1,721,018 research outputs found

    Multiple effects of CDK4/6 inhibition in cancer: From cell cycle arrest to immunomodulation

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    Dysregulation of the cell cycle is a hallmark of cancer that leads to aberrant cellular proliferation. CDK4/6 are cyclin-dependent kinases activated in response to proliferative signaling, which induce RB hyper-phosphorylation and hence activation of E2F transcription factors, thus promoting cell cycle progression through the S phase. Pharmacologic inhibition of CDK4/6 by palbociclib, ribociclib, or abemaciclib has been showing promising activity in multiple cancers with the best results achieved in combination with other agents. Indeed, CDK4/6 inhibitors are currently approved in combination with endocrine therapy for the treatment of estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer. Moreover, a number of clinical trials are currently underway to test the efficacy of combining CDK4/6 inhibitors with different drugs not only in breast but also in other types of cancer. Beyond the inhibition of cell proliferation, CDK4/6 inhibitors have recently revealed new effects on cancer cells and on tumor microenvironment. In particular, it has been reported that these agents induce a senescent-like phenotype, impact on cell metabolism and exert both immunomodulatory and immunogenic effects. Here we describe recent data on the anti-tumor effects of CDK4/6 inhibitors as single agents or in combined therapies, focusing in particular on their metabolic and immunomodulatory activities

    Immunotherapeutic approaches in malignant pleural mesothelioma

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    Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant disease affecting the mesothelium, commonly associated to asbestos exposure. The current therapeutic actions, based on cisplatin/pemetrexed treatment, are limited due to the late stage at which most patients are diagnosed and to the intrinsic chemo-resistance of the tumor. Another relevant point is the absence of approved therapies in the second line setting following progression of MPM after chemotherapy. Considering the poor prognosis of the disease and the fact that the incidence of this tumor is expected to increase in the next decade, novel therapeutic approaches are urgently needed. In the last few years, several studies have investigated the efficacy and safety of immune-checkpoint inhibitors (ICIs) in the treatment of unresectable advanced MPM, and a number of trials with immunotherapeutic agents are ongoing in both first line and second line settings. In this review, we describe the most promising emerging immunotherapy treatments for MPM (ICIs, engineered T cells to express chimeric antigen receptors (CARs), dendritic cells (DCs) vaccines), focusing on the biological and immunological features of this tumor as well as on the issues surrounding clinical trial design

    Going Beyond Counting First Authors in Author Co-citation Analysis

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    The 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

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    “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
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