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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
#22
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
#23
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
#24
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
#25
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
#26
REVIEW
Umberto Tosi, Mark Souweidane
Diffuse intrinsic pontine glioma (DIPG) was first described by Harvey Cushing, the father of modern neurosurgery, a century ago. Since then, the classification of this tumor changed significantly, as it is now part of the broader family of diffuse midline gliomas (DMGs), a heterogeneous group of tumors of midline structures encompassing the entire rostro-caudal space, from the thalamus to the spinal cord. DMGs are characterized by various epigenetic events that lead to chromatin remodeling similarities, as two decades of studies made possible by increased tissue availability showed...
January 2, 2024: Cancers
#27
JOURNAL ARTICLE
Martin van den Bent, Amanda M Saratsis, Marjolein Geurts, Enrico Franceschi
H3 K27M-mutant diffuse glioma is a recently identified brain tumor associated with poor prognosis. As of 2016, it is classified by the World Health Organization as a distinct form of grade IV glioma. Despite recognition as an important prognostic and diagnostic feature in diffuse glioma, radiation remains the sole standard of care and no effective systemic therapies are available for H3K27M mutant tumors. This review will detail treatment interventions applied to diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG) prior to the identification of the H3 K27M mutation, the current standard-of-care for H3 K27M-mutant diffuse glioma treatment, and ongoing clinical trials listed on w w w...
December 15, 2023: Neuro-oncology
#28
JOURNAL ARTICLE
Dan Wang, Kun Yan, Hongxing Yu, Haocheng Li, Wei Zhou, Yaqiang Hong, Shuning Guo, Yi Wang, Cheng Xu, Changcun Pan, Yujie Tang, Nian Liu, Wei Wu, Liwei Zhang, Qiaoran Xi
Diffuse intrinsic pontine glioma (DIPG) is the most aggressive pediatric brain tumor, and the oncohistone H3.3K27M mutation is associated with significantly worse clinical outcomes. Despite extensive research efforts, effective approaches for treating DIPG are lacking. Through drug screening, we identified the combination of gemcitabine and fimepinostat as a potent therapeutic intervention for H3.3K27M DIPG. H3.3K27M facilitated gemcitabine-induced apoptosis in DIPG, and gemcitabine stabilized and activated p53, including increasing chromatin accessibility for p53 at apoptosis-related loci...
December 14, 2023: Cancer Research
#29
JOURNAL ARTICLE
Yan Hu, Peishan Hu, Xiaozhong Peng
Diffuse intrinsic pontine glioma (DIPG) remains intractable to conventional treatments. While targeted therapy and immuno-oncology advances offer hope, few strategies show promising results. In a recent article in Cancer Cell, Ausejo-Mauleon et al. introduce TIM-3 blockade as a potential breakthrough for DIPG treatment by targeting cancer cells and regulating the immune microenvironment simultaneously.
December 12, 2023: Trends in Molecular Medicine
#30
REVIEW
Wei Zhou, Kun Yan, Qiaoran Xi
The BMP (Bone morphogenetic protein) signaling pathway plays a central role in metazoan biology, intricately shaping embryonic development, maintaining tissue homeostasis, and influencing disease progression. In the context of cancer, BMP signaling exhibits context-dependent dynamics, spanning from tumor suppression to promotion. Cancer stem cells (CSCs), a modest subset of neoplastic cells with stem-like attributes, exert substantial influence by steering tumor growth, orchestrating therapy resistance, and contributing to relapse...
December 5, 2023: Cell Regeneration
#31
JOURNAL ARTICLE
Y-Z He, Q Zhou, W-Y Deng, L-Y Huang, Y-Y Lu, Y-Y Ruan, H Du
OBJECTIVE: Brainstem tumors present a significant challenge in surgical treatment, and the prognostic factors in children are lacking. This study aimed to investigate clinical characteristics and prognostic factors of surgical treatment in children with brainstem tumors. PATIENTS AND METHODS: 50 children with brainstem tumors who underwent surgical treatment, including frameless- or frame-based stereotactic biopsy and resection, were included and followed up for clinical and biological analysis...
November 2023: European Review for Medical and Pharmacological Sciences
#32
JOURNAL ARTICLE
Diana Buzova, Jan Frohlich, Danica Zapletalova, Marco Raffaele, Oriana Lo Re, Desislava K Tsoneva, Jaroslav Sterba, Jan Cerveny, Manlio Vinciguerra
Introduction: Pediatric brain tumours (PBT) are one of the most common malignancies during childhood, with variable severity according to the location and histological type. Certain types of gliomas, such a glioblastoma and diffuse intrinsic pontine glioma (DIPG), have a much higher mortality than ependymoma and medulloblastoma. Early detection of PBT is essential for diagnosis and therapeutic interventions. Liquid biopsies have been demonstrated using cerebrospinal fluid (CSF), mostly restricted to cell free DNA, which display limitations of quantity and integrity...
2023: Frontiers in Molecular Biosciences
#33
JOURNAL ARTICLE
Dazhuan Eric Xin, Yunfei Liao, Rohit Rao, Sean Ogurek, Soma Sengupta, Mei Xin, William L Seibel, Richard T Graham, Carl Koschmann, Q Richard Lu
BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG/DMG) are devastating pediatric brain tumors with extraordinarily limited treatment options and uniformly fatal prognosis. Histone H3K27M mutation is a common recurrent alteration in DIPG and disrupts epigenetic regulation. We hypothesize that genome-wide H3K27M-induced epigenetic dysregulation makes tumors vulnerable to epigenetic targeting. METHODS: We performed a screen of compounds targeting epigenetic enzymes to identify potential inhibitors for the growth of patient-derived DIPG cells...
November 27, 2023: Neuro-oncology
#34
JOURNAL ARTICLE
Benedicte Grebstad Tune, Heena Sareen, Branka Powter, Smadar Kahana-Edwin, Adam Cooper, Eng-Siew Koh, Cheok S Lee, Joseph W Po, Geoff McCowage, Mark Dexter, Lucy Cain, Geraldine O'Neill, Victoria Prior, Jonathan Karpelowsky, Maria Tsoli, Lars O Baumbusch, David Ziegler, Tara L Roberts, Paul DeSouza, Therese M Becker, Yafeng Ma
Genetic histone variants have been implicated in cancer development and progression. Mutations affecting the histone 3 (H3) family, H3.1 (encoded by HIST1H3B and HIST1H3C ) and H3.3 (encoded by H3F3A ), are mainly associated with pediatric brain cancers. While considered poor prognostic brain cancer biomarkers in children, more recent studies have reported H3 alterations in adult brain cancer as well. Here, we established reliable droplet digital PCR based assays to detect three histone mutations (H3.3-K27M, H3...
October 27, 2023: Biomedicines
#35
JOURNAL ARTICLE
Mónica Gasanz Garicochea, Isabel Martínez-Romera, Marta Pilar Osuna-Marco, Blanca López-Ibor Aliño
The objective of the article is to report the case of three patients with diffuse intrinsic pontine glioma (DIPG) treated with immunotherapy. In particular we report the data related to the treatments' efficacy and tolerance.To achieve this, we review the medical records in the Paediatric Oncology and Haematology Unit of HM Hospitales/Centro Integral Oncológico Clara Campal (CIOCC). We focused on patients diagnosed with DIPG who were administered oncolytic viruses followed by immune checkpoint inhibitors (ICI) (pembrolizumab, anti PD-1) plus a concomitant antiangiogenic agent (bevacizumab)...
November 8, 2023: European Journal of Hospital Pharmacy. Science and Practice
#36
JOURNAL ARTICLE
Rel Gerald Boukaka, Pierre-Aurélien Beuriat, Federico Di Rocco, Alexandre Vasiljevic, Alexandru Szathmari, Carmine Mottolese
INTRODUCTION: Brainstem tumors represent a challenge. Their management and prognosis vary according to anatomopathological findings and genetic and bio-molecular fingerprints. We present our experience with pediatric brainstem tumors. MATERIAL AND METHODS: All patients admitted for a brainstem tumor at the Pediatric Neurosurgical Unit at Hôpital Femme Mère Enfant hospital between January 1997 and December 2019 were considered. Patients data were obtained through a retrospective review of the medical records; follow-up was from the last outpatient consultation...
2023: Frontiers in Pediatrics
#37
JOURNAL ARTICLE
Maria Chiara Lo Greco, Roberto Milazzotto, Rocco Luca Emanuele Liardo, Pietro Valerio Foti, Stefano Palmucci, Antonio Basile, Stefano Pergolizzi, Corrado Spatola
To investigate the clinical impact of multiple courses of irradiation on pediatric patients with progressive diffuse intrinsic pontine glioma (DIPG), we conducted a retrospective case series on three children treated at our institution from 2018 to 2022. All children were candidates to receive systemic therapy with vinorelbine and nimotuzumab. Radiotherapy was administered to a total dose of 54 Gy. At any disease progression, our local tumor board evaluated the possibility of offering a new course of radiotherapy...
October 11, 2023: Brain Sciences
#38
JOURNAL ARTICLE
Iker Ausejo-Mauleon, Sara Labiano, Daniel de la Nava, Virginia Laspidea, Marta Zalacain, Lucía Marrodán, Marc García-Moure, Marisol González-Huarriz, Irati Hervás-Corpión, Laasya Dhandapani, Silvestre Vicent, Maria Collantes, Iván Peñuelas, Oren J Becher, Mariella G Filbin, Li Jiang, Jenna Labelle, Carlos A O de Biagi-Junior, Javad Nazarian, Sandra Laternser, Timothy N Phoenix, Jasper van der Lugt, Mariette Kranendonk, Raoull Hoodendijk, Sabine Mueller, Carlos De Andrea, Ana C Anderson, Elizabeth Guruceaga, Carl Koschmann, Viveka Nand Yadak, Jaime Gállego Pérez-Larraya, Ana Patiño-García, Fernando Pastor, Marta M Alonso
Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain stem tumor and the leading cause of pediatric cancer-related death. To date, these tumors remain incurable, underscoring the need for efficacious therapies. In this study, we demonstrate that the immune checkpoint TIM-3 (HAVCR2) is highly expressed in both tumor cells and microenvironmental cells, mainly microglia and macrophages, in DIPG. We show that inhibition of TIM-3 in syngeneic models of DIPG prolongs survival and produces long-term survivors free of disease that harbor immune memory...
October 3, 2023: Cancer Cell
#39
JOURNAL ARTICLE
Payton Martinez, Genna Nault, Jenna Steiner, Michael F Wempe, Angela Pierce, Breauna Brunt, Mathew Slade, Jane J Song, Andrew Mongin, Kang-Ho Song, Nicholas Ellens, Natalie Serkova, Adam L Green, Mark Borden
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) have been shown to cause BBB opening, allowing larger chemotherapeutics to enter the parenchyma. Panobinostat is an example of a promising in vitro agent in DIPG with poor clinical efficacy due to low BBB penetrance. In this study, we hypothesized that using FUS to disrupt the BBB allows higher concentrations of panobinostat to accumulate in the tumor, providing a therapeutic effect...
2023: Neuro-oncology advances
#40
Erik R Peterson, Peter Sajjakulnukit, Andrew J Scott, Caleb Heaslip, Anthony Andren, Kari Wilder-Romans, Weihua Zhou, Sravya Palavalasa, Navyateja Korimerla, Angelica Lin, Alexandra Obrien, 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...
September 11, 2023: Research Square
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