypothesized that inhibition of the endogenous PP2A inhibitors or activation of PP2A would decrease tumorigenicity in human neuroblastoma cells. Four human neuroblastoma cell lines were utilized...
October 1, 2018: Translational Oncology
Paula A Bousquet, Sebastian Meltzer, Linda Sønstevold, Ying Esbensen, Svein Dueland, Kjersti Flatmark, Beathe Sitter, Tone Frost Bathen, Therese Seierstad, Kathrine Røe Redalen, Lars Eide, Anne Hansen Ree
Tumor hypoxia contributes to therapy resistance and metastatic progression of locally advanced rectal cancer (LARC). We postulated that the tumor mitochondrial metabolism, manifested by reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) damage, reflects how hypoxic conditions connect to cancer-induced systemic inflammation and poor outcome. Levels of ROS and mtDNA damage were analyzed in three colorectal cancer (CRC) cell lines cultured for 24 hours under normoxia (21% O2 ) or hypoxia (0.2% O2 ) and serum sampled at the time of diagnosis from 35 LARC patients participating in a prospective therapy study...
September 28, 2018: Translational Oncology
Matthew C Hernandez, Lin Yang, Jennifer L Leiting, Takaaki Sugihara, John R Bergquist, Tommy Ivanics, Rondell Graham, Mark J Truty
BACKGROUND: Patient-derived xenografts (PDX) provide histologically accurate cancer models that recapitulate patient malignant phenotype and allow for highly correlative oncologic in-vivo downstream translational studies. Primary PDX engraftment failure has significant negative consequences on programmatic efficiency and resource utilization and is due to either no tumor growth or development of lymphoproliferative tumors. We aimed to determine if secondary engraftment of previously cryopreserved patient tumor tissues would allow salvage of PDX models that failed previous primary engraftment and increase overall engraftment efficiency...
September 28, 2018: Translational Oncology
Ivy Wilkinson-Ryan, Melissa M Pham, Petra Sergent, Laura J Tafe, Brent L Berwin
Epithelial ovarian cancer (EOC) is a deadly gynecologic malignancy, but animal models for the study of EOC pathophysiology and drug efficacy are limited. Based on the finding that women with EOC are at risk for metastasis at a trocar site after laparoscopy, we developed a syngeneic murine model of port-site metastasis of EOC. We leveraged the ID8 murine EOC cell line to induce intra-peritoneal tumors in mice. Once durable intraperitoneal tumor was confirmed with bioluminescence imaging, intra-abdominal wall tumors were induced by abdominal wall puncture with a hollow bore needle...
September 26, 2018: Translational Oncology
Martina Semelakova, Stèphane Grauzam, Prabhakar Betadthunga, Jessica Tiedeken, Sonya Coaxum, David M Neskey, Steven A Rosenzweig
Here we demonstrate an interaction between neural precursor cell expressed, developmentally-downregulated 9 (NEDD9) and the cytoskeletal proteins vimentin and non-muscle myosin IIA (NMIIA), based on co-immunoprecipitation and mass spectrometric sequence identification. Vimentin was constitutively phosphorylated at Ser56 but vimentin associated with NEDD9-was not phosphorylated at Ser56. In contrast, NMIIA bound to NEDD9 was phosphorylated on S1943 consistent with its function in invasion and secretion. Treatment of cells with the vimentin-targeting steroidal lactone withaferin A had no effect on vimentin turnover as previously reported, instead causing NEDD9 cleavage and cell death...
September 26, 2018: Translational Oncology
Elgar S Quabius, Julius Loehr, Dirk Haaser, Veronika Günther, Nico Maass, Christoph Röcken, Micaela Mathiak, Ibrahim Alkatout, Markus Hoffmann
In HNSCC, protein- and mRNA-expression of the antileukoproteinase SLPI are significantly inverse correlated with HPV-infection suggesting that elevated expression of SLPI protects against HPV-infections. Moreover, SLPI-expression is up-regulated in HNSCC-patients reporting a smoking habit. Here, we investigate the described correlation in other HPV-driven cancers, namely vulvar squamous cell carcinoma (VSCC). FFPE samples of 99 VSCC were analyzed by PCR for HPV-DNA-expression and by RT-qPCR for SLPI-mRNA-expression...
September 26, 2018: Translational Oncology
Jae Won Yun, Soomin Lee, Daeun Ryu, Semi Park, Woong-Yang Park, Je-Gun Joung, Jeongyun Jeong
BACKGROUND: Prostate cancers exhibit intratumor heterogeneity (ITH), like other cancer types. The ITH may affect diverse phenotypes such as treatment response, drug resistance, and clinical outcomes. It is crucial to consider ITH to understand tumorigenesis. METHODS: Genomic and transcriptomic profiles of prostate cancer patients were investigated to determine which markers are correlated with the degree of tumor heterogeneity. In addition, the correlation between the immune activity and clonality of tumors was examined...
September 25, 2018: Translational Oncology
I Z Gutiérrez-Martínez, J F Rubio, Z L Piedra-Quintero, O Lopez-Mendez, C Serrano, E Reyes-Maldonado, C Salinas-Lara, A Betanzos, M Shibayama, A Silva-Olivares, A Candelario-Martinez, M A Meraz-Ríos, M Schnoor, N Villegas-Sepúlveda, P Nava
Epithelial cells lining the intestinal mucosa constitute a selective-semipermeable barrier acting as first line of defense in the organism. The number of those cells remains constant during physiological conditions, but disruption of epithelial cell homeostasis has been observed in several pathologies. During colitis, epithelial cell proliferation decreases and cell death augments. The mechanism responsible for these changes remains unknown. Here, we show that the pro-inflammatory cytokine IFNγ contributes to the inhibition of epithelial cell proliferation in intestinal epithelial cells (IECs) by inducing the activation of mTORC1...
September 25, 2018: Translational Oncology
Daniela Bianconi, Merima Herac, Daniel Spies, Markus Kieler, Robert Brettner, Matthias Unseld, Katrin Fürnkranz, Barbara Famler, Margit Schmeidl, Christoph Minichsdorfer, Christoph Zielinski, Gerwin Heller, Gerald W Prager
Stratification of patients with pancreatic ductal adenocarcinoma (PDAC) remains a key challenge in the field of clinical oncology. No predictive biomarkers have yet been found for any available treatment options. Previously, we identified SERPINB7 as a putative biomarker for PDAC and thus, herein, we aimed to validate our previous findings and assessed the predictive value of SERPINB7. Patients who underwent surgery and received gemcitabine (gem) or gemcitabine plus nab-paclitaxel (gem/nab) as adjuvant therapy, between 2011 and 2017, were included in this study (n = 57)...
September 20, 2018: Translational Oncology
Alexey Surov, Hans Jonas Meyer, Anne Kathrin Höhn, Osama Sabri, Sandra Purz
BACKGROUND: Our purpose was to evaluate associations of combined 18 F-FDG-PET and MRI parameters with histopathological features in head and neck squamous cell carcinoma (HNSCC). METHODS: Overall, 22 patients with HNSCC were acquired (10 with G1/2 tumors and 12 with G3 tumors).18 F-FDG-PET/CT and MRI was performed and maximum standardized uptake value (SUVmax ), total lesion glycolysis (TLG) and metabolic tumor volume (MTV) were estimated. Neck MRI was obtained on a 3 T scanner...
September 18, 2018: Translational Oncology
Gian Carlo Mattiucci, Alessio G Morganti, Francesco Cellini, Milly Buwenge, Riccardo Casadei, Andrea Farioli, Sergio Alfieri, Alessandra Arcelli, Federica Bertini, Felipe A Calvo, Silvia Cammelli, Lorenzo Fuccio, Lucia Giaccherini, Alessandra Guido, Joseph M Herman, Gabriella Macchia, Bert W Maidment, Robert C Miller, Francesco Minni, William F Regine, Michele Reni, Stefano Partelli, Massimo Falconi, Vincenzo Valentini
BACKGROUND: Presurgical carbohydrate antigen 19-9 (CA19-9) level predicts overall survival (OS) in resected pancreatic adenocarcinoma (PaC). The aim of this pooled analysis was to evaluate if presurgical CA19-9 level can also predict local control (LC) and distant metastasis-free survival (DMFS). METHODS: Seven hundred patients with PaC from eight institutions who underwent surgical resection ± adjuvant treatment between 2000 and 2014 were analyzed. Patients were divided based on four presurgical CA19-9 level cutoffs (5, 37, 100, 353 U/ml)...
September 17, 2018: Translational Oncology
Clarissa A Whitehead, Hong P T Nguyen, Andrew P Morokoff, Rodney B Luwor, Lucia Paradiso, Andrew H Kaye, Theo Mantamadiotis, Stanley S Stylli
The most common primary central nervous system tumor in adults is the glioblastoma multiforme (GBM). The highly invasive nature of GBM cells is a significant factor resulting in the inevitable tumor recurrence and poor patient prognosis. Tumor cells utilize structures known as invadopodia to faciliate their invasive phenotype. In this study, utilizing an array of techniques, including gelatin matrix degradation assays, we show that GBM cell lines can form functional gelatin matrix degrading invadopodia and secrete matrix metalloproteinase 2 (MMP-2), a known invadopodia-associated matrix-degrading enzyme...
September 13, 2018: Translational Oncology
Lei Qin, Xiang Li, Angie Li, Suchun Cheng, Jinrong Qu, Katherine Reinshagen, Jiani Hu, Nathan Himes, Gao Lu, Geoffrey S Young
PURPOSE: To validate Gaussian normalized cerebral blood volume (GN-nCBV) by association with overall survival (OS) in newly diagnosed glioblastoma patients and compare this association with current standard white matter normalized cerebral blood volume (WN-nCBV). METHODS: We retrieved spin-echo echo-planar dynamic susceptibility contrast MRI acquired after maximal resection and prior to radiation therapy between 2006 and 2011 in 51 adult patients (28 male, 23 female; age 23-87 years) with newly diagnosed glioblastoma...
September 11, 2018: Translational Oncology
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