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Medulloblastoma

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https://www.readbyqxmd.com/read/28650469/a-compartmentalized-phosphoinositide-signaling-axis-at-cilia-is-regulated-by-inpp5e-to-maintain-cilia-and-promote-sonic-hedgehog-medulloblastoma
#1
S E Conduit, V Ramaswamy, M Remke, D N Watkins, B J Wainwright, M D Taylor, C A Mitchell, J M Dyson
Sonic Hedgehog (SHH) signaling at primary cilia drives the proliferation and progression of a subset of medulloblastomas, the most common malignant paediatric brain tumor. Severe side effects associated with conventional treatments and resistance to targeted therapies has led to the need for new strategies. SHH signaling is dependent on primary cilia for signal transduction suggesting the potential for cilia destabilizing mechanisms as a therapeutic target. INPP5E is an inositol polyphosphate 5-phosphatase that hydrolyses PtdIns(4,5)P2 and more potently, the phosphoinositide (PI) 3-kinase product PtdIns(3,4,5)P3...
June 26, 2017: Oncogene
https://www.readbyqxmd.com/read/28649600/oncolytic-herpes-virus-rrp450-shows-efficacy-in-orthotopic-xenograft-group-3-4-medulloblastomas-and-atypical-teratoid-rhabdoid-tumors
#2
Adam W Studebaker, Brian J Hutzen, Christopher R Pierson, Kellie B Haworth, Timothy P Cripe, Eric M Jackson, Jeffrey R Leonard
Pediatric brain tumors including medulloblastoma and atypical teratoid/rhabdoid tumor are associated with significant mortality and treatment-associated morbidity. While medulloblastoma tumors within molecular subgroups 3 and 4 have a propensity to metastasize, atypical teratoid/rhabdoid tumors frequently afflict a very young patient population. Adjuvant treatment options for children suffering with these tumors are not only sub-optimal but also associated with many neurocognitive obstacles. A potentially novel treatment approach is oncolytic virotherapy, a developing therapeutic platform currently in early-phase clinical trials for pediatric brain tumors and recently US Food and Drug Administration (FDA)-approved to treat melanoma in adults...
September 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28648642/hpi-amf-inhibition-halts-the-development-of-the-aggressive-phenotype-of-breast-cancer-stem-cells
#3
Juan Carlos Gallardo-Pérez, Alhelí Adán-Ladrón de Guevara, Alvaro Marín-Hernández, Rafael Moreno-Sánchez, Sara Rodríguez-Enríquez
Cancer stem cells are responsible for tumor recurrence and metastasis. A new highly reproducible procedure for human breast cancer MCF-7 stem cells (BCSC) isolation and selection was developed by using a combination of hypoxia/hypoglycemia plus taxol and adriamycin for 24h. The BCSC enriched fraction (i) expressed (2-15 times) the typical stemness protein markers CD44+, ALDH1A3 and Oct 3/4; (ii) increased its clonogenicity index (20-times), invasiveness profile (>70%), migration capacity (100%) and ability to form mammospheres, compared to its non-metastatic MCF-7 counterpart...
June 22, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28647700/molecular-proteomic-characterization-of-a-pediatric-medulloblastoma-xenograft
#4
George T Tsangaris, Konstantinos Dimas, Angeliki Malamou, Angeliki Katsafadou, Chrissa Papathanasiou, Dimitrios J Stravopodis, Constantinos E Vorgias, Maria Gazouli, Athanasios K Anagnostopoulos
BACKGROUND/AIM: Medulloblastoma (MBL), an archetypal primitive neuroectodermal tumor of the cerebellum, is the most common pediatric central nervous system malignancy representing approximately 20% of all childhood brain tumors. Herein, we report on a new xenotransplantable tumor cell line, derived from a 6-year-old female patient with cerebellar medulloblastoma, and the completele proteome molecular characterization of subsequent tumors from MBL xenotrasplanted mice. MATERIALS AND METHODS: Tumors were grown in nude mice as subcutaneous xenografts (MBLX) composed of small round cells with hyperchromatic nuclei and scant cytoplasm...
July 2017: Cancer Genomics & Proteomics
https://www.readbyqxmd.com/read/28646413/integrated-in-silico-in-vitro-identification-and-characterization-of-the-sh3-mediated-interaction-between-human-pttg-and-its-cognate-partners-in-medulloblastoma
#5
Jiangang Liu, Dapeng Wang, Yanyan Li, Hui Yao, Nan Zhang, Xuewen Zhang, Fangping Zhong, Yulun Huang
The human pituitary tumor-transforming gene is an oncogenic protein which serves as a central hub in the cellular signaling network of medulloblastoma. The protein contains two vicinal PxxP motifs at its C terminus that are potential binding sites of peptide-recognition SH3 domains. Here, a synthetic protocol that integrated in silico analysis and in vitro assay was described to identify the SH3-binding partners of pituitary tumor-transforming gene in the gene expression profile of medulloblastoma. In the procedure, a variety of structurally diverse, non-redundant SH3 domains with high gene expression in medulloblastoma were compiled, and their three-dimensional structures were either manually retrieved from the protein data bank database or computationally modeled through bioinformatics technique...
June 24, 2017: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28640708/medulloblastoma-from-myth-to-molecular
#6
Vijay Ramaswamy, Michael D Taylor
Current therapies for medulloblastoma were introduced primarily in the 1980s and consist of predominantly cytotoxic, nontargeted approaches. Mortality from medulloblastoma remains significant. In addition, many survivors suffer from severe treatment-related effects of radiation and cytotoxic chemotherapy. Further intensification of nonspecific therapy is unlikely to offer additional benefits, because survival rates have reached a plateau. Recent publications in medulloblastoma have revolved largely around the recognition that medulloblastoma per se does not exist, but rather, that there are a group of histologically similar but clinically and molecularly distinct entities that have been grouped under that rubric...
June 22, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28638988/same-day-genomic-and-epigenomic-diagnosis-of-brain-tumors-using-real-time-nanopore-sequencing
#7
Philipp Euskirchen, Franck Bielle, Karim Labreche, Wigard P Kloosterman, Shai Rosenberg, Mailys Daniau, Charlotte Schmitt, Julien Masliah-Planchon, Franck Bourdeaut, Caroline Dehais, Yannick Marie, Jean-Yves Delattre, Ahmed Idbaih
Molecular classification of cancer has entered clinical routine to inform diagnosis, prognosis, and treatment decisions. At the same time, new tumor entities have been identified that cannot be defined histologically. For central nervous system tumors, the current World Health Organization classification explicitly demands molecular testing, e.g., for 1p/19q-codeletion or IDH mutations, to make an integrated histomolecular diagnosis. However, a plethora of sophisticated technologies is currently needed to assess different genomic and epigenomic alterations and turnaround times are in the range of weeks, which makes standardized and widespread implementation difficult and hinders timely decision making...
June 21, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28637687/inhibition-of-cdk4-6-by-palbociclib-significantly-extends-survival-in-medulloblastoma-patient-derived-xenograft-mouse-models
#8
Michelle L Cook Sangar, Laura A Genovesi, Madison W Nakamoto, Melissa J Davis, Sue E Knoblaugh, Pengxiang Ji, Amanda Millar, Brandon Wainwright, James M Olson
  <p>Bioinformatics analysis followed by in vivo studies in patient-derived xenograft models were used to identify and validate CDK 4/6 inhibition as an effective therapeutic strategy for medulloblastoma, particularly Group 3 MYC-amplified tumors which have the worst clinical prognosis.</p> <br />Experimental Design: <p>A protein interaction network derived from a Sleeping Beauty mutagenesis model of medulloblastoma was used to identify potential novel therapeutic targets.  The top hit from this analysis was validated in vivo using patient-derived xenograft models of medulloblastoma implanted subcutaneously in the flank and orthotopically in the cerebellum of mice...
June 21, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28627017/functional-expression-of-calcium-permeable-canonical-transient-receptor-potential-4-containing-channels-promotes-migration-of-medulloblastoma-cells
#9
Wei-Chun Wei, Wan-Chen Huang, Yu-Ping Lin, Esther B E Becker, Olaf Ansorge, Veit Flockerzi, Daniele Conti, Giovanna Cenacchi, Maike D Glitsch
Aberrant intracellular Ca(2+) signalling contributes to the formation and progression of a range of distinct pathologies including cancers. Rises in intracellular Ca(2+) concentration occur in response to Ca(2+) influx through plasma membrane channels and Ca(2+) release from intracellular Ca(2+) stores, which can be mobilised in response to activation of cell surface receptors. OGR1 (Ovarian cancer G protein coupled Receptor 1, aka GPR68) is a proton-sensing Gq -coupled receptor that is most highly expressed in cerebellum...
June 19, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28625899/medulloblastoma-with-atypical-dynamic-imaging-changes-a-case-report-with-literature-review
#10
Shuang-Shuang Song, Jian-Hong Wang, Wei-Wei Fu, Ying Li, Qing-Lan Sui, Xue-Jun Liu
OBJECTIVE: We analyzed a case of medulloblastoma with atypical dynamic imaging changes retrospectively to summarized the atypical MRI features of medulloblastoma by reviewing the literature. METHODS: One atypical case of medulloblastoma in the cerebellar hemisphere confirmed by pathology was analyzed retrospectively, and the literature about it was reviewed. RESULTS: The radiologic findings of the patient were based on three examinations. The first examination showed that the cortex of the bilateral cerebellar hemisphere had diffuse nodular thickening, with a high signal on DWI imaging and significant enhancement...
June 15, 2017: World Neurosurgery
https://www.readbyqxmd.com/read/28623325/fluorescence-lifetime-imaging-microscopy-a-novel-diagnostic-tool-for-metastatic-cell-detection-in-the-cerebrospinal-fluid-of-children-with-medulloblastoma
#11
Sivan Gershanov, Shalom Michowiz, Helen Toledano, Gilad Yahav, Orit Barinfeld, Avraham Hirshberg, Haim Ben-Zvi, Gabriel Mircus, Mali Salmon-Divon, Dror Fixler, Nitza Goldenberg-Cohen
In pediatric brain tumours, dissemination of malignant cells within the central nervous system confers poor prognosis and determines treatment intensity, but is often undetectable by imaging or cytology. This study describes the use of fluorescence lifetime (FLT) imaging microscopy (FLIM), a novel diagnostic tool, for detection of metastatic spread. The study group included 15 children with medulloblastoma and 2 with atypical teratoid/rhabdoid tumour. Cells extracted from the tumour and the cerebrospinal fluid (CSF) 2 weeks postoperatively and repeatedly during chemo/radiotherapy were subjected to nuclear staining followed by FLT measurement and cytological study...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28623006/a-longevity-study-with-enhancer-substances-selegiline-bpap-detected-an-unknown-tumor-manifestation-suppressing-regulation-in-rat-brain
#12
J Knoll, K Baghy, S Eckhardt, P Ferdinandy, M Garami, L G Harsing, P Hauser, Z Mervai, T Pocza, Z Schaff, D Schuler, I Miklya
AIMS: First proof to show that (-)-deprenyl/selegiline (DEP), the first selective inhibitor of MAO-B, later identified as the first β-phenylethylamine (PEA)-derived synthetic catecholaminergic activity enhancer (CAE) substance and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP), the tryptamine-derived presently known most potent, selective, synthetic enhancer substance, are specific markers of unknown enhancer-sensitive brain regulations. MAIN METHODS: Longevity study disclosing the operation of tumor-manifestation-suppressing (TMS) regulation in rat brain...
June 13, 2017: Life Sciences
https://www.readbyqxmd.com/read/28620006/cancer-surveillance-in-gorlin-syndrome-and-rhabdoid-tumor-predisposition-syndrome
#13
REVIEW
William D Foulkes, Junne Kamihara, D Gareth R Evans, Laurence Brugières, Franck Bourdeaut, Jan J Molenaar, Michael F Walsh, Garrett M Brodeur, Lisa Diller
Gorlin syndrome and rhabdoid tumor predisposition syndrome (RTPS) are autosomal dominant syndromes associated with an increased risk of childhood-onset brain tumors. Individuals with Gorlin syndrome can manifest a wide range of phenotypic abnormalities, with about 5% of family members developing medulloblastoma, usually occurring in the first 3 years of life. Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including Patched1 (PTCH1) and Suppressor of fused (SUFU)SUFU mutation carriers appear to have an especially high risk of early-onset medulloblastoma...
June 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28618224/design-synthesis-and-structure-activity-relationship-of-tetrahydropyrido-4-3-d-pyrimidine-derivatives-as-potent-smoothened-antagonists-with-in-vivo-activity
#14
Wenfeng Lu, Yongqiang Liu, Haikuo Ma, Jiyue Zheng, Sheng Tian, Zhijian Sun, Lusong Luo, Jiajun Li, Hongjian Zhang, Zeng-Jie Yang, Xiaohu Zhang
Medulloblastoma is one of the most prevalent brain tumors in children. Aberrant hedgehog (Hh) pathway signaling is thought to be involved in the initiation and development of medulloblastoma. Vismodegib, the first FDA-approved cancer therapy based on inhibition of aberrant hedgehog signaling, targets smoothened (Smo), a G-protein coupled receptor (GPCR) central to the Hh pathway. Although vismodegib exhibits promising therapeutic efficacy in tumor treatment, concerns have been raised from its non-linear pharmacokinetic (PK) profiles at high doses partly due to low aqueous solubility...
June 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28616573/yap-and-the-hippo-pathway-in-pediatric-cancer
#15
REVIEW
Atif A Ahmed, Abdalla D Mohamed, Melissa Gener, Weijie Li, Eugenio Taboada
The Hippo pathway is an important signaling pathway that controls cell proliferation and apoptosis. It is evolutionarily conserved in mammals and is stimulated by cell-cell contact, inhibiting cell proliferation in response to increased cell density. During early embryonic development, the Hippo signaling pathway regulates organ development and size, and its functions result in the coordinated balance between proliferation, apoptosis, and differentiation. Its principal effectors, YAP and TAZ, regulate signaling by the embryonic stem cells and determine cell fate and histogenesis...
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28609654/intertumoral-heterogeneity-within-medulloblastoma-subgroups
#16
Florence M G Cavalli, Marc Remke, Ladislav Rampasek, John Peacock, David J H Shih, Betty Luu, Livia Garzia, Jonathon Torchia, Carolina Nor, A Sorana Morrissy, Sameer Agnihotri, Yuan Yao Thompson, Claudia M Kuzan-Fischer, Hamza Farooq, Keren Isaev, Craig Daniels, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Ji Yeoun Lee, Wieslawa A Grajkowska, Marta Perek-Polnik, Alexandre Vasiljevic, Cecile Faure-Conter, Anne Jouvet, Caterina Giannini, Amulya A Nageswara Rao, Kay Ka Wai Li, Ho-Keung Ng, Charles G Eberhart, Ian F Pollack, Ronald L Hamilton, G Yancey Gillespie, James M Olson, Sarah Leary, William A Weiss, Boleslaw Lach, Lola B Chambless, Reid C Thompson, Michael K Cooper, Rajeev Vibhakar, Peter Hauser, Marie-Lise C van Veelen, Johan M Kros, Pim J French, Young Shin Ra, Toshihiro Kumabe, Enrique López-Aguilar, Karel Zitterbart, Jaroslav Sterba, Gaetano Finocchiaro, Maura Massimino, Erwin G Van Meir, Satoru Osuka, Tomoko Shofuda, Almos Klekner, Massimo Zollo, Jeffrey R Leonard, Joshua B Rubin, Nada Jabado, Steffen Albrecht, Jaume Mora, Timothy E Van Meter, Shin Jung, Andrew S Moore, Andrew R Hallahan, Jennifer A Chan, Daniela P C Tirapelli, Carlos G Carlotti, Maryam Fouladi, José Pimentel, Claudia C Faria, Ali G Saad, Luca Massimi, Linda M Liau, Helen Wheeler, Hideo Nakamura, Samer K Elbabaa, Mario Perezpeña-Diazconti, Fernando Chico Ponce de León, Shenandoah Robinson, Michal Zapotocky, Alvaro Lassaletta, Annie Huang, Cynthia E Hawkins, Uri Tabori, Eric Bouffet, Ute Bartels, Peter B Dirks, James T Rutka, Gary D Bader, Jüri Reimand, Anna Goldenberg, Vijay Ramaswamy, Michael D Taylor
While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma...
June 12, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28609651/from-one-to-many-further-refinement-of-medulloblastoma-subtypes-offers-promise-for-personalized-therapy
#17
Abhishek Bavle, D Williams Parsons
There is significant intertumoral heterogeneity within the four molecular subgroups of medulloblastoma. In this issue of Cancer Cell, Cavalli et al. apply similarity network fusion to gene expression and DNA methylation data to identify 12 medulloblastoma subtypes with distinct molecular and clinical profiles, making an important step toward molecularly tailored therapy.
June 12, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28605510/phase-i-study-of-oral-sonidegib-lde225-in-pediatric-brain-and-solid-tumors-and-a-phase-ii-study-in-children-and-adults-with-relapsed-medulloblastoma
#18
Mark W Kieran, Julia Chisholm, Michela Casanova, Alba A Brandes, Isabelle Aerts, Eric Bouffet, Simon Bailey, Sarah Leary, Tobey J MacDonald, Francoise Mechinaud, Kenneth J Cohen, Riccardo Riccardi, Warren Mason, Darren Hargrave, Stacey Kalambakas, Priya Deshpande, Feng Tai, Eunju Hurh, Birgit Geoerger
Background.: Sonidegib (LDE225) is a potent, selective Hedgehog (Hh) inhibitor of SMOOTHENED. This study explored the safety and pharmacokinetics (PK) of sonidegib in children with relapsed/recurrent tumors followed by a phase II trial in pediatric and adult patients with relapsed medulloblastoma (MB) to assess tumor response. Methods.: Pediatric patients aged ≥1-<18 years were included according to a Bayesian design starting at 372mg/m2 of continuous once daily oral sonidegib...
June 9, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28599306/panobinostat-a-histone-deacetylase-inhibitor-suppresses-leptomeningeal-seeding-in-a-medulloblastoma-animal-model
#19
Ji Hoon Phi, Seung Ah Choi, Pil Ae Kwak, Ji Yeoun Lee, Kyu-Chang Wang, Do Won Hwang, Seung-Ki Kim
Leptomeningeal seeding is a strong negative prognostic factor for medulloblastoma (MB). The mechanism of leptomeningeal seeding is unclear but may involve epigenetic regulation. In this study, we evaluated the feasibility of a histone deacetylase (HDAC) inhibitor, panobinostat, in the suppression of MB leptomeningeal seeding.Panobinostat decreased the cell viability and proliferation, inducing cell cycle arrest and apoptosis in MB cell lines. The migration and adhesion capabilities were significantly decreased...
May 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28598542/overexpression-of-minichromosome-maintenance-protein-10-in-medulloblastoma-and-its-clinical-implications
#20
Daniel Senfter, Erdogan Pekcan Erkan, Erdener Özer, Gerhard Jungwirth, Sibylle Madlener, Marcel Kool, Thomas Ströbel, Nurten Saydam, Okay Saydam
BACKGROUND: Overexpression of minichromosome maintenance (MCM) proteins 2, 3, and 7 is associated with migration and invasion in medulloblastoma (MB). However, expression profiling of all prereplication complex (pre-RC) has not been addressed in MBs. PROCEDURE: We performed mRNA expression profiling of a large set of pre-RC elements in cell lines and tumor tissues of MB. RNAi technology was employed for functional studies in MB cell lines. RESULTS: Our data showed that most of the pre-RC components are significantly overexpressed in MB...
June 9, 2017: Pediatric Blood & Cancer
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