tbuckley/cabot-search huggingface dataset:
TMIC-49. ACTIVATION OF THE Wnt/β-CATENIN SIGNALING PATHWAY IN GLIOMA STEM CELLS IMPACTS ENDOTHELIAL CELL-CELL INTERACTION
Authors: Amélie Vézina, Mark Gilbert, Sadhana Jackson
Journal: Neuro-Oncology (2018)

The presence of invasive glioma stem cells (GSC) in glioblastoma (GBM) enhances therapy resistance and disease recurrence. Low permeability and high selectivity of the blood-brain barrier (BBB) limits CNS drug delivery of effective treatment against GSC growth. Moreover, increased Wnt/β-catenin signaling in GBM is associated with radio-resistance and proliferation. Interestingly, the Wnt-subtype of medulloblastoma is characterized by activating mutations of β-catenin and associated with a good prognosis linked to a highly permeable BBB. We propose that activation of WNT/β-catenin signaling in GSCs will decrease brain endothelial cell-cell junctional integrity thereby increasing BBB permeability in the tumor microenvironment. We used CHIR99021, a glycogen synthase kinase 3β inhibitor, to activate Wnt/β-catenin signaling in a human derived primary GSC line, GSC923. Human brain microvascular endothelial cells (HBMEC) were treated with conditioned media from GSC923 treated with or without CHIR99021 for 24 hours. Endothelial barrier function was evaluated by electrical cell impedance using the ACEA xCELLigence system. Data was reported by changes in cell index to reflect cell-cell interaction integrity. Junctional expression was evaluated by qPCR, immunoblotting and immunofluorescence. Mass spectrometry of GSC media was evaluated for specific Wnt/β-catenin downstream proteins which impact the BBB. HBMEC cell index was decreased by approximately 60% when treated with conditioned medium from Wnt/β-catenin activated GSC923 cells; suggesting decreased cell-cell interactions and increased permeability. Gene expression of the endothelial junctional proteins, CLAUDIN-3, -5, OCCLUDIN, ZO-1, VE-CADHERIN, PECAM1, and CTNNB1 were decreased by approximately 20–50%. Immunofluorescence and mass spectrometry analysis studies are ongoing. Our findings suggest that disruption of brain endothelial junctional interactions occur in a paracrine manner under the Wnt/β-catenin signaling axis from glioma stem cells to HBMEC. Modulation of intratumoral Wnt/β-catenin signaling, particularly in highly resistant GSCs, may enhance chemotherapy drug delivery, potentially expanding the drug portfolio and improving the prognosis of GBM.
Systematic Review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol
Authors: Peter W.F. Wilson, Tamar S. Polonsky, Michael D. Miedema, Amit Khera, Andrzej S. Kosinski, Jeffrey T. Kuvin
Journal: Journal of the American College of Cardiology (2018)
IMMU-47. HARNESSING ZIKA VIRUS (ZIKV) ONCOLYTIC ACTIVITY IN BRAIN TUMORS
Authors: Arijita Jash, Jennifer Govero, Pei-Yong Shi, Jeremy Rich, Michael S Diamond, Milan G Chheda
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is a highly lethal immunosuppressive brain cancer that contains glioblastoma stem-like cells (GSCs). GSCs are at least partly responsible for tumor maintenance, progression, recurrence and resistance and are thus potential therapeutic targets. ZIKV, a flavivirus, preferentially infects and kills glioblastoma stem cells (GSCs) compared to differentiated tumor progeny and normal neural cells (Zhu, Z. et al. Zika virus has oncolytic activity against glioblastoma stem cells. J. Exp. Med.2017). We are actively investigating if ZIKV-mediated tumor clearance is dependent on the dual mechanism of action of selective tumor cell killing and the induction of systemic anti-tumor immunity. In anticipation of possible clinical use of ZIKV as a GSC therapy, we have introduced mutations in the ZIKV genome that will (1) prevent 2-’O methylation of viral RNA and render it sensitive to inhibition by IFIT1, (2) prevent the generation of non-coding subgennomic (sfRNA) viral RNA that antagonizes type I IFN immunity, (3) limit viral dissemination, and (4) make reversion to the pathogenic virus a highly unlikely event. We are in the process of testing in vivo the efficacy of tumor killing and control of these modified viruses, compared to the parental control. Additionally, we are investigating the effect of ZIKV in controlling patient-derived GSCs in vivo using NSG (non-obese diabetic severe combined immune deficiency, IL2Rγ-null) mice. Lastly, we will present preliminary data on ZIKV treatment followed by immune checkpoint blockade. These findings will further advance the potential use of ZIKV in GBM oncolytic virotherapy.
THU0510 Hypersensitivity, alexithymia and disease characteristics of patients presenting with symptoms of fibromyalgia
Authors: H. Jacobs, B.A. Grillet, D. De Bacquer
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Fibromyalgia (FM) is characterised by chronic widespread pain and other symptoms such as fatigue, sleep disturbances and cognitive problems. Psychosocial factors and personality traits may be present in a variable degree and may play a role in the perception, coping and treatment of FM. <h3>Objectives</h3> We looked for symptoms of hyperventilation, depression, anxiety and burn-out as well as for personality traits such as hypersensitivity and alexithymia in a large sample of patients. We looked at differences in prevalence of these symptoms in the population when selected by the 1990 FM classification criteria and by the 2010 diagnostic FM criteria. <h3>Methods</h3> A large group of patients presenting on the Unit of Physical Medicine between 2014 and 2017 with chronic widespread pain was analysed and grouped depending on the 1990 ACR classification criteria for FM on one hand and the 2010 ACR diagnostic criteria for FM on the other hand. Self-administered tools used were the Nijmegen questionnaire (hyperventilation), the Aron questionnaire (hypersensitivity), the HADS questionnaire (anxiety and depression), the BMS-10 questionnaire (burn-out) and the TAS alexithymia questionnaire. <h3>Results</h3> Out of 1085 patients, 828 (76%) fulfilled the 1990 ACR classification criteria for FM. Hyperventilation (score ≥12) was found in 97% and hypersensitivity (score ≥12) in 75%. Symptoms of anxiety and depression (scores≥11) were observed in 59% and 36% respectively. Burn-out (score ≥4.5) was seen in 40% of patients while a high TAS score (≥8) was found in 70% of patients. Overall, 906 patients fulfilled the 2010 ACR diagnostic criteria for FM. The distributions of disease characteristics and personality traits in this population were very similar. Only 38 out of these 906 patients had a wide spread pain index (WPI) of 3 to 6. <h3>Conclusions</h3> A significant number of patients demonstrated high levels of anxiety, more than depression. Hypersensitivity and alexithymia were also found to be highly prevalent. There was a substantial level of hyperventilation. It may be useful to consider all these characteristics in the development of treatment programs for FM patients. Results were similar when groups were selected by 1990 ACR classification criteria for FM or by the 2010 ACR diagnostic criteria for FM. Only a minority of patients had a WPI of 3 to 6. <h3>References</h3> [1] Van Dixhoorn J, et al. 1985. [2] Wolfe, et al. 1990. [3] Aron, et al. 1997. [4] Maslach, et al. 1996. [5] Wolfe, et al. 2010. [6] Maes, et al. 2014. <h3>Disclosure of Interest</h3> None declared
Effect of Intensive Patient Education vs Placebo Patient Education on Outcomes in Patients With Acute Low Back Pain
Authors: Adrian C. Traeger, Hopin Lee, Markus Hübscher, Ian W. Skinner, G. Lorimer Moseley, Michael K. Nicholas, Nicholas Henschke, Kathryn M. Refshauge, Fiona M. Blyth, Chris J. Main, Julia M. Hush, Serigne Lo, James H. McAuley
Journal: JAMA Neurology (2018)

Many patients with acute low back pain do not recover with basic first-line care (advice, reassurance, and simple analgesia, if necessary). It is unclear whether intensive patient education improves clinical outcomes for those patients already receiving first-line care.To determine the effectiveness of intensive patient education for patients with acute low back pain.This randomized, placebo-controlled clinical trial recruited patients from general practices, physiotherapy clinics, and a research center in Sydney, Australia, between September 10, 2013, and December 2, 2015. Trial follow-up was completed in December 17, 2016. Primary care practitioners invited 618 patients presenting with acute low back pain to participate. Researchers excluded 416 potential participants. All of the 202 eligible participants had low back pain of fewer than 6 weeks' duration and a high risk of developing chronic low back pain according to Predicting the Inception of Chronic Pain (PICKUP) Tool, a validated prognostic model. Participants were randomized in a 1:1 ratio to either patient education or placebo patient education.All participants received recommended first-line care for acute low back pain from their usual practitioner. Participants received additional 2 × 1-hour sessions of patient education (information on pain and biopsychosocial contributors plus self-management techniques, such as remaining active and pacing) or placebo patient education (active listening, without information or advice).The primary outcome was pain intensity (11-point numeric rating scale) at 3 months. Secondary outcomes included disability (24-point Roland Morris Disability Questionnaire) at 1 week, and at 3, 6, and 12 months.Of 202 participants randomized for the trial, the mean (SD) age of participants was 45 (14.5) years and 103 (51.0%) were female. Retention rates were greater than 90% at all time points. Intensive patient education was not more effective than placebo patient education at reducing pain intensity (3-month mean [SD] pain intensity: 2.1 [2.4] vs 2.4 [2.2]; mean difference at 3 months, -0.3 [95% CI, -1.0 to 0.3]). There was a small effect of intensive patient education on the secondary outcome of disability at 1 week (mean difference, -1.6 points on a 24-point scale [95% CI, -3.1 to -0.1]) and 3 months (mean difference, -1.7 points, [95% CI, -3.2 to -0.2]) but not at 6 or 12 months.Adding 2 hours of patient education to recommended first-line care for patients with acute low back pain did not improve pain outcomes. Clinical guideline recommendations to provide complex and intensive support to high-risk patients with acute low back pain may have been premature.Australian Clinical Trial Registration Number: 12612001180808.
INNV-20. UTILITY OF TELEHEALTH FOR SPECIALTY NEUROFIBROMATOSIS (NF) CARE
Authors: Justin Jordan, Marlon Seijo, Vanessa Merker, Shivkumar Bhadola, Raquel Thalheimer, Scott R Plotkin
Journal: Neuro-Oncology (2018)

Telehealth allows for evaluation and management to be delivered over long distances, which may particularly benefit patients with rare neurological diseases. We performed a retrospective cohort study of patients receiving telehealth-based care in our NF clinic, and used ArcGIS to calculate driving distance and time from patients home to clinic. 109 patients (70 female, median age: 37 years) had telehealth visits from May 2016-March 2018, eighteen (17%) of whom had multiple telehealth visits. Patient diagnosis was 33% NF1, 42% NF2, 8% Schwannomatosis, and 17% other, compared to our clinic population of 58% NF1, 31% NF2, 6% Schwannomatosis and 5% other. Only 7 patients (6%) were pediatric, compared to 15% pediatric population in our NF clinic. Telehealth visit indication was 62% routine follow up, 26% new test result follow up, 6% evaluation of a new problem, and 6% on-therapy follow up. The plan developed by telehealth visits included 24% new radiology ordered, 7% new medication ordered, 18% new specialty consultation ordered, and 51% no change in previous plan. Telehealth saved patients a median round trip drive of 108 miles (IQR 388 miles) and a median driving time of 170 minutes (IQR 292 minutes). Telehealth improved NF specialty care through more accessible routine follow up, and urgent evaluation of new symptoms in 6% of patients. Telehealth visits led to new testing, referrals, or medications in 49% of cases, showing that telehealth fulfills a distinct need for services while saving patients time and travel. Adult patients were overrepresented among telehealth cases compared to our general clinic volume, suggesting that in-person examination of children may be preferred by NF providers or families. Given difficulties in access to specialty care, telehealth offers an opportunity to extend care for patients with rare neurological diseases who live at a distance from specialty centers.
Abstract 10360: Prognostic Impact of Early Revascularization in Patients With Cardiac Arrest Due to Acute Coronary Syndrome Undergoing Extracorporeal Cardiopulmonary Resuscitation
Authors: Norihiro Kuroki, Daisuke Abe, Tooru Iwama, Kazuya Tateishi, Masakazu Kaneko, Tomohiko Harunari, Yoshiaki Yui, Takao Yuba, Kou Suzuki, Kazuhiro Sugiyama, Akiko Akashi, Yuichi Hamabe, Akira Sato
Journal: Circulation (2015)

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) and emergency revascularization has been reported to improve survival in patients with refractory cardiac arrest complicated by acute coronary syndrome (ACS). However the best timing for this therapy is not clear. We investigated the relationship between the time interval from collapse to revascularization and mortality for ECPR in the patients with non-ST and ST elevation ACS. Methods: A cohort of 228 patients who underwent ECPR at our hospital was registered from January 2005 to April 2015. After excluding 121 patients with non-ACS, we analyzed the clinical outcome which was defined as all-cause death at 30 days of the remaining 107 patients (63±11years old, 90% male). We divided patients into 3 groups according to collapse to revascularization time; Group1 (time&lt;90min: n=28), Group2 (90≦time&lt;180min: n=40) and Goup3 (time≧180min or unsuccessful of revascularization: n=39). Results: 43 patients was non-ST elevation ACS. 81 patients underwent emergency revascularization. 29 patients had 30 days survival. Platelet and bicarbonate ion was higher in Group1. Lactate level was lower in Group1. But other baseline characteristics did not differ. Kaplan-Meier curve showed Group1 was better outcome compared with other groups (p&lt;0.0001 log-rank) (Figure). Multivariate analysis revealed that independent predictors of 30 days in-hospital mortality were longer time interval from collapse to revascularization (per increase OR: 1.05, 95%CI:1.01-1.08, p&lt;0.01), lactate level (OR:0.42 , 95%CI:0.22-0.83, p=0.01) and other factors. Incidence of all-cause death at 30 days was significantly higher both ST and non-ST elevation ACS in Group3 than in Group 1 and 2; (ST elevation in Group3 vs 2 and 1: 84% vs 58%; p&lt;0.05) (non-ST: 100% vs 70% ;p&lt;0.01). Conclusions: Shorter time interval from collapse to revascularization predict better clinical outcome in patients with non-ST and ST elevation ACS undergoing ECPR.
EXTH-64. IMIPRIDONES CAUSE METABOLIC REPROGRAMMING AND ELICIT UNIQUE VULNERABILITIES IN PRECLINICAL MODEL SYSTEMS OF GLIOBLASTOMA
Authors: Chiaki Ishida, Yiru Zhang, Mike-Andrew Westhoff, Georg Karpel-Massler, Varun Vijay Prabhu, Joshua Allen, Markus Siegelin
Journal: Neuro-Oncology (2018)

The purpose of this study is to improve the efficacy of imipridones, a novel class of AKT/ERK inhibitors. The lead compound ONC201 has entered clinical testing for glioblastoma (GBM) and recently chemically modified imipridones, ONC206 and ONC212, have been designed. Transcriptome, untargeted liquid chromatography/mass spectrometry and extracellular flux analysis unraveled the mechanism of action of novel imipridone compounds, ONC206 and ONC212. We used orthotopic patient-derived GBM xenografts to assess preclinical treatment efficacy. Imipridones inhibit the proliferation of patient-derived xenograft and stem-like glioblastoma cell cultures in vitro and in multiple xenograft models in vivo. ONC212 demonstrated the highest efficacy. High levels of c-myc predict susceptibility to cell death induction by imipridones and increased host survival in orthotopic patient-derived xenografts. At 1h, imipridones inhibit AKT and ERK signaling, accompanied by dephosphorylation of GSK3b. GSK3b phosphorylates c-myc at threonine 58, leading to its proteasomal degradation. Imipridone mediated suppression of c-myc inhibits both glycolysis and oxidative phosphorylation. In turn, energy deprivation leads to a compensatory activation of the serine-one carbon-glycine (SOG) pathway. Interference with the SOG pathway through novel inhibitors of phosphoglycerate dehydrogenase (PHGDH) results in synergistic apoptosis induction in vitro and in vivo. These observations suggest that c-myc expression predicts therapeutic responses to imipridones and that imipridone mediated inhibition of c-myc leads to suppression of tumor cell energy metabolism, eliciting unique metabolic vulnerabilities that can be exploited for clinical relevant drug combination therapies.
TMOD-08. GROWTH IMPAIRMENT UNDER CONDITIONS FAVORING MITOCHONDRIAL OXIDATIVE METABOLISM IN A YEAST MODEL OF CANCER-ASSOCIATED ISOCITRATE DEHYDROGENASE MUTATION
Authors: Sophie Fiola, Elie Ganni, Rita Lo, Elena Kuzmin, Roberto Diaz
Journal: Neuro-Oncology (2018)

The use of the budding yeast Saccharomyces cerevisiae as a model system to study cancer allows for faster, more efficient elucidation of various molecular mechanisms, including mutation rate by fluctuation analysis, cell cycle analysis by flow cytometry, metabolism via growth rate analysis, and functional genomics via genomic array screening. The vast majority of low grade gliomas (LGGs) carry somatic mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) genes. IDH1 and IDH2 catalyze the oxidative decarboxylation of isocitrate to a-ketoglutarate (a-KG) in an NADP+ dependent manner. A point mutation (R132H in IDH1 and R172H in IDH2) confers the neomorphic ability for the enzyme reduce a-KG to D-2-hydroxyglutarate (D2-HG). In S. cerevisae, the NADP+ dependent isocitrate dehydrogenases are encoded by three different genes, IDP1, IDP2 and IDP3. We have successfully generated a yeast model that carries the analogous mutation in the yeast IDP1 gene (IDP1R148H). The allele was inserted at the HO locus, which does not alter the endogenous IDP1 gene. In this way, the resulting strain carries both a wild-type and mutant allele of IDP, more closely mimicking the metabolic state of glioma cells. We have validated this insertion by PCR, sequencing, and tetrad analysis. The production of the mutant IDP1R148H protein was detected by Western blot. The IDP1R148H strain shows normal growth on glucose and galactose-containing solid media, but reduced growth on glycerol-containing solid media compared to parental or IDP1WT strains. Impaired growth of yeast when glycerol is the sole carbon source suggests a defect in mitochondrial oxidative metabolism. This observation is consistent with a previous yeast IDP1R148H model which showed extensive mitochondrial DNA loss and respiration defects. Taken together, we have developed a model of IDH-mutant LGGs in S. cerevisiae that can be further utilized to study molecular mechanisms underlying tumorigenesis of LGGs.
Abstract 10940: Distensibility of the Pulmonary Circulation During Exercise in Heart Failure
Authors: Bishnu P Dhakal, Rajeev Malhotra, Paul P Pappagianopoulos, Aaron S Eisman, Gregory D Lewis
Journal: Circulation (2015)

Background: Pulmonary vascular distensibility (PVD) permits the pulmonary arteries to increase in size to accommodate increased blood flow and is measured as the percent increase in pulmonary vessel diameter per mmHg increase in pressure. We hypothesized that impaired PVD is related to reduced functional capacity in patients with heart failure (HF) or pulmonary arterial hypertension (PAH). Methods and Results: Patients with HF and preserved ejection fraction (HFpEF, n=48), HF and reduced ejection fraction (HFrEF, n=55), PAH (n=18), and age matched controls (n=30) underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and first-pass radionuclide ventriculography. PVD was lowest in the PAH group (mean±SD 0.36±0.25% per mmHg) and intermediate in the HFpEF and HFrEF groups (0.92±0.39 and 0.84±0.33% per mmHg, respectively) compared to controls (1.39±0.32, P&lt;0.0001 for all three, Fig. 1A). PVD was strongly associated with measurements of right ventricular-pulmonary vascular function during exercise including change in RVEF (ρ=0.39, P&lt;0.0001, Fig. 1B) and change in pulmonary vascular resistance (ρ=-0.51, P&lt;0.0001) with exercise. PVD was an independent predictor of peak VO2 in a multivariate model that included age, gender, hemoglobin, resting cardiac index, resting LVEF, and resting mean pulmonary artery pressure. 14 out of 26 HFrEF patients who were treated with sildenafil (25-75 mg orally TID) for 12 weeks demonstrated a 24.6% increase in PVD (p=0.015) compared to no change in PVD in those treated with placebo (n=12). Conclusions: Pulmonary vascular distensibility is reduced in patients with HF and PAH and is closely related to functional capacity and RV systolic function during exercise. Furthermore, distensibility was modifiable with selective pulmonary vasodilator therapy, suggesting that distensibility of the pulmonary vessels may be an important therapeutic target in the treatment of HF and pulmonary hypertension.
Accreditation—a verification ritual lacking verification
Authors: Ian G Wilson
Journal: BMJ (2018)

The King’s Fund found that Care Quality Commission (CQC) audits had little impact on the quality of care.1 Oxebridge has put this in the wider context, saying that placing confidence in related systems from the International Organization for Standardization (ISO) does not prevent loss of life.2

Compliance with such standards is equated with “quality.” But these standards lack anything more …
CSIG-29. THE DUAL PI3K/mTOR-PATHWAY INHIBITOR GDC-0084 ACHIEVES ANTITUMOR ACTIVITY IN BREAST CANCER BRAIN METASTASES IN VITRO AND IN VIVO
Authors: Franziska Ippen, Christopher Alvarez-Breckenridge, Benjamin Kuter, Alexandria Fink, Ivanna Bihun, Tristan Penson, Jianfang Ning, Hiroaki Wakimoto, Priscilla Brastianos
Journal: Neuro-Oncology (2018)

Breast cancer is the second most common primary tumor leading to brain metastases in adult cancer patients. Previous studies have shown that the PI3K/AKT/mTOR pathway in breast cancer brain metastasis is activated in up to 70% of analyzed tumors. However, there are no approved agents targeting this pathway in breast cancer brain metastases at present. GDC-0084 is a dual brain penetrant PI3K/mTOR-inhibitor that has already demonstrated promising response rates in a preclinical glioblastoma model. The aim of this study was to analyze the efficacy of this compound in a breast cancer brain metastases model in vitro and in vivo using PIK3CA-mutant and PIK3CA-wildtype cell lines. In vitro methods included cell viability, apoptosis, growth inhibition assays, cell cycle analysis, Western blots and immunohistochemistry. In vivo, the effect of GDC-0084 was evaluated in an orthotopic intracranial mouse model with bioluminescent imaging. GDC-0084 induced apoptosis in PIK3CA-mutant breast cancer brain metastases cell lines and growth inhibition in PIK3CA-wildtype cell lines in vitro and markedly inhibited tumor growth of PIK3CA-mutant cell lines in vivo. The results of this study highlight the importance of brain-penetrant agents targeting the PI3K/AKT/mTOR-pathway and suggest that GDC-0084 might be a promising treatment option for breast cancer brain metastases patients in the future.
Sixty seconds on . . . the Human Cell Atlas
Authors: Ingrid Torjesen
Journal: BMJ (2018)

On a journey into the human body. This is a reference atlas of all human cells (www.humancellatlas.org) that has the potential to “impact almost every aspect of biology and medicine, leading to a richer understanding of life’s most fundamental units and principles.” 

The developers certainly hope so. They predict it will enable scientists to “boldly go where no man has gone before” in a sense—but not literally as in the mid 60s sci fi movie in …