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REVIEW
Luke J Weisbrod, Anand Thiraviyam, Raghupathy Vengoji, Nicole Shonka, Maneesh Jain, Winson Ho, Surinder K Batra, Afshin Salehi
Diffuse intrinsic pontine glioma (DIPG) is a childhood malignancy of the brainstem with a dismal prognosis. Despite recent advances in its understanding at the molecular level, the prognosis of DIPG has remained unchanged. This article aims to review the current understanding of the genetic pathophysiology of DIPG and to highlight promising therapeutic targets. Various DIPG treatment strategies have been investigated in pre-clinical studies, several of which have shown promise and have been subsequently translated into ongoing clinical trials...
April 10, 2024: Cancer Letters
#2
JOURNAL ARTICLE
Erik R Peterson, Peter Sajjakulnukit, Andrew J Scott, Caleb Heaslip, Anthony Andren, Kari Wilder-Romans, Weihua Zhou, Sravya Palavalasa, Navyateja Korimerla, Angelica Lin, Alexandra O'Brien, Ayesha Kothari, Zitong Zhao, Li Zhang, Meredith A Morgan, Sriram Venneti, Carl Koschmann, Nada Jabado, Costas A Lyssiotis, Maria G Castro, Daniel R Wahl
BACKGROUND: Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT) but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain. METHODS: We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways...
April 9, 2024: Cancer & Metabolism
#3
JOURNAL ARTICLE
Evan Dimentberg, Marie-Pier Marceau, Alexandre Lachance, Samuel Bergeron-Gravel, Stephan Saikali, Louis Crevier, Catherine Bourget, Cynthia Hawkins, Nada Jabado, Panagiota Giannakouros, Samuele Renzi, Valérie Larouche
Diffuse intrinsic pontine gliomas are lethal tumors with a prognosis generally less than 1 year. Few cases of survivors of 5 years or more have been reported. This case report highlights the journey of a 9.5-year survivor who underwent 3 rounds of focal radiotherapy; she experienced 6 years of progression-free survival following the first round but ultimately succumbed to her disease. An autopsy revealed a favorable IDH1 mutation and the absence of H3K27M. This case reiterates the importance of extensive molecular analyses in diffuse intrinsic pontine gliomas and explores the potential benefit of re-irradiation in patients with positive responses and long periods of remission...
April 4, 2024: Journal of Pediatric Hematology/oncology
#4
JOURNAL ARTICLE
Yongjuan Chen, Aaminah Khan, Christopher Katsinas, Filip Michniewicz, Jessie Goldberg, Laura Franshaw, Maria Tsoli, David S Ziegler
BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) pose a significant challenge as a highly aggressive and currently incurable form of pediatric brain cancer, necessitating the development of novel therapeutic strategies. Omacetaxine, an FDA-approved protein synthesis inhibitor for treating certain hematological malignancies, was investigated for its potential antitumor effects against preclinical DIPG models. METHODS: We employed primary DIPG cultures to study omacetaxine's cytotoxicity and its impact on colony formation...
2024: Neuro-oncology advances
#5
JOURNAL ARTICLE
Louise Evans, Rick Walker, Jennifer MacDiarmid, Himanshu Brahmbhatt, Antoinette Anazodo, Geoffrey McCowage, Andrew J Gifford, Maria Kavallaris, Toby Trahair, David S Ziegler
BACKGROUND: Recurrent or refractory solid and central nervous system (CNS) tumours in paediatric patients have limited treatment options and carry a poor prognosis. The EnGeneIC Dream Vector (EDV) is a novel nanocell designed to deliver cytotoxic medication directly to the tumour. The epidermal growth factor receptor is expressed in several CNS and solid tumours and is the target for bispecific antibodies attached to the EDV. OBJECTIVE: To assess the safety and tolerability of EGFR-Erbitux receptor EnGeneIC Dream Vector with mitoxantrone (E EDVsMit ) in children with recurrent / refractory solid or CNS tumours expressing EGFR...
March 28, 2024: Targeted Oncology
#6
REVIEW
Clément Berthelot, Paul Huchedé, Adrien Bertrand-Chapel, Pierre-Aurélien Beuriat, Pierre Leblond, Marie Castets
The BMP pathway is one of the major signaling pathways in embryonic development, ontogeny and homeostasis, identified many years ago by pioneers in developmental biology. Evidence of the deregulation of its activity has also emerged in many cancers, with complex and sometimes opposing effects. Recently, its role has been suspected in Diffuse Midline Gliomas (DMG), among which Diffuse Intrinsic Pontine Gliomas (DIPG) are one of the most complex challenges in pediatric oncology. Genomic sequencing has led to understanding part of their molecular etiology, with the identification of histone H3 mutations in a large proportion of patients...
March 15, 2024: International Journal of Molecular Sciences
#7
JOURNAL ARTICLE
Toon Van Genechten, Maxime De Laere, Jolien Van den Bossche, Barbara Stein, Kim De Rycke, Caroline Deschepper, Katja Hazes, Renke Peeters, Marie-Madeleine Couttenye, Katrien Van De Walle, Ella Roelant, Sabine Maes, Stephanie Vanden Bossche, Sven Dekeyzer, Manon Huizing, Kim Caluwaert, Griet Nijs, Nathalie Cools, Joris Verlooy, Koen Norga, Stijn Verhulst, Sebastien Anguille, Zwi Berneman, Eva Lion
INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) and paediatric high-grade glioma (pHGG) are aggressive glial tumours, for which conventional treatment modalities fall short. Dendritic cell (DC)-based immunotherapy is being investigated as a promising and safe adjuvant therapy. The Wilms' tumour protein (WT1) is a potent target for this type of antigen-specific immunotherapy and is overexpressed in DIPG and pHGG. Based on this, we designed a non-randomised phase I/II trial, assessing the feasibility and safety of WT1 mRNA-loaded DC (WT1/DC) immunotherapy in combination with conventional treatment in pHGG and DIPG...
March 18, 2024: BMJ Open
#8
JOURNAL ARTICLE
Héctor González-Álvarez, Deeba Ensan, Tao Xin, Jong Fu Wong, Carlos A Zepeda-Velázquez, Julien Cros, Laurent Hoffer, Taira Kiyota, Brian J Wilson, Ahmed Aman, Owen Roberts, Methvin B Isaac, Alex N Bullock, David Smil, Rima Al-Awar
Despite decades of research on new diffuse intrinsic pontine glioma (DIPG) treatments, little or no progress has been made on improving patient outcomes. In this work, we explored novel scaffold modifications of M4K2009 , a 3,5-diphenylpyridine ALK2 inhibitor previously reported by our group. Here we disclose the design, synthesis, and evaluation of a first-in-class set of 5- to 7-membered ether-linked and 7-membered amine-linked constrained inhibitors of ALK2. This rigidification strategy led us to the discovery of the ether-linked inhibitors M4K2308 and M4K2281 and the amine-linked inhibitors M4K2304 and M4K2306 , each with superior potency against ALK2...
March 18, 2024: Journal of Medicinal Chemistry
#9
JOURNAL ARTICLE
John H Lee, Katherine G Holste, Momodou G Bah, Andrea T Franson, Hugh J L Garton, Cormac O Maher, Karin M Muraszko
OBJECTIVE: Given the lack of a definitive treatment and the poor prognosis of patients with diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG), socioeconomic status (SES) may affect treatment access and therefore survival. Therefore, this study aimed to examine the relationship between SES and treatment modalities, progression-free survival (PFS), and overall survival (OS) in children with DMG/DIPG. METHODS: A retrospective, single-institution review was conducted of medical records of patients ≤ 18 years of age who had DMG or DIPG that was diagnosed between 2000 and 2022...
March 15, 2024: Journal of Neurosurgery. Pediatrics
#10
JOURNAL ARTICLE
Theophilos Tzaridis, Robert J Wechsler-Reya
Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor with a need for novel therapies. So far, monotherapies have failed to prolong survival for these patients, and combinatorial strategies have often shown severe, dose-limiting toxicities. In this issue of the JCI, Duchatel, Jackson, and colleagues address this challenge by introducing a drug combination that mitigates side effects and overcomes resistance. After identifying the PI3K/mTOR pathway as a therapeutic vulnerability, they treated DIPG-bearing mice with paxalisib and saw responses but also observed hyperglycemia as a severe side effect...
March 15, 2024: Journal of Clinical Investigation
#11
JOURNAL ARTICLE
Ayşe Özkan, Begül Yağcı Küpeli, Serhan Küpeli, Gülay Sezgin, İbrahim Bayram
PURPOSE: Pediatric diffuse intrinsic pontine glioma (DIPG) is a fatal disease associated with a median survival of < 1 year despite aggressive treatments. This retrospective study analyzed the treatment outcomes of patients aged < 18 years who were diagnosed with DIPG between 2012 and 2022 and who received different chemotherapy regimens. METHODS: After radiotherapy, patients with DIPG received nimotuzumab-vinorelbine combination or temozolomide-containing therapy...
March 13, 2024: Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery
#12
JOURNAL ARTICLE
Ashley R Tetens, Allison M Martin, Antje Arnold, Orlandi V Novak, Adrian Idrizi, Rakel Tryggvadottir, Jordyn Craig-Schwartz, Athanasia Liapodimitri, Kayleigh Lunsford, Michael I Barbato, Charles G Eberhart, Adam C Resnick, Eric H Raabe, Michael A Koldobskiy
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a uniformly lethal brainstem tumor of childhood, driven by histone H3 K27M mutation and resultant epigenetic dysregulation. Epigenomic analyses of DIPG have shown global loss of repressive chromatin marks accompanied by DNA hypomethylation. However, studies providing a static view of the epigenome do not adequately capture the regulatory underpinnings of DIPG cellular heterogeneity and plasticity. METHODS: To address this, we performed whole-genome bisulfite sequencing on a large panel of primary DIPG specimens and applied a novel framework for analysis of DNA methylation variability, permitting the derivation of comprehensive genome-wide DNA methylation potential energy landscapes that capture intrinsic epigenetic variation...
2024: Neuro-oncology advances
#13
REVIEW
Nikhil P Mankuzhy, Kathryn R Tringale, Ira J Dunkel, Sameer Farouk Sait, Mark M Souweidane, Yasmin Khakoo, Matthias A Karajannis, Suzanne Wolden
BACKGROUND: Re-irradiation (reRT) increases survival in locally recurrent diffuse intrinsic pontine glioma (DIPG). There is no standard dose and fractionation for reRT, but conventional fractionation (CF) is typically used. We report our institutional experience of reRT for DIPG, which includes hypofractionation (HF). METHODS: We reviewed pediatric patients treated with brainstem reRT for DIPG at our institution from 2012 to 2022. Patients were grouped by HF or CF...
May 2024: Pediatric Blood & Cancer
#14
REVIEW
Stuart L Marcus, Mark P de Souza
ALA PDT, first approved as a topical therapy to treat precancerous skin lesions in 1999, targets the heme pathway selectively in cancers. When provided with excess ALA, the fluorescent photosensitizer PpIX accumulates primarily in cancer tissue, and ALA PDD is used to identify bladder and brain cancers as a visual aid for surgical resection. ALA PDT has shown promising anecdotal clinical results in recurrent glioblastoma multiforme. ALA SDT represents a noninvasive way to activate ALA PDT and has the potential to achieve clinical success in the treatment of both intracranial and extracranial cancers...
February 10, 2024: Cancers
#15
JOURNAL ARTICLE
Sofia Wallin, Ingrid Øra, Gabriela Prochazka, Johanna Sandgren, Caroline Björklund, Gustaf Ljungman, Hartmut Vogt, Torben Ek, Cornelis M van Tilburg, Anna Nilsson
BACKGROUND: Advances in treatment of childhood malignancies have improved overall cure rates to 80%. Nevertheless, cancer is still the most common cause of childhood mortality in Sweden. The prognosis is particularly poor for relapse of high-risk malignancies. In the international INFORM registry, tumor tissue from patients with relapsed, refractory, or progressive pediatric cancer as well as from very-high risk primary tumors is biologically characterized using next-generation sequencing to identify possible therapeutic targets...
2024: Frontiers in Oncology
#16
JOURNAL ARTICLE
Ryan J Duchatel, Evangeline R Jackson, Sarah G Parackal, Dylan Kiltschewskij, Izac J Findlay, Abdul Mannan, Dilana E Staudt, Bryce C Thomas, Zacary P Germon, Sandra Laternser, Padraic S Kearney, M Fairuz B Jamaluddin, Alicia M Douglas, Tyrone S Beitaki, Holly P McEwen, Mika L Persson, Emily A Hocke, Vaibhav Jain, Michael Aksu, Elizabeth E Manning, Heather C Murray, Nicole M Verrills, Claire Xin Sun, Paul Daniel, Ricardo E Vilain, David A Skerrett-Byrne, Brett Nixon, Susan Hua, Charles E de Bock, Yolanda Colino-Sanguino, Fatima Valdes-Mora, Maria Tsoli, David S Ziegler, Murray J Cairns, Eric H Raabe, Nicholas A Vitanza, Esther Hulleman, Timothy N Phoenix, Carl Koschmann, Frank Alvaro, Christopher V Dayas, Christopher L Tinkle, Helen Wheeler, James R Whittle, David D Eisenstat, Ron Firestein, Sabine Mueller, Santosh Valvi, Jordan R Hansford, David M Ashley, Simon G Gregory, Lindsay B Kilburn, Javad Nazarian, Jason E Cain, Matthew D Dun
Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma - DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR-Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across DIPG patient models, highlighting the therapeutic potential of the blood-brain barrier penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors...
February 6, 2024: Journal of Clinical Investigation
#17
JOURNAL ARTICLE
Katarzyna B Leszczynska, Amanda Freitas-Huhtamäki, Chinchu Jayaprakash, Monika Dzwigonska, Francisca N L Vitorino, Cynthia Horth, Kamil Wojnicki, Bartlomiej Gielniewski, Paulina Szadkowska, Beata Kaza, Javad Nazarian, Maciej K Ciolkowski, Joanna Trubicka, Wieslawa Grajkowska, Benjamin A Garcia, Jacek Majewski, Bozena Kaminska, Jakub Mieczkowski
Diffuse intrinsic pontine gliomas (DIPGs) are deadly pediatric brain tumors, non-resectable due to brainstem localization and diffusive growth. Over 80% of DIPGs harbor a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine-to-methionine substitution (H3K27M). Patients with DIPG have a dismal prognosis with no effective therapy. We show that histone deacetylase (HDAC) inhibitors lead to a significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines. We discover that the SB939-mediated H3...
January 31, 2024: Cell Reports
#18
JOURNAL ARTICLE
Morena Miciaccia, Francesca Rizzo, Antonella Centonze, Gianfranco Cavallaro, Marialessandra Contino, Domenico Armenise, Olga Maria Baldelli, Roberta Solidoro, Savina Ferorelli, Pasquale Scarcia, Gennaro Agrimi, Veronica Zingales, Elisa Cimetta, Simone Ronsisvalle, Federica Maria Sipala, Paola Loguercio Polosa, Cosimo Gianluca Fortuna, Maria Grazia Perrone, Antonio Scilimati
Diffuse intrinsic pontine glioma (DIPG), affecting children aged 4-7 years, is a rare, aggressive tumor that originates in the pons and then spreads to nearby tissue. DIPG is the leading cause of death for pediatric brain tumors due to its infiltrative nature and inoperability. Radiotherapy has only a palliative effect on stabilizing symptoms. In silico and preclinical studies identified ONC201 as a cytotoxic agent against some human cancer cell lines, including DIPG ones. A single-crystal X-ray analysis of the complex of the human mitochondrial caseinolytic serine protease type C ( h ClpP) and ONC201 (PDB ID: 6DL7) allowed h ClpP to be identified as its main target...
January 19, 2024: Pharmaceuticals
#19
JOURNAL ARTICLE
Maria Wiese, Bente Pohlmeier, Klaudia Kubiak, Fatma E El-Khouly, Maren Sitte, Angel M Carcaboso, Joshua N Baugh, Thomas Perwein, Gunther Nussbaumer, Michael Karremann, Gerrit H Gielen, Gabriela Salinas, Christof M Kramm
BACKGROUND AND AIM: Pediatric high-grade gliomas (pedHGG) comprise a very poor prognosis. Thus, parents of affected children are increasingly resorting to complementary and alternative medicine (CAM), among those Boswellia extracts. However, nothing is known about the therapeutic effectiveness of their active substances, Boswellic acids (BA) in pedHGG. Thus, we aimed to investigate if the three main Boswellic acids (BA) present in Boswellia plants, alpha-boswellic acid (α-BA), beta-boswellic acid (β-BA) and 3-acetyl-11-keto-beta-boswellic acid (AKBA) hold any promising potential for treatment of affected pedHGG patients...
January 2024: Journal of Traditional and Complementary Medicine
#20
JOURNAL ARTICLE
Xiaoou Li, Xiong Xiao, Yi Wang, Guocan Gu, Tian Li, Yi Wang, Chunzhao Li, Peng Zhang, Nan Ji, Yang Zhang, Liwei Zhang
The objective of this study was to investigate IL13Ra2 expression in brainstem glioma (BSG) and its correlation with key markers, functions, and prognostic implications, evaluating its therapeutic potential. A total of 80 tumor samples from BSG patients were analyzed. Multiplex immunofluorescence was used to examine six markers-IL13Ra2, H3.3K27M, CD133, Ki67, HLA-1, and CD4-establishing relationships between IL13Ra2 and these markers. Survival analysis, employing Kaplan-Meier and Cox proportional hazard regression models, encompassed 66 patients with complete follow-up...
January 3, 2024: Cancers
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