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Jun S Wei, Igor B Kuznetsov, Shile Zhang, Young K Song, Shahab Asgharzadeh, Sivasish Sindiri, Xinyu Wen, Rajesh Patidar, Sushma Nagaraj, Ashley Walton, Jaime M Guidry Auvil, Daniela S Gerhard, Aysen Yuksel, Daniel R Catchpoole, Stephen M Hewitt, Paul M Sondel, Robert C Seeger, John M Maris, Javed Khan
PURPOSE: High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease including a focus on tumor-infiltrating lymphocytes (TILs). EXPERIMENTAL DESIGN: We performed deep RNA-seq on pre-treatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas...
May 21, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Xiaobo Zhu, Yuqiao Li, Shikai Zhao, Shouguo Zhao
Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) are critically involved in tumor progression. In current study, we reported a novel lncRNA signature correlated with bladder cancer development. Particularly, the lncRNA long stress-induced noncoding transcript 5 (LSINCT5) is significantly upregulated in human bladder cancer cell lines and tumor specimens. Meanwhile, high LSINCT5 expression correlates with poor prognosis, enhances tumor sphere formation and invasion in vitro. In vivo xenograft tumor growth is also elevated by LSINCT5 overexpression...
May 14, 2018: Biochemical and Biophysical Research Communications
Timothy L Lochmann, Krista M Powell, Jungoh Ham, Konstantinos V Floros, Daniel A R Heisey, Richard I J Kurupi, Marissa L Calbert, Maninderjit S Ghotra, Patricia Greninger, Mikhail Dozmorov, Madhu Gowda, Andrew J Souers, C Patrick Reynolds, Cyril H Benes, Anthony C Faber
High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential. We performed high-throughput drug screening of epigenetic-targeted therapies across a large and diverse tumor cell line panel and uncovered the hypersensitivity of neuroblastoma cells to GSK-J4, a small-molecule dual inhibitor of lysine 27 of histone 3 (H3K27) demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), and histone demethylase Jumonji D3 (JMJD3). Mechanistically, GSK-J4 induced neuroblastoma differentiation and endoplasmic reticulum (ER) stress, with accompanying up-regulation of p53 up-regulated modulator of apoptosis (PUMA) and induction of cell death...
May 16, 2018: Science Translational Medicine
Sanda Alexandrescu, Vera Paulson, Adrian Dubuc, Azra Ligon, Hart G Lidov
INTRODUCTION: The PHOX2B gene regulates neuronal maturation in the brain stem nuclei associated with cardiorespiratory function, and in the autonomic sympathetic and enteric nervous system. PHOX2B expression is a reliable immunomarker for peripheral neuroblastic tumors, however no systematic evaluation of CNS embryonal tumors was included in the studies. We encountered two cases in which the differential diagnosis included neuroblastoma and CNS embryonal tumor, and we hypothesized that PHOX2B immunostain would be helpful establishing the diagnosis...
May 14, 2018: Histopathology
Saurabh Agarwal, Giorgio Milazzo, Kimal Rajapakshe, Ronald Bernardi, Zaowen Chen, Eveline Barberi, Jan Koster, Giovanni Perini, Cristian Coarfa, Jason M Shohet
The MYC oncogenes and p53 have opposing yet interrelated roles in normal development and tumorigenesis. How MYCN expression alters the biology and clinical responsiveness of pediatric neuroblastoma remains poorly defined. Neuroblastoma is p53 wild type at diagnosis and repression of p53 signaling is required for tumorigenesis. Here, we tested the hypothesis that MYCN amplification alters p53 transcriptional activity in neuroblastoma. Interestingly, we found that MYCN directly binds to the tetrameric form of p53 at its C-terminal domain, and this interaction is independent of MYCN/MAX heterodimer formation...
April 17, 2018: Oncotarget
Ana P Berbegall, Dominik Bogen, Ulrike Pötschger, Klaus Beiske, Nick Bown, Valérie Combaret, Raffaella Defferrari, Marta Jeison, Katia Mazzocco, Luigi Varesio, Ales Vicha, Shifra Ash, Victoria Castel, Carole Coze, Ruth Ladenstein, Cormac Owens, Vassilios Papadakis, Ellen Ruud, Gabriele Amann, Angela R Sementa, Samuel Navarro, Peter F Ambros, Rosa Noguera, Inge M Ambros
BACKGROUND: In neuroblastoma (NB), the most powerful prognostic marker, the MYCN amplification (MNA), occasionally shows intratumoural heterogeneity (ITH), i.e. coexistence of MYCN-amplified and non-MYCN-amplified tumour cell clones, called heterogeneous MNA (hetMNA). Prognostication and therapy allocation are still unsolved issues. METHODS: The SIOPEN Biology group analysed 99 hetMNA NBs focussing on the prognostic significance of MYCN ITH. RESULTS: Patients <18 months (18 m) showed a better outcome in all stages as compared to older patients (5-year OS in localised stages: <18 m: 0...
May 14, 2018: British Journal of Cancer
Selvi Kunnimalaiyaan, Victoriana K Schwartz, Iris Alao Jackson, T Clark Gamblin, Muthusamy Kunnimalaiyaan
BACKGROUND: Neuroblastoma (NB) is a devastating disease. Despite recent advances in the treatment of NB, about 60% of high-risk NB will have relapse and therefore long-term event free survival is very minimal. We have reported that targeting glycogen synthase kinase-3 (GSK-3) may be a potential strategy to treat NB. Consequently, investigating LY2090314, a clinically relevant GSK-3 inhibitor, on NB cellular proliferation and may be beneficial for NB treatment. METHODS: The effect of LY2090314 was compared with a previously studied GSK-3 inhibitor, Tideglusib...
May 11, 2018: BMC Cancer
Yingge Wang, Shan Gao, Weiguang Wang, Yuting Xia, Jingyan Liang
Neuroblastoma, one of the most common types of cancer in childhood, is commonly treated with surgery, radiation and chemotherapy. However, prognosis and survival remain poor for children with high‑risk neuroblastoma. Therefore, the identification of novel, effective therapeutic targets is necessary. N‑Myc, a proto‑oncogene protein encoded by the v‑myc avial myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) gene, is associated with tumorigenesis. In the present study, the effect of N‑Myc silencing on MYCN‑amplified CHP134 and BE‑2C neuroblastoma cells was evaluated, and the underlying molecular mechanism was investigated...
May 3, 2018: Molecular Medicine Reports
Kleopatra Georgantzi, Erik G Sköldenberg, Mats Stridsberg, Per Kogner, Åke Jakobson, Eva Tiensuu Janson, Rolf H B Christofferson
Chromogranin A (CgA) and neuron specific enolase (NSE) are important markers in adult neuroendocrine tumors (NET). Neuroblastoma (NB) has certain neuroendocrine properties. The aim of this study was to correlate blood concentrations of CgA, chromogranin B (CgB), and NSE to prognostic factors and outcome in children with NB. Blood samples from 92 patients with NB, 12 patients with benign ganglioneuroma (GN), 21 patients with non-NB solid tumors, 10 patients with acute leukemias, and 69 healthy children, were analyzed...
May 8, 2018: Pediatric Hematology and Oncology
Yuka Takeda, Hideki Sano, Asuka Kawano, Kazuhiro Mochizuki, Nobuhisa Takahashi, Shogo Kobayashi, Yoshihiro Ohara, Kazuhiro Tasaki, Mitusuaki Hosoya, Atsushi Kikuta
BACKGROUND: Ganglioneuroblastoma, nodular is defined as a composite tumor of biologically distinct clones. The peripheral neuroblastic tumors in this category are characterized by the presence of grossly visible neuroblastoma nodules coexisting with ganglioneuroblastoma, intermixed, or with ganglioneuroma. Making a correct diagnosis of ganglioneuroblastoma, nodular is often difficult by biopsy or partial tumor resection, because the neuroblastic nodule could be hidden and not sampled for pathological examination...
May 3, 2018: Journal of Medical Case Reports
Sarah Andrea Roth, Øyvind H Hald, Steffen Fuchs, Cecilie Løkke, Ingvild Mikkola, Trond Flægstad, Johannes Schulte, Christer Einvik
Neuroblastoma is the most common diagnosed tumor in infants and the second most common extracranial tumor of childhood. The survival rate of patients with high-risk neuroblastoma is still very low despite intensive multimodal treatments. Therefore, new treatment strategies are needed. In recent years, miRNA-based anticancer therapy has received growing attention. Advances in this novel treatment strategy strongly depends on the identification of candidate miRNAs with broad-spectrum antitumor activity. Here, we identify miR-193b as a miRNA with tumor suppressive properties...
April 6, 2018: Oncotarget
Robin W Jansen, Marcus C de Jong, Irsan E Kooi, Selma Sirin, Sophia Göricke, Hervé J Brisse, Philippe Maeder, Paolo Galluzzi, Paul van der Valk, Jacqueline Cloos, Iris Eekhout, Jonas A Castelijns, Annette C Moll, Josephine C Dorsman, Pim de Graaf
Purpose To identify associations between magnetic resonance (MR) imaging features and gene expression in retinoblastoma. Materials and Methods A retinoblastoma MR imaging atlas was validated by using anonymized MR images from referral centers in Essen, Germany, and Paris, France. Images were from 39 patients with retinoblastoma (16 male and 18 female patients [the sex in five patients was unknown]; age range, 5-90 months; inclusion criterion: pretreatment MR imaging). This atlas was used to compare MR imaging features with genome-wide messenger RNA (mRNA) expression data from 60 consecutive patients obtained from 1995 to 2012 (35 male patients [58%]; age range, 2-69 months; inclusion criteria: pretreatment MR imaging, genome-wide mRNA expression data available)...
May 1, 2018: Radiology
Tomoro Hishiki, Kimikazu Matsumoto, Miki Ohira, Takehiko Kamijo, Hiroyuki Shichino, Tatsuo Kuroda, Akihiro Yoneda, Toshinori Soejima, Atsuko Nakazawa, Tetsuya Takimoto, Isao Yokota, Satoshi Teramukai, Hideto Takahashi, Takashi Fukushima, Takashi Kaneko, Junichi Hara, Michio Kaneko, Hitoshi Ikeda, Tatsuro Tajiri, Akira Nakagawara
BACKGROUND: The Japanese Children's Cancer Group (JCCG) Neuroblastoma Committee (JNBSG) conducted a phase II clinical trial for high-risk neuroblastoma treatment. We report the result of the protocol treatment and associated genomic aberration studies. METHODS: JN-H-07 was a single-arm, late phase II trial for high-risk neuroblastoma treatment with open enrollment from June 2007 to February 2009. Eligible patients underwent five courses of induction chemotherapy followed by high-dose chemotherapy with hematopoietic stem cell rescue...
April 26, 2018: International Journal of Clinical Oncology
Xian-Yang Qin, Harukazu Suzuki, Masao Honda, Hikari Okada, Shuichi Kaneko, Ikuyo Inoue, Etsuko Ebisui, Kosuke Hashimoto, Piero Carninci, Keita Kanki, Hideki Tatsukawa, Naoto Ishibashi, Takahiro Masaki, Tomokazu Matsuura, Hiroyuki Kagechika, Kan Toriguchi, Etsuro Hatano, Yohei Shirakami, Goshi Shiota, Masahito Shimizu, Hisataka Moriwaki, Soichi Kojima
Hepatocellular carcinoma (HCC) is a highly lethal cancer that has a high rate of recurrence, in part because of cancer stem cell (CSC)-dependent field cancerization. Acyclic retinoid (ACR) is a synthetic vitamin A-like compound capable of preventing the recurrence of HCC. Here, we performed a genome-wide transcriptome screen and showed that ACR selectively suppressed the expression of MYCN, a member of the MYC family of basic helix-loop-helix-zipper transcription factors, in HCC cell cultures, animal models, and liver biopsies obtained from HCC patients...
April 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
Desheng Kong, Linlin Zhao, Lili Sun, Shengjin Fan, Huibo Li, Yanqiu Zhao, Zhibo Guo, Leilei Lin, Lin Cui, Ke Wang, Wenjia Chen, Yihui Zhang, Jin Zhou, Yinghua Li
Dickkopf-3 (DKK3) is frequently down-regulated by promoter hypermethylation and is closely associated with a poor prognosis in many cancers. Our previous studies have shown that miR-708 down-regulates DKK3 at the post-transcriptional level in B-ALL. However, whether transcriptional mechanisms lead to DKK3 silencing remains unclear. Here, we analysed the promoter regions of DKK3 by bioinformatics and found binding sites for MYCN. A dual-luciferase reporter gene assay and ChIP experiments revealed that MYCN negatively regulates DKK3 at the transcriptional level in B-ALL cell lines, and using bisulphite sequencing PCR, we affirmed that MYCN has no effect on the methylation of the DKK3 promoter...
April 19, 2018: Journal of Cellular and Molecular Medicine
Matthew W Webb, Jianping Sun, Michael A Sheard, Wei-Yao Liu, Hong-Wei Wu, Jeremy R Jackson, Jemily Malvar, Richard Sposto, Dylan Daniel, Robert C Seeger
Tumor-associated macrophages can promote growth of cancers. In neuroblastoma, tumor-associated macrophages have greater frequency in metastatic versus loco-regional tumors, and higher expression of genes associated with macrophages helps to predict poor prognosis in the 60% of high-risk patients who have MYCN-non-amplified disease. The contribution of cytotoxic T-lymphocytes to anti-neuroblastoma immune responses may be limited by low MHC class I expression and low exonic mutation frequency. Therefore, we modelled human neuroblastoma in T-cell deficient mice to examine whether depletion of monocytes/macrophages from the neuroblastoma microenvironment by blockade of CSF-1R can improve the response to chemotherapy...
April 17, 2018: International Journal of Cancer. Journal International du Cancer
Dawei Zhang, Haiyan Li, Juping Xie, Decan Jiang, Liangqi Cao, Xuewei Yang, Ping Xue, Xiaofeng Jiang
The aim of the present study was to elucidate whether, and how, long intergenic non-protein coding RNA 1296 (LINC01296) is involved in the modulation of human cholangiocarcinoma (CCA) development and progression. Microarray data analysis and reverse transcription-quantitative polymerase chain reaction analysis demonstrated that LINC01296 was significantly upregulated in human CCA compared with nontumor tissues. Furthermore, the expression of LINC01296 in human CCA was positively associated with tumor severity and clinical stage...
April 5, 2018: International Journal of Oncology
Chi Yan Ooi, Daniel R Carter, Bing Liu, Chelsea Mayoh, Anneleen Beckers, Amit Lalwani, Zsuzsanna Nagy, Sara De Brouwer, Bieke Decaesteker, Tzong-Tyng Hung, Murray D Norris, Michelle Haber, Tao Liu, Katleen De Preter, Frank Speleman, Belamy B Cheung, Glenn M Marshall
Neuroblastoma is a pediatric cancer of the sympathetic nervous system where MYCN amplification is a key indicator of poor prognosis. However, mechanisms by which MYCN promotes neuroblastoma tumorigenesis are not fully understood. In this study, we analyzed global miRNA and mRNA expression profiles of tissues at different stages of tumorigenesis from TH-MYCN transgenic mice, a model of MYCN-driven neuroblastoma. Based on a Bayesian learning network model in which we compared pre-tumor ganglia from TH-MYCN+/+ mice to age-matched wild-type controls, we devised a predicted miRNA-mRNA interaction network...
April 2, 2018: Cancer Research
Maria V Corrias, Stefano Parodi, Andrei Tchirkov, Tim Lammens, Ales Vicha, Claudia Pasqualini, Catarina Träger, Yania Yáñez, Sandro Dallorso, Luigi Varesio, Roberto Luksch, Genevieve Laureys, Dominique Valteau-Couanet, Adela Canete, Ulrike Pöetschger, Ruth Ladenstein, Susan A Burchill
BACKGROUND: The purpose of this study was to evaluate whether levels of neuroblastoma mRNAs in bone marrow and peripheral blood from stage M infants (≤12 months of age at diagnosis, MYCN amplified) and toddlers (between 12 and 18 months, any MYCN status) predict event-free survival (EFS). METHODS: Bone marrow aspirates and peripheral blood samples from 97 infants/toddlers enrolled in the European High-Risk Neuroblastoma trial were collected at diagnosis in PAXgene™ blood RNA tubes...
March 30, 2018: Pediatric Blood & Cancer
Eduardo Cambruzzi
PURPOSE: Medulloblastoma (MDB) is a small cell poorly differentiated embryonal tumor of the cerebellum, which more frequently compromises children. Overall prognosis is favorable, but dependent of stage, histopathological pattern and molecular group. Approximately 30% of the affected patients will die from the disease. WHO 2016 Classification of Tumors of the Central Nervous System (CNS) has been classified MDB into four principal groups: WNT-activated MDB, SHH-activated MDB, group 3 MDB, and group 4 MDB...
March 26, 2018: Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery
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