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The multi-factorial nature of clinical multidrug resistance in cancer
No full textCurative cancer therapy remains a major challenge particularly in cancers displaying multidrug resistance (MDR). The MDR phenotype is characterized by cross-resistance to a wide array of anticancer drugs harboring distinct structures and mechanisms of action. The multiple factors involved in mediating MDR may include host factors, tumor factors as well as tumor-host interactions. Among the host factors are genetic variants and drug-drug interactions. The plethora of tumor factors involves decreased drug uptake primarily via impaired influx transporters, increased drug efflux predominantly due to the overexpression of MDR efflux transporters of the ATP-binding cassette superfamily or due to drug efflux mediated by extracellular vesicles (EVs) or drug-loaded lysosomes undergoing exocytosis, deregulation of cell death mechanisms (i.e. anti-apoptotic modalities), enhanced DNA damage repair, epigenetic alterations and/or deregulation of microRNAs. The intratumor heterogeneity and dynamics, along with cancer stem cell plasticity, are important tumor factors. Among the tumor-host interactions are the role of the tumor microenvironment, selective pressure of various stressor conditions and agents, acidic pH and the intracellular transfer of traits mediated by EVs. The involvement of these diverse factors in MDR, highlights the need for precision medicine and real-time personalized treatments of individual cancer patients. In this review, written by a group of researchers from COST Action STRATAGEM "New diagnostic and therapeutic tools against multidrug resistant tumors", we aim to bring together these multidisciplinary and interdisciplinary features of MDR cancers. Importantly, it is becoming increasingly clear that deciphering the molecular mechanisms underlying anticancer drug resistance, will pave the way towards the development of novel precision medicine treatment modalities that are able to surmount distinct and well-defined mechanisms of anticancer drug resistance
The hydropathy index of the HCDR3 region of the B-Cell receptor identifies two subgroups of IGHV-mutated chronic lymphocytic leukemia patients with distinct outcome
No full textThe HCDR3 sequences of the B-cell receptor (BCR) undergo constraints in length, amino acid use, and charge during maturation of B-cell precursors and after antigen encounter, leading to BCR and antibodies with high affinity to specific antigens. Chronic lymphocytic leukemia consists of an expansion of B-cells with a mixed immature and "antigen-experienced" phenotype, with either a mutated (M-CLL) or unmutated (U-CLL) tumor BCR, associated with distinct patient outcomes. Here, we investigated the hydropathy index of the BCR of 138 CLL patients and its association with the IGHV mutational status and patient outcome. Overall, two clearly distinct subgroups of M-CLL patients emerged, based on a neutral (mean hydropathy index of -0.1) vs. negatively charged BCR (mean hydropathy index of -1.1) with molecular features closer to those of B-cell precursors and peripheral/mature B-cells, respectively. Despite that M-CLL with neutral HCDR3 did not show traits associated with a mature B-cell repertoire, important differences in IGHV gene usage of tumor cells and patient outcome were observed in this subgroup of patients once compared to both U-CLL and M-CLL with negatively charged HCDR3 sequences. Compared to M-CLL with negatively charged HCDR3 sequences, M-CLL with neutral HCDR3 sequences showed predominance of men, more advanced stages of the disease, and a greater frequency of genetic alterations-e.g., del(17p)-together with a higher rate of disease progression and shorter time to therapy (TTT), independently of other prognostic factors. Our data suggest that the hydropathy index of the HCDR3 sequences of CLL cells allows the identification of a subgroup of M-CLL with intermediate prognostic features between U-CLL and the more favorable subgroup of M-CLL with a negatively charged BCR.</p
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
CD20+ T cells in monoclonal B cell lymphocytosis and chronic lymphocytic leukemia: frequency, phenotype and association with disease progression
Get PDFIntroduction: In monoclonal B cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), the expansion of malignant B cells disrupts the normal homeostasis and interactions between B cells and T cells, leading to
immune dysregulation. CD20+ T cells are a subpopulation of T cells that appear to be involved in autoimmune diseases and cancer. Methods: Here, we quantified and phenotypically characterized CD20+ T cells from MBL subjects and CLL patients using flow cytometry and correlated our findings with the B-cell receptor mutational status and other features of the disease. Results and discussion: CD20+ T cells were more represented within the CD8+T cell compartment and they showed a predominant memory Tc1 phenotype. CD20+ T cells were less represented in MBL and CLL patients vs healthy controls, particularly among those with unmutated IGVH gene. The expansion of malignant B cells was accompanied by phenotypic and functional changes in CD20+ T cells, including an increase in follicular helper CD4+ CD20+ T cells and CD20+ Tc1 cells, in addition to the expansion of the TCR Vb 5.1 in CD4+ CD20+T cells in CLL.info:eu-repo/semantics/publishedVersio
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
Hypoxia as a driver of resistance to immunotherapy
Get PDFHypoxia, a hallmark of solid tumors, determines the selection of invasive and aggressive malignant clones displaying resistance to radiotherapy, conventional chemotherapy or targeted therapy. The recent introduction of immunotherapy, based on immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cells, has markedly transformed the prognosis in some tumors but also revealed the existence of intrinsic or acquired drug resistance. In the current review we highlight hypoxia as a culprit of immunotherapy failure. Indeed, multiple metabolic cross talks between tumor and stromal cells determine the prevalence of immunosuppressive populations within the hypoxic tumor microenvironment and confer upon tumor cells resistance to ICPIs and CAR T-cells. Notably, hypoxia-triggered angiogenesis causes immunosuppression, adding another piece to the puzzle of hypoxia-induced immunoresistance. If these factors concurrently contribute to the resistance to immunotherapy, they also unveil an unexpected Achille’s heel of hypoxic tumors, providing the basis for innovative combination therapies that may rescue the efficacy of ICPIs and CAR T-cells. Although these treatments reveal both a bright side and a dark side in terms of efficacy and safety in clinical trials, they represent the future solution to enhance the efficacy of immunotherapy against hypoxic and therapy-resistant solid tumors.CR unit receives funding from the Italian Association of Cancer Research (AIRC; IG21408). ABSR unit is supported by Foundation for Science and Technology (FCT), Portugal (UID/NEU/04539/2019, UIDB/ 04539/2020 and UIDP/04539/2020). J.D.L.R. unit is funded by Fondo de Investigación Sanitaria—Instituto de Salud Carlos III (FIS—ISCIII, Ministry of Health of Spain; PI18/00591 and PT17/0009/0008) and by the FEDER European Union’s program. J.D.L.R. and C. R. are Vice-Chair and Chair of the COST-Action STRATAGEM (CA17104). All authors are members of STRATAGEM (CA17104)
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
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