tbuckley/cabot-search huggingface dataset:
OP0202 STRESS-ACTIVATED MIR-204 GOVERNS SENESCENT PHENOTYPES OF CHONDROCYTES TO PROMOTE OSTEOARTHRITIS DEVELOPMENT
Authors: Y. Cho, D. Kang, J. H. Kim
Journal: Annals of the Rheumatic Diseases (2020)

Background: A progressive loss of cartilage matrix leads to the development of osteoarthritis (OA). Matrix homeostasis is disturbed in OA cartilage as the result of reduced production of cartilage-specific matrix and increased secretion of catabolic mediators by chondrocytes. Chondrocyte senescence is a crucial cellular event contributing to such imbalance in matrix metabolism during OA development. Objectives: We sought to identify a previously unknown, senescence-associated signaling pathway in chondrocytes linked to major OA cartilage manifestations such as PG loss and cartilage degeneration. Methods: We particularly aimed to screen miRNAs whose inhibition could effectively modulate senescent phenotypes of chondrocytes to treat OA. We investigated the regulatory mechanisms of miR-204 under various stress-eliciting stimuli in primary cultured human and mouse chondrocytes. We examined the in vivo effects of miR-204 overexpression and its antagonism in surgically induced OA mouse models. DMM surgery was used to induce posttraumatic OA in 12-week-old mice. Small RNAs were delivered to mouse knee joints by intra-articular injection. Various OA manifestations including cartilage destruction, subchondral bone sclerosis, osteophyte maturity, and synovial inflammation in mice were histologically inspected. Results: We identify miR-204 as a senescence-associated microRNA (miRNA) which is markedly upregulated in OA cartilage. The upregulated miR-204 simultaneously targets multiple components of the sulfated proteoglycan (PG) biosynthesis pathway, effectively shutting down PG anabolism. Ectopic expression of the miR-204 in joints triggers spontaneous cartilage loss and OA development, whereas inhibition of miR-204 ameliorates experimental OA, with concomitant recovery of PG synthesis and suppression of inflammatory senescence-associated secretory phenotype (SASP) factors in cartilage Conclusion: we unravel a stress-activated senescence pathway that underlies disrupted matrix homeostasis in OA cartilage. References: [1]O. H. Jeon, C. Kim, R.-M. Laberge, M. Demaria, S. Rathod, A. P. Vasserot, J. W. Chung, D. H. Kim, Y. Poon, N. David, D. J. Baker, J. M. van Deursen, J. Campisi, J. H. Elisseeff, Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017) Disclosure of Interests: None declared
Atrial Fibrillation Following Transcatheter Aortic Valve Implantation: Do We Underestimate its Frequency and Impact?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Bernard Iung, Dominique Himbert, Alec Vahanian
Journal: Journal of the American College of Cardiology (2012)
NCOG-36. FIRST HEALTH UTILITIES OF GLIOBLASTOMA PATIENTS USING TTFIELDS TREATMENT
Authors: Gordon Chavez, Christina Proescholdt
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Despite the importance of Health State Utilities for health policy and medical decision making, there are no publications that provide high quality utility values estimated from glioblastoma multiforme (GBM) patients. Published health economic evaluations for GBM treatments rely on utilities determined by Garside et al. (2007), which used the standard gamble method in healthy panel members of the UK National Health System. There are no published utilities for GBM estimated from a general population sample, and there are no utility estimates whatsoever for Tumor Treating Fields (TTFields) users. METHODS We designed a study to remedy this major deficit by eliciting utilities directly from GBM patients using the EuroQol 5-Dimension (EQ-5D) survey. The EQ-5D is a widely used and NICE-recommended tool for the estimation of health state utilities. The survey is composed of a questionnaire that asks patients to specify their health state along 5 dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Statistical models provided by EuroQol’s network of researchers convert this data into health state utility estimates. RESULTS The EQ-5D questionnaire is administered to active patients using TTFields treatment during the study duration, allowing the elicitation of health preference measures for different glioblastoma health states based on: progression status (progressed vs. non-progressed), current treatments (TTFields only vs. TTFields + others) and time-from-diagnosis (0-12 months vs. &amp;gt; 12 months) CONCLUSION These results are important for understanding the patient preferences using TTFields treatment and communicating these preferences to decision makers. This study is the first to provide direct, high quality utility measures in glioblastoma patients using TTFields treatment.
RARE-27. DOUBLE MUTATIONS: DIFFERENT GERMLINE AND TUMOR MUTATIONS LEAD TO POOR OUTCOMES
Authors: Molly Hemenway, Anan Nellan, Nicholas Foreman, Alexandra Suttman, Kami Schneider
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND As genetic testing for both germline and tumor mutations has increased in completeness, complexity, and availability, more mutations and their impact on patient outcomes have been identified. METHODS A retrospective review of pediatric patients who have identified germline mutations and a different tumor mutation was conducted. Data collected included demographics, tumor type, germline mutation status, tumor mutation status, relapse status, and patient outcome. RESULTS Six patients aged 8–13 years old (median age 10 years) were identified for analysis. Four patients had pilocytic astrocytoma and two had pilomyxoid astrocytoma. One of the patients with pilocytic astrocytoma also had MPNST diagnosed very early at age 9. The combination of germline/tumor mutations is as follows: Neurofibromatosis Type I (NF1)/BRAF v600e, NF1, CHEK2/MYB-QKI, NF1, Klinefelter, ATM, MUTYH, GPC3/BRAF-KIAA fusion, NF1/BRAF-KIAA (2 patients), and Marfan’s/BRAF-KIAA. The number of relapses per patient following initial diagnosis range from 3–7 with an average of 3.3. Four of the patients are alive and on therapy, which two are deceased. The two deceased patients both had NF1/BRAF-KIAA fusions and pilocytic astrocytomas. CONCLUSIONS Patients with differing and compounded germline and tumor molecular genetic mutations have worse outcomes. These patients have more relapses and death when compared to those patients with one mutation, either germline or tumor. Broad molecular testing and germline testing for mutations is crucial in determining patient risk for poor outcomes.
Incidental Detection of Radiotracer Uptake in Intracranial Dermoid Cyst on 18F-Prostate-Specific Membrane Antigen PET/CT During Staging for Prostate Carcinoma
Authors: Nir Hod, Daniel Levin, Rosa Novoa, Sophie Lantsberg
Journal: Clinical Nuclear Medicine (2020)

Abstract A 68-year-old man underwent 18 F–prostate-specific membrane antigen (PSMA) PET/CT for staging of a newly diagnosed prostate adenocarcinoma. Unexpectedly, PET/CT revealed high focal 18 F-PSMA brain uptake, which initially was suspected for a brain metastasis. Corresponding CT and MRI scans revealed characteristic imaging features of an intracranial dermoid cyst at this site. This is an exceptional location for a dermoid cyst, which had been followed up conservatively with no substantial changes. This case shows that dermoid cyst should be added to the reported list of benign neoplasms that shows “false-positive” PSMA uptake during evaluation of patients with prostate carcinoma, representing a potential interpretative pitfall.
Abstract 11648: Cardioprotection in Diabetic Cardiomyopathy via Upregulation of Atp-sensitive K+ Channels
Authors: Arkady Uryash, Jose A Adams, Jose R Lopez
Journal: Circulation (2019)

Background: ATP-sensitive K+ (KATP) channels couple metabolic status of the cell with membrane excitability and have been implicated in cardioprotective signaling including ischemia, and hypoxia. D...
TBIO-15. MODELING DEVELOPMENTAL GENE EXPRESSION DYNAMICS AT CELLULAR RESOLUTION TO INTERPRET PEDIATRIC BRAIN TUMOR TRANSCRIPTIONAL PROGRAMS
Authors: Selin Jessa, Nisha Kabir, Maria Vladoiu, Steven Hébert, Michael D Taylor, Nada Jabado, Claudia L Kleinman
Journal: Neuro-Oncology (2020)

Abstract A central challenge in understanding the biology of pediatric brain tumors is defining the cellular and molecular context where oncogenesis occurs. We hypothesize that spatiotemporally restricted cell types are uniquely susceptible to specific genetic alterations, which alter normal neurodevelopmental programs and ultimately lead to oncogenesis. The resulting tumors retain some transcriptomic features of their lineage of origin. To delineate these origins, we assembled a densely sampled developmental time course of the mouse forebrain and pons, doubling our recently published single-cell atlas. This dataset comprises &amp;gt;100,000 cells at 9 timepoints from E10-P6. However, while single cell transcriptomics reveal rich gene dynamics during cell differentiation, interpretation of individual genes can be challenging due to data sparsity. Leveraging this time-series, we present strategies to model and visualize the expression of a given gene across differentiation of distinct lineages. We demonstrate an interactive web app to interrogate the expression of genes or gene sets during brain development, extract temporally correlated genes, and search active transcription factor regulatory modules. Finally, we profile the expression of core transcriptional programs of several pediatric brain tumor entities during development. Our analyses reveal genes with restricted expression patterns that elucidate tumor etiology. More broadly, these resources harness single cell data to enable exploration of neurodevelopmental gene programs with great relevance to pediatric brain tumor oncogenesis.
LGG-57. SIGNALLING MECHANISMS IN PAEDIATRIC LOW-GRADE GLIOMA
Authors: Ankit Patel, Tania Jones, Lewis Woodward, Arran Dokal, Vinothini Rajeeve, Pedro Cutillas, Thomas Stone, Thomas Jacques, Denise Sheer
Journal: Neuro-Oncology (2020)

Abstract Paediatric low-grade gliomas (pLGGs) constitute the largest group of childhood CNS tumours. They often cause significant disability and morbidity, despite their indolent growth and the good survival rate of patients. The most common genetic alterations in these tumours, KIAA1549:BRAF fusion and BRAFV600E mutation, lead to abnormal activation of MAPK signalling. The central role of this pathway in pLGG development is emphasized by the occasional presence of other MAPK-activating alterations such as RTK mutations. It is not known how these different aberrations can induce the variety of clinical phenotypes seen in pLGG. Here, we compared pilocytic astrocytomas (PAs) containing the KIAA1549:BRAF fusion with glioneuronal tumours (GNTs) containing the BRAFV600E mutation, to identify differentially activated downstream targets of the MAPK pathway. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used as a multi-proteomic approach. Kinase Set Enrichment Analysis (KSEA) using PhosphositePlus and NetworkIN was used to determine relative enrichment of kinase activity in the tumours compared to healthy control brain tissue. Significant similarities and differences were found in the two tumour types. For example, more robust MAPK activation was found in the GNTs than in PAs. However, while PI3K/AKT1/mTOR signalling was active in both PAs and GNTs, there was statistically higher activation in the PAs. In both tumour types, there was significant reduction in casein kinase 2 activity, which likely affects nuclear translocation of ERK and, in turn, alters the range of its phosphorylated substrates. We will present these data together with transcriptomics to further characterise the downstream targets of these genetic alterations.
To each child their own coronavirus
Authors: Laetitia Martinerie, Delphine Bernoux, Lisa Giovannini-Chami, Alexandre Fabre
Journal: BMJ (2020)

Pyrite grains, with appendages composed of either quartz or carbonate, occur in the Lower Algal zone of the Gunflint Formation, Ontario, and the Biwabik Formation of Minnesota. The pyrite grains with appendages appear to have been propelled through solid rock by the force of crystallization of quartz or carbonate, leaving a record of their path in the form of a carbonate- or quartz-filled trail.
Impact of Geography on Care Delivery and Survival for Noncurable Pancreatic Adenocarcinoma: A Population-Based Analysis
Authors: Elliott K. Yee, Natalie G. Coburn, Laura E. Davis, Alyson L. Mahar, Victoria Zuk, Vaibhav Gupta, Ying Liu, Craig C. Earle, Julie Hallet
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: Little is known about how the geographic distribution of cancer services may influence disparities in outcomes for noncurable pancreatic adenocarcinoma. We therefore examined the geographic distribution of outcomes for this disease in relation to distance to cancer centers. Methods: We conducted a retrospective population-based analysis of adults in Ontario, Canada, diagnosed with noncurable pancreatic adenocarcinoma from 2004 through 2017 using linked administrative healthcare datasets. The exposure was distance from place of residence to the nearest cancer center providing medical oncology assessment and systemic therapy. Outcomes were medical oncology consultation, receipt of cancer-directed therapy, and overall survival. We examined the relationship between distance and outcomes using adjusted multivariable regression models. Results: Of 15,970 patients surviving a median of 3.3 months, 65.6% consulted medical oncology and 38.5% received systemic therapy. Regions with comparable outcomes were clustered throughout Ontario. Mapping revealed regional discordances between outcomes. Increasing distance (reference, ≤10 km) was independently associated with lower likelihood of medical oncology consultation (relative risks [95% CI] for 11–50, 51–100, and ≥101 km were 0.90 [0.83–0.98], 0.78 [0.62–0.99], and 0.77 [0.55–1.08], respectively) and worse survival (hazard ratios [95% CI] for 11–50, 51–100, and ≥101 km were 1.08 [1.04–1.12], 1.17 [1.10–1.25], and 1.10 [1.02–1.18], respectively), but not with likelihood of receiving therapy. Receipt of therapy seems less sensitive to distance, suggesting that distance limits entry into the cancer care system via oncology consultation. Regional outcome discordances suggest inefficiencies within and protective factors outside of the cancer care system. Conclusions: These findings provide a basis for clinicians to optimize their practices for patients with noncurable pancreatic adenocarcinoma, for future studies investigating geographic barriers to care, and for regional interventions to improve access.
LGG-32. CLINICAL OUTCOME OF PEDIATRIC GLIOMAS IN SINGLE INSTITUTION
Authors: Hiroyuki Uchida, Nayuta Higa, Hajime Yonezawa, Tatsuki Oyoshi, Koji Yoshimoto
Journal: Neuro-Oncology (2020)

Abstract Gliomas in children are rarer than in adult, then treatment strategies might vary from facility to facility. We report clinical features and outcome of pediatric glioma in our institution. Twenty-nine patients diagnosed with glioma, exclude ependymoma, 14 boys and 15 girls, among 98 pediatric brain tumor patients treated at Kagoshima University Hospital since 2006 were reviewed histopathology, extent of resection, adjuvant therapy and outcome, etc. Mean age at surgery was 10.4 (S.D. 5.6) years. Median follow-up period was 19.1 months. Histopathological diagnosis comprised 8 pilocytic astrocytoma, 3 ganglioglioma, 2 subependymal giant cell astrocytoma, 5 WHO grade Ⅱ astrocytoma, 8 glioblastoma, and desmoplastic infantile astrocytoma, anaplastic astrocytoma and astroblastoma were one case each. Tumor resection was performed in 24 cases, and 5 cases underwent biopsy. Chemotherapy was performed in 15 cases and irradiation was performed in 9 cases. Out of 5 WHO grade Ⅱ astrocytoma cases, 2 cases underwent biopsy following chemotherapy, 1 case underwent biopsy only and other 1 case underwent total resection. The four cases show long survival ranged from 71 to 136 months without irradiation. All of eight glioblastoma cases show poor prognosis ranged from 8.6 to 26.7 months regardless of chemo-radiotherapy. In management for pediatric brain tumor patients, irradiation is often laid over until recurrence. In WHO grade Ⅱ astrocytoma, the treatment strategy might be reasonable using appropriate chemotherapy even though biopsy cases.
Conduct Disorders and Empathy Development
Authors: Paul J. Frick, Emily C. Kemp
Journal: Annual Review of Clinical Psychology (2020)

Childhood conduct disorders, a serious mental health concern, put children at risk for significant mental health problems throughout development. Elevations on callous-unemotional (CU) traits designate a subgroup of youth with conduct disorders who have unique causal processes underlying their problem behavior and are at a particularly high risk for serious impairment relative to others with these disorders. As a result, these traits have recently been integrated into major diagnostic classification systems for conduct disorders. Given that CU traits are partly defined by deficits in empathy, we review research on empathy development in typically developing children and use this research to ( a) advance theories on the specific emotional deficits that may be associated with CU traits, ( b) explain the severe pattern of aggressive behavior displayed by children with elevated CU traits, and ( c) suggest possible ways to enhance prevention and treatment for children with conduct disorders and elevated CU traits.
TAMI-04. TUMOR TREATING FIELDS (TTFIELDS) HINDER GLIOMA CELL MOTILITY THROUGH REGULATION OF MICROTUBULE AND ACTIN DYNAMICS
Authors: Tali Voloshin, Rosa Schneiderman, Alexandra Volodin, Reuben Shamir, Noa Kaynan, Einav Zeevi, Lilach Koren, Anat Klein-Goldberg, Rom Paz, Moshe Giladi, Zeev Bomzon, Uri Weinberg, Yoram Palti
Journal: Neuro-Oncology (2020)

Abstract The ability of glioma cells to invade adjacent brain tissue remains a major obstacle to therapeutic disease management. Therefore, the development of novel treatment modalities that disrupt glioma cell motility could facilitate greater disease control. Tumor Treating Fields (TTFields), encompassing alternating electric fields within the intermediate frequency range, is an anticancer treatment delivered to the tumor region through transducer arrays placed non-invasively on the skin. This novel loco-regional treatment has demonstrated efficacy and safety and is FDA-approved in patients with glioblastoma and malignant pleural mesothelioma. TTFields are currently being investigated in other solid tumors in ongoing trials, including the phase 3 METIS trial (brain metastases from NSCLC; NCT02831959). Although established as an anti-mitotic treatment, the anti-metastatic potential of TTFields and its effects on cytoskeleton rapid dynamics during cellular motility warrant further investigation. Previous studies have demonstrated that TTFields inhibits metastatic properties of cancer cells. Identification of a unifying mechanism connecting the versatile TTFields-induced molecular responses is required to optimize the therapeutic potential of TTFields. In this study, confocal microscopy, computational tools, and biochemical analyses were utilized to show that TTFields disrupt glioma cellular polarity by interfering with microtubule assembly and directionality. Under TTFields application, changes in microtubule organization resulted in activation of GEF-H1, which led to an increase in active RhoA levels and consequent focal adhesion formation with actin cytoskeleton architectural changes. Furthermore, the optimal TTFields frequency for inhibition of invasion in glioma cells was 300 kHz, which differed from the optimal anti-mitotic frequency leading to glioma cell death of 200 kHz. The inhibitory effect of TTFields on migration was observed at fields intensities of 0.6 V/cm RMS (below the threshold of 1 V/cm RMS previously reported for cytotoxic effects). Together, these data identify discrete TTFields effects that disrupt processes crucial for glioma cell motility.
10P Genomic profiles of CD47 in breast tumours predict outcome and are associated with immune activation and enrichment of pro-tumoral macrophage markers
Authors: A. Ocaña, M.D.M. Noblejas Lopez, M. Baliu-Piqué, C. Nieto-Jiménez, F.J. Cimas, E.C. Morafraile, A. Pandiella, Á.L. Corbí, B. Győrffy
Journal: Annals of Oncology (2020)
BIOM-09. MULTIPLEX ANALYSIS OF CSF EXTRACELLULAR VESICLES OF INTRASPINAL TUMORS
Authors: Franz Ricklefs, Ines Stevic, Christian Mende, Joshua Welsh, Jennifer Jones, Manfred Westphal, Katrin Lamszus, Sven Eicker
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND: Extracellular vesicles (EVs) play an important role in cell-cell communication in different types of tumors, carrying multiple layers of biological functional molecules, including proteins, RNA, DNA and lipids. We previously demonstrated that extracellular vesicles (EV) from central nervous system tumors reflect the molecular subtype of the original tumor and mediate an exchange of pro-oncogenic signals. Their implication as biomarkers in tumor disease is under current investigation. It is unclear, however, to what extent cerebrospinal fluid (CSF) EVs from intraspinal tumors are utilizable for diagnostical purposes and how their marker profiles overlap with EVs derived from non tumorous EVs. We analyzed CSF EVs of intraspinal tumors to define CSF EV profiles that allow tumor subtype classification. METHODS: EVs were isolated from CSF of patients suffering from intraspinal meningioma (n=5), ependymoma (n=7) and neurinoma (n=5). Patients suffering from normal pressure hydrocephalus were used as controls (n=5). EVs were analyzed by multiplex bead based assay, immunoblotting, electron microscopy and NTA. RESULTS: CSF EVs were 97.21 ± 3.37nm (intraspinal tumor patients) and 101.6 ± 3.68nm (controls) in sizes and showed vesicular structures by electron microscopy. Particle number were not significantly different between both groups (p = 0.103). Using our 37 protein mutliplex EV profiling kit we found 29 proteins to be expressed in a sufficient manner on CSF EVs. CSF EVs of intraspinal meningioma showed elevated CD62P, HLA-DR, CD40, CD42a and CD45 expression levels, while ependymoma showed decreased levels of CD9, CD63, CD81, whereas neurinomas had elevated levels of SSEA-3 and CD25. CONCLUSION: This is the first comprehensive analysis of CSF EV of intraspinal tumor patients. CSF EV display distinct subpopulations that may allow tumor classification and long-term surveillance. However as tumor-specific EVs may be rare, there is still the need to identify markers that can enrich tumor-specific EVs for molecular profiling.