tbuckley/cabot-search huggingface dataset:
Firearm Homicides and Suicides in Major Metropolitan Areas — United States, 2012–2013 and 2015–2016
Authors: Scott R. Kegler, Linda L. Dahlberg, James A. Mercy
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Firearm homicides and suicides represent a continuing public health concern in the United States. During 2015-2016, a total of 27,394 firearm homicides (including 3,224 [12%] among persons aged 10-19 years) and 44,955 firearm suicides (including 2,118 [5%] among persons aged 10-19 years) occurred among U.S. residents (1). This report updates an earlier report (2) that provided statistics on firearm homicides and suicides in major metropolitan areas during 2006-2007 and 2009-2010, and places continued emphasis on youths, in recognition of the importance of early prevention efforts. Firearm homicide and suicide rates were determined for the 50 most populous U.S. metropolitan statistical areas (MSAs)* during 2012-2013 and 2015-2016 using mortality data from the National Vital Statistics System (NVSS) and population data from the U.S. Census Bureau. In contrast to the earlier report, which indicated that firearm homicide rates among persons of all ages had been declining both nationally and in large MSAs overall, current findings show that rates have returned to levels comparable to those observed during 2006-2007. Consistent with the earlier report, these findings show that firearm suicide rates among persons aged ≥10 years have continued to increase, both nationally and in large MSAs overall. Although firearm suicide rates among youths remain notably lower than those among persons of all ages, youth rates have also increased both nationally and in large MSAs collectively. These findings can inform ongoing development and monitoring of strategies directed at reducing firearm-related violence.
ESCMID generic competencies in antimicrobial prescribing and stewardship: towards a European consensus
Authors: O.J. Dyar, B. Beović, C. Pulcini, E. Tacconelli, M. Hulscher, B. Cookson, D. Ashiru-Oredope, I. Barcs, H.S. Blix, F. Buyle, M. Chowers, M. Čižman, B. Cookson, J.L. Del Pozo, A. Deptula, U. Dumpis, D. Florea, E. van de Garde, Y. Geffen, C.G. Giske, S. Grau, E. Hajdú, M. Hell, Ł. Hondo, K. Hussein, B. Huttner, W. Kern, S. Kernéis, V. Knepper, D. Kofteridis, T. Kostyanev, E. Kuijper, H. Lebanova, R. Lewis, C.M. Cordina, R. Matulionyte, F. Maurer, P. Messiaen, J. Miciuleviciene, A. Mrhar, M. Nabuurs-Franssen, R. Naesens, C. Oxacelay, L. Pagani, J.R. Paño-Pardo, M. Paul, G. Petrikkos, C. Pluess-Suard, G.A. Popescu, U. Porsche, J. Prins, C. Pulcini, J. Rello, J. Rodríguez-Baño, G.M. Rossolini, B. Salzberger, K. Seme, G.S. Simonsen, M. Sînziana, S. Skovgaard, I. Smith, U. Sönsken, A. Soriano, I. Sviestiņa, E. Szilagyi, T. Tängdén, P. Tattevin, C. Tsioutis, A. Vilde, M. Wanke-Rytt, A. Wechsler-Fördös, P. Zarb
Journal: Clinical Microbiology and Infection (2018)

ObjectiveTo develop a consensus-based set of generic competencies in antimicrobial prescribing and stewardship for European prescribers through a structured consensus procedure.MethodsThe RAND-modified Delphi procedure comprised two online questionnaire rounds, a face-to-face meeting between rounds, and a final review. Our departure point was a set of competencies agreed previously by consensus among a UK multi-disciplinary panel, and which had been subsequently revised through consultation with ESCMID Study Group representatives. The 46 draft competency points were reviewed by an expert panel consisting of specialists in infectious diseases and clinical microbiology, and pharmacists. Each proposed competency was assessed using a nine-point Likert scale, for relevance as a minimum standard for all independent prescribers in all European countries.ResultsA total of 65 expert panel members participated, from 24 European countries (one to six experts per country). There was very high satisfaction (98%) with the final competencies set, which included 35 competency points, in three sections: core concepts in microbiology, pathogenesis and diagnosing infections (11 points); antimicrobial prescribing (20 points); and antimicrobial stewardship (4 points).ConclusionsThe consensus achieved enabled the production of generic antimicrobial prescribing and stewardship competencies for all European independent prescribers, and of possible global utility. These can be used for training and can be further adapted to the needs of specific professional groups.
PDTM-17. DUAL TARGETING OF SHH SIGNALING AND BCL-xL FUNCTION AS A NOVEL TREATMENT FOR MEDULLOBLASTOMA
Authors: Katherine Veleta, Timothy Gershon
Journal: Neuro-Oncology (2018)

Medulloblastoma is markedly more sensitive to radiation and chemotherapy than other malignant brain tumors. We have previously shown that medulloblastomas radiation sensitivity of depends on the function of the internal apoptosis pathway. We tested whether this pathway could be directly activated, without radiation, by targeting the anti-apoptotic protein BCL-xL. Conditional deletion of Bcl-xL in in cerebellar progenitors induced precipitous apoptosis as these cells exited the cell cycle. Bcl-xL deletion in SHH-driven medulloblastomas in SmoM2 mice also impaired tumor growth and caused focal regions of tumor necrosis. However, Bcl-xL-deleted medulloblastomas eventually progressed. Expression microarray analysis showed increased Cdk2 in Bcl-xL-deleted tumors, suggesting that Bcl-xL deletion selected for tumor cells that rapidly re-entered the cell cycle. Consistent with the idea that proliferating cells are relatively protected from BCL-xL dependence, we found that proliferating cerebellar progenitors evade apoptosis through SHH-dependent expression of the BCL-xL homolog MCL-1. To address this potential mechanism of resistance in on-going work, we are combining Bcl-xL deletion with SHH inhibition, testing the hypothesis that forced cell cycle exit will reduce MCL-1 and sensitize medulloblastomas to BCL-xL disruption. Based on our data, we propose combined targeting of the SHH signaling and BCL-xL function as a new approach to medulloblastoma treatment.
Allergen‐specific IgE over time in women before, during and after pregnancy
Authors: Anna M. Hedman, Cecilia Lundholm, Annika Scheynius, Johan Alm, Ellika Andolf, Göran Pershagen, Catarina Almqvist
Journal: Allergy (2018)

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ACTR-32. 5-ALA FLUORESCENCE IS A POWERFUL MARKER FOR DETECTION OF UNEXPECTED GLIOBLASTOMA TISSUE DURING SURGERY OF RADIOLOGICALLY SUSPECTED LOW-GRADE GLIOMAS
Authors: Petra A Mercea, Arthur Hosmann, Shawn Hervey-Jumper, Adelheid Woehrer, Barbara Kiesel, Jonathan Weller, Joanna J Phillips, Georg Widhalm, Mitchel Berger
Journal: Neuro-Oncology (2018)

Precise tissue sampling during resection of suspected low-grade gliomas (LGG) is the basis for an accurate histopathological diagnosis to enable adequate patient management. In the course of malignant transformation of initial LGG, small intratumoral areas of glioblastoma tissue can potentially arise that might be unrecognized during surgery and thus result in treatment failure. Recently, 5-aminolevulinic acid (5-ALA) induced fluorescence was identified as intraoperative marker for visualization of focal intratumoral WHO grade III areas. The aim of this study is thus to clarify if 5-ALA is also capable to identify areas of unexpected glioblastoma tissue during surgery of radiologically suspected LGG. Our database at the Medical University of Vienna and University of California, San Francisco was screened for adult patients with 5-ALA fluorescence-guided resection of a suspected glioma with non-significant MRI contrast-enhancement (CE; no, patchy/faint or focal CE). In this study, only patients with newly diagnosed lesions were included. In contrast, recurrent gliomas and biopsy only cases were excluded. In all patients, histopathological diagnosis was established according to the WHO classification. Altogether, 7 patients (median age: 53 years, range: 30–66 years) with histological diagnosis of a glioblastoma were identified despite initial radiological suspicion of LGG. Of these, no CE was found on preoperative MRI in two cases (29%), patchy/faint CE in two cases (29%) and focal CE in three cases (42%). During surgery, intratumoral areas with focal 5-ALA induced fluorescence were observed in all 7 patients. In contrast, no visible fluorescence was found in the remaining intratumoral regions. Our study indicates that 5-ALA induced fluorescence is able to identify intratumoral areas containing even focal glioblastoma tissue in radiologically suspected LGG. Thus, the 5-ALA technique will in future markedly improve tissue sampling during resection of suspected LGG to allow a precise histopathological diagnosis and optimized postoperative patient management.
ATIM-28. PHASE 2 STUDY OF ERC1671 PLUS BEVACIZUMAB VS BEVACIZUMAB PLUS PLACEBO IN RECURRENT GBM INTERIM RESULTS AND CORRELATIONS WITH CD4+ T LYMPHOCYTE COUNTS
Authors: Daniela A Bota, Jinah Chung, Manisha Dandekar, Jose A Carrillo, Xiao-tang Kong, Dan Beverly Fu, Frank P K Hsu, Alex H Schönthal, Florence M Hofman, Thomas C Chen, Raphael Zidovetzki, Chrystel Pretto, Ankie Strik, Virgil E J C Schijns, Apostolos Stathopoulos
Journal: Neuro-Oncology (2018)

ERC1671 is an allogeneic/autologous therapeutic glioblastoma (GBM) vaccine composed of whole, inactivated tumor cells mixed with tumor cell lysates derived from the patient and three GBM donors. Previously published compassionate use data showed an overall survival (OS) of 43 weeks (10 months) in patients with a good performance status. In this double-blinded, randomized, phase 2 study bevacizumab-naïve patients with recurrent GBM were randomized after surgery to receive either ERC1671 in combination with GM-CSF and cyclophosphamide plus bevacizumab, or placebo plus bevacizumab. The trial is registered with ClinicalTrials.gov (NCT01903330). Interim Nine patients, with a KPS 70, were randomized and treated. At the time of further progression, these patients were unblinded, as stipulated by the protocol, which revealed that four had received vaccine, four had received placebo, and one was non-evaluable. Median OS of patients treated with ERC1671 plus bevacizumab was 12 months, with one patient surviving >2 years. In the group treated with placebo plus bevacizumab, median OS was shorter at 7.5 months, with all patients having succumbed within 1 year. Toxicity analysis showed an equal distribution of adverse events (AE) between the vaccine and placebo groups, with no grade 4 or 5 toxicities. The maximal CD4+ T lymphocyte count in the peripheral blood correlated with OS in the ERC1671 but not in the placebo group. The addition of ERC1671/GM-CSF/cyclophosphamide to bevacizumab resulted in a potential survival benefit with minimal additional toxicity. The maximal CD4+ T lymphocyte count in the peripheral blood correlated with OS. The study is ongoing with the addition of two other sites.
TMIC-53. IDENTIFICATION OF MYELOID CELL-DERIVED TRANSCRIPTS IN GLIOBLASTOMA
Authors: Frank Szulzewsky, Sonali Arora, Dolores Hambardzumyan, Eric Holland
Journal: Neuro-Oncology (2018)

Glioblastoma-associated microglia and macrophages/monocytes (GAMs) constitute the most abundant type of immune cells in glioblastoma. To date there is still insufficient knowledge about the expression profiles and activation states of these cells. We have previously performed RNA-Seq and microarray on CD11b+ freshly isolated human and mouse GAMs. Here we combine this data with analysis from published whole tumor TCGA data to identify new myeloid-derived transcripts in glioblastoma. We first re-analyzed our previously published human GAMs RNA-Seq dataset for genes that are at least 4-fold up regulated in comparison to naïve microglia and displayed an absolute log2 expression greater than 7. Subsequently, we queried the TCGA glioblastoma dataset to identify genes that showed a high correlation to the myeloid markers CD68, CD14, and AIF1. We found that the expression of IBSP, FCGBP, MARCO, RNASE1, CTSL, SPP1, and GPNMB significantly correlated with the expression of the different myeloid markers. In addition, the correlation was the highest in the proneural subtype samples, which have previously been shown to harbor the highest percentage of myeloid cells. Three of these genes (Spp1, Ctsl, and Gpnmb) were also highly expressed in murine GAMs. Finally, we performed immunofluorescence stainings for CTSL and GPNMB in human GBM samples and PDGF-driven mouse tumors and could show that both proteins were highly abundant in IBA1+ myeloid cells in both human and mouse samples. Conclusively, we have identified several new myeloid-specific genes in glioblastoma that might pose potential new targets. Subsequent studies will be necessary to evaluate the role of these genes in glioblastoma.
Tumor induced upregulation of TWIST and SNAIL Repress VE Cadherin promoter activity via AKT and ERK/MAPK pathways
Authors: W.Bradford Carter, Guilian Niu, Niranjan Yanamandra
Journal: Cancer Research (2007)

2803  Endothelial integrity is dependent on intercellular adherens junctions formed by complexes of Vascular Endothelial (VE) cadherin and catenins. VE cadherin is a single-chain transmembrane protein that forms homophilic intercellular interactions specific to endothelial cells (EC) and mediates EC adhesion. In epithelial cells, E cadherin similarly anchors intercellular junctions, and down-regulation of E cadherin induces tumor invasion. During extravasation, cancer cells induce EC dissociation and loss of VE cadherin. While TWIST and SNAIL are transcriptional repressors of the E cadherin promoter, very little is known about TWIST and SNAIL regulation of VE-cadherin. In this study, we explored the hypothesis that TWIST and SNAIL upregulation in EC represses the VE cadherin promoter and disrupts EC integrity. In our study, human dermal microvessel endothelial cells (HDMEC) exposed to 24 hr conditioned media from SKBr-3 and MCF-7 breast cancer cells showed decreased expression of VE cadherin and upregulation of TWIST and SNAIL proteins by Western blot and qPCR. Using a Luciferase reporter construct, decreased VE cadherin promoter activity was seen in 293-T cells transfected with SNAIL cDNA. Further, Western blot data showed activated AKT and ERK/MAPK pathways in ECs exposed to conditioned media from SKBr-3 and MCF-7 cells. Blockade of AKT and ERK/MAPK pathways abrogated both VE cadherin down-regulation and SNAIL and TWIST upregulation. Taken together our results suggest that tumor released factors upregulate TWIST and SNAIL in HDMEC by AKT and ERK/MAPK kinase dependent pathways. These transcriptional repressors down-regulate the VE cadherin promoter leading to loss of VE cadherin in EC. Further, loss of VE cadherin disrupts EC integrity, facilitating tumor extravasation and metastataic progression. Optimizing EC stabilization to support EC barrier function may provide a “firewall” that may work synergistically with anti-angiogenic therapies.
CBMT-12. FATTY ACID SYNTHASE POSITIVE EVs AS NOVEL BIOMARKERS IN BRAIN CANCER.
Authors: Franz Ricklefs, Cecile Maire, Katharina Kolbe, Mareike Holz, Jakob Matschke, Sean Lawler, E Antonio Chiocca, Manfred Westphal, Katrin Lamszus
Journal: Neuro-Oncology (2018)

Extracellular vesicles (EVs) are known for their important role in cancer progression and hold considerable potential as tumor biomarkers. However, purification of tumor-specific EVs from plasma is still a pressing need since contamination by normal host cell-EVs, results in compromised analytical sensitivity. Fatty acid synthase (FASN) was recently shown by us to be present on EVs from cultured glioma cells. Here we analyzed circulating patient EVs for the expression of FASN, CD9, CD81 and CD63. Plasma EVs from patients with glioblastoma (n=24), anaplastic astrocytoma (n=6) and healthy controls (n=16) as well as EVs from early passage glioma stem cells (GSCs) were analyzed for FASN, CD9, CD81, CD63 by imaging flow cytometry (IFC). EVs were further investigated by nanoparticle tracking analysis (NTA), electron microscopy and immunoblotting. Glioblastomas, anaplastic astrocytomas and normal brain tissue specimens were analyzed for FASN by Western blotting and immunohistochemistry. FASN is elevated in glioblastoma tissue compared to noncancerous brain and FASN expression levels correlate with WHO grade (p+/CD81+and FASN+/CD63+EVs are present in plasma from patients with glioblastoma and anaplastic astrocytoma as determined by IFC (p+EVs and double positive (CD9+/CD63+, CD9+/CD81+or CD63+/CD81+) EVs (p CONCLUSION: FASN expression is elevated on circulating EVs from patients with malignant gliomas and FASN is a promising marker for the identification and enrichment of glioma-derived plasma EVs, an important prerequisite for in-depth genetic, epigenetic and transcriptional analyses that could inform clinicians on molecular alterations and help monitoring treatment efficacy.
CSIG-20. GBP2 ENHANCES GLIOBLASTOMA INVASION THROUGH STAT3/FIBRONECTION PATHWAY
Authors: Shuye Yu, Ming Li
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is the most common and deadliest form of brain tumor in adults. Guanylate-binding protein 2 (GBP2) is an interferon-inducible large GPTase with antimicrobial activities. However, its biological function in cancer remains largely unknown. Here we show that GBP2 expression is highly elevated in GBM tumor and cell lines, particularly those of the mesenchymal subtype. High GBP2 expression is associated with poor outcomes for GBM patients. GBP2 deregulation has no obvious effects on GBM cell proliferation in vitro. GBP2 overexpression significantly promotes GBM cell migration and invasion, and GBP2 silencing by RNA interference exhibits opposite effects. We further show that fibronectin (FN1) is dramatically induced by GBP2 expression at both mRNA and protein levels, and FN1 is essential for GBP2-promoted GBM invasive capacity. Inhibition of STAT3 pathway prevents GBP2-promoted FN1 induction and cell invasion. Consistently, GBP2 dramatically promotes GBM tumor growth and invasion in mice, and GBP2 expression significantly shortens the survival time of the mice with tumor. Together, these findings establish the role of GBP2/STAT3/FN1 signaling cascade in GBM invasion and suggest GBP2 may serve as a novel potential therapeutic target for inhibiting GBM invasion.
Abstract 16717: Customizable High-density Microelectrode Arrays for Murine Cardiac Electrophysiology
Authors: Pradeep S Rajendran, Olujimi A Ajijola, Rio Vetter, Andre Snellings, John D Tompkins, Arjun Deb, Daryl R Kipke, Kalyanam Shivkumar, Jeffrey L Ardell
Journal: Circulation (2016)

Introduction: Mouse models offer robust approaches to study cardiac physiology and pathophysiology in part due to the ability to manipulate their genome. Traditional methods for recording murine cardiac electrophysiologic (EP) data involve electrocardiograms and small catheters in vivo which provide limited spatial resolution, or optical mapping ex vivo which requires electromechanical uncoupling. Objective: To develop high-density microelectrode arrays for high-fidelity, high-resolution recording of murine cardiac EP data. Methods & Results: We have developed high-density microelectrode arrays for recording unipolar electrocardiograms and pacing from the epicardial surface of the murine heart (Fig. 1A). These arrays are composed of a thin-film polymer with a grid of addressable electrode sites. The highly flexible polymer substrate maintains conformal contact with the heart as it beats. The design space for the arrays include grid dimensions from approximately 200 μm to 8 cm and 16 to 512 electrodes, wit...
COMP-09. HFE EXPRESSION ALTERS OUTCOMES IN BRAIN TUMORS
Authors: Darya Nesterova, Sang Lee, Lindsay Stetson, Justin Lathia, Joshua Rubin, Kristin Waite, Michael Berens, James Connor
Journal: Neuro-Oncology (2018)

Iron homeostasis is essential for cellular energy production particularly in rapidly dividing cells. The HFE protein is critical for regulating cellular iron uptake. To explore the impact of HFE expression in glioblastoma (GBM) and other brain tumors, we utilized TCGA GBM and GBMLGG databases from GlioVis. Within the GBMLGG database which includes lower grade tumors, high expression of HFE was associated with significantly poorer survival. In GBM patients with high HFE expression survival was also significantly worse compared to low HFE expression. There was a strong positive correlation between high HFE expression and tumor grade, with the highest expression in GBM. HFE expression was also correlated to GBM subtype. The lowest expression was in the proneural subtype and the highest in the mesenchymal subtype consistent again with high expression associated with worse prognosis. Normally MGMT methylation is associated with better outcome. However, when combined with high HFE expression there is a significant reduction in survival time (12.9 vs. 20.8 months). To identify the possible molecular basis for these survival differences, we interrogated the reverse phase protein array data (RPPA) for TCGA datasets and discovered a correlation between high HFE expression and expression of a number of proteins. Annexin-1 has the highest correlation of expression with HFE. This protein plays a critical role in innate immune response through the generation of proinflammatory mediators and modulates migration and the phagocytotic ability of neutrophils and macrophages. We have previously shown that mutations in the HFE protein alter macrophage phenotype. Mutations in the HFE gene, the most common autosomal recessive polymorphism found in Caucasians, reportedly impacts the progression of a number of diseases including GBMs. This study identifies HFE as a negative modulator of outcome in brain tumors.
Further Lessons in <i>Pneumocystis</i> Pneumonia Prophylaxis
Authors: Gabriela Schmajuk, Jinoos Yazdany
Journal: JAMA Internal Medicine (2018)

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