tbuckley/cabot-search huggingface dataset:
P08.01 Tumor cell subpopulation changes during intracranial glioblastoma patient derived xenograft recurrence following radiation, temozolomide, or combination therapy
Authors: A. U. Ahmed, C. M. Horbinski, R. Stupp, M. S. Lesniak, C. D. James
Journal: Neuro-Oncology (2017)

We’ve established a model for recurrent GBM by treating mice bearing previously untreated, luciferase-modified, intracranial GBM PDX, with radiation (RT) (2 Gy/day, M-F), temozolomide (TMZ) only (10 mg/kg/day, M-F), or concurrent RT/TMZ. PDX respond to treatment by showing a reduced rate of increase in tumor bioluminescence (RT only), or decreased tumor bioluminescence (TMZ only or RT/TMZ), but with eventual tumor growth requiring animal euthanasia at 5.5 (RT only), 26.5 (TMZ only), or 38 (RT/TMZ) days beyond the median survival of untreated control animal subjects. All survival extensions are significant relative to untreated control mice (p<0.05). To examine the effects of treatment on tumor cell subpopulations in intracranial PDX, we employed flow cytometric analyses of human leukocyte antigen (HLA) positive GBM cells, using a panel of markers (CD133, CD15, ABCG2, SOX2, EZH2, HIF1A, MGMT, and H3K27me3). RT alone did not cause a significant enrichment for any specific subpopulation, as identified using the markers indicated above. In contrast, PDX exposed to TMZ monotherapy or RT/TMZ combination therapy showed enrichment for CD133+HIF1A+ cells (p<0.005). PDX treated with RT/TMZ were also enriched for CD133+CD15+, and additionally showed enrichment for CD133+SOX2+ and CD133+EZH2+ cells (p<0.005 for each). Perhaps not so surprisingly, recurrent tumors that had been treated with TMZ or RT/TMZ showed increased cellular positivity for MGMT (Control 0.78% vs. TMZ 3.4% p<0.005 and RT/TMZ 4.3% p<0.0005), though, paradoxically, these tumors also showed increased cellular positivity for EZH2 (Control 0.38% vs. TMZ 3.0% p=ns and RT/TMZ 7.8% p<0.0005) and a product of EZH2 activity, H3K27me3 (Control 0.55% vs. TMZ 18.2% p<0.0005 and RT/TMZ 4.3% p=ns), which is associated with transcriptional suppression. Corresponding immunohistochemical analysis is ongoing, with results to be presented at the meeting. In total, our data indicate that, in recurrent tumors, cell subpopulation selection/enrichment depends on the type of therapy administered, which should, in turn, influence the selection of salvage therapy for treating recurrent GBM. Supported by NIH grants NS095642 and NS096376.
Abstract P035: The Nucleolar Protein Nucleophosmin Regulates Mitosis Progression in Cardiac Progenitor Cells
Authors: Daniele Avitabile, Balaji Sundararaman, Silvia Truffa, Mark A Sussman
Journal: Circulation Research (2011)

Besides its notorious function during ribosome biogenesis, emerging evidence suggests a central role for the nucleolus in controlling many other important cellular processes such as stress response, proliferation and mitosis. Here we show that the nucleolar protein Nucleophosmin (NPM) is necessary for the correct progression of mitosis in primary cultures of cardiac progenitor cells (CPCs). Methods: CPCs were cultured on Permanox chamber slides at high confluence and fixed with 4% PFA. CPCs were blocked in cytokinesis with 2μ M cytochalasin B (CytB) for 18 hours. Silencing of NPM (ShNPM) or scramble (ShSc) was performed by specific shRNA expressing lenti viral vectors. Confocal microscopy, co-immunoprecipitation and proximity ligation assay (PLA), FACS analysis and Cyquant assay were employed to study protein localization and interaction, cell death and proliferation respectively. Results: ShNPM infected CPCs showed reduced proliferation with no apparent cell death compared to scramble. Cells in prometa and metaphase significantly increased after NPM knock down. ShNPM-CPC showed 50% decrease in the number of cells that complete mitosis as assessed by counting binucleated cells after CytB treatment. NPM localized in the nucleolus during interphase as assessed by co-staining with nucleostemin (NS), a highly expressed nucleolar protein. NS and NPM decorate the chromosome periphery from prometaphase to anaphase and return to the newly forming nucleolus at the end of telophase. The phosphorylated form of NPM at threonine 199 (pNPM) was found to co-localize with spindle components such us NUMA and α-tubulin specifically at methaphase. NPM was also found to co-precipitate and directly interact with α-tubulin as shown by in-situ protein interaction assay (PLA) in the cytoplasm during interphase and at the centrosome and spindle during mitosis. Conclusion: This is the first study to detail the role of nucleolar proteins during CPCs mitosis. Our findings demonstrate a central role for NPM during metaphase transition, possibly thorough interaction with components of the spindle and in particular with α-tubulin.
Diagnosis of major depression is too broad
Authors: J Watt
Journal: BMJ (1995)

Definition ofdepression is questionable EDITOR,-Mynors-Wallis and colleagues claim that problem solving treatment and amitriptyline are equally effective in major depressive disorder.'Even though they required their patients to meet the research diagnostic criteria for depression, just how severely depressed they were comes into question.To be eligible to take part in the study patients had to score just 13 on the Hamilton depression rating scale.Drug licensing authorities, such as the Committee on Safety of Medicines and the Food and Drug Administration, and most
P11.08 Systematic drug repurposing for faster cures of pediatric cancer identifies that Digoxin prolongs survival in a PDOX model of group 4 medulloblastoma
Authors: L. Huang, S. G. Injac, H. Zhao, Q. Lin, M. Kogiso, C. Man, X. Li, C. Lau, S. T. C. Wong
Journal: Neuro-Oncology (2017)

Background: Medulloblastoma (MB) is the most common malignant brain tumor of childhood. While the current standard care for MB leads to long term survival in approximately 75 % of patients; recurrent and refractory MB continues to have dismal outcomes. In addition, long term survivors face significant treatment-related sequelae especially poor neurocognitive outcomes. Drug repositioning for known drugs is a promising potential strategy not only for drug discovery but also for accelerated translation into the clinical setting. To systematically explore thousands of known drugs available, we integrated computational biology and empirical biology methods to find old drugs for new indications in MB. Results: A non-parametric, bootstrapping based simulated annealing (NPBSA) algorithm was employed to identify driver signaling pathways for over 1,800 patients with Group 3 and Group 4 MB through an integrative analysis on their mRNA expression, DNA-copy number, DNA-methylation and DNA-seq profiles. Then, drug functional networks were constructed based on gene expression profiles under drug treatment as well as chemical structures and were clustered into drug modules with potential mechanisms of action. By evaluating targeted effects of 1,309 drugs from connectivity map database within each drug module in driver signaling pathways, we identified a group of known cardiac glycosides that top ranked among the total drug candidates for the Group 3 and 4 MB subtypes. In addition to traditional chemotherapeutic agents, members of the cardiac aminoglycoside family were repeatedly identified as potential therapeutic agents for MB. These findings were validated in multiple MB-derived cell lines which showed high rates of growth inhibition by cardiac aminoglycosides compared to controls. To evaluate if this growth inhibition in vitro correlated to prolonged survival in vivo, an extensively characterized patient-derived orthotopic-xenograft (PDOX) model of Group 4 MB (ICb-1078MB) was treated with digoxin (2 mg/kg i.p.) for 2 cycles of 14 days. Digoxin treatment significantly prolonged survival to 113 days from a median of 92 days in untreated controls (p=0.001). Histological evaluation of recurrent tumors following digoxin treatment demonstrated changes in the pattern of tumor spread, vascularity and necrosis compared to untreated controls. Conclusions: Leveraging big data in the domains of pharmacogenomics and the notion of drug functional networks and driver signaling pathways represents a powerful tool to repurpose known drugs for new indications in pediatric cancers. Using this integrative biology approach, we identified the cardiac aminoglycosides family generally and Digoxin, specifically, as potential novel agents in the treatment of pediatric medulloblastoma.
P09.42 Are we performing too many staging CT scans for solitary high grade tumours? Could service provision be improved?
Authors: J. Pesic-Smith
Journal: Neuro-Oncology (2017)

Introduction: Experience suggests that when high grade lesions are referred staging CT scans are uniformly performed, in many cases inappropriately. This could be costly and an inappropriate use of resources. We aimed to perform a pilot study to investigate whether there was a discrepancy between advised and performed staging CT scans. Design and Methods/Subjects: The neuro-oncology multidisciplinary meeting records were reviewed for solitary high grade lesion referrals. In total 80 patients over a 14 month period were identified. Clinical information including radiological diagnosis and any previous history of malignancy was recorded. The MDT outcomes and recommendations, on call neurosurgery emergency referrals database and the report of the initial diagnostic imaging were reviewed to identify whether staging CT had been advised. We then searched for imaging and reviewed the MDT outcomes for the same patients to identify those who underwent staging imaging. Results: Radiological diagnosis was high grade glioma in 49 patients (61.3%), metastasis in 19 patients (23.8%), ­lymphoma in 4 patients (5%) and unknown in 8 patients (10%). Staging CT was advised in 29 patients (36.3%); by neurosurgery registrar 18 patients, MDT 6 patients and radiologist 5 patients; CT was not advised in 48 patients (60%), and unknown in 3 patients (3.8%). 48 patients (60%) underwent a staging CT scan whilst 31 (38.8%) did not and it was not known in 1 patient (1.3%). There were no primary malignant lesions found on staging CT scans that were performed without being advised. Conclusions: Our pilot study shows that a significant number of staging CT scans are being performed when not advised by the receiving neurosurgical team. This could have an impact on cost to the NHS and use of resources. A larger prospective study is planned to investigate these initial findings further.
ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use
Authors: Neena S. Abraham, Mark A. Hlatky, Elliott M. Antman, Deepak L. Bhatt, David J. Bjorkman, Craig B. Clark, Curt D. Furberg, David A. Johnson, Charles J. Kahi, Loren Laine, Kenneth W. Mahaffey, Eamonn M. Quigley, James Scheiman, Laurence S. Sperling, Gordon F. Tomaselli
Journal: Journal of the American College of Cardiology (2010)
P10.11 Adjuvant Temozolomide and radiation for Anaplastic Oligodendroglioma: A single center experience
Authors: K. Haresh, S. Mallick
Journal: Neuro-Oncology (2017)

BACKGROUND: Adjuvant management of anaplastic Oligodendroglial tumors (AOTs) is controversial. Outcomes with temozolomide (TMZ)-based adjuvant chemo- radiation (ACRT) have been inadequately explored. METHODS: We analysed our database between 2000 and 2014. All patients were treated with maximally safe surgical resection followed by post-operative radiation. Radiation dose was 60 Gy in 30 fractions. Patients treated after 2007 also received concurrent daily temozolomide(TMZ) (75 mg/m2) then four weeks later, adjuvant TMZ started at 150 mg/m2 day 1 to 5 every 28 days and escalated to 200 mg/m2 after the 2nd cycle. Kaplan Meier method was used to estimate survival, and the impact of various factors on survival of patients with ODG was estimated using log rank. Results: We analysed data of 81 patients. Median age was 40 years (Range: 7-77 years). 39 (48.1%) underwent gross/near total resection; 26 (32.1%) underwent a subtotal resection; 14(17.3%) underwent decompression and 2(2.5%) patient had unknown resection status. Median MIB labelling index was 20 (Range: 5-45).Median radiotherapy dose was 60 Gy (Range 40-60). 50 patients (61.7%) received concurrent chemotherapy while 44(54.3%) also received adjuvant chemotherapy. In patients receiving temozolomide based chemoradiation grade III or IV thrombocytopenia was noted in 10% cases, and 2% had grade III or IV neutropenia.Median number of adjuvant chemotherapy cycles was 6 (range: 1 to 12). Median follow-up was 25 months. Estimated median progression free survival (PFS) was 5.2 years. 2 and 5 year PFS were 76.2% and 50.5% respectively. Median overall survival was 6.71 years. Univariate analysis for prognostic factors influencing survival did not find any significant factor associated with better survival in anaplastic ODG. CONCLUSION: Adjuvant Temozolomide with radiation is a safe and feasible approach in the treatment of anaplastic ODG and should be evaluated in randomized trial.
OS05.7 Seizures in grade III gliomas: natural history and response to treatments
Authors: R. Rudà, F. Mo
Journal: Neuro-Oncology (2017)

Introduction: Grade III gliomas are traditionally considered less epileptogenic than grade II gliomas; however, there is lack of studies focused specifically on seizures in grade III gliomas in the MRI era. Based on WHO 2016 classification grade II and III gliomas with favorable molecular markers and similar prognosis have been grouped together in the category of lower-grade gliomas. Moreover, the presence of IDH1 mutation has been associated with a higher risk of seizures. The aim of this retrospective study was to describe the natural history and response to treatments of seizures in a cohort of grade III gliomas taking into account the molecular markers as well. Patients and methods. We collected patients with an histological diagnosis of grade III astrocytoma, oligodendroglioma and oligoastrocytoma according to WHO 2007 with at least one seizure in the disease course, who were followed at our Institution from 1995 to 2015. We evaluated seizure type and frequency, and seizure control after surgery, radiotherapy, chemotherapy and chemoradiation, respectively. RESULTS: We analyzed a cohort of 133 patients with grade III glioma (91 de novo and 42 from previous grade II tumors), and compared with a retrospective series of grade II gliomas. Overall, seizures in grade III gliomas were the presenting symptom in 88% of patients, while occurring later in the disease course in 12%, and were simple partial (54%), generalized (19%) and partial complex (13%). Seizure frequency was ≥ 1/day in 5% of grade III and 18% of grade II gliomas. Grade III gliomas with IDH1 mutation showed a higher seizure frequency (≥ 1 seizure/day in 9%) than grade III IDH1 wild-type (≥ 1 seizure/day in 0%), similarly to grade II gliomas. After surgery 70% of patients were seizure free (Engel Class I) in both grade III and II gliomas. Regarding patients with grade III gliomas a seizure reduction ≥50% was observed in 61% following radiotherapy, 52.4% following TMZ or PCV, and 38% following chemoradiation. In comparison, regarding patients with grade II gliomas a seizure reduction ≥50% was observed in 70% following radiotherapy, 79.7% following chemotherapy and 40% following chemoradiation. Grade III gliomas with IDH1 mutation and 1p19q codeletion showed a better seizure reduction (71% after radiotherapy and 64% after chemotherapy) than grade III gliomas IDH1 wild type (60% after radiotherapy and 38% after chemotherapy), similarly to grade II gliomas. CONCLUSIONS: This study confirms the lower epileptogenicity of grade III versus grade II gliomas and suggests that the impact of adjuvant antineoplastic treatments on seizure control is lower in grade III versus grade II gliomas. Moreover, grade III gliomas IDH1 mutated have a higher seizure frequency and a better seizure control after antineoplastic treatments than IDH1 wild-type tumors.
P03.08 Pathological Analysis of Xenografts with Malignant Glioma After Anti-angiogenic Therapy
Authors: J. Ishida, K. Kurozumi, T. Ichikawa, T. Shimizu, Y. Otani, K. Fujii, Y. Tomita, Y. Hattori, I. Date
Journal: Neuro-Oncology (2017)

Introduction: Malignant gliomas are known to secrete high levels of vascular endothelial growth factor (VEGF). Bevacizumab, which is a monoclonal antibody to VEGF, has demonstrated convincing therapeutic benefits in patients with glioblastoma. However, several reports have shown that anti-VEGF therapy induced invasive proliferation. Materials and Methods: We examined the effects of bevacizumab-induced invasive changes in glioma xenografts. U87ΔEGFR and Gli36Δ5 cells were stereotactically injected into the brain of nude mice or rats. Five days after tumor cell implantation, bevacizumab was administered intraperitoneally three times a week. At 18 days after tumor implantation, the brains were removed and observed histopathologically by an immunohistochemical assay and a transmission electron microscope. We analyzed the pathological changes which were treated with bevacizumab compared to the untreated group. Results: The bevacizumab treatment led to increased tumor cell invasion in spite of decreased angiogenesis and tumor size. Both immunohistochemical staining by collagen type I and transmission electron microscopic analysis demonstrated the remarkable increase of extracellular components in contrast to the decrease of angiogenesis. Conclusions: This study showed that the anti-angiogenic treatment with bevacizumab was effective to decrease vessels and tumor mass of malignant glioma, however it changed the microenvironment, including extracellular components around malignant glioma. The elucidation of this mechanism might contribute to the treatment of bevacizumab-refractory glioma.
P18.13 Cross sectional study of sleeping problems in glioma patients
Authors: C. Marosi, D. Strobl, G. Saletu-Zyhlarz, K. U. Dieckmann, M. Preusser, G. Widhalm, B. Flechl
Journal: Neuro-Oncology (2017)

Background: Patients with primary brain tumours often suffer from fatigue and have a number of disease-specific symptoms and treatment side effects which may impair health related quality of life (HRQOL) significantly. Upon clinical experience, patients with aggressive brain tumours (WHO grade III and IV) often complain about various sleep problems. Methods and Patients: 120 adult patients with the secured diagnosis of a primary brain tumour, attending the neuro-oncological department of the medical university of Vienna from February 2012 to July 2012, were included in a cross sectional study, receiving the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS) and the EORTC QLQ-C30 and the EORTC QLQ-BN20. Data are described and rated through the defined standards of each questionnaire. Results: 55 % of Patients qualify as ‘bad sleepers’ according to PSQI (more than 5 points on the global score) with certain subgroups having prevalence rates of 70 % and higher. Men have higher numbers of ‘bad sleepers’ than women (57 % vs 52 %, respectively). ESS scores were similar to normative scores from a large German general population sample. QLQ-C30 showed high levels of patients with fatigue symptoms (90 %), followed by financial insecurity (56 % of patients), insomnia (53 % of patients) and pain (51 % of patients). Overall HRQOL according to QLQ-C30 was rather low with 62 points across all patients enlisted. QLQ-BN20 showed future uncertainty (86 % of patients), drowsiness (77 % of patients), communication deficit (71 % of patients) and motor dysfunction (64 % of patients) as the most prevalent problems affecting quality of life. Patients with tumour recurrence (in comparison to patients receiving first-line-therapy and patients in remission) scored worst on nearly all questionnaire items. Conclusion: Fatigue and sleep disorders affect many glioma patients throughout the whole course of disease and are particularly severe after tumour recurrence. This strongly impacts the patients HRQOL and their ability to cope with problems of daily life. Therefore, neuro-oncologists as well as other doctors in interaction with those patients should always be aware of quality of sleep and fatigue.
Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis
Authors: Athimalaipet V. Ramanan, Andrew D. Dick, Ashley P. Jones, Andrew McKay, Paula R. Williamson, Sandrine Compeyrot-Lacassagne, Ben Hardwick, Helen Hickey, Dyfrig Hughes, Patricia Woo, Diana Benton, Clive Edelsten, Michael W. Beresford
Journal: New England Journal of Medicine (2017)

Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, is effective in the treatment of juvenile idiopathic arthritis (JIA). We tested the efficacy of adalimumab in the treatment of JIA-associated uveitis.In this multicenter, double-blind, randomized, placebo-controlled trial, we assessed the efficacy and safety of adalimumab in children and adolescents 2 years of age or older who had active JIA-associated uveitis. Patients who were taking a stable dose of methotrexate were randomly assigned in a 2:1 ratio to receive either adalimumab (at a dose of 20 mg or 40 mg, according to body weight) or placebo, administered subcutaneously every 2 weeks. Patients continued the trial regimen until treatment failure or until 18 months had elapsed. They were followed for up to 2 years after randomization. The primary end point was the time to treatment failure, defined according to a multicomponent intraocular inflammation score that was based on the Standardization of Uveitis Nomenclature criteria.The prespecified stopping criteria were met after the enrollment of 90 of 114 patients. We observed 16 treatment failures in 60 patients (27%) in the adalimumab group versus 18 treatment failures in 30 patients (60%) in the placebo group (hazard ratio, 0.25; 95% confidence interval [CI], 0.12 to 0.49; P<0.0001 [the prespecified stopping boundary]). Adverse events were reported more frequently in patients receiving adalimumab than in those receiving placebo (10.07 events per patient-year [95% CI, 9.26 to 10.89] vs. 6.51 events per patient-year [95% CI, 5.26 to 7.77]), as were serious adverse events (0.29 events per patient-year [95% CI, 0.15 to 0.43] vs. 0.19 events per patient-year [95% CI, 0.00 to 0.40]).Adalimumab therapy controlled inflammation and was associated with a lower rate of treatment failure than placebo among children and adolescents with active JIA-associated uveitis who were taking a stable dose of methotrexate. Patients who received adalimumab had a much higher incidence of adverse events and serious adverse events than those who received placebo. (Funded by the NIHR Health Technology Assessment Programme and Arthritis Research UK; SYCAMORE EudraCT number, 2010-021141-41 .).
Smad1/5 is required for erythropoietin-mediated suppression of hepcidin in mice
Authors: Chia-Yu Wang, Amanda B. Core, Susanna Canali, Kimberly B. Zumbrennen-Bullough, Sinan Ozer, Lieve Umans, An Zwijsen, Jodie L. Babitt
Journal: Blood (2017)
Three cases of mcr-1-positive colistin-resistant Escherichia coli bloodstream infections in Italy, August 2016 to January 2017
Authors: Marta Corbella, Bianca Mariani, Carolina Ferrari, Francesco Comandatore, Erika Scaltriti, Piero Marone, Patrizia Cambieri
Journal: Eurosurveillance (2017)

We describe three cases of bloodstream infection caused by colistin-resistant Escherichia coli in patients in a tertiary hospital in Italy, between August 2016 and January 2017. Whole genome sequencing detected the mcr-1 gene in three isolated strains belonging to different sequence types (STs). This occurrence of three cases with mcr-1 -positive E. coli belonging to different STs in six months suggests a widespread problem in settings where high multidrug resistance is endemic such as in Italy.