tbuckley/cabot-search huggingface dataset:
HGG-21. IDENTIFICATION OF SMALL MOLECULE KINASE INHIBITORS WITH SPECIFIC ACTIVITY IN PEDIATRIC GLIOMA
Authors: Erin Simonds, Nima Aghaeepour, Geraldine Cayanan, Joshua Park, Garry Nolan, William Weiss
Journal: Neuro-Oncology (2017)

HYPOTHESIS: We hypothesize that pediatric high-grade glioma (pedHGG) tumors are sustained by pro-survival and pro-growth kinase signaling pathways that are distinct from adult GBM and normal brain, and can thereby be specifically targeted with small molecule inhibitors. METHODS: We performed a high-throughput chemical genetic screen using the GSK-PKISv1 library of 310 small molecule kinase inhibitors. These chemically diverse compounds have been tested in cell-free kinase inhibition assays measuring 203 unique kinases (37% of the human kinome), providing information on their efficacy against common and orphan kinases. We initially screened 5 high-grade glioma cell lines: 2 supratentorial pedHGG (KNS-42, SU-pcGBM2), 1 brainstem pedHGG (SU-DIPG-IV), and 2 adult supratentorial GBM (U251 MG, GBM43). We also screened immortalized normal human astrocytes to control for nonspecific cytotoxicity. In the initial screen, cells were treated at 1 μM for 24h, then measured for changes in viability, cell cycle, and apoptosis. Of the initial 310 compounds, 15 were selected for follow-up screening based on evidence of specific killing of pedHGG. To identify mechanisms underlying each compound’s activity, we leveraged the available cell-free kinome data and cross-referenced this against gene expression data from pedHGG and adult GBM tumors. RESULTS: Follow-up screening in 8 cell lines revealed 6 lead compounds that had efficacy against multiple pedHGG lines while sparing normal astrocytes and multiple adult GBM lines. The 6 lead compounds had diverse chemical backbones and patterns of activity across in cell-free kinase assays. The top targets of these compounds include some well-known glioma oncogenes (i.e. PDGFRA, EGFR), as well as novel targets (i.e. ERBB4, PYK2, HIPK1, LTK). CONCLUSIONS: Our chemical genetic approach identified 6 diverse small molecule kinase inhibitors with evidence of specific activity against pedHGG cell lines. Genetic and pharmacological validation of the putative targets of these compounds is underway to prioritize candidates for clinical translation.
N-BLR, a primate-specific non-coding transcript leads to colorectal cancer invasion and migration
Authors: Isidore Rigoutsos, Sang Kil Lee, Su Youn Nam, Simone Anfossi, Barbara Pasculli, Martin Pichler, Yi Jing, Cristian Rodriguez-Aguayo, Aristeidis G. Telonis, Simona Rossi, Cristina Ivan, Tina Catela Ivkovic, Linda Fabris, Peter M. Clark, Hui Ling, Masayoshi Shimizu, Roxana S. Redis, Maitri Y. Shah, Xinna Zhang, Yoshinaga Okugawa, Eun Jung Jung, Aristotelis Tsirigos, Li Huang, Jana Ferdin, Roberta Gafà, Riccardo Spizzo, Milena S. Nicoloso, Anurag N. Paranjape, Maryam Shariati, Aida Tiron, Jen Jen Yeh, Raul Teruel-Montoya, Lianchun Xiao, Sonia A. Melo, David Menter, Zhi-Qin Jiang, Elsa R. Flores, Massimo Negrini, Ajay Goel, Menashe Bar-Eli, Sendurai A. Mani, Chang Gong Liu, Gabriel Lopez-Berestein, Ioana Berindan-Neagoe, Manel Esteller, Scott Kopetz, Giovanni Lanza, George A. Calin
Journal: Genome biology (2017)

Non-coding RNAs have been drawing increasing attention in recent years as functional data suggest that they play important roles in key cellular processes. N-BLR is a primate-specific long non-coding RNA that modulates the epithelial-to-mesenchymal transition, facilitates cell migration, and increases colorectal cancer invasion. We performed multivariate analyses of data from two independent cohorts of colorectal cancer patients and show that the abundance of N-BLR is associated with tumor stage, invasion potential, and overall patient survival. Through in vitro and in vivo experiments we found that N-BLR facilitates migration primarily via crosstalk with E-cadherin and ZEB1. We showed that this crosstalk is mediated by a pyknon, a short ~20 nucleotide-long DNA motif contained in the N-BLR transcript and is targeted by members of the miR-200 family. In light of these findings, we used a microarray to investigate the expression patterns of other pyknon-containing genomic loci. We found multiple such loci that are differentially transcribed between healthy and diseased tissues in colorectal cancer and chronic lymphocytic leukemia. Moreover, we identified several new loci whose expression correlates with the colorectal cancer patients' overall survival. The primate-specific N-BLR is a novel molecular contributor to the complex mechanisms that underlie metastasis in colorectal cancer and a potential novel biomarker for this disease. The presence of a functional pyknon within N-BLR and the related finding that many more pyknon-containing genomic loci in the human genome exhibit tissue-specific and disease-specific expression suggests the possibility of an alternative class of biomarkers and therapeutic targets that are primate-specific.
Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice
Authors: Qiaoqiao Shi, Saba Chowdhury, Rong Ma, Kevin X. Le, Soyon Hong, Barbara J. Caldarone, Beth Stevens, Cynthia A. Lemere
Journal: Science Translational Medicine (2017)

C3 deficiency protects against hippocampal neurodegeneration and cognitive decline in aged APP/PS1 mice despite abundant Aβ plaques.
The incidence of concussion and risk of subsequent concussions in professional rugby league
Authors: Lisa Hodgson, Conor Gissane, Peter Walker, Paul Maruff, David Darby
Journal: British Journal of Sports Medicine (2017)

Objective Recognition and management of concussion within sport is a hot topic as research suggests that the mismanagement can lead to extended time out of play and morbidity after retirement. This study aimed to identify the incidence and risk following concussion within the Rugby Football League and if full recovery from concussion increases the risk of subsequent concussions. Design Retrospective study Method Participant players were those who held a professional contract between 2006–2012. It is mandatory to provide an annual baseline test and following any diagnosed concussion, with full symptom resolution, a valid return to play test. Concussion test data was provided by CogState Australia from tests performed over 7 seasons. Results Over the 7 seasons 4762 players suffered 470 concussion (2.65/1000 hours, 95% Confidence Interval 2.4 to 2.9). The odds of sustaining 1 concussion was 7%, the odds of receiving 2 or more was 1%, and 0.3% 3 or more concussions. The time between concussions for any individual who suffered two or more concussions was on average 355 days. The average return to play time was 1.46 days following the first return to play test. Conclusions This report is the first to follow rugby league players over a prolonged period and, the first to demonstrate the risk of subsequent concussions. In rugby league, concussions managed correctly and fully resolved were not shown to have detrimental effects on future concussions, and in general there is a lack of evidence linking appropriately managed concussions in other sports to detrimental future effects. Competing interests Lisa Hodgson, Conor Gissane, Peter Walker David Darby – None. Paul Maruff – Full time employee of CogState. David Darby – Former Founder and Director of Cogstate.
Eltrombopag, a novel, oral platelet growth factor, increases platelet counts in thrombocytopenic patients and healthy subjects
Authors: J. Bussel, M. Saleh, D. Provan, N. Stone, J. M. Hamilton, H. Hassani, B. Mayer, J. Uhl, J. Jenkins, J. Glaspy
Journal: Journal of Clinical Oncology (2006)

8602 Background: Eltrombopag (SB-497115) is a novel, first in class, orally bioavailable, thrombopoietin receptor agonist that induces differentiation and proliferation of megakaryocyte progenitors and has been shown to increase platelet counts in preclinical and clinical studies. Methods: In two randomized, placebo-controlled trials, eltrombopag was administered as oral tablets, once daily for 10 days to 73 healthy male subjects at doses of 5–75mg in an ascending dose cohort study, and to 103 (64 female/39 male) adult chronic immune thrombocytopenic purpura (ITP) patients, with a platelet count of &lt;30×10 9 /L, once daily for 6 weeks at doses of 30–75mg in a parallel dose cohort study. The primary efficacy endpoint in the Phase II ITP trial was the proportion of subjects with a platelet count &gt;50×10 9 /L after 6 weeks of dosing. Results: In healthy subjects, eltrombopag induced a dose dependent increase in the platelet counts. Mean maximal platelet count increases were 24.1 % at 30mg, 42.9 % at 50mg, and 50.4 % at 75mg. In 95 eligible ITP patients, platelet counts increased from &lt;30 to &gt;50×10 9 /L in 16% (4/25) of subjects on placebo, and in the eltrombopag groups in 28% (7/25, p=ns) on 30mg, 67% (16/24, p&lt;0.001) on 50mg and 86% (18/21, p&lt;0.001) on 75mg eltrombopag. The median platelet counts in each treatment arm after 6 weeks of dosing were 16×10 9 /L on placebo, 29×10 9 /L on 30mg, 132×10 9 L on 50mg, and 202×10 9 /L on 75mg. The dose dependent effect was not significantly affected by the splenectomy status, background immunosuppressant use, or baseline platelet count (greater than or less than 15×10 9 /L). Conclusions: The platelet count data from these clinical studies suggests that eltrombopag could be an effective therapy for the treatment of thrombocytopenia. Eltrombopag is being tested in further studies involving patients with ITP and chronic liver disease, and cancer patients receiving thrombocytopenic chemotherapy. [Table: see text]
Severe Morbidity and Mortality Associated With Influenza in Children and Young Adults—Michigan, 2003
Journal: JAMA (2003)

THE MICHIgan Department of Community Health (MDCH) received reports of severe unexplained illnesses and deaths in children and young adults aged Ͻ21 years residing in Michigan.Subsequently, two of the deaths were found to be associated with influenza, including one with neurologic complications.To identify cases of severe influenza in otherwise healthy children and young adults aged Ͻ21 years, MDCH conducted enhanced surveillance for influenzaassociated illness.This report summarizes the findings of this ongoing investigation, which indicate the need to better define the frequency of serious complications from influenza in healthy children and to incorporate such findings into evaluations of current vaccine recommendations for children.Enhanced surveillance for influenzaassociated severe illnesses and deaths focused on children and young adults aged Ͻ21 years at low risk * for influenza complications who had illness onset or death after January 1, 2003.Severe influenzaassociated illnesses included nonrespiratory complications requiring hospital admission (e.g., myocarditis, rhabdomyolysis, encephalitis, encephalopathy, and prolonged seizures) or any complications requiring intensive care unit (ICU) admission.Influenza infections were confirmed by viral culture, rapid antigen test, immunofluorescence, or immunohistochemical staining (IHC).Sur-
Sublingual immunotherapy provides long‐term relief in allergic rhinitis and reduces the risk of asthma: A retrospective, real‐world database analysis
Authors: S. Zielen, P. Devillier, J. Heinrich, H. Richter, U. Wahn
Journal: Allergy (2017)

Abstract Background Allergy immunotherapy ( AIT ) is the only treatment for allergic rhinitis ( AR ) and/or allergic asthma ( AA ) with long‐term efficacy. However, there are few real‐life data on the progression of AR and/or AA in patients receiving AIT . Objectives To assess the real‐world, long‐term efficacy of grass pollen sublingual immunotherapy ( SLIT ) tablets in AR and their impact on asthma onset and progression. Methods In a retrospective analysis of a German longitudinal prescription database, AR patients treated with grass pollen SLIT tablets were compared with a control group not having received AIT . Multiple regression analysis was used to compare changes over time in rescue symptomatic AR medication use after treatment cessation, asthma medication use, and the time to asthma onset in the two groups. Results After applying all selection criteria, 2851 SLIT and 71 275 control patients were selected for the study. After treatment cessation, AR medication use was 18.8 percentage points lower (after adjustment for covariates, and relative to the pretreatment period) in SLIT tablet group than in the non‐ AIT group ( P &lt;.001). Asthma onset was less frequent in SLIT tablet group than in non‐ AIT group (odds ratio: 0.696, P =.002), and time to asthma was significantly longer (hazard ratio: 0.523; P =.003). After SLIT cessation, asthma medication use fell by an additional 16.7 percentage points (relative to the pretreatment period) in the SLIT tablet group vs the non‐ AIT group ( P =.004). Conclusions Real‐world treatment of AR patients with grass pollen SLIT tablets was associated with slower AR progression, less frequent asthma onset, and slower asthma progression.
Factors associated with risk of central nervous system relapse in patients with non‐core binding factor acute myeloid leukemia
Authors: Elias Jabbour, Naval Guastad Daver, Nicholas James Short, Xuelin Huang, Hsiang‐Chun Chen, Abhishek Maiti, Farhad Ravandi, Jorge Cortes, Simon Abi Aad, Guillermo Garcia‐Manero, Zeev Estrov, Tapan Kadia, Susan O'Brien, Bouthaina Dabaja, Carlos Bueso‐Ramos, Paolo Strati, Carol Bivins, Sherry Pierce, Hagop Kantarjian
Journal: American Journal of Hematology (2017)

Central nervous system (CNS) relapse is uncommon in patients with acute myeloid leukemia (AML) with the use of high-dose cytarabine containing chemotherapy regimens. The clinical and molecular features associated with a higher risk of CNS relapse are not well defined. We assessed the incidence and outcome of CNS relapses among 1245 patients with relapsed/refractory AML referred to our institution between 2000 and 2014. CNS leukemia relapse was observed in 51 patients (4.1%). Using a multivariate regression model and after adjusting for age, FLT3-ITD mutation (OR = 2.33; P = .02) and elevated LDH (>1000 IU/L, OR = 1.99; P = .04) were independent predictive factors for CNS relapse. Patients under 64 years of age with 0, 1, or 2 baseline adverse features had a probability of 3.8%, 7.0%-8.0%, and 13.9% for developing CNS disease, respectively. Our study identifies patients with AML at higher risk for CNS relapse in whom prophylactic CNS therapy may be warranted.
First-Episode Schizophrenia and Diabetes Risk
Authors: Chiara C. Bortolasci, Michael Berk, Ken Walder
Journal: JAMA Psychiatry (2017)

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Abstract 57: First Induced Heart Failure Model in Adult Zebrafish by Chronic Isoproterenol Treatment
Authors: Mandy Kossack, Hugo A Katus, Patrick Most, David Hassel
Journal: Circulation Research (2015)

Impaired β-adrenergic signal transduction is a common molecular alteration found in heart failure (HF). Chronic catecholamine release and overstimulation of β-adrenergic receptors (β-ARs) in the failing heart results in their desensitization, largely mediated through upregulation of the G-protein coupled receptor kinase 2 (GRK2), and consequently to the progression into HF. Chronic activation of β-ARs by isoproterenol (iso) infusion efficiently induces HF in mice, while therapeutic targeting of GRK2 in HF animal models preserves cardiac function, highlighting their significance in HF progression. Zebrafish represents an established model to evaluate genetic causes of HF and to screen for novel therapeutic targets. However, the contribution of the β-A system in zebrafish models of HF is not known. We here systematically analyzed the effect of iso on heart function in larval and adult zebrafish. Larvae first responded to iso with 3 days of age (d). Here, β-AR stimulation resulted in the activation of conserved signaling components and in the induction of common stress responsive genes. Chronic β-AR stimulation for 5 days induced signs of HF accompanied by similar expression changes seen in mammals. As heart phenotypes are usually not analyzed in larval zebrafish beyond 3d, our data implicates that previous studies neglected a possible impact of β-AR signaling, particularly important when screening for therapeutic components. Adult zebrafish recently emerged as an attractive cardiac model, especially for regenerative medicine. Echocardiography revealed that in adult zebrafish hearts, iso robustly enhanced cardiac function. Chronic β-AR stimulation for 14 days efficiently induced HF symptoms. Consistent with mammals, we found reduced expression of β-ARs and elevated expression of GRK2 and ANP. Additionally, these fish develop essential characteristics accompanied with HF, including increased cell death and elevated inflammation. In conclusion, we show that β-AR function in zebrafish is comparable to that in mammals. Further, we present the first iso-induced HF model in adult zebrafish, thereby introducing adult zebrafish as a particularly valuable model to study the pathogenesis of HF and to test for novel therapeutic strategies to treat HF.
GENE-04. PEDIATRIC MALIGNANT EPITHELIOID GLIONEURONAL TUMOR: PATHOLOGICAL, CLINICAL, AND MOLECULAR CHARACTERIZATION OF A RARE AND DEADLY MALIGNANCY
Authors: Abhishek Bavle, Enrique Ramos, Jacquelyn Reuther, Frank Lin, Oliver Hampton, David Wheeler, Andrew Jea, Arnold Paulino, Murali Chintagumpala, Sharon Plon, Angshumoy Roy, Adekunle Adesina, Will Parsons
Journal: Neuro-Oncology (2017)

BACKGROUND: Malignant epithelioid glioneuronal tumor (MEGNT) is a rare high-grade brain tumor that exhibits both glial and neuronal differentiation and is not included in the current World Health Organization (WHO) classification. Limited case series describe a highly aggressive tumor with poor survival and have shed little light on MEGNT biology. AIM: The objective of our study was to molecularly characterize a cohort of MEGNTs in order to provide insight into tumor biology and identify potential therapeutic targets. METHODS: An integrated genomic strategy, including exome, transcriptome, and targeted mutation panel sequencing as well as copy number array analysis, was used to evaluate tumor samples obtained from 8 children with MEGNT. Clinical information was obtained by chart review. RESULTS: Outcomes were dismal for these patients despite aggressive surgery (gross total resection x 6) followed by involved field radiation therapy (XRT), with a median event-free survival of 6 months and 4 of 8 patients dead of disease. Frequent and potentially targetable genetic alterations were detected in the MAPK pathway in 4 of 8 cases (BRAF V600E x 3, NTRK2-BEND5) and in PI3K/MTOR pathway genes in 3 of 8 cases (TSC1 x 2, PTEN). Additional aberrations related to the MAPK pathway were identified in 4 patients, including high copy gains in MET and KIT and 2 novel fusions (SOS1-MAP4K3 and MAP3K11-GFAP) which were validated by targeted sequencing and require further functional characterization. Other alterations in known high-grade glioma genes were also detected, including homozygous CDKN2A/B loss (n=3), TP53 mutation (n=2), and amplification events involving MYCN, CDK6, MET, and KIT. CONCLUSION: MEGNT is an aggressive tumor with poor response to conventional therapies. The frequency of potentially-targetable molecular alterations identified in this study indicates an opportunity to test the use of novel targeted agents for children with these tumors.
Psychodynamic Therapy: As Efficacious as Other Empirically Supported Treatments? A Meta-Analysis Testing Equivalence of Outcomes
Authors: Christiane Steinert, Thomas Munder, Sven Rabung, Jürgen Hoyer, Falk Leichsenring
Journal: American Journal of Psychiatry (2017)

Pharmacotherapy, cognitive-behavioral therapy (CBT), and psychodynamic therapy are most frequently applied to treat mental disorders. However, whether psychodynamic therapy is as efficacious as other empirically supported treatments is not yet clear. Thus, for the first time the equivalence of psychodynamic therapy to treatments established in efficacy was formally tested. The authors controlled for researcher allegiance effects by including representatives of psychodynamic therapy and CBT, the main rival psychotherapeutic treatments (adversarial collaboration).The authors applied the formal criteria for testing equivalence, implying a particularly strict test: a priori defining a margin compatible with equivalence (g=0.25), using the two one-sided test procedure, and ensuring the efficacy of the comparator. Independent raters assessed effect sizes, study quality, and allegiance. A systematic literature search used the following criteria: randomized controlled trial of manual-guided psychodynamic therapy in adults, testing psychodynamic therapy against a treatment with efficacy established for the disorder under study, and applying reliable and valid outcome measures. The primary outcome was "target symptoms" (e.g., depressive symptoms in depressive disorders).Twenty-three randomized controlled trials with 2,751 patients were included. The mean study quality was good as demonstrated by reliable rating methods. Statistical analyses showed equivalence of psychodynamic therapy to comparison conditions for target symptoms at posttreatment (g=-0.153, 90% equivalence CI=-0.227 to -0.079) and at follow-up (g=-0.049, 90% equivalence CI=-0.137 to -0.038) because both CIs were included in the equivalence interval (-0.25 to 0.25).Results suggest equivalence of psychodynamic therapy to treatments established in efficacy. Further research should examine who benefits most from which treatment.