1,721,060 research outputs found
Unusual Course of a Diffuse Midline Glioma Exhibits Upcoming Therapeutic Options through Novel Molecular Genetic Analyses
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
EXPLORATION OF ANGIOGENESIS INHIBITION IN NEUROBLASTOMA AND CHARACTERIZATION OF ESCAPE MECHANISMS
No full textAdulte ou pédiatrique, les tumeurs solides ont besoin d’oxygène et de nutriments pour se développer et métastaser. Leur apport est assuré par la néo-vascularisation tumorale issue d’un processus multifactoriel appelé l’angiogénèse. Son équilibre est maintenu par une balance entre facteurs pro- et anti-angiogéniques. Elle fait partie des principales cibles pour traiter les cancers et l’inhibition de la voie VEGF en est un facteur clé. Cependant, la réponse aux agents anti-angiogéniques a montré, malgré des résultats encourageants, un effet transitoire associé à l’apparition d’une résistance adaptative de la tumeur.Nous avons étudié l’inhibition de l’angiogénèse et les mécanismes potentiels d’échappement dans les tumeurs pédiatriques solides, et principalement dans le neuroblastome. Le neuroblastome est une tumeur originaire de la crête neurale et atteint généralement l’enfant jeune. Nous avons exploré l’effet anti-tumoral de l’inhibition sélective des récepteurs 1, 2, 3 du VEGF à l’aide de l’inhibiteur à tyrosine kinase axitinib dans divers modèles précliniques de neuroblastome. L’axitinib a montré une activité anti-tumorale modérée associée à une inhibition de la vascularisation. Néanmoins, après un traitement prolongé in vitro, les cellules tumorales IGR-N91-Luc deviennent résistantes à l’axitinib. Elles prolifèrent normalement mais secrètent de «l’ hepatocyte growth factor» (HGF) et activent la voie MAPK. In vivo, le traitement prolongé par axitinib entraîne le développement d’un phénotype plus agressif de la tumeur avec l’augmentation du nombre d’animaux présentant des métastases, associée à une activation de la voie SRC. Ceci nous a conduit à explorer l’effet d’une inhibition ciblant principalement VEGFR2 et MET (récepteur à l’HGF) avec le cabozantinib. Ainsi nous avons contrôlé le développement tumoral en inhibant la néo-vascularisation et l’activation de SRC, et induit la mort cellulaire dans le modèle orthotopique IGR-N91-Luc et inhibé le développement métastatique dans le modèle systémique IMR-32-Luc. Par ailleurs, nous avons étendu notre exploration à d’autres facteurs jouant un rôle dans l’angiogénèse comme FGFR ou PDGFR car ils représentent, comme MET, de puissants oncogènes. Pour cibler simultanément VEGFR et PDGFR, nous avons utilisé l’inhibiteur multi-kinase regorafenib. In vivo, à des doses bien tolérées qui permettent un traitement prolongé, le regorafenib a montré une activité anti-tumorale significative. Cet effet a été associé principalement à une forte inhibition de la vascularisation mais également à l’induction de la mort cellulaire. En élargissant notre étude à d’autres modèles de tumeurs pédiatriques, nous avons observé que son activité est indépendante du type histologique. Compte tenu du caractère oncogénique de PDGFR, nous avons évalué cet inhibiteur dans des modèles présentant une amplification du gène PDGFRA, qui entraine une surexpression et une activation forte du récepteur. Combiné avec des thérapies standards capables d’induire des dommages à l’ADN telles que l’irradiation ou l’irinotecan, l’effet du regorafenib a été potentialisé, notamment dans les modèles amplifiés pour le gène PDGFRA se traduisant par des régressions tumorales. Ces évaluations précliniques soutiennent le développement d’une nouvelle stratégie thérapeutique pour les enfants atteints de tumeurs solides.Solid tumors either adult or pediatric need oxygen and nutrients to grow and metastasize. Their input is provided by tumor neovascularization after a multifactorial process called angiogenesis. Balance is maintained by equilibrium between pro and anti-angiogenic factors. It is one of the main targets for treating cancers and the inhibition of the VEGF pathway is a key factor. However, despite encouraging results, the response to anti-angiogenic agents showed a transient effect associated with the development of an adaptive tumor resistance. We studied the inhibition of angiogenesis and potential escape mechanisms in solid pediatric tumors, mainly in neuroblastoma. Neuroblastoma is a solid tumor derived from the neural crest and it usually affects childhood. We investigated the anti-tumor effect of selective inhibition of VEGF receptors 1, 2, 3 using the tyrosine kinase inhibitor axitinib in various preclinical neuroblastoma l models. Axitinib showed a moderate anti-tumor activity associated with the inhibition of vascularization. However, after prolonged treatment in vitro, tumor cells IGR-N91-Luc become resistant to axitinib. They proliferate normally but secrete the "hepatocyte growth factor" (HGF) and activate the MAPK pathway. In vivo, prolonged treatment by axitinib results in the development of a more aggressive tumor phenotype with an increase in the number of animals exhibiting metastases associated with an activation of SRC signaling. This led us to explore the effect of inhibiting concomitant VEGFR2 and MET (HGF receptor), main cabozantinib targets. So we stabilized tumor growth by inhibiting the neovascularization and activation of SRC, induced cell death in the orthotopic model IGR-N91-Luc and inhibited metastatic development in the IMR-32-Luc systemic model. In addition, we extended our exploration of other factors that play a role in angiogenesis like FGFR or PDGFR because they represent, like MET, powerful oncogenes. To simultaneously target VEGFR and PDGFR, we used the multi-kinase inhibitor regorafenib. In vivo, at well-tolerated doses that allow prolonged treatment, regorafenib showed significant anti-tumor activity. This effect was mainly associated with a strong inhibition of vascularization, but also (with) induction of cell death. By expanding our study to other models of pediatric tumors, we observed that its activity was independent of histologic type. Given the oncogenic character of PDGFR, we evaluated the inhibitor in models which present a PDGFRA gene amplification, which results in a strong activation of the receptor. Combined with standard therapies that can induce DNA damages such as irinotecan or radiation, the effect of regorafenib was potentiated, mainly in PDGFRA gene amplified models, where tumor regressions were obtained. These preclinical evaluations support the development of a new therapeutic strategy for children with solid tumors
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Estabelecimento e caracterização de modelos resistentes e matastaticos de osteossarcoma humano in vitro e in vivo
Full text linkDoutoramento em BiologiaOsteossarcoma é uma doença rara, sendo o tipo mais comum de tumor maligno do osso. O pico de incidência ocorre durante a adolescência e desenvolve-se principalmente nos ossos longos. Os tratamentos atuais incluem quimioterapia antes e após a cirurgia e a ressecção cirúrgica de todos os locais envolvidos (tumor primário e metástases quando presente). As metástases, principalmente nos pulmões, são um grande problema no diagnóstico (20-30% dos pacientes) e durante a história natural do osteossarcoma (cerca de 30% de recaída), afetam uma percentagem considerável de pacientes e são considerados os maiores problemas desta doença. Biologicamente, os osteossarcomas são um dos tumores mais complexos observados nas crianças, no que diz respeito à heterogeneidade, anomalias moleculares e cromossómicas e ao seu microambiente específico. A resistência aos agentes quimioterápicos utilizados no tratamento do osteossarcoma também é um fator prognóstico de alto risco de recaída, independentemente da quimioterapia utilizada. É urgente compreender os mecanismos relacionados a esses fenómenos e desenvolver novos quimioterápicos para superar esses problemas e aumentar a taxa de sobrevivência do paciente.
O desenvolvimento de novos fármacos requer múltiplos modelos pré-clínicos adequados para mimetizar a complexidade genómica do osteossarcoma que se desenvolve-se num microambiente ósseo e metastático nos pulmões, apesar dos tratamentos quimioterápicos habituais. Nesta tese, foram desenvolvidos e caracterizados diferentes modelos pré-clínicos clinicamente relevantes in vitro e in vivo, incluindo modelos resistentes bioluminescentes, de modo a melhor compreender esta doença e alguns dos mecanismos de resistência relacionados.
Desenvolvemos, em primeiro lugar, dois modelos ortotópicos xenotransplantados derivados de linhas celulares (CDX) bioluminescentes (Luc/mKate2), capazes de desenvolver metástases espontaneamente. As células bioluminescentes foram injetadas ortotopicamente, em diferentes contextos: imune (estirpes de ratinhos de laboratório - nude e NSG) e ósseo (intratibial e paratibial com ativação do periósteo). O sistema IVIS SpectrumCT, combinando tomografia computadorizada longitudinal (TC) e bioluminescência, foi utilizado para acompanhar o crescimento primário do tumor e a disseminação metastática em tempo real. O contexto imune murino, o contexto genético dos dois modelos CDX e o contexto ósseo (intratibial ou paratibial) influenciaram o enxerto tumoral, o crescimento primário do tumor e o comportamento agressivo local (osteocondensação e osteólise), bem como a disseminação metastática para os pulmões, ossos e baço (uma localização incomum em seres humanos). Observou-se também que a estirpe de ratinhos NSG e a injeção intratibial apresentam melhores características para o desenvolvimento de modelos que a injeção paratibial ou a estirpe de ratinhos nude. Seguidamente, desenvolvemos modelos resistentes bioluminescentes in vitro, aos principais medicamentos utilizados no osteossarcoma, nomeadamente metotrexato (5modelos) e doxorrubicina (1modelo), por exposição contínua a esses medicamentos. Realizando o mesmo procedimento, não foi obtida resistência à mafosfamida. Investigamos os mecanismos da resistência adquirida relacionados com estas drogas e observamos comportamentos diferenciais in vitro e in vivo (com modelos CDX ortotópicos bioluminescentes) das linhas resistentes e respetivas linhas parentais. Um mecanismo de resistência na linha celular resistente à doxorrubicina foi observado, nomeadamente a indução da proteína PgP. Mostramos diferentes mecanismos de resistência adquirida ao metotrexato de acordo com o backgroud genético das linhas celulares, que afetam a expressão génica e provocam alterações no número de cópias ao nível dos cromossomas. Foram observados diferentes comportamentos dos modelos resistentes bioluminescentes ortotópicos (CDX) in vivo em comparação com as respetivas linhas parentais.
Finalmente, utilizando amostras de osteossarcoma humano provenientes de biópsias de pacientes em recidiva após a quimioterapia habitual, foram desenvolvidos modelos resistentes xenotransplantados derivados do paciente (PDX), quer subcutaneamente quer ortotopicamente (no osso). A caracterização desses modelos está em curso, em particular a comparação das características moleculares destes (sequenciamento completo do exoma e sequenciamento do ARN) com as do tumor do paciente na recaída e do mesmo no diagnóstico.
Todos esses modelos desenvolvidos em diferentes contextos in vitro e in vivo trazem informações complementares para outros tipos de modelos de osteossarcoma já existentes. Estes modelos são necessários para obter mais informações sobre os diferentes processos que envolvem o desenvolvimento inicial, a progressão e a sensibilidade/resistência ao tratamento no osteossarcoma. Permitem ajudar ainda a avaliação de novos quimioterápicos, de modo a encontrar soluções para a atual falta de terapias eficientes no osteossarcoma.Osteosarcoma is a rare disease and the most common type of malignant bone tumor. The peak incidence occurs during the adolescence and the disease develops mainly in long bones. Current treatments include chemotherapy before and after surgery and surgical resection of all the involved sites (primary tumor and metastasis when present). Metastases mainly in the lungs are a major challenge at diagnosis (20-30% of the patients) and during the natural history of osteosarcoma (around 30% of relapse, most being metastatic), affect a considerable percentage of patients with osteosarcoma, being considered the biggest problem of this disease. Biologically, osteosarcomas are one of the most complex tumours in children in regard to tumour heterogeneity, molecular and chromosomal abnormalities, and their specific microenvironment. Resistance to the chemotherapeutic agents used in osteosarcoma is also a prognostic factor of high risk of relapse, whatever the chemotherapy used. It is urgent to understand the mechanisms related with these phenomena and develop new drugs in order to overcome these challenges and increase patient survival.
New drug development requires suitable multiple pre-clinical models to better mimic the genomic complexity of osteosarcoma which develops in a bone microenvironment and in a metastatic setting in the lungs, despite usual chemotherapeutic treatments. In this thesis, we developed and characterised different and clinically relevant in vitro and in vivo preclinical models, including bioluminescent resistant models in order to understand better this disease and some of the resistant mechanism related.
First, two bioluminescent (Luc/mKate2) cell line derived xenograft (CDX) models were developed in an orthotopic bone setting able to spontaneously metastasize. Bioluminescent cells were injected orthotopically, in different immune (nude and NSG mouse strains) and bone (intratibial and paratibial with periosteum activation) contexts. IVIS SpectrumCT system, combining longitudinal computed tomography (CT) and bioluminescence, was used to follow primary tumor growth and metastatic spread in real-time. The murine immune context, the genetic background of the two CDX-models, and the bone context (intratibial or paratibial) influenced tumor engraftment, primary tumor growth and local aggressive behavior (osteocondensation and osteolysis) as well as metastatic spread to lungs, bone, and spleen (an unusual localization in humans). It was also observed that intratibial injection in NSG mice showed better characteristics for model development than paratibial injection or nude mice recipient. We further developed in vitro bioluminescent models that were resistant to the main drugs used in osteosarcoma, methotrexate (5 models) and doxorubicin (one model), by continuous exposure to these drugs. With the same technique no resistance was obtained for mafosfamide. We explored the mechanism of the acquired resistance to these drugs and observed the differential in vitro and in vivo behaviors (with CDX bioluminescent orthotopic models) of the resistant lines and their parental counterpart. A multidrug phenomenon by PgP induction was observed in the doxorubicin resistant cells. We show different mechanisms of acquired resistance to methotrexate according to the genetic background of the cell lines affecting either gene expression and copy number abnormalities. Different in vivo behavior of the resistant bioluminescent orthotopic CDX models compared to their parental counterparts were observed.
Finally, using human biopsy samples of osteosarcoma relapsing after usual anti-osteosarcoma chemotherapy were developed resistant patient-derived xenograft (PDX) models, either in subcutaneous as in orthotopic bone setting. The characterization of these models are still ongoing, in particular the comparison of their molecular characteristics, i.e. using whole exome and RNA sequencing, in comparison with the patient tumor at relapse and with the same patient tumor at diagnosis.
All these multiple models developed in different in vitro and in vivo contexts bring complementary information to other types of existing osteosarcoma models. They are needed to get more insight into the different processes involving osteosarcoma initiation, progression and in particular treatment sensitivity/resistance. They will further help drug testing to find solution to the current lack of efficient new drugs in osteosarcoma
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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