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https://www.readbyqxmd.com/read/29760279/histone-h3k27-methylation-is-required-for-nhej-and-genome-stability-by-modulating-the-dynamics-of-fancd2-on-chromatin
#1
Ye Zhang, Jian-Feng Chang, Jin Sun, Lu Chen, Xiao-Mei Yang, Huan-Yin Tang, Yuan-Ya Jing, Xuan Kang, Zhi-Min He, Jun-Yu Wu, Hui-Min Wei, Da-Liang Wang, Rong-Gang Xu, Rui-Bao Zhu, Ying Shen, Shi-Yang Zeng, Chen Wang, Kui-Nan Liu, Yong Zhang, Zhi-Ying Mao, Ci-Zhong Jiang, Fang-Lin Sun
Dysregulation of homeostatic balance in di- and tri-methyl H3K27 levels or that caused by mis-sense mutations of histone H3 (H3K27M) was reported to be associated with various types of cancers. In this study, we found that reduction in H3K27me2/3 caused by H3.1K27M, a mutation of H3 variants found in DIPG patients, dramatically attenuated the presence of 53BP1 foci and NHEJ repair capability in HDF cells. H3.1K27M cells showed increased rates of genomic insertions/deletions (In/Dels) and copy number variations (CNVs), as well as augmented p53-dependent apoptotic cells...
May 14, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29760046/dual-hdac-and-pi3k-inhibition-abrogates-nf%C3%AE%C2%BAb-and-foxm1-mediated-dna-damage-response-to-radiosensitize-pediatric-high-grade-gliomas
#2
Sharmistha Pal, David Kozono, Xiaodong Yang, Wojciech Fendler, Whitney Fitts, Jing Ni, John A Alberta, Jean Zhao, Kevin X Liu, Jie Bian, Nathalene Truffaux, William A Weiss, Adam C Resnick, Pratiti Bandopadhayay, Keith L Ligon, Steven G Dubois, Sabine Mueller, Dipanjan Chowdhury, Daphne A Haas-Kogan
Aberrant chromatin remodeling and activation of the phosphatidylinositol 3-kinase (PI3K) pathway have been identified as important mediators of pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) pathogenesis. As inhibition of these pathways are promising therapeutic avenues and radiation is the only modality to prolong survival of DIPG patients, we sought to explore radiosensitizing functions of such inhibition and explore mechanisms of action of such agents. Here we demonstrate that combined treatment with radiotherapy and CUDC-907, a novel first-in-class dual inhibitor of histone deacetylases (HDAC) and PI3K, evokes a potent cytotoxic response in pHGG and DIPG models...
May 14, 2018: Cancer Research
https://www.readbyqxmd.com/read/29755954/immune-response-generated-with-the-administration-of-autologous-dendritic-cells-pulsed-with-an-allogenic-tumoral-cell-lines-lysate-in-patients-with-newly-diagnosed-diffuse-intrinsic-pontine-glioma
#3
Daniel Benitez-Ribas, Raquel Cabezón, Georgina Flórez-Grau, Mari Carmen Molero, Patricia Puerta, Antonio Guillen, Sonia Paco, Angel M Carcaboso, Vicente Santa-Maria Lopez, Ofelia Cruz, Carmen de Torres, Noelia Salvador, Manel Juan, Jaume Mora, Andres Morales La Madrid
Background and objective: Diffuse intrinsic pontine glioma (DIPG) is a lethal brainstem tumor in children. Dendritic cells (DCs) have T-cell stimulatory capacity and, therefore, potential antitumor activity for disease control. DCs vaccines have been shown to reactivate tumor-specific T cells in both clinical and preclinical settings. We designed a phase Ib immunotherapy (IT) clinical trial with the use of autologous dendritic cells (ADCs) pulsed with an allogeneic tumors cell-lines lysate in patients with newly diagnosed DIPG after irradiation (radiation therapy)...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29753957/brainstem-blood-brain-barrier-disruption-using-focused-ultrasound-a-demonstration-of-feasibility-and-enhanced-doxorubicin-delivery
#4
Saira Alli, Carlyn A Figueiredo, Brian Golbourn, Nesrin Sabha, Megan Yijun Wu, Andrew Bondoc, Amanda Luck, Daniel Coluccia, Colin Maslink, Christian Smith, Heiko Wurdak, Kullervo Hynynen, Meaghan O'Reilly, James T Rutka
Magnetic Resonance Image-guided Focused Ultrasound (MRgFUS) has been used to achieve transient BBB opening without tissue injury. Delivery of a targeted ultrasonic wave causes an interaction between administered microbubbles and the capillary bed resulting in enhanced vessel permeability. The use of MRgFUS in the brainstem has not previously been shown but could provide value in the treatment of tumours such as Diffuse Intrinsic Pontine Glioma (DIPG) where the intact BBB has contributed to the limited success of chemotherapy...
May 10, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29750396/a-phase-1-2-dose-finding-safety-and-activity-study-of-cabazitaxel-in-pediatric-patients-with-refractory-solid-tumors-including-tumors-of-the-central-nervous-system
#5
Peter E Manley, Tanya Trippett, Amy A Smith, Margaret E Macy, Sarah E S Leary, Jessica Boklan, Kenneth J Cohen, Stewart Goldman, Lindsay B Kilburn, Girish Dhall, Jeanne Devin, Cynthia E Herzog, Sonia Partap, Floris Fauchet, Emmy Badreddine, John P Bernard, Susan N Chi
BACKGROUND: This phase 1/2 study (NCT01751308) evaluated cabazitaxel in pediatric patients. Phase 1 determined the maximum tolerated dose (MTD) in patients with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. Phase 2 evaluated activity in pediatric recurrent high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). PROCEDURE: In phase 1, a 3 + 3 dose-escalation study design was followed. Cabazitaxel was administered at a starting dose of 20 mg/m2 ...
May 11, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29746912/topical-delivery-of-anthramycin-ii-influence-of-binary-and-ternary-solvent-systems
#6
Tasnuva Haque, Khondaker Miraz Rahman, David E Thurston, Jonathan Hadgraft, Majella E Lane
Anthramycin (ANT) is a member of the pyrolobenzodiazepine family and is a potent cytotoxic agent. Previously, we reported the topical delivery of ANT from a range of solvents that may also act as skin penetration enhancers (SPEs). The skin penetration and uptake was monitored for simple solutions of ANT in propylene glycol (PG), dipropylene glycol (DiPG), Transcutol P (TC), isopropyl myristate (IPM), propylene glycol monocaprylate (PGMC) and propylene glycol monolaurate (PGML). The amounts of PG, DiPG and TC that were taken up by, and that penetrated the skin were also measured, with a clear dependence of ANT penetration on the rate and extent of PG and TC permeation...
May 7, 2018: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29746225/clinical-radiologic-pathologic-and-molecular-characteristics-of-long-term-survivors-of-diffuse-intrinsic-pontine-glioma-dipg-a-collaborative-report-from-the-international-and-european-society-for-pediatric-oncology-dipg-registries
#7
Lindsey M Hoffman, Sophie E M Veldhuijzen van Zanten, Niclas Colditz, Joshua Baugh, Brooklyn Chaney, Marion Hoffmann, Adam Lane, Christine Fuller, Lili Miles, Cynthia Hawkins, Ute Bartels, Eric Bouffet, Stewart Goldman, Sarah Leary, Nicholas K Foreman, Roger Packer, Katherine E Warren, Alberto Broniscer, Mark W Kieran, Jane Minturn, Melanie Comito, Emmett Broxson, Chie-Schin Shih, Soumen Khatua, Murali Chintagumpala, Anne Sophie Carret, Nancy Yanez Escorza, Timothy Hassall, David S Ziegler, Nicholas Gottardo, Hetal Dholaria, Renee Doughman, Martin Benesch, Rachid Drissi, Javad Nazarian, Nada Jabado, Nathalie Boddaert, Pascale Varlet, Géraldine Giraud, David Castel, Stephanie Puget, Chris Jones, Esther Hulleman, Piergiorgio Modena, Marzia Giagnacovo, Manila Antonelli, Torsten Pietsch, Gerrit H Gielen, David T W Jones, Dominik Sturm, Stefan M Pfister, Nicolas U Gerber, Michael A Grotzer, Elke Pfaff, André O von Bueren, Darren Hargrave, Guirish A Solanki, Filip Jadrijevic Cvrlje, Gertjan J L Kaspers, William P Vandertop, Jacques Grill, Simon Bailey, Veronica Biassoni, Maura Massimino, Raphaël Calmon, Esther Sanchez, Brigitte Bison, Monika Warmuth-Metz, James Leach, Blaise Jones, Dannis G van Vuurden, Christof M Kramm, Maryam Fouladi
Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia...
May 10, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29742880/diffuse-intrinsic-pontine-glioma-clinical-features-molecular-genetics-and-novel-targeted-therapeutics
#8
REVIEW
Ryan K Mathew, James T Rutka
Diffuse intrinsic pontine glioma (DIPG) is a deadly paediatric brain cancer. Transient response to radiation, ineffective chemotherapeutic agents and aggressive biology result in rapid progression of symptoms and a dismal prognosis. Increased availability of tumour tissue has enabled the identification of histone gene aberrations, genetic driver mutations and methylation changes, which have resulted in molecular and phenotypic subgrouping. However, many of the underlying mechanisms of DIPG oncogenesis remain unexplained...
May 2018: Journal of Korean Neurosurgical Society
https://www.readbyqxmd.com/read/29741745/prospective-feasibility-and-safety-assessment-of-surgical-biopsy-for-patients-with-newly-diagnosed-diffuse-intrinsic-pontine-glioma
#9
Nalin Gupta, Liliana C Goumnerova, Peter Manley, Susan N Chi, Donna Neuberg, Maneka Puligandla, Jason Fangusaro, Stewart Goldman, Tadanori Tomita, Tord Alden, Arthur DiPatri, Joshua B Rubin, Karen Gauvain, David Limbrick, Jeffrey Leonard, J Russel Geyer, Sarah Leary, Samuel Browd, Zhihong Wang, Sandeep Sood, Anne Bendel, Mahmoud Nagib, Sharon Gardner, Matthias A Karajannis, David Harter, Kanyalakshmi Ayyanar, William Gump, Daniel C Bowers, Bradley Weprin, Tobey J MacDonald, Dolly Aguilera, Barunashish Brahma, Nathan J Robison, Erin Kiehna, Mark Krieger, Eric Sandler, Philipp Aldana, Ziad Khatib, John Ragheb, Sanjiv Bhatia, Sabine Mueller, Anu Banerjee, Amy-Lee Bredlau, Sri Gururangan, Herbert Fuchs, Kenneth J Cohen, George Jallo, Kathleen Dorris, Michael Handler, Melanie Comito, Mark Dias, Kellie Nazemi, Lissa Baird, Jeff Murray, Neal Lindeman, Jason L Hornick, Hayley Malkin, Claire Sinai, Lianne Greenspan, Karen D Wright, Michael Prados, Pratiti Bandopadhayay, Keith L Ligon, Mark W Kieran
Background: Diagnosis of diffuse intrinsic pontine gliomas (DIPG) has relied on imaging studies since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets. Methods: Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG...
May 5, 2018: Neuro-oncology
https://www.readbyqxmd.com/read/29662203/potent-antitumor-efficacy-of-anti-gd2-car-t-cells-in-h3-k27m-diffuse-midline-gliomas
#10
Christopher W Mount, Robbie G Majzner, Shree Sundaresh, Evan P Arnold, Meena Kadapakkam, Samuel Haile, Louai Labanieh, Esther Hulleman, Pamelyn J Woo, Skyler P Rietberg, Hannes Vogel, Michelle Monje, Crystal L Mackall
Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10 , and recent results suggest benefit in central nervous system malignancies11-13 . Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2...
April 16, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29621254/il-13-receptors-as-possible-therapeutic-targets-in-diffuse-intrinsic-pontine-glioma
#11
Noah E Berlow, Matthew N Svalina, Michael J Quist, Teagan P Settelmeyer, Viktor Zherebitskiy, Mari Kogiso, Lin Qi, Yuchen Du, Cynthia E Hawkins, Esther Hulleman, Xiao-Nan Li, Sakir H Gultekin, Charles Keller
Diffuse intrinsic pontine glioma (DIPG) is a universally fatal childhood cancer of the brain. Despite the introduction of conventional chemotherapy and radiotherapy, improvements in survival have been marginal and long-term survivorship is uncommon. Thus, new targets for therapeutics are critically needed. Early phase clinical trials exploring molecularly-targeted therapies against the epidermal growth factor receptor (EGFR) and novel immunotherapies targeting interleukin receptor-13α2 (IL-13Rα2) have demonstrated activity in this disease...
2018: PloS One
https://www.readbyqxmd.com/read/29594041/dnx-2401-an-oncolytic-virus-for-the-treatment-of-newly-diagnosed-diffuse-intrinsic-pontine-gliomas-a-case-report
#12
Sonia Tejada, Ricardo Díez-Valle, Pablo D Domínguez, Ana Patiño-García, Marisol González-Huarriz, Juan Fueyo, Cande Gomez-Manzano, Miguel Angel Idoate, Joanna Peterkin, Marta M Alonso
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive glial brain tumors that primarily affect children, for which there is no curative treatment. Median overall survival is only one year. Currently, the scientific focus is on expanding the knowledge base of the molecular biology of DIPG, and identifying effective therapies. Oncolytic adenovirus DNX-2401 is a replication-competent, genetically modified virus capable of infecting and killing glioma cells, and stimulating an anti-tumor immune response. Clinical trials evaluating intratumoral DNX-2401 in adults with recurrent glioblastoma have demonstrated that the virus has a favorable safety profile and can prolong survival...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29551750/effects-of-fkbp12-and-type-ii-bmp-receptors-on-signal-transduction-by-alk2-activating-mutations-associated-with-genetic-disorders
#13
Aiko Machiya, Sho Tsukamoto, Satoshi Ohte, Mai Kuratani, Mai Fujimoto, Keigo Kumagai, Kenji Osawa, Naoto Suda, Alex N Bullock, Takenobu Katagiri
Various substitution mutations in ALK2, a transmembrane serine/threonine kinase receptor for bone morphogenetic proteins (BMPs), have been identified in patients with genetic disorders such as fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine glioma (DIPG) and heart defects. In this study, we characterized the ALK2 mutants R258G, G328V and F246Y, which were identified in patients with severe FOP, DIPG and unusual hereditary skeletal dysplasia, respectively. Both R258G and G328V were gain-of-function mutations, but F246Y was equivalent to wild-type ALK2...
March 15, 2018: Bone
https://www.readbyqxmd.com/read/29512900/phase-1-trial-pharmacokinetics-and-pharmacodynamics-of-dasatinib-combined-with-crizotinib-in-children-with-recurrent-or-progressive-high-grade-and-diffuse-intrinsic-pontine-glioma
#14
Alberto Broniscer, Sujuan Jia, Belinda Mandrell, Dima Hamideh, Jie Huang, Arzu Onar-Thomas, Amar Gajjar, Susana C Raimondi, Ruth G Tatevossian, Clinton F Stewart
BACKGROUND: Progressive/recurrent high-grade and diffuse intrinsic pontine gliomas (DIPGs) are fatal. Treatments targeting molecular pathways critical for these cancers are needed. METHODS: We conducted a phase 1 study (rolling-six design) to establish the safety and maximum tolerated dose (MTD) of dasatinib, an oral platelet-derived growth factor receptor A (PDGFRA) inhibitor, and crizotinib, an oral c-Met inhibitor, in such patients. Pharmacokinetics of both agents were performed...
March 7, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29484440/importance-of-immune-monitoring-approaches-and-the-use-of-immune-checkpoints-for-the-treatment-of-diffuse-intrinsic-pontine-glioma-from-bench-to-clinic-and-vice-versa-review
#15
Jorge Augusto Borin Scutti
On the basis of immunological results, it is not in doubt that the immune system is able to recognize and eliminate transformed cells. A plethora of studies have investigated the immune system of patients with cancer and how it is prone to immunosuppression, due in part to the decrease in lymphocyte proliferation and cytotoxic activity. The series of experiments published following the demonstration by Dr Allison's group of the potential effect of anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) paved the way for a new perception in cancer immunotherapy: Immune checkpoints...
April 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29484131/dual-targeting-of-mitochondrial-function-and-mtor-pathway-as-a-therapeutic-strategy-for-diffuse-intrinsic-pontine-glioma
#16
Maria Tsoli, Jie Liu, Laura Franshaw, Han Shen, Cecilia Cheng, MoonSun Jung, Swapna Joshi, Anahid Ehteda, Aaminah Khan, Angel Montero-Carcabosso, Pierre J Dilda, Philip Hogg, David S Ziegler
Diffuse Intrinsic Pontine Gliomas (DIPG) are the most devastating of all pediatric brain tumors. They mostly affect young children and, as there are no effective treatments, almost all patients with DIPG will die of their tumor within 12 months of diagnosis. A key feature of this devastating tumor is its intrinsic resistance to all clinically available therapies. It has been shown that glioma development is associated with metabolic reprogramming, redox state disruption and resistance to apoptotic pathways...
January 26, 2018: Oncotarget
https://www.readbyqxmd.com/read/29456798/-18-f-radiolabeled-panobinostat-allows-for-positron-emission-tomography-guided-delivery-of-a-histone-deacetylase-inhibitor
#17
Harikrishna Kommidi, Umberto Tosi, Uday B Maachani, Hua Guo, Christopher S Marnell, Benedict Law, Mark M Souweidane, Richard Ting
Histone deacetylase (HDAC) inhibition is becoming an increasingly popular approach to treat cancer, as HDAC overexpression is common in many malignancies. The blood-brain barrier (BBB) prevents systemically delivered drugs from reaching brain at effective concentration, making small-molecule-HDAC inhibition in brain tumors particularly challenging. To circumvent the BBB, novel routes for administering therapeutics are being considered in the clinic, and a need exists for drugs whose deliveries can be directly imaged, so that effective delivery across the BBB can be monitored...
February 8, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29435175/rest-upregulates-gremlin-to-modulate-diffuse-intrinsic-pontine-glioma-vasculature
#18
Shavali Shaik, Bridget Kennis, Shinji Maegawa, Keri Schadler, Yang Yanwen, Keri Callegari, Rishi R Lulla, Stewart Goldman, Javad Nazarian, Veena Rajaram, Jason Fangusaro, Vidya Gopalakrishnan
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive glial tumor that occurs in children. The extremely poor median and 5-year survival in children afflicted with DIPG highlights the need for novel biology-driven therapeutics. Here, we have implicated the chromatin remodeler and regulator of brain development called RE1 Silencing Transcription Factor (REST), in DIPG pathology. We show that REST protein is aberrantly elevated in at least 21% of DIPG tumors compared to normal controls. Its knockdown in DIPG cell lines diminished cell growth and decreased their tumorigenicity in mouse intracranial models...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29397521/end-of-life-care-of-children-with-diffuse-intrinsic-pontine-glioma
#19
Fyeza Hasan, Kevin Weingarten, Adam Rapoport, Eric Bouffet, Ute Bartels
The end-of-life management of children with diffuse intrinsic pontine glioma (DIPG) is challenging. Families cope with debilitating symptoms and make complex decisions regarding their child's care. However, there is little evidence guiding palliative care provision for these children. Our objective was to describe the dying trajectory of children with DIPG, their symptoms, the care they require and the end-of-life decisions made for them. This retrospective cohort study analyzed the end-of-life care of 41 consecutive patients with DIPG who died between January 2001 and June 2010...
February 3, 2018: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29393845/h3-k27m-mutant-gliomas-in-adults-vs-children-share-similar-histological-features-and-adverse-prognosis
#20
Bette K Kleinschmidt-DeMasters, Jean M Mulcahy Levy
BACKGROUND: H3 K27M mutation was originally described in pediatric diffuse intrinsic pontine gliomas (DIPGs), but has been recently recognized to occur also in adult midline diffuse gliomas, as well as midline tumors with other morphologies, including gangliogliomas (GGs), anaplastic GGs, pilocytic astrocytomas (PAs), and posterior fossa ependymomas. In a few patients with H3 K27M;mutant tumors with these alternate morphologies, longer survival has been reported, making grading difficult for the neuropathologist...
March 2018: Clinical Neuropathology
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