tbuckley/cabot-search huggingface dataset:
STEM-03. WAVE1 KNOCKDOWN ENHANCES THE ANTITUMOR EFFICACY IN PRIMARY GLIOBLASTOMA NEUROSPHERES
Authors: Sriya Namagiri, Shilpa Thammegowda, Hannah Sur, Amélie Vézina, Ashis Chowdhury, Dragan Maric, Arunakumar Gangaplara, Nancy Edwards, Sadhana Jackson, Abhik Ray-Chaudhury, John Heiss, Yeshavanth Kumar Banasavadi-Siddegowda
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Despite multi-model therapies that include maximal surgical resection, radiation, chemotherapy, and tumor treating fields, the median survival of Glioblastoma (GBM) patients is around 15 months. WASP-family verprolin homologous protein 1 (WAVE1) is a downstream effector that receives signals from small GTPases to regulate the actin cytoskeleton. WAVE1’s interaction with arp2/3 modulates critical roles, such as cell motility and morphologic changes. Expression of WAVE1 has been implicated in leukemia, ovarian, and prostate cancer. In this study, we tested the role of WAVE1 in GBM tumor biology. METHODS Expression of WAVE1 in normal brain and GBM tumor specimens was assessed by immunohistochemistry (IHC). The relevance of targeting WAVE1 for GBM therapy was evaluated in vitro by western blot, proliferation assay, cell cycle analysis, apoptosis assay, migration assay, and neurosphere formation assay using scrambled and target specific WAVE1-siRNA in patient-derived primary GBM neurospheres (GBMNS). RESULTS IHC data shows that the expression of WAVE1 is higher in GBM tumor samples than in low-grade gliomas and normal brain tissues. WAVE1 expression is upregulated in GBMNS compared to normal human astrocytes. WAVE1 knockdown significantly decreased the proliferation, migration, and self-renewal of GBMNS without affecting its cell cycle progression. Furthermore, WAVE1 depletion did not show any alterations in the apoptotic cell population, indicating that WAVE1 knockdown has a cytostatic effect on GBMNS. CONCLUSION Expression of WAVE1 positively correlates with GBM, and its knockdown imparts antitumor efficacy through cytostasis.
IMMU-13. DUAL IGF1R/IR INHIBITOR IN COMBINATION WITH GD2-CAR T-CELLS AS A POTENT THERAPEUTIC STRATEGY FOR H3K27M-MUTANT DIFFUSE MIDLINE GLIOMAS
Authors: Emmanuel de Billy, Marsha pellegrino, Biagio De Angelis, Pietro Businaro, Domenico Orlando, Giulia Pericoli, Lucia Lisa Petrilli, Sabrina Rossi, Roberta Ferretti, Nicola Maestro, Luca Massimi, Marco Pezzullo, Cristiano De Stefanis, Rossella Rota, Francesco Ferrari, Elisa Salviato, Andrea Carai, Ignazio Caruana, Franco Locatelli, Angela Mastronuzzi, Concetta Quintarelli, Maria Vinci
Journal: Neuro-Oncology (2020)

Abstract Diffuse midline gliomas (DMG) are aggressive paediatric brain tumors for which there is no effective treatment. Recent pre-clinical studies suggest that adoptive transfer of chimeric antigen receptor (CAR) T-cells targeting the disialoganglioside antigen GD2 (GD2-CAR) has a significant therapeutic potential for H3K27M-mutant DMG. Still, some tumor cells resist to treatment suggesting that a multimodal approach may be necessary to treat more efficiently the disease. Our aim was to identify chemical compounds that, in combination with CAR T-cells, would enhance anti-tumor efficacy. After having confirmed the GD2 expression in tissue samples and patient-derived H3K27M-mutant DMG cells, we developed a high throughput cell-based assay to screen 40 kinase inhibitors in combination with T-cells expressing the GD2-CAR.CD28.4-1BB.z construct. The screening led to the identification of the dual IGF1R/IR antagonists, BMS-754807 and linsitinib, which, in combination with GD2-CAR T-cells, improved antitumor activity by 25% (p&amp;lt;0.0001) and 20% (p&amp;lt;0.0001) respectively, compared to GD2-CAR T-cells alone. The two compounds inhibited tumor cell proliferation through IGF1R/IR dependent mechanisms at a concentration which did not affect CAR T-cell expansion. Linsitinib, but not BMS-754807, decreased GD2-CAR T-cells exhaustion and increased their memory profile. Furthermore, linsitinib attenuated the expression of 10 out of 71 DMG genes involved in immunomodulation (e.g. IL33, VEGFC, STAT5A) and regulated upon tumor/CAR T-cells co-culture. Finally, we confirmed the anti-tumor activity of the new linsitinib/GD2-CAR T-cells combination strategy in a DMG H3K27M-mutant 3D culture model. Our work supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for H3K27M-mutant DMG therapy.
HGG-42. CLINICAL FEATURES AND TREATMENT OUTCOME OF MALIGNANT GLIOMAS IN CHILDREN AND ADOLESCENTS
Authors: Hajime Yonezawa, Hiroyuki Uchida, Nayuta Higa, Tatsuki Oyoshi, Koji Yoshimoto
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Malignant gliomas in children and adolescents are rare. They are difficult to treat and are associated with an extremely poor prognosis. SUBJECTS AND METHODS The treatment and outcomes of WHO grade IV -gliomas and diffuse intrinsic pontine gliomas (DIPG) in children and adolescents (Age 4–39, median 28) treated at our institute since 2001 were retrospectively reviewed. Thirty-five cases were included in this study. Nine cases were located in their brain stem and 2 of them were diagnosed as DIPG clinically without biopsy. Three (brain stem -2, thalamus- 1) cases were diffuse midline glioma H3 K27 M mutant. Remaining 30 cases were diagnosed histologically as glioblastoma. Expect for 2 cases, all were irradiated. Twenty-four cases were treated with temozolomide (TMZ). Bevacizumab (BEV) was administrated as an initial therapy in 10 cases (concomitant with TMZ in 9 cases) and was administrated at the time of relapse in 9 cases. In summary, 19 cases were treated with BEV. RESULTS Median survival time (MST) of all cases was 16.8 (4.4 -152.3) months. In total, BEV did not prolonged overall survival (OS), MST 16.02 vs 14.44, (p=0.498). Among adolescents (age 15–39), patients treated with BEV had a trend of longer OS but did not reached statistical significance, MST 19.64 vs 10.76 (p=0.167). An extent of resection and KPS =&amp;gt;70 at discharge from hospital were beneficial factors associated with prolonged OS. CONCLUSION As well as in elderly cases, multidisciplinary treatment including resection, radiation and chemotherapy including BEV improves outcomes.
EXTH-29. INHIBITION OF LYSINE-SPECIFIC HISTONE DEMETHYLASE 1A (KDM1A/LSD1) SENSITIZES GLIOBLASTOMA CELLS TO CHEMO AND RADIATION THERAPY
Authors: Salvador Alejo, Bridgitte Palacios, Prabhakar Pitta Venkata, Yihong Chen, Yi He, Suryavathi Viswanadhapalli, Uday Pratap, Siyuan Zheng, Andrew Brenner, Ratna Vadlamudi, Gangadhara Sareddy
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Despite treatment advances, glioblastoma (GBM) is the deadliest tumor of the central nervous system. Patients face a dismal 15-month median survival and average 5-year survival rate of 13%. Current standard of care includes surgical resection, external beam radiation therapy, and adjuvant chemotherapy with temozolomide (TMZ). Unfortunately, GBM patients often relapse and succumb to their disease. Recently, we have shown that lysine-specific histone demethylase 1A (KDM1A/LSD1) is overexpressed in GBM. In this study, we tested the hypothesis that KDM1A is essential for DNA damage response (DDR), inhibiting KDM1A thereby sensitizes GBM to either TMZ or radiation therapy. METHODS KDM1A knockout (KDM1A-KO) and knockdown (KDM1A-KD) cells were generated using CRISPR/Cas9 and KDM1A specific shRNA, respectively. Cell viability, clonogenic survival, and apoptotic assays were used to study the effect of KDM1A-KO, -KD, or pharmacological KDM1A inhibitors (NCD-38 and NCL-1) on radiation and TMZ sensitization. Mechanistic studies were conducted using RNA-seq, RT-qPCR, and western blot analysis. Furthermore, in vivo efficacy of KDM1A inhibitor and TMZ was established using orthotopic models of GBM. RESULTS Cell viability, survival, and apoptotic assays demonstrated that knockout/knockdown or inhibition of KDM1A sensitized GBM cells to both TMZ or radiation therapy. KDM1A inhibitors used in combination with radiation or TMZ significantly increased apoptosis in GBM cells. RNA-seq analysis and signaling studies showed attenuation of DDR pathways in KDM1A-KD cells. Radiation or TMZ treatment enhanced DNA damage in KDM1A-KD cells compared to controls. Importantly, combination of KDM1A inhibitor and TMZ significantly reduced in vivo tumor progression and improved overall survival in orthotopic GBM murine models. CONCLUSIONS Our results provide strong evidence that KDM1A inhibition sensitizes GBM to TMZ or radiation therapy via modulation of DDR. This suggests combination of KDM1A inhibitors with TMZ or radiation therapy could serve as a novel treatment for GBM patients.
Functional Determinants of Cell Cycle Plasticity and Sensitivity to CDK4/6 Inhibition
Authors: Vishnu Kumarasamy, Paris Vail, Ram Nambiar, Agnieszka K. Witkiewicz, Erik S. Knudsen
Journal: Cancer Research (2020)

Intrinsic or acquired resistance to clinically approved CDK4/6 inhibitors has emerged as a major obstacle that hinders their utility beyond ER
Genetic Contribution to Common Heart Failure—Not So Rare?
Authors: Elizabeth M. McNally, Christopher J. O’Donnell
Journal: JAMA Cardiology (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
m<sup>6</sup>A regulator-based methylation modification patterns characterized by distinct tumor microenvironment immune profiles in colon cancer
Authors: Wei Chong, Liang Shang, Jin Liu, Zhen Fang, Fengying Du, Hao Wu, Yang Liu, Zhe Wang, Yang Chen, Shengtao Jia, Liming Chen, Leping Li, Hao Chen
Journal: Theranostics (2020)

Recent studies have highlighted the biological significance of RNA N6-methyladenosine (m6A) modification in tumorigenicity and progression. However, it remains unclear whether m6A modifications also have potential roles in immune regulation and tumor microenvironment (TME) formation. Methods: In this study, we curated 23 m6A regulators and performed consensus molecular subtyping with NMF algorithm to determine m6A modification patterns and the m6A-related gene signature in colon cancer (CC). The ssGSEA and CIBERSORT algorithms were employed to quantify the relative infiltration levels of various immune cell subsets. An PCA algorithm based m6Sig scoring scheme was used to evaluate the m6A modification patterns of individual tumors with an immune response. Results: Three distinct m6A modification patterns were identified among 1307 CC samples, which were also associated with different clinical outcomes and biological pathways. The TME characterization revealed that the identified m6A patterns were highly consistent with three known immune profiles: immune-inflamed, immune-excluded, and immune-desert, respectively. Based on the m6Sig score, which was extracted from the m6A-related signature genes, CC patients can be divided into high and low score subgroups. Patients with lower m6Sig score was characterized by prolonged survival time and enhanced immune infiltration. Further analysis indicated that lower m6Sig score also correlated with greater tumor mutation loads, PD-L1 expression, and higher mutation rates in SMGs (e.g., PIK3CA and SMAD4). In addition, patients with lower m6Sig scores showed a better immune responses and durable clinical benefits in three independent immunotherapy cohorts. Conclusions: This study highlights that m6A modification is significantly associated with TME diversity and complexity. Quantitatively evaluating the m6A modification patterns of individual tumors will strengthen our understanding of TME characteristics and promote more effective immunotherapy strategies.
54P Impact of comorbidity and venous thromboembolism on outcome in real-life non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibition (ICI)
Authors: B. Bjoernhart, C. Kristiansen, K.H. Hansen, K. Wedervang, C.H. Nyhus, T.L. Jørgensen, J. Herrstedt, T. Schytte
Journal: Annals of Oncology (2020)
UK phase IV, observational study to assess quality of life in patients (pts) with pancreatic neuroendocrine tumours (pNETS) receiving treatment with everolimus: The “real-world” OBLIQUE study
Authors: J. Ramage, P. Punia, O. Faluyi, A. Frilling, T. Meyer, G. Kapur, J. Cave, J. Wadsley, S. Cummins, D. Farrugia, N. Starling, L. Wall, R. Saharan, J.W. Valle
Journal: Annals of Oncology (2016)
IMMU-12. PHASE I/II TRIAL OF IMMUNOTHERAPY WITH FUSIONS OF DENDRITIC CELLS AND TUMOR CELLS FOR RELAPSED OR REFRACTORY BRAIN TUMORS IN CHILDREN AND YOUNG ADULTS
Authors: Masayoshi Yamaoka, Yasuharu Akasaki, Jun Takei, Masaharu Akiyama, Tetsunori Tasaki, Toya Ohashi, Hiroyuki Ida, Takaaki Yanagisawa
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND/OBJECTIVES Relapsed or refractory brain tumors in childhood continue to have a dismal prognosis in spite of intensive multidisciplinary treatment. Cancer immunotherapy is newly developed to be expected as next promising treatment for highly aggressive pediatric cancer. This trial was designed to evaluate the safety and effectiveness of an immunotherapy with fusions of dendritic cells (DCs) and tumor cells in patients with malignant brain tumors. METHODS Patients with histopathologically confirmed malignant and recurrent/refractory brain tumor were eligible for this immunotherapy trial. Autologous cultured tumor cells obtained from surgical specimens were fused with autologous DCs using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region and repeated 3–10 times in each 28–84 days cycle. Treatment-related toxicity, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS Six patients were enrolled, three with high grade glioma and three with ependymoma. Median age at first course of immunotherapy was 10 years (range 8–25 years) and median follow-up time from the first course of immunotherapy was 13.5 months (range 3–33 months). All patients with immunotherapy were well tolerated to this treatment with no adverse events except local erythema in injected site. Median progression free survival and overall survival were 18 months and 18.5 months, respectively. CONCLUSIONS FC immunotherapy with autologous DCs and tumor cells for brain tumor in children and young adults were extremely well tolerated and showed encouraging responses in this series. Further phase II study of FC immunotherapy is planned to improve survival and reduce treatment related morbidity.
RARE-04. INTELLECTUAL DEVELOPMENT IN CHILDREN WITH PEDIATRIC CRANIOPHARYNGIOMA AFTER TUMOR REMOVAL
Authors: Tatsuki Oyoshi, Shingo Fujio, Nayuta Higa, Hajime Yonezawa, Koji Yoshimoto
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Intellectual assessment in children with craniopharyngioma after tumor removal is still unknown. We assessed intellectual development in children who underwent microsurgical resection in our institute over the last twelve years. MATERIALS AND METHODS Ten children among 41 patients with craniopharyngioma treated and followed at Kagoshima University Hospital between 2007 and 2019 were reviewed. We also assessed intellectual development in 10 years or younger children with craniopharyngioma one year after tumor removal. Intelligence was assessed using the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-Ⅳ). RESULTS Ten children underwent microsurgical tumor removal. The mean age at surgery was 5.8 (range 1–10) years. Transcranial approach was performed in 8 children, transsphenoidal approach in two children. The mean follow up period was 110 months. Gamma knife surgery (GKS) was performed in 6 children less than 6 months after first surgery. Regional recurrences occurred in 5 children, and additional GKS was performed in four children, second microsurgical removal in one child. Severe obesity with a transient electrolyte imbalance occurred in one child. Eight children with GH deficiency underwent GH replacement therapy. Eight children were assessed working memory index (WMI), processing speed index (PSI), Perceptual reasoning index (PRI), and verbal comprehension index (VCI) using WISC 4. Each mean value of WMI, PSI, and PRI was lower than VCI, except for 2 children with normal full scale intelligence quotient. CONCLUSION WMI, PSI and PRI in children with intellectual disabilities were lower tendency than VCI after surgical removal of craniopharyngiomas in the present study.
MBCL-25. PILOT STUDY OF A SURGERY AND CHEMOTHERAPY-ONLY APPROACH IN THE UPFRONT THERAPY OF CHILDREN WITH WNT-POSITIVE STANDARD RISK MEDULLOBLASTOMA: UPDATED OUTCOMES
Authors: Kenneth Cohen, Susan Chi, Cynthia Hawkins, Fausto Rodriguez, Wendy London, Robert Craig Castellino, Dolly Aguilera, Stacie Stapleton, David Ashley, Daniel Landi, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Wnt+ medulloblastoma (WPM) is a favorable subtype with EFS &amp;gt; 90% when treating postoperatively with craniospinal irradiation and posterior fossa boost (CSI/XRT) followed by adjuvant chemotherapy. This pilot study explored the safety of omitting radiation in standard-risk WPM. METHODS Subjects had to meet standard-risk criteria (&amp;lt; 1.5 cm2 residual tumor, no metastatic spread, no anaplasia) and have a WPM. Subjects received chemotherapy following the COGACNS0331 AAB-AAB-AAB (A=cisplatin/CCNU/VCR; B=cyclophosphamide/vincristine) backbone. RESULTS Six children were enrolled on study treatment prior to early study closure. Subject #1 completed planned protocol therapy but relapsed 3 months following the completion of therapy. Subject #2 completed planned protocol therapy but relapsed 6 months following the completion of therapy. In both cases, relapse was local and disseminated. Further accrual was halted. Both subjects were salvaged with CSI/XRT followed by adjuvant chemotherapy. Of the remaining 4 subjects, two had recently completed planned protocol therapy at the time of study closure and received CSI/XRT while in remission and remain in remission approximately one year from the completion of treatment. One subject aborted protocol therapy and transitioned to a Head Start regimen and remains in remission 10 months from completion of therapy. The final subject had just completed protocol therapy and had new areas of restricted diffusion concerning for early relapse. Went on to receive CSI/XRT but subsequently relapsed and is now receiving salvage chemotherapy. CONCLUSIONS Chemotherapy following ACNS0331, omitting CSI/XRT, appears to be insufficient for the treatment of non-metastatic WPM.
High Expression of CD40 on BCP-ALL Blasts Is an Independent Risk Factor Associated with Improved Survival and Enhanced Capacity To Upregulate the Death Receptor CD95.
Authors: Anja Troeger, Ludmila Glouchkova, Birgit Ackermann, Gabriele Escherich, Roland Meisel, Helmut Hanenberg, Gritta Janka, Ulrich Goebel, Hans-Juergen Laws, Dagmar Dilloo
Journal: Blood (2006)
MBRS-70. FUNCTIONAL DEPENDENCY BETWEEN REST AND DNMT1 IN MEDULLOBLASTOMA
Authors: Shinji Maegawa, Tara Dobson, Yue Lu, Marcos Estecio, Arif Harmanci, Vidya Gopalakrishnan
Journal: Neuro-Oncology (2020)

Abstract Medulloblastomas exhibit poor neuronal lineage specification. Expression of RE1 Silencing Transcription Factor (REST), a repressor of neurogenesis, is aberrantly elevated in human sonic hedgehog (SHH) medulloblastomas. Constitutive REST expression in mice (RESTTG) drives medulloblastoma genesis and promotes tumor progression in the context of Ptch1 haploinsufficiency (Ptch+/−), implicating it as a driver of tumorigenesis. Tumor formation in Ptch+/−/RESTTG mice showed significantly decreased latency and increased penetrance compared to that in Ptch+/− mice. Since REST silences gene expression by chromatin remodeling, we sought to identify cooperating epigenetic events that contributed to its oncogenic activity. To this end, we performed a loss of function screen employing a bar-coded library of short hairpin RNAs against epigenes, to identify candidates whose loss could create a proliferative vulnerability in the context of REST-elevation. This screen identified DNA methyltransferase 1 (DNMT1) as a high-priority epigenetic modifier. DNMT1 and the Ubiquitin like with PHD and Ring finger domain 1 (UHRF1) proteins are essential for methylation of hemi-methylated DNA at the replication fork during S-phase. Their expression is downregulated during neuronal differentiation. In human SHH-medulloblastoma tumors, REST and UHRF1 expression are positively correlated with higher levels of both genes noted specifically in the SHH-beta subtype, and is associated with poor prognosis. The requirement for DNMT1/UHRF1 in the context of REST elevation, was established by RNA-Seq and Reduced Representation Bisulfite Sequencing (RRBS), which revealed hypermethylation and downregulated expression of REST-target genes needed for neurogenesis. Thus, DNMT1/UHRF1 is a functional and potential therapeutic vulnerability in REST-elevated SHH medulloblastomas.
THER-04. IS THERE A ROLE FOR CANNABIDIOL IN THE TREATMENT OF CHILDHOOD BRAIN TUMOURS?
Authors: George Lockwood, Amelia Hatfield, Mohamed Mabrouk, Saoirse E O’Sullivan, Richard G Grundy, Lisa C D Storer
Journal: Neuro-Oncology (2020)

Abstract Brain tumours are the leading cause of cancer related death in children with limited treatment options and high recurrence rates. Recent evidence suggests there may be anti-tumoral properties of cannabinoids, and of cannabidiol (CBD) in particular. We evaluated the effect of CBD on paediatric brain tumour cell lines in 2D and 3D spheroids; pHGG (SF188), ependymoma (BxD-1425EPN) and human astrocytes. At the CBD EC50 concentration, astrocytic cell death was insignificant. 3D spheroids decreased in size by approximately 20% when cultured in CBD compared to cells only after 5-day exposure. Cell death increased with time after a single dose of CBD. Western Blot showed an increase in Lc3b expression (autophagy) after 24 hours incubation (early cell death) with CBD in both BxD-1425EPN and SF188 with PARP expression (apoptosis) increased after 5 days incubation (late cell death). Cell cycle analysis showed a decrease of cells in G1 and no change in G2 indicating cell cycle arrest. In hypoxia, SF188 and BxD-1425EPN cells showed decreased cell death after 24 hours and 5 days when compared to normoxia and an EC50 within acceptable limits could not be achieved. SF188 cells pre-treated with receptor antagonists indicate that CBD was not acting through CB1, CB2, GPR18, PPARα or PPARγ receptors but may act as a partial agonist of the TRPV1 and 5-HT1A receptors and a full agonist of the GPR55 receptor (resazurin assay). This provides evidence that CBD is effective at killing paediatric brain tumour cells and does not have a significant effect on normal astrocytes.