tbuckley/cabot-search huggingface dataset:
HGG-26. H3G34V MUTATION AFFECTS GENOMIC H3K36 METHYLATION IN PEDIATRIC GLIOMA
Authors: Tina Huang, Andrea Piunti, Elizabeth Bartom, Jin Qi, Rintaro Hashizume, Ali Shilatifard, Amanda Saratsis
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Histone H3.3 mutation (H3F3A) occurs in 50% of cortical pediatric high-grade gliomas. This mutation replaces glycine 34 with arginine or valine (G34R/V), impairing SETD2 activity (H3K36-specific trimethyltransferase), resulting in reduced H3K36me on H3G34V nucleosomes relative to wild-type. This contributes to genomic instability and drives distinct gene expressions associated with tumorigenesis. However, it is not known if this differential H3K36me3 enrichment is due to H3G34V mutant protein alone. Therefore, we set to elucidate the effect of H3G34V on genomic H3K36me3 enrichment in vitro. METHODS Doxycycline-inducible short hairpin RNA (shRNA) against H3F3A was delivered via lentivirus to established H3G34V mutant pediatric glioma cell line KNS42, and H3G34V introduced into H3.3 wild type normal human astrocytes (NHA). Transfections were confirmed by western blot, fluorescent imaging, and flow cytometry, with resulting H3.3WT and H3K36me3 expression determined by western blot. H3.3WT, H3K36me3, and H3G34V ChIP-Seq was performed to evaluate genomic enrichment. RESULTS Complete knockdown of H3G34V was achieved with DOX-induced shRNA, with no change in total H3.3, suggesting disproportionate allelic frequency of genes encoding H3.3 (H3F3A and H3F3B). Modest increase in H3K36me3 occurred after H3F3A-knockdown from KNS42, suggesting H3G34V alone impacts observed H3K36me3 levels. Distinct H3K36me3 genomic enrichment was observed with H3G34V knock-in. CONCLUSIONS We demonstrate that DOX-inducible knockdown of H3F3A in an H3G34V mutant pediatric glioma cells and H3G34V mutation transduction in wild-type astrocytes affects H3K36me3 expression. Further evaluation by ChIP-Seq analysis for restoration of wild-type genomic H3K36me3 enrichment patterns with H3G34V knockdown, and mutant H3K36me3 patterns with H3G34V transduction, is currently underway.
Abstract 10802: The Fibrosis-4 Index Predicts the Mortality of Patients With Pulmonary Hypertension Due to Left Sided-Heart Disease
Authors: Koichi Sugimoto, Akiomi Yoshihisa, Takuya Goto, Tetsuro Yokokawa, Masayoshi Oikawa, Atsushi Kobayashi, Kazuhiko Nakazato, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2018)

Background: The prognostic factors of pulmonary hypertension due to left heart disease (LHD-PH) are still unclear. Congestive hepatopathy frequently coincides with LHD-PH. Fibrosis-4 index (FIB-4 i...
Author Correction: Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration
Authors: Amit U. Joshi, Paras S. Minhas, Shane A. Liddelow, Bereketeab Haileselassie, Katrin I. Andreasson, Gerald W. Dorn, Daria Mochly-Rosen
Journal: Nature Neuroscience (2020)
Coordination of fatty acid synthesis and cell proliferation by transcription factor Sp1 in MCF-7 human breast cancer cells
Authors: Suying Lu, Michael Archer
Journal: Cancer Research (2007)

LB-237  Many human cancers including breast cancer exhibit increased denovo fatty acid synthesis with overexpression of fatty acid synthase (FAS). Unlike normal cells and tissues that preferentially utilize circulating fatty acids derived from the diet, cancers synthesize fatty acids endogenously for membrane biosynthesis to sustain cell proliferation. The transcription factor Sp1 is highly expressed in a variety of cancers. Sp1 regulates gene expression by interacting with GC-rich promoter sequences. Genes that regulate cell cycle progression often contain such promoter sequences, and Sp1 is critical for their expression. The promoter region of FAS also has Sp1 binding sites, and Sp1 together with sterol regulatory element-binding protein-1 (SREBP-1) has been shown to regulate FAS expression in hepatocytes. Here, we hypothesize that Sp1 coordinately regulates FAS and cell cycle progression in estrogen-responsive MCF-7 breast cancer cells. Based on previous studies, to up-regulate Sp1 activity we treated MCF-7 cells with 100 nM 17β-estradiol (E2) for 48 h. To down-regulate Sp1 activity, we treated the cells for 48 h with 0.025 or 0.05 nM mithramycin, a known inhibitor of Sp1, or we transfected the cells with Sp1 siRNA, then maintained them for 72 h. Cell proliferation, cell cycle progression and expression of FAS and cell cycle regulatory proteins were measured. E2 treatment stimulated cell proliferation, accelerated the G0/G1 to S phase transition, and increased FAS and cyclin D1 expression. In contrast, mithramycin treatment or Sp1 siRNA transfection inhibited cell proliferation, led to G0/G1 cell cycle arrest, and decreased FAS and cyclin D1 expression. Furthermore, the effects of E2 were mitigated by mithramycin or Sp1 siRNA, and the effects of mithramycin or Sp1 siRNA were mitigated by E2. Other G1 cell cycle regulatory proteins such as cdk2, cdk4 and cyclin E were unaffected by these various treatments. We have also shown that inhibition of fatty acid synthesis by 5-(tetradecyloxy)-2-furoric acid (TOFA), a known inhibitor of acetyl-CoA carboxylase (ACC), decreased cell proliferation, caused G0/G1 cell cycle arrest, and suppressed the expression of Sp1 and cyclin D1. Our results indicate that Sp1 coordinately regulates the expression of FAS and cyclin D1 in MCF-7 cells, suggesting that Sp1 is involved in synchronizing fatty acid synthesis with cell cycle progression. The synchronization of these two biological processes by Sp1 could be exploited as a strategy for cancer therapy.
BIOL-07. MIR-212 FUNCTIONS AS A TUMOR SUPPRESSOR GENE IN GROUP 3 MEDULLOBLASTOMA VIA TARGETING NUCLEAR FACTOR I/B (NFIB)
Authors: Naveenkumar Perumal, Ranjana Kanchan, David Doss, Pranita Atri, Ramakanth Chirravuri Venkata, Ishwor Thapa, Mohd Nasser, Surinder Batra, Sidharth Mahapatra
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB), the most frequent malignant pediatric brain tumor is subdivided into four primary subgroups, i.e. wingless-type (WNT), sonic hedgehog (SHH), group 3, and group 4. Haploinsufficiency of chromosome 17p13.3 and c-myc amplification distinguish high-risk group 3 tumors, which are associated with rapid metastasis, recurrence and early mortality. We sought to identify the role of miR-212, which resides on chromosome 17p13.3, in the pathophysiology of group 3 MB. RNA expression analyses revealed dramatically reduced levels of miR-212 in group 3 tumors and cell lines mainly through epigenetic silencing via histone modifications (deacetylation). Restoring in vitro miR-212 expression reduced tumor cell proliferation, colony formation, wound healing, migration and invasion with decreased p-AKT and p-ERK levels in group 3 MB cell lines. Interestingly, a shift in differential c-myc phosphorylation (from serine-62 to threonine-58) was also discovered with miR-212 expression, resulting in reduced total c-myc levels, concurrent with elevated cellular apoptosis. In turn, pro-apoptotic binding partners of c-myc, i.e. Bin-1 and P19ARF, were upregulated in these cells. These findings were recapitulated in stable inducible miR-212 expressing tumor cells. Using a combination of transcriptomic data and a dual luciferase assay, we isolated an important oncogenic target of miR-212, i.e, NFIB, a nuclear transcription factor implicated in metastasis and recurrence. Increased expression of NFIB was confirmed in group 3 tumors, with poor survival shown in high NFIB-expressing patients. As prior, transient NFIB silencing in vitro reduced not only tumor cell proliferation, colony formation, wound healing, migration and invasion, but also medullosphere formation along with decreased expression of stem cell markers (Nanog, Oct4, Sox2, CD133), confirming its role in tumor recurrence possibly via augmenting tumor stemness. Taken together, these results substantiate the tumor suppressive role of miR-212 in group 3 MB and provide a potential new oncogenic target implicated in tumor recurrence, NFIB.
PPM1D Mutations in MDS Patients with Deletion of Chromosome 5q
Authors: Victoria Panagiota, Manja Meggendorfer, Rabia Shahswar, Christian Kandziora, Piroska Klement, Johannes Schiller, Gudrun Göhring, Jan Krönke, Claudia Haferlach, Christina Ganster, Katayoon Shirneshan, Annika Gutermuth, Uwe Platzbecker, Christian Thiede, Ulrich Germing, Thomas Schroeder, Guido Kobbe, Sabrina Klesse, Christian Koenecke, Brigitte Schlegelberger, Nicolaus Kröger, Detlef Haase, Konstanze Dohner, Wolfgang R. Sperr, Peter Valent, Arnold Ganser, Felicitas Thol, Torsten Haferlach, Michael Heuser
Journal: Blood (2017)
NCOG-12. STEREOTACTIC RADIOSURGERY FOR VESTIBULAR SCHWANNOMAS IN NEUROFIBROMATOSIS TYPE 2 PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Umberto Tosi, Omri Maayan, Anjile An, Miguel Lavieri, Sergio Guadix, Antonio DeRosa, Paul Christos, Susan Pannullo, Philip Stieg, Andrew Brandmaier, Jonathan Knisely, Rohan Ramakrishna
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND One of the hallmarks of neurofibromatosis type 2 (NF2) is the presence of bilateral vestibular schwannomas (VSs) that result in progressive hearing loss and compression of nearby brainstem structures causing cranial nerve palsies. Treatment of these tumors remains challenging, as both surgical removal and expectant management can result in symptom progression. Stereotactic radiosurgery (SRS) has recently been investigated for the management of NF2-associated VSs; however, the role, promises, and pitfalls of this treatment modality remain unclear. METHODS Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Reviews were searched for studies assessing SRS outcome in NF2-associated VSs only. Primary endpoints included tumor control, serviceable hearing, presence of tinnitus, and cranial nerve V and VII symptoms. RESULTS A total of 16 studies (589 patients harboring 750 tumors) was included in this analysis. Clinical tumor control was achieved in 88% of cases (95% CI: 80%-95%); salvage surgery was needed in 8% (95% CI: 4%-13%) of cases. Treatment resulted in a worsening of pre-treatment serviceable hearing (OR of 0.26, p &amp;lt; 0.01), in an increase of facial nerve impairment (OR of 1.62, p &amp;lt; 0.01), and showed a trend for increase trigeminal nerve impairment as well (OR of 1.42, p = 0.07). The incidence of vestibular symptoms and hydrocephalus requiring shunting could not be assessed since these measures were not reported consistently. CONCLUSIONS The treatment of NF2-associated VS continues to pose a challenge, as current SRS regimens result in impaired hearing and worse cranial nerve comorbidities, despite achieving high tumor control. It remains unclear if these findings have to be intended as treatment complications or, rather, continuous disease progression despite tumor control.
Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial
Authors: Caicun Zhou, Gongyan Chen, Yunchao Huang, Jianying Zhou, LiZhu Lin, Jifeng Feng, Zhehai Wang, Yongqian Shu, Jianhua Shi, Yi Hu, QiMing Wang, Ying Cheng, Fengying Wu, Jianhua Chen, Xiaoyan Lin, Yongsheng Wang, Jianan Huang, Jiuwei Cui, Lejie Cao, Yunpeng Liu, Yiping Zhang, Yueyin Pan, Jun Zhao, LiPing Wang, Jianhua Chang, Qun Chen, Xiubao Ren, Wei Zhang, Yun Fan, Zhiyong He, Jian Fang, Kangsheng Gu, XiaoRong Dong, Tao Zhang, Wei Shi, Jianjun Zou
Journal: The Lancet Respiratory Medicine (2020)
CSIG-10. GENOTYPE – KINOME GUIDED DEVELOPMENT OF PRECISION EGFR-TARGETED THERAPEUTICS FOR GLIOBLASTOMA
Authors: Erin Smithberger, Abigail Shelton, Madison Butler, Allie Stamper, Ryan Bash, Steven Angus, Michael East, Gary Johnson, Michael Berens, Frank Furnari, C Ryan Miller
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is an aggressive primary brain tumor with poor survival and limited treatment options. However, it is an attractive candidate for precision therapeutic approaches due to the frequency of amplification and/or activating mutations in the epidermal growth factor receptor (EGFR) gene and the availability of several brain penetrant second- and third-generation EGFR tyrosine kinase inhibitors (TKI). We used comprehensive molecular profiling of a panel of genetically engineered mouse astrocyte models to examine whether mutational profiles, particularly EGFR and PTEN status, could be used to identify kinases upregulated in specific mutational backgrounds. Using RNA-seq and multiplex inhibitor bead/mass spectrometry (MIB-MS) to analyze the kinase transcriptomes and proteomes, respectively, we have identified several potential targets for combination therapy. Overexpression of wild type EGFR in immortalized, Cdkn2a-/- astrocytes resulted in mild rewiring of the GBM kinome. Only 5 kinases aside from EGFR itself were overexpressed on either the transcript or protein levels. One overexpressed kinase, Hck, has been shown to be involved in cell survival, proliferation, adhesion, and migration. In contrast, overexpression of EGFRvIII, a constitutively active, extracellular domain truncation mutant of EGFR, resulted in significant alteration of the GBM kinome – 81 kinases showed differential expression, with 27 upregulated. One potentially attractive target among these was Cdk6, a drug-targetable, prognostically significant cyclin-dependent kinase implicated in proliferation, migration, and invasion. Finally, overexpression of EGFRvIII in cells lacking Pten dysregulated 46 kinases, including 15 upregulated. One particularly interesting target in these cells was Ddr2, a tyrosine kinase involved in migration, invasion, and extracellular matrix remodeling. We conclude that Hck, Cdk6, and Ddr2 represent attractive targets for therapeutic intervention in their relevant genetic contexts. These findings also suggest that molecular diagnostics for EGFR and PTEN status may be useful in guiding development of rational, EGFR TKI-centric drug combinations.
Management and Outcome of Patients with Diffuse Large B-Cell Lymphoma Relapsed after Autologous Hemopoietic Stem Cell Transplantation (auto-HSCT): A Retrospective Analysis of the Lymphoma Working Party (LWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Authors: Eva Gonzalez-Barca, Ariane Boumendil, Didier Blaise, Marek Trněný, Tamas Masszi, Hervé Finel, Mariagrazia Michieli, Jörg Thomas Bittenbring, Giuseppe Gritti, John A. Snowden, Mark Bishton, Benedetto Bruno, Sonia González de Villambrosia, Andrea Janikova, Xavier Leleu, Achilles Anagnostopoulos, Xavier Poire, Martina Crysandt, Zübeyde Nur Özkurt, Elisabeth Vandenberghe, Maija Itälä-Remes, Jean-Yves Cahn, Esa Jantunen, Wilfried Schroyens, Johan Maertens, Albert Esquirol, Peter Dreger, Silvia Montoto, Anna Sureda
Journal: Blood (2017)
SURG-07. DETECTION OF GLIOMA INFILTRATION AT THE TUMOR MARGIN USING QUANTITATIVE STIMULATED RAMAN SCATTERING MICROSCOPY
Authors: Melike Pekmezci, Ramin Morshed, Pranathi Chunduru, Balaji Pandian, Jacob Young, Javier Villanueva-Meyer, Tarik Tihan, Emily Sloan, Manish Aghi, Annette Molinaro, Mitchel Berger, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Differentiating neoplastic tumor tissues from normal brain at the infiltrative tumor margin remains challenging. Stimulated Raman scattering microscopy (SRM) is a rapid, label-free technique that provides microscopic imaging of unprocessed tissues. However, it has never been studied as a tool to enhance extent of resection. METHODS In this single center study, patients with WHO II-IV gliomas undergoing surgical resection were included. Margin samples were taken with corresponding stereotactic coordinates. Each tumor margin sample was analyzed using (1) H&amp;E, (2) SRM, and (3) immunohistochemical (IHC) stains for IDH1-R132H or p53. Specimens were imaged fresh with SRM, inked for orientation and placed in formalin for routine processing. Stained slides were scored by 3-neuro-pathologists using a semiquantitative 2-tiered scoring system for the presence or absence of residual tumor. SRM microscopy images were segmented into cellularity. The intraobserver measure of agreement between modalities for each pathologist was calculated using Cohen’s kappa. RESULTS A total of 31 patients and 179 margin specimens were acquired. Postoperative MRI confirmed that 169 (94%) of glioma margin sample coordinates were indeed at the tumor margins (10 of 179 were not true margins). All 10 samples which were not true margins were identified as having residual tumor by SRM. IHC semiquantitative scoring of margin specimen confirmed 72 of 128 samples (56%) had residual tumor. Similarly, H&amp;E-scoring confirmed 82 of 169 samples (49%) and 82 of 167 samples (49%) by SRM-scoring had residual tumor. Intraobserver agreements between all 3 modalities confirmed agreement: IHC-SRM was near perfect (K-0.84, CI-0.750-0.94); IHC-H&amp;E substantial, (K-0.67 CI-0.54-0.80); SRM-H&amp;E agreement substantial (K-0.72 CI-0.62-0.83). Margin samples with residual tumor demonstrated higher tissue cellularity when compared with samples without tumor (p&amp;lt; 0.0001). CONCLUSIONS SRM allows for identification of residual microscopic disease at the infiltrative tumor margin and therefore may be a promising tool to enhance extent of resection.
RARE-62. VISUAL FUNCTION IN CHILDREN WITH CRANIOPHARYNGIOMA AT DIAGNOSIS: A SYSTEMATIC REVIEW
Authors: Myrthe Nuijts, Nienke Veldhuis, Inge Stegeman, Hanneke van Santen, Giorgio Porro, Saskia Imhof, Antoinette Schouten van Meeteren
Journal: Neuro-Oncology (2020)

Abstract Childhood craniopharyngioma is a rare and slow growing brain tumour, often located in the sellar and suprasellar region. It commonly manifests with visual impairment, increased intracranial pressure and hypothalamic and/or pituitary deficiencies. Visual impairment in childhood adversely affects a child’s daily functioning and quality of life. We systematically reviewed the literature to provide an extensive overview of the visual function in children with craniopharyngioma at diagnosis in order to estimate the diversity, magnitude and relevance of the problem of visual impairment. Of the 543 potentially relevant articles, 84 studies met our inclusion criteria. Visual impairment at diagnosis was reported in 1041 of 2071 children (50.3%), decreased visual acuity was reported in 546 of 1321 children (41.3%) and visual field defects were reported in 426 of 1111 children (38.3%). Other ophthalmological findings described were fundoscopic (32.5%) and orthoptic abnormalities (12.5%). Variations in ophthalmological testing methods and ophthalmological definitions precluded a meta-analysis. The results of this review confirm the importance of ophthalmological examination in children with craniopharyngioma at diagnosis in order to detect visual impairment and provide adequate support. Future studies should focus on long-term visual follow-up of childhood craniopharyngioma in response to different treatment strategies to provide insight in risks and ways to prevent further loss of vision.
Well-dispersed platelet lysate entrapped nanoparticles incorporate with injectable PDLLA-PEG-PDLLA triblock for preferable cartilage engineering application
Authors: Qian Tang, Thou Lim, Li-Yan Shen, Gang Zheng, Xiao-Juan Wei, Chang-Qing Zhang, Zhen-Zhong Zhu
Journal: Biomaterials (2020)
CTNI-31. INTERIM RESULTS OF A PHASE I/IIA STUDY TO EVALUATE THE SAFETY AND EFFICACY OF BBB OPENING WITH THE SONOCLOUD-9 IMPLANTABLE ULTRASOUND DEVICE IN RECURRENT GLIOBLASTOMA PATIENTS PRIOR TO IV CARBOPLATIN
Authors: Ahmed Idbaih, François Ducray, Roger Stupp, Nathalie Baize, Olivier Chinot, John de Groot, Jacques Guyotat, Adam Sonabend, Philippe Menei, Henry Dufour, Jeffrey Weinberg, Carole Desseaux, Michael Canney, Charlotte Schmitt, Alexandre Carpentier
Journal: Neuro-Oncology (2020)

Abstract Low intensity pulsed ultrasound (LIPU), in combination with systemic injection of microbubbles, can be used to transiently disrupt the blood-brain barrier (BBB) and increase brain-drug concentrations. In pre-clinical models, carboplatin can be enhanced by a factor of 5x in the brain using LIPU and increase the survival of GBM-bearing mice. In clinical studies, a single emitter, implantable ultrasound device (SonoCloud-1) was used to disrupt the BBB in 19 rGBM patients prior to carboplatin chemotherapy (NCT02253212). The feasibility of this approach was demonstrated, and safe acoustic parameters were determined. The primary objective of this subsequent Phase 1/2a study (NCT03744026) was to demonstrate the safety of BBB disruption over a larger volume, including the tumor and surrounding peritumoral region using a nine-emitter version of the device (SonoCloud-9). This study was a 3 + 3 design using escalating numbers of activated 1-cm diameter emitters (3, 6, 9). GBM patients at any recurrence, with a maximum tumor size of &amp;lt; 70 mm were included. The SonoCloud-9 device was implanted during tumor debulking/resection surgery and replaced the bone flap. The device was activated every four weeks for 270 seconds, concomitantly with DEFINITY® microbubbles to disrupt the BBB prior to administration of carboplatin. Magnetic resonance imaging was performed to verify safety and the extent of BBB disruption. As of June 2020, the escalation phase of the study (9 patients) was complete, with a median of four monthly cycles of sonication and carboplatin chemotherapy per patient. No DLTs were observed. The overall tolerance of the SonoCloud-9 implant was good, with only a few, transient, and manageable related adverse events. The safety of administration of multiple repeat treatments of BBB opening using nine emitters of the device at an acoustic pressure of 1.03 MPa will be confirmed in an additional 12 patients to be included in the ongoing expansion phase.