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Abdulraheem Alshareef, Meredith S Irwin, Nidhi Gupta, Hai-Feng Zhang, Moinul Haque, Scott D Findlay, Bo Kyung Alex Seong, Justine Lai, Mohammed Rayis, Sadeq Al-Dandan, Raymond Lai
ALK missense mutations are detected in 8% of neuroblastoma (NB) tumors at diagnosis and confer gain-of-function oncogenic effects. The mechanisms by which the expression of wild-type or mutant ALK , which is detectable in the majority of cases, is regulated are not well understood. We have identified a novel ALK transcript characterized by the retention of intron 19 ( ALK-I19 ). ALK-I19 was detected in 4/4 NB cell lines, but not other non-NB cells with ALK aberrations. The functional significance of ALK-I19 was determined by specific siRNA knockdown of this transcript, which resulted in substantially decreased expression of the fully-spliced ALK transcripts (FS- ALK ) and a significant reduction in cell growth...
February 13, 2018: Oncotarget
Sumati Gupta, Kelly Doyle, Timothy L Mosbruger, Andrew Butterfield, Alexis Weston, Allison Ast, Mohan Kaadige, Anupam Verma, Sunil Sharma
Lysine-Specific Demethylase 1 (LSD1) over-expression correlates with poorly differentiated neuroblastoma and predicts poor outcome despite multimodal therapy. We have studied the efficacy of reversible and specific LSD1 inhibition with HCI-2509 in neuroblastoma cell lines and particularly the effect of HCI-2509 on the transcriptomic profile in MYCN amplified NGP cells. Cell survival assays show that HCI-2509 is cytotoxic to poorly differentiated neuroblastoma cell lines in low micromole or lower doses. Transcriptional profiling of NGP cells treated with HCI-2509 shows a significant effect on p53, cell cycle, MYCN and hypoxia pathway gene sets...
February 9, 2018: Oncotarget
Pauline Depuydt, Valentina Boeva, Toby D Hocking, Robrecht Cannoodt, Inge M Ambros, Peter F Ambros, Shahab Asgharzadeh, Edward F Attiyeh, Valérie Combaret, Raffaella Defferrari, Matthias Fischer, Barbara Hero, Michael D Hogarty, Meredith S Irwin, Jan Koster, Susan Kreissman, Ruth Ladenstein, Eve Lapouble, Geneviève Laureys, Wendy B London, Katia Mazzocco, Akira Nakagawara, Rosa Noguera, Miki Ohira, Julie R Park, Ulrike Pötschger, Jessica Theissen, Gian Paolo Tonini, Dominique Valteau-Couanet, Luigi Varesio, Rogier Versteeg, Frank Speleman, John M Maris, Gudrun Schleiermacher, Katleen De Preter
Background: Neuroblastoma is characterized by substantial clinical heterogeneity. Despite intensive treatment, the survival rates of high-risk neuroblastoma patients are still disappointingly low. Somatic chromosomal copy number aberrations have been shown to be associated with patient outcome, particularly in low- and intermediate-risk neuroblastoma patients. To improve outcome prediction in high-risk neuroblastoma, we aimed to design a prognostic classification method based on copy number aberrations...
March 5, 2018: Journal of the National Cancer Institute
Sara Bolin, Anna Borgenvik, Camilla U Persson, Anders Sundström, Jun Qi, James E Bradner, William A Weiss, Yoon-Jae Cho, Holger Weishaupt, Fredrik J Swartling
Medulloblastoma (MB) is the most common malignant brain tumor in children. MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively...
March 7, 2018: Oncogene
Presha Rajbhandari, Gonzalo Lopez, Claudia Capdevila, Beatrice Salvatori, Jiyang Yu, Ruth Rodriguez-Barrueco, Daniel Martinez, Mark Yarmarkovich, Nina Weichert-Leahey, Brian J Abraham, Mariano J Alvarez, Archana Iyer, Jo Lynne Harenza, Derek Oldridge, Katleen De Preter, Jan Koster, Shahab Asgharzadeh, Robert C Seeger, Jun S Wei, Javed Khan, Jo Vandesompele, Pieter Mestdagh, Rogier Versteeg, A Thomas Look, Richard A Young, Antonio Iavarone, Anna Lasorella, Jose M Silva, John M Maris, Andrea Califano
High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator (MR) proteins that were conserved across independent cohorts...
March 6, 2018: Cancer Discovery
Marianna Szemes, Alexander Greenhough, Zsombor Melegh, Sally Malik, Aysen Yuksel, Daniel Catchpoole, Kelli Gallacher, Madhu Kollareddy, Ji Hyun Park, Karim Malik
Neuroblastoma is one of the commonest and deadliest solid tumours of childhood, and is thought to result from disrupted differentiation of the developing sympathoadrenergic lineage of the neural crest. Neuroblastoma exhibits intra- and intertumoural heterogeneity, with high risk tumours characterised by poor differentiation, which can be attributable to MYCN-mediated repression of genes involved in neuronal differentiation. MYCN is known to co-operate with oncogenic signalling pathways such as Alk, Akt and MEK/ERK signalling, and, together with c-MYC has been shown to be activated by Wnt signalling in various tissues...
March 2, 2018: Neoplasia: An International Journal for Oncology Research
Bram De Wilde, Anneleen Beckers, Sven Lindner, Althoff Kristina, Katleen De Preter, Pauline Depuydt, Pieter Mestdagh, Tom Sante, Steve Lefever, Falk Hertwig, Zhiyu Peng, Le-Ming Shi, Sangkyun Lee, Elien Vandermarliere, Lennart Martens, Björn Menten, Alexander Schramm, Matthias Fischer, Johannes Schulte, Jo Vandesompele, Frank Speleman
Genetically engineered mouse models have proven to be essential tools for unraveling fundamental aspects of cancer biology and for testing novel therapeutic strategies. To optimally serve these goals, it is essential that the mouse model faithfully recapitulates the human disease. Recently, novel mouse models for neuroblastoma have been developed. Here, we report on the further genomic characterization through exome sequencing and DNA copy number analysis of four of the currently available murine neuroblastoma model systems ( ALK, Th- MYCN, Dbh- MYCN and Lin28b )...
February 2, 2018: Oncotarget
Eleanor M O'Brien, Joanna L Selfe, Ana Sofia Martins, Zoë S Walters, Janet M Shipley
BACKGROUND: MYCN is amplified in small cell lung cancers and several pediatric tumors, including alveolar rhabdomyosarcomas and neuroblastomas. MYCN protein is known to play a key oncogenic role in both alveolar rhabdomyosarcomas and neuroblastomas. MYCN opposite strand (MYCNOS) is a gene located on the antisense strand to MYCN that encodes alternatively spliced transcripts, two of which (MYCNOS-01 and MYCNOS-02) are known to be expressed in neuroblastoma and small cell lung cancer with reciprocal regulation between MYCNOS-02 and MYCN reported for neuroblastomas...
February 21, 2018: BMC Cancer
Risa Niemas-Teshiba, Ryosuke Matsuno, Larry L Wang, Xao X Tang, Bill Chiu, Jasmine Zeki, Jeannine Coburn, Kimberly Ornell, Arlene Naranjo, Collin Van Ryn, Wendy B London, Michael D Hogarty, Julie M Gastier-Foster, A Thomas Look, Julie R Park, John M Maris, Susan L Cohn, Robert C Seeger, Shahab Asgharzadeh, Naohiko Ikegaki, Hiroyuki Shimada
Neuroblastomas with a high mitosis-karyorrhexis index (High-MKI) are often associated with MYCN amplification, MYCN protein overexpression and adverse clinical outcome. However, the prognostic effect of MYC-family protein expression on these neuroblastomas is less understood, especially when MYCN is not amplified. To address this, MYCN and MYC protein expression in High-MKI cases (120 MYCN amplified and 121 non- MYCN amplified) was examined by immunohistochemistry. The majority (101) of MYCN -amplified High-MKI tumors were MYCN(+), leaving one MYC(+), 2 both(+), and 16 both(-)/(+/-), whereas non- MYCN -amplified cases appeared heterogeneous, including 7 MYCN(+), 36 MYC(+), 3 both(+), and 75 both(-)/(+/-) tumors...
January 19, 2018: Oncotarget
Jieping Li, Wenlin Gong, Xiaoxue Li, Ruirong Wan, Fengzhen Mo, Zhenghua Zhang, Panpan Huang, Zixi Hu, Zongqiang Lai, Xiaoling Lu, Yongxiang Zhao
Hepatocellular carcinoma (HCC) is one of the most common cancers around the world. Multiple etiologic factors such as virus and environment can lead to HCC. It is a challenge for us to successfully detect early HCC due to the lack of effective characterized and specific biomarkers. However, if the early diagnosis is successfully realized, it provides crucial chance for HCC patients to receive effective treatment as early as possible. Dickkopf-1 (DKK-1) is a secretary glycoprotein, which negatively regulates Wnt pathway through binding to surface receptors LRP5/6 and Kremen 1/2...
August 1, 2018: Journal of Nanoscience and Nanotechnology
Régis Afonso Costa, Héctor N Seuánez
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. This malignancy shows a wide spectrum of clinical outcome and its prognosis is conditioned by manifold biological and genetic factors. We investigated the tumor genetic profile and clinical data of 29 patients with NB by multiplex ligation-dependent probe amplification (MLPA) to assess therapeutic risk. In 18 of these tumors, MYCN status was assessed by fluorescence in situ hybridization (FISH). Copy number variation was also determined for confirming MLPA findings in two 6p loci...
February 17, 2018: Molecular Biology Reports
Tingting Wang, Lingling Liu, Xuyong Chen, Yuqing Shen, Gaojian Lian, Nilay Shah, Andrew M Davidoff, Jun Yang, Ruoning Wang
Heightened aerobic glycolysis and glutaminolysis are characteristic metabolic phenotypes in cancer cells. Neuroblastoma (NBL), a devastating pediatric cancer, is featured by frequent genomic amplification of MYCN, a member of the Myc oncogene family that is primarily expressed in the early stage of embryonic development and required for neural crest development. Here we report that an enriched glutaminolysis gene signature is associated with MYCN amplification in children with NBL. The partial knockdown of MYCN suppresses glutaminolysis in NBL cells...
February 14, 2018: Cell Death & Disease
(no author information available yet)
Excess MYCN binds noncanonical enhancers as well as promoters to drive tumor-specific gene expression.
February 9, 2018: Cancer Discovery
Ryosuke Matsuno, Andrew J Gifford, Junming Fang, Mikako Warren, Robyn E Lukeis, Toby Trahair, Tohru Sugimoto, Araz Marachelian, Shahab Asgharzadeh, John M Maris, Naohiko Ikegaki, Hiroyuki Shimada
Background Although MYCN (aka N-myc) amplification is reported in ∼20% of neuroblastomas, MYC (aka C-myc) amplification appears to be a rare event in this disease. As of today, only 2 MYC-amplified neuroblastomas have been briefly mentioned in the literature. Methods We studied here the clinicopathological features of 3 MYC-amplified neuroblastomas. Results All 3 patients (2 females and 1 male) had stage 4 disease. One female is currently alive and well 52 months after the diagnosis, while the other female and male patients died of disease 24 and 20 months after the diagnosis, respectively...
January 1, 2018: Pediatric and Developmental Pathology
Shan Guan, Jiaxiong Lu, Yanling Zhao, Yang Yu, Hui Li, Zhenghu Chen, Zhongcheng Shi, Haoqian Liang, Mopei Wang, Kevin Guo, Xiangmei Chen, Wenjing Sun, Shayahati Bieerkehazhi, Xin Xu, Surong Sun, Saurabh Agarwal, Jianhua Yang
Maternal embryonic leucine zipper kinase (MELK) is known to modulate intracellular signaling and control cellular processes. However, the role of MELK in oncogenesis is not well defined. In this study, using two microarray datasets of neuroblastoma (NB) patients, we identified that MELK expression is significantly correlated to poor overall survival, unfavorable prognosis, and high-risk status. We found that MELK is a direct transcription target of MYCN and MYC in NB, and MYCN increases MELK expression via direct promoter binding...
January 5, 2018: Oncotarget
Viktor Arnhold, Karin Schmelz, Jutta Proba, Annika Winkler, Jasmin Wünschel, Joern Toedling, Hedwig E Deubzer, Annette Künkele, Angelika Eggert, Johannes H Schulte, Patrick Hundsdoerfer
Fewer than 50% of patients with high-risk neuroblastoma survive five years after diagnosis with current treatment protocols. Molecular targeted therapies are expected to improve survival. Although MDM2 has been validated as a promising target in preclinical models, no MDM2 inhibitors have yet entered clinical trials for neuroblastoma patients. Toxic side effects, poor bioavailability and low efficacy of the available MDM2 inhibitors that have entered phase I/II trials drive the development of novel MDM2 inhibitors with an improved risk-benefit profile...
January 5, 2018: Oncotarget
Mathieu Gauthé, Matthieu Breton, Nina Jehanno, Cécile Cellier, Jean Michon, Sabine Sarnacki, Gudrun Schleiermacher, Myriam Wartski
BACKGROUND: The aim of this study was to assess the prognostic value of postoperative 123I-MIBG scintigraphy, including systematic SPECT/CT and semiquantification of the uptake at the surgical site, in a prospective series of NB patients. METHODS: Patients operated for neuroblastoma and who had benefited from postoperative 123I-MIBG scintigraphy were prospectively and consecutively included. Completeness of surgery was assessed on operative report. One month postoperative 123I-MIBG scintigraphy included planar acquisition and SPECT/CT...
February 5, 2018: Quarterly Journal of Nuclear Medicine and Molecular Imaging
Francesca Ferrucci, Roberto Ciaccio, Sara Monticelli, Paolo Pigini, Simone di Giacomo, Stefania Purgato, Daniela Erriquez, Roberto Bernardoni, Murray Norris, Michelle Haber, Giorgio Milazzo, Giovanni Perini
Childhood neuroblastoma, a disease of the sympathetic nervous system, is the most common solid tumour of infancy, remarkably refractory to therapeutic treatments. One of the most powerful independent prognostic indicators for this disease is the amplification of the MYCN oncogene, which occurs at high levels in approximately 25% of neuroblastomas. Interestingly, amplification and not just expression of MYCN has a strong prognostic value, although this fact appears quite surprising as MYCN is a transcription factor that requires dimerising with its partner MAX, to exert its function...
February 2, 2018: Biochimica et Biophysica Acta
Shusuke Akamatsu, Takahiro Inoue, Osamu Ogawa, Martin E Gleave
Treatment-related neuroendocrine prostate cancer is a lethal form of prostate cancer that emerges in the later stages of castration-resistant prostate cancer treatment. Treatment-related neuroendocrine prostate cancer transdifferentiates from adenocarcinoma as an adaptive response to androgen receptor pathway inhibition. The incidence of treatment-related neuroendocrine prostate cancer has been rising due to the increasing use of potent androgen receptor pathway inhibitors. Typically, treatment-related neuroendocrine prostate cancer is characterized by either low or absent androgen receptor expression, small cell carcinoma morphology and expression of neuroendocrine markers...
February 3, 2018: International Journal of Urology: Official Journal of the Japanese Urological Association
Lindi Chen, Arman Esfandiari, William Reaves, Annette Vu, Michael D Hogarty, John Lunec, Deborah A Tweddle
Cell lines established from the TH-MYCN transgenic murine model of neuroblastoma are a valuable preclinical, immunocompetent, syngeneic model of neuroblastoma, for which knowledge of their p53 pathway status is important. In this study, the Trp53 status and functional response to Nutlin-3 and ionising radiation (IR) were determined in 6 adherent TH-MYCN transgenic cell lines using Sanger sequencing, western blot analysis and flow cytometry. Sensitivity to structurally diverse MDM2 inhibitors (Nutlin-3, MI-63, RG7388 and NDD0005) was determined using XTT proliferation assays...
January 31, 2018: International Journal of Oncology
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