1,720,972 research outputs found
Genomic biomarkers and underlying mechanism of benefit from BCG immunotherapy in non-muscle invasive bladder cancer
No full textINTRODUÇÃO E OBJETIVOS: O tratamento padrão do carcinoma urotelial não músculo invasivo da bexiga (CNMIB) consiste na ressecção transuretral do tumor vesical (RTU) seguida de terapia intravesical com Bacillus Calmette-Guérin (BCG). Entretanto, cerca de 25-45% dos pacientes não apresentam benefício deste tratamento e, até o momento, não há biomarcadores validados para guiar a seleção de pacientes. A identificação de biomarcadores preditivos de resposta é de fundamental importância para maximizar o uso clínico do BCG em pacientes com maior chance de benefício e potencialmente reduzir o risco de desabastecimento do BCG. Os objetivos deste estudo foram identificar biomarcadores genômicos e caracterizar o mecanismo de benefício da imunoterapia com BCG no tratamento do CNMIB. MÉTODOS: Trinta e cinco pacientes portadores de CNMIB tratados com BCG intravesical no Instituto do Câncer do Estado de São Paulo entre 2009 e 2016 foram retrospectivamente identificados. Os pacientes foram classificados como BCG-responsivos (BCG-R) ou não-responsivos (BCG-NR) e material arquivado de tecido tumoral foi obtido para realização do sequenciamento do exoma total. A carga mutacional tumoral (tumor mutational burden; TMB) e a carga de neoantígenos (neoantigen load; NAL) foram correlacionadas com taxa de resposta (TR) e sobrevida livre de recorrência (SLR). A presença de mutações deletérias em genes de reparo de DNA (DDR) foi comparada entre os grupos BCG-R (N= 17) e BCG-NR (N= 18). RESULTADOS: TMB e NAL foram maiores no grupo BCG-R em comparação com BCG-NR, sendo a mediana do TMB de 4,9 vs. 2,8 mutações/Mb (P=0,017) e NAL 100 vs. 65 neoantígenos (P=0,032). Pacientes com alto TMB apresentaram maior TR e SLR em comparação com TMB baixo (TR 71% vs. 28%, P=0,011 e SLR 38 vs. 15 meses, P=0,009) e o mesmo foi observado em pacientes com NAL alto vs. baixo (TR 71% vs. 28%, P=0.011 e SLR 36 vs. 18.5 meses, xii P=0.017). A presença de mutações em genes DDR foi associada a melhor SLR (35.5 vs. 11 meses, P=0,017). CONCLUSÕES: Nesta coorte, melhores desfechos de tratamento com BCG intravesical foram observados em pacientes com TMB alto, NAL alto e mutação em genes DDR. Caso estes resultados sejam confirmados em estudos maiores, TMB pode ser validado como biomarcador preditivo de resposta ao BCG e eventualmente poderá ser incorporado a outros potenciais biomarcadores para maximizar resultados do tratamento. Além disto, os resultados deste estudo indicam que o BCG pode induzir resposta imune anti-tumoral através do reconhecimento de neoantígenos. Estes achados aumentam o entendimento dos mecanismos imunogênicos do BCG e suporta investigação clínica com imunoterapia para o CNMIB.INTRODUCTION AND OBJECTIVES: The standard of care therapy for high-risk non-muscle invasive bladder cancer (NMIBC) include complete transurethral resection of the bladder tumor (TURBT) followed by intravesical therapy with Bacillus Calmette-Guérin (BCG). However, 25-45% of the patients will not benefit from BCG immunotherapy and, to date, there is no validated predictive biomarker to guide patient selection. The identification of predictive biomarkers is critical to maximize clinical use in patients more likely to benefit from therapy and potentially reduce the risk of BCG supply shortages. The objectives of this study are to identify genomic biomarkers and characterize the underlying mechanism of benefit from BCG immunotherapy in NMIBC. METHODS: We retrospectively identified 35 patients with NMIBC treated with TURBT and intravesical BCG immunotherapy from 2009 to 2016 at the Instituto do Cancer do Estado de São Paulo. Patients were classified as BCG- responsive (BCG-R) and BCG-unresponsive (BCG-UR) and pre-treatment archival index-tumors were obtained for whole-exome sequencing analysis. Tumor mutation burden (TMB) and neoantigen load (NAL) were correlated with BCG response rate (RR) and recurrence-free survival (RFS). The presence of deleterious mutations in DNA damage repair (DDR) genes was also compared between BCG-responsive (BCG-R, N= 17) and unresponsive (BCG-UR, N= 18) subgroups. RESULTS: Tumor mutational burden and neoantigen load were higher in BCG-R compared to BCG-UR patients (median TMB 4.9 vs. 2.8 mutations/Mb, P=0.017 and median NAL 100 vs. 65 neoantigens, P=0.032). Improved response rate and recurrence-free survival were observed in patients with high vs. low TMB (RR 71% vs. 28%, P=0.011 and RFS 38.0 vs. 15.0 months, P=0.009) and with high vs. low NAL (RR 71% vs. 28%, P=0.011 and RFS 36.0 vs. 18.5 months, P=0.017). The presence of deleterious mutations in DDR genes was associated with improved RFS (35.5 vs. 11.0 months, P=0.017). CONCLUSIONS: In our cohort, improved outcomes after BCG xiv immunotherapy were observed in patients with high TMB, high NAL and deleterious mutations in DDR genes. If these results are confirmed in larger cohorts, TMB could be a predictive biomarker to BCG and hopefully will be integrated to other biomarkers to maximize the benefit to available therapies. Moreover, our study provides evidence that BCG may induce tumor-specific immune response by enhancing the recognition of neoantigens. These findings improve our understanding of the mechanisms behind BCG-mediated immunity and provide further support for clinical investigation of immunotherapy in NMIBC
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Variations on the Author
Get PDF“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
Get PDFWe 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
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe 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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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