tbuckley/cabot-search huggingface dataset:
Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosis
Authors: Maria Luigia Carbone, Gilliane Chadeuf, Sandrine Heurtebise-Chrétien, Xavier Prieur, Thibault Quillard, Yann Goueffic, Nathalie Vaillant, Marc Rio, Laure Castan, Maxim Durand, Céline Baron-Menguy, Julien Aureille, Juliette Desfrançois, Angela Tesse, Raul M. Torres, Gervaise Loirand
Journal: Journal of Clinical Investigation (2017)

Abnormal activity of the renin-angiotensin-aldosterone system plays a causal role in the development of hypertension, atherosclerosis, and associated cardiovascular events such as myocardial infarction, stroke, and heart failure. As both a vasoconstrictor and a proinflammatory mediator, angiotensin II (Ang II) is considered a potential link between hypertension and atherosclerosis. However, a role for Ang II-induced inflammation in atherosclerosis has not been clearly established, and the molecular mechanisms and intracellular signaling pathways involved are not known. Here, we demonstrated that the RhoA GEF Arhgef1 is essential for Ang II-induced inflammation. Specifically, we showed that deletion of Arhgef1 in a murine model prevents Ang II-induced integrin activation in leukocytes, thereby preventing Ang II-induced recruitment of leukocytes to the endothelium. Mice lacking both LDL receptor (LDLR) and Arhgef1 were protected from high-fat diet-induced atherosclerosis. Moreover, reconstitution of Ldlr-/- mice with Arhgef1-deficient BM prevented high-fat diet-induced atherosclerosis, while reconstitution of Ldlr-/- Arhgef1-/- with WT BM exacerbated atherosclerotic lesion formation, supporting Arhgef1 activation in leukocytes as causal in the development of atherosclerosis. Thus, our data highlight the importance of Arhgef1 in cardiovascular disease and suggest targeting Arhgef1 as a potential therapeutic strategy against atherosclerosis.
CMET-27. NATURAL LANGUAGE PROCESSING FOR THE AUTOMATED QUANTIFICATION OF BRAIN METASTASES IN RADIOLOGY FREE TEXT REPORTS
Authors: David Cote, Joeky Senders, Aditya Karhade, Saksham Gupta, Nayan Lamba, Brooke Hancock, Timothy Smith, Omar Arnaout
Journal: Neuro-Oncology (2017)

Optimum treatment for patients diagnosed with brain metastases remains a clinical dilemma that depends on the number of metastases present. Whereas a patient with a single metastasis benefits from surgery followed by radiation, a patient with many may not. In this study, we report the use of natural language processing (NLP) to identify the number of metastases present based on free-text radiology reports in an effort to facilitate high throughput retrospective analysis. A total of 2172 radiology reports for patients diagnosed with brain metastases were retrieved. The reports were randomized into six blocks, and each block was manually annotated by two independent reviewers for the number of metastases, using a binary classification (one versus >1 metastasis). The annotated reports were divided into training and test sets. An NLP algorithm using bag-of-words technique was developed using the Anaconda distribution (Continuum Analytics) running Python 2.7.1. The classifications of the NLP method were then compared with the manual annotations of our test set, which were based on consensus of human classification. Accuracy, precision, recall, and F1 measure were calculated for the NLP method. The manual review was completed in 27 days; mean discordance rate was 36.2%. The overall accuracy of the best logistic regression classifier was 84.6% on the training data and 82.8% on the hold-out test data. The precision and recall were both 83%, and the F1-score was 0.83. The algorithm required 28.9 minutes for training, after which it is able to classify the entire dataset in a less than 0.2 second. The model was incorporated into a user-friendly interface that allows for future report classification. NLP is a powerful method for the high-throughput evaluation of free-text radiology reports that can have high sensitivity and specificity. Use of NLP can accelerate retrospective clinical research with improved accuracy over manual chart review.
Abiraterone acetate (AA) in pre- and post-docetaxel (DX) setting for metastatic castration resistant prostate cancer (mCRPC): a monoinstitutional experience focused on cardiovascular events and on their impact on clinical outcomes
Authors: F. Boccardo, A. Cavo, E. Zanardi, C. Fabbroni, L. Zinoli, A. Di Meglio, E. Arboscello, A. Bellodi, P. Spallarossa, C. Cattrini, C. Messina, A. Rubagotti
Journal: Annals of Oncology (2017)
OA 05.01 First-Line Dacomitinib versus Gefitinib in Advanced Non-Small-Cell Lung Cancer with EGFR Mutation Subgroups
Authors: Y. Wu, Y. Cheng, X. Zhou, K.H. Lee, K. Nakagawa, S. Niho, F. Tsuji, R. Rosell, J. Corral, M.R. Migliorino, A. Pluzanski, R. Linke, E. Sbar, T. Wang, H. Zhang, T. Mok
Journal: Journal of Thoracic Oncology (2017)
CBIO-08. DIRECTED NEURONAL DIFFERENTIATION IN GBM BY SUPPRESSION OF TAZ
Authors: Alessandra Audia, Arvid Das, Farah Mukheef, Ze-yan Zhang, Erik Sulman, Krishna Bhat
Journal: Neuro-Oncology (2017)

IDH-mutant (IDH-MUT) glioma patients show highly improved prognosis compared to those with wild-type IDH. However, IDH mutations are rare in the more aggressive grade IV glioblastomas and introducing IDH mutations in mouse neural cells does not induce gliomagenesis. This is a paradox, given that IDH mutation is considered an early oncogenic event and the mutated IDH produces the oncometabolite 2-hydroxyglutarate. Here we identify a previously unknown mechanism that explains this paradox. We found that IDH-MUT patient tumors expressing a molecular signature enriched in genes associated with neuronal differentiation survive the longest (~11 years) and these same tumors have significantly lower expression of the Mesenchymal master regulator TAZ, which is epigenetically silenced. Concordantly, IDH-MUT/TAZ-low glioma stem-like cells (GSCs) show remarkable neuronal differentiation induced by retinoic acid, whereas IDH-WT/TAZ-high GSCs are resistant to this process implying that IDH status and TAZ levels dictate propensity to neurogenesis. TAZ overexpression in IDH-MUT GSCs caused inhibition of retinoic acid neuronal differentiation and conversely CRISPR/Cas9-mediated knockout of TAZ in IDH-WT GSCs promotes this process as judged by alteration in genes regulating neurogenesis as well as cellular morphology resembling neurons (dendritic branching etc.). Furthermore, injection of TAZ in the dorsal ectoderm of Xenopus embryos caused a defect in neural development affirming the role of TAZ as a negative regulator of neurogenesis. We are currently examining the mechanisms by which TAZ blocks neurogenesis and the in vivo consequences of concomitant TAZ knockout with retinoic acid treatment in intracranial models. Taken together, our studies uncover a role for TAZ as a barrier for terminal neuronal differentiation and that differentiation therapy with retinoic acid is possible for IDH-WT gliomas if combined with a TAZ inhibitor.
Surtos de parvovirus B19 em três escolas portuguesas
Authors: G Gonçalves, A M Correia, P Palminha, H Rebelo de Andrade, A Alves
Journal: Eurosurveillance (2005)

O artigo seguinte descreve o estudo do surto de exantemas agudos em criancas de tres escolas da cidade de Braga em Portugal. Analises de laboratorio, realizados para cinco casos, mostraram que a doenca nao era associada com o virus do sarampo ou da rubeola, e confirmaram a infeccao pelo parvorviru B19. Foram contaminadas 41 criancas : 12 no jardin de infancia, 17 na escola secondaria e 12 na escola primaria. So um empregado trabalhando no jardin de infanciafoi contaminado. Oito casos foram identificados entre os contactos familiais; dois eram irmaos, um no jardin de infanciae o outro na escola secondaria aonde occoreu o surto apos o do jardin de infancia. Os valores estimados da taxa de reproduccao de base R0 eram muito baixas e e provavel que existem casos infecciosos asimtomaticos. As autoridadas sanitarias locais publicaram documentos escritos e encontraram os membros do pessoal e os pais. Foram informados os estabelecimentos de cuidados primarios assim como o departamento de obstetricia do hospital local. O objetivo da eliminacao do sarampo esta proximo, como em toda Europa, com coberturas vacinais muito altas, assim e possivel que uma proporcao importante de exantemas nao vesiculares sejam devidos a infeccoes por B19. Isso deveria ser considerado para implementar e controlar as actividades de vigilância, no contexto dos programas de eliminacao do sarampo e da rubeola.
Deletion of claudin-10 rescues claudin-16–deficient mice from hypomagnesemia and hypercalciuria
Authors: Tilman Breiderhoff, Nina Himmerkus, Hoora Drewell, Allein Plain, Dorothee Günzel, Kerim Mutig, Thomas E. Willnow, Dominik Müller, Markus Bleich
Journal: Kidney International (2017)
Long-term intraocular pressure reduction with intracameral polycaprolactone glaucoma devices that deliver a novel anti-glaucoma agent
Authors: Jean Kim, Max Kudisch, Nina Rosa Konichi da Silva, Hiroyuki Asada, Eri Aya-Shibuya, Michele M. Bloomer, Sri Mudumba, Robert B. Bhisitkul, Tejal A. Desai
Journal: Journal of Controlled Release (2017)
P1.04-013 Phase 1b Multi-Indication Study of the Antibody Drug Conjugate Anetumab Ravtansine in Patients with Mesothelin-Expressing Advanced or Recurrent Malignancies
Authors: A. Adjei, A. Walter, L. Cupit, J. Siegel, A. Holynskyj, B. Childs, C. Elbi
Journal: Journal of Thoracic Oncology (2017)
CSIG-22. A CD133-Akt-Wnt SIGNALING AXIS PROVIDES FUNCTIONAL INSIGHT INTO THE ROLE OF CD133 IN GLIOBLASTOMA BRAIN TUMOR-INITIATING CELLS
Authors: Branavan Manoranjan, Chitra Venugopal, Sujeivan Mahendram, Minomi Subapanditha, Neil Savage, Maleeha Qazi, Parvez Vora, Jason Moffat, Bradley Doble, Sheila Singh
Journal: Neuro-Oncology (2017)

Current transcriptional profiles of adult glioblastoma (GBM) recognize the activation of distinct signaling programs. Single-cell sequencing efforts have provided greater resolution of core developmental pathways implicated in disease progression and relapse. Of note, the Wnt pathway is activated in a subset of patients, despite the lack of recurrent activating mutations in human GBM. Given the description of CD133 as a marker of tumor-initiating cells in a number of human cancers associated with activated Wnt signaling, we investigated the role of CD133 in human GBM as a novel Wnt regulator. CD133high GBM lines were found to have greater Wnt levels when compared to CD133low lines. To establish a signaling axis between CD133 and Wnt we investigated the CD133-dependent activation of Akt and the subsequent downstream inhibition of GSK leading to beta-catenin activation. Ectopic expression of CD133 resulted in increased pAKT, pGSK (Ser 9), and beta-catenin. To further describe the context-dependent role for Akt activation of Wnt through GSK inhibition, CD133high lines were treated with the Akt inhibitor, MK-2006, which decreased pAKT, pGSK (Ser 9), and beta-catenin. In order to validate the tumorigenic potential of Wnt-activated cells, a Wnt reporter was used to isolate cells with endogenous Wnt signaling. Wnt-active cells maintained an increased self-renewal and tumor-initiating capacity when compared to Wnt-inactive cells. Xenografts generated from Wnt active cells had a reduced survival advantage as these contained an enhanced expression of stemness genes when compared to Wnt-inactive xenografts. To develop a rationale clinical therapeutic, we used RWO3, a novel humanized antibody directed at CD133. In vivo treatment with RW03 showed a significant reduction in activated Wnt signaling, highlighting the role of CD133 in modulating the Wnt pathway. Our work establishes a CD133-Akt-Wnt signaling axis in GBM through the functional characterization of CD133 and subsequent context-specific Akt-dependent regulation of the canonical Wnt pathway.
Avaliação da vigilância das doenças meningocócicas na Europa
Authors: C Trotter, S Samuelsson, A Perrocheau, S de Greeff, H de Melker, S Heuberger, M Ramsay
Journal: Eurosurveillance (2005)

Na maior parte dos paises, a vigilância das doencas meningococicas esta basada numa combinacao de sistemas de declaracao obrigatoria e de notificacao pelos laboratorios, considerando-se que os dois subestimam o peso da doenca. A incidencia das doencas meningococicas varia entre os paises da Europa, e embora existem muitas razoes para explicar isto, e importante quantificar o grau de sub-avaliacao para poder validar as comparacoes internacionais. Presentamos aqui uma revisao das publicacoes sobre a avaliacao das doencas meningococicas na Europa e sobre os metodos disponiveis para estimar o grau de sub- notificacao. Resulta que a sensibilidade dos sistemas de vigilância e variavel segundo os paises e no tempo, a diferenca vai de 40% a 96%. Foram identificados cinco metodos apropriados para levar a cabo estudos de avaliacao, desde simples inqueritos comparativos ate tecnicas mais complicadas como a captura-recaptura e as analises de regressao. Estes estudos podem ser utilisados para identificar os pontos fracos dos dados de vigilância e melhorar estes sistemas. Estes resultados tambem sao pertinentes para a vigilância de outras doencas transmissiveis, especialmente aquelas com menor mortalidade e menor impacto publico que as doencas meningococicas para as quais uma avaliacao seria util.
PUB039 FDG-PET Scanning Has a Limited Role in the Management of Low and Intermediate Grade Neuroendocrine Tumors of Lung
Authors: A. Feczko, M. Cattoni, E. Vallieres, L. Brown, A. Sarkeshik, S. Margaritora, A. Siclliani, P.L. Filosso, F. Guerrera, A. Alessandra Siclliani, N. Rotolo, F. Farjah, G. Wandell, K. Costas, C. Mann, M. Hubka, S. Kaplan, C. Wilshire, A. Farivar, R. Aye, B. Louie
Journal: Journal of Thoracic Oncology (2017)
PDTM-22. IDENTIFYING REGULATORS OF METASTASIS IN MEDULLOBLASTOMA SUBGROUPS
Authors: Timothy Phoenix, Rachel Hartley
Journal: Neuro-Oncology (2017)

Medulloblastoma (MB), the most common malignant pediatric brain tumor, comprises of four molecularly and clinically distinct subgroups (termed WNT, SHH, Group3, and Group4). Across all subgroups, metastatic dissemination is a feature of high-risk disease and very poor outcome. WNT-MB, considered low-risk, are rarely metastatic and contain activating mutations in CTNNB1; Group3-MB, commonly classified as high-risk, are frequently metastatic and contain genomic alterations resulting in elevated MYC expression. Depending on subgroup identity, recurrent MB tend to occur at primary or metastatic sites, but all subgroups commonly display MYC or MYCN amplifications and p53 loss at relapse while maintaining their primary subgroup molecular identity. To understand MB subgroup specific regulation of metastatic frequency, we are examining the role of CTNNB1 and MYC alterations in Wnt and Group3-MB mouse models. Transduction of Wnt-MB cells with Myc promotes Wnt-MB proliferation in vitro, and drives rapid in vivo tumor development with significantly shorter latency than control Wnt-MB. On the other hand, Activation of Wnt signaling in Group3-MB cells does not significantly impact proliferation, but does inhibit migratory ability in vitro. Experiments to characterize in vivo metastasis properties of Wnt-MB+Myc and Group3-MB+Ctnnb1 are ongoing, along with comparison of gene expression profiles to identify downstream mechanisms that promote subgroups specific growth and migration phenotypes.
METB-12. METABOLIC RE-PROGRAMING MEDIATES BIDIRECTIONAL SHIFT BETWEEN TRANSCRIPTIONAL SUBCLASSES AND DRIVES TUMOR HETEROGENEITY
Authors: Dieter Henrik Heiland, Annette Gaebelein, Melanie Borries, Jakob Wörner, Maria Stella Carro, Stefan Weber, Irina Mader, Oliver Schnell
Journal: Neuro-Oncology (2017)

The highly heterogeneous nature of malignant brain tumors maintains limited response to therapy and unfavorable clinical prognosis. The underlying molecular mechanisms of transcriptional re-programing that drive tumor heterogeneity are in the focus of research. This study reported an adaptive mechanism of malignant glioma in various metabolic environments, which potently drives transcriptional re-programming and tumor heterogeneity. In a first step, multiple biopsies (total n=138) were obtained from three de-novo glioblastoma multiforme patients and underwent a metabolic and transcriptional profiling. A metabolic landscape was explored marked by varying stages of hypoxia and creatine enrichment with a strong correlation to specific local transcriptional pattern. In the presence of environmental enriched creatine and GABA, the proneural expression subtype was mainly observed where lactate was found to be highly associated with the mesenchymal phenotype. In a second step, patient derived glioblastoma stem-like cells (GSC) were obtained and cultured in either hypoxia, creatine- supplemented or combined conditions for 24h and 48h. This environmental cell-model showed a synergistic effect of up-regulating the GABA signaling and a simultaneous inhibition of HIF signaling in a creatine-supplemented environment. This affected the transcriptional landscape with a shift toward a proneural subtype expression followed by a slowing of cell migration and proliferation. These findings were verified by additional HIF and GABA inhibition, which partially rescued the proneural shift. In a heterogeneous tumor, different stages of hypoxia and environmental creatine enrichment were observed, which required a permanent adaptation of the tumor to varying environmental conditions. These findings suggest that metabolic adaptation plays a major role in transcriptional heterogeneity of malignant brain tumors. Exploiting or targeting metabolic adaption could potentially serve as a future therapeutic option for malignant brain tumors.
P3.03-013 Identification of Proteosomal Catalytic Subunit PSMA6 as a Therapeutic Target for Lung Cancer through a Pooled shRNA Screen
Authors: M. Sato, T. Kakumu, D. Goto, T. Kato, N. Yogo, T. Hase, M. Morise, T. Fukui, K. Yokoi, Y. Sekido, L. Girard, J. Minna, L. Byers, J. Heymach, K. Coombes, M. Kondo, Y. Hasegawa
Journal: Journal of Thoracic Oncology (2017)
IMMU-55. PHARMACOLOGIC INHIBITION OF PROTEIN PHOSPHATASE-2A, WITH NOVEL INHIBITOR LB-100, ACHIEVES DURABLE IMMUNE-MEDIATED ANTITUMOR ACTIVITY WHEN COMBINED WITH PD1 BLOCKADE
Authors: Winson SC Ho, Herui Wang, Kovach John, Dominic Maggio, John Heiss, Mark R Gilbert, Rongze Lu, Zhengping Zhuang
Journal: Neuro-Oncology (2017)

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase. Mounting evidences suggest that inhibition of PP2A could enhance cancer immunity. LB-100 is a novel small molecule inhibitor of PP2A that is well tolerated in a Phase I trial. We hypothesized that inhibition of PP2A may enhance effect of checkpoint inhibition. Mice were inoculated subcutaneously with CT26.CL25 murine colon cancer cells. When tumors were 50-100 mm3, mice were randomized into treatment groups: control (PBS), anti-PD1, LB-100 and anti-PD1/LB-100 combination. Where indicated, mice received CD8-depleting antibodies. Tumors were harvested after two treatments and FACS analysis performed to evaluate tumor infiltrating lymphocytes. CD3 or naïve CD4 cells were harvested from splenocytes. CD3 cells were activated for 3 hours before staining for phospho-protein. For differentiation experiments, naïve CD4 cells were cultured with TGF-b or IL-4 for induction of regulatory or Th2 CD4 T cells respectively. FACS analysis was performed on matured lymphocytes and cytokine secretion was measured using ELISA. While single-agent treatment with LB-100 or anti-PD1 was insufficient to decrease tumor burden, combination therapy led to complete regression of tumor in >50% of animals. This therapeutic effect was negated by temporary CD8 T cell ablation. TILS analysis demonstrated an increase in CD8 and a decrease in regulatory CD4 T cells. CD8 cells had enhanced IFN-g and TNF production. In vitro, LB-100 increased mTORC1 signaling as measured by pS6 phosphorylation, resulting in decreased differentiation of naïve CD4 T-cells into T-regulatory and Th2 lineage in their respective skewing conditions. In addition, secretion of Th1 cytokines, including IFN-g, TNF and IL2 were significantly increased in both Th1 and Th2 conditions. These data indicate that pharmacologic inhibition of PP2A by LB-100 can achieves durable immune-mediated antitumor activity when combined with PD1 blockade and highlights the potential of PP2A inhibition to enhance cancer immunotherapy.
A Tale of Two Countries
Authors: Vaibhav Kumar
Journal: Annals of Internal Medicine (2017)

Letters7 November 2017A Tale of Two CountriesVaibhav Kumar, MDVaibhav Kumar, MDFrom Tufts Medical Center, Boston, Massachusetts.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0392 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Having completed my internal medicine residency training in Boston and the equivalent core medical training in the United Kingdom, I found DeWitt's viewpoint (1) particularly interesting. When I reflect on my personal experiences, the autonomy afforded to individual clinicians in the United States, in addition to the relative ease of access to advanced health care technologies, is a definite and possibly understated bonus of training and practicing here. However, the considerable administrative duties associated with practicing in this country are a notable challenge. Physicians in the United Kingdom are largely removed from the struggles of coding patients' ...References1. DeWitt DE. A tale of two countries: how I saw more patients with more joy in internal medicine practice. Ann Intern Med. 2017;166:669-70. [PMID: 28346950]. doi:10.7326/M17-0244 LinkGoogle Scholar2. Sinsky C, Colligan L, Li L, Prgomet M, Reynolds S, Goeders L, et al. Allocation of physician time in ambulatory practice: a time and motion study in 4 specialties. Ann Intern Med. 2016;165:753-60. LinkGoogle Scholar3. Woolhandler S, Himmelstein DU. Administrative work consumes one-sixth of U.S. physicians' working hours and lowers their career satisfaction. Int J Health Serv. 2014;44:635-42. [PMID: 25626223] CrossrefMedlineGoogle Scholar4. Erickson SM, Rockwern B, Koltov M, McLean RM; Medical Practice and Quality Committee of the American College of Physicians. Putting patients first by reducing administrative tasks in health care: a position paper of the American College of Physicians. Ann Intern Med. 2017;166:659-61. [PMID: 28346948]. doi:10.7326/M16-2697 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From Tufts Medical Center, Boston, Massachusetts.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L17-0392. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoA Tale of Two Countries: How I Saw More Patients With More Joy in Internal Medicine Practice Dawn E. DeWitt A Tale of Two Countries Dawn E. DeWitt Metrics 7 November 2017Volume 167, Issue 9Page: 686KeywordsConflicts of interestDisclosureForecastingHealth careInternational Classification of DiseasesResidency ePublished: 7 November 2017 Issue Published: 7 November 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...