1,720,965 research outputs found
Hanging in the balance: KIR and their role in disease
No full textThe killer cell immunoglobulin-like receptors (KIR) are a recently discovered family of activating and inhibitory receptors that control natural killer (NK) cell function. KIR exist as a diverse family of receptors that have evolved rapidly by both gene duplication and recombination events. These findings were unexpected for a family of genes involved primarily in the innate immune response. These findings together with the observation that several of these genes have human leukocyte antigen (HLA) class I ligands, have led to a flurry of investigation into how KIR participate in viral infections, autoimmune diseases and malignancies. This review summarizes the major features of these genes and discusses how they may be involved in both disease pathogenesis and its amelioration
Rectal cancer staging post neoadjuvant therapy - how should the changes be assessed?
No full textAims:To compare the utility and reproducibility of tumour regression grade scoring systems during histopathological assessment of rectal cancers resected after neoadjuvant (i.e. pre-operative) chemoradiotherapy. Methods and results:? The histopathological features of tumour regression were assessed independently in 54 rectal cancer resection specimens using three scoring systems: the Tumour Regression Grade (TRG), modified Rectal Cancer Regression Grade (m-RCRG) and RCPath Cancer Dataset (RCPath) methods. Good interobserver agreement was achieved for all three systems (? scores: TRG system 0.719, m-RCRG system 0.734, RCPath system 0.742). Both observers diagnosed complete tumour regression and little/no regression in 11 cases (20% of all cases) and four cases (11% of all cases), respectively. A mean of 5.6 tumour blocks/case were taken and the mean lymph node yield was 8.4/case. Conclusions:? All three scoring systems were usable in a diagnostic setting. The clinical significance of differing degrees of tumour regression is not yet universally agreed and, with this in mind, the m-RCRG system provided the optimum balance between applicability and the accurate recording of low, moderate and high degrees of tumour regression, thus facilitating future clinicopathological studies of moderate and high degrees of tumour regression and clinical outcome
Lack of specificity of cell-surface protease targeting of a cytotoxic hyperfusogenic gibbon ape leukaemia virus envelope glycoprotein
No full textBackground: In a strategy termed Protease Targeting, retroviral vectors carrying an EGF infectivity-blocking domain fused to the N-terminus of the envelope SU via a MMP (matrix metalloproteinase)-cleavable linker were successfully used to target gene delivery to EGF receptor-(EGF-R-)positive tumour cells over-expressing MMPs. In the current study, we aimed to investigate whether this strategy could be applied to (a) limit the cytotoxic activity of a hyperfusogenic GALV therapeutic gene, and (b) enhance the immune-stimulatory properties of GALV via local, MMP-mediated release human granulocyte-macrophage colony stimulating factor (GM-CSF).Methods: We generated GALV envelope expression constructs displaying EGF or GM-CSF blocking ligands at the N-terminus of GALV envelope SU via a non-cleavable, Factor Xa protease or MMP-cleavable linker and investigated their cytotoxicity on MMP-positive and negative cell lines.Results: The unmodified hyperfusogenic GALV envelope was cytotoxic to all cell lines tested. The non-cleavable linker GALV envelope constructs caused no cytotoxicity, demonstrating efficient inhibition by the displayed domains. Moderate activation of fusion of the protease-cleavable linker constructs was observed in all cell lines, regardless of their level of MMP expression and of the specificity of the linker. High levels of the blocking domain were detected in the cell supernatants due to dissociation of the surface unit (SU) from the transmembrane (TM) component of the GALV envelope glycoprotein TM.Conclusions: Unlike protease targeting in the context of retroviral vectors, protease activation of the cytotoxicity of GALV envelope by cleavage of a fusion blocking ligand at the cell surface does not appear to be specifically mediated by cell-surface MMPs. In addition, shedding of the SU-fusion protein from the TM limits the general applicability of this strategy for cancer gene therapy. Specificity of cell-cell fusion mediated by GALV envelope cannot be manipulated in the same fashion as virus-cell fusion
Viral antigen mediated NKp46 activation of NK cells results in tumor rejection via NK-DC crosstalk
No full textNatural killer (NK) cells play a critical role in antitumor immunity, their activation being regulated through NK cell receptors. Although the endogenous ligands for these receptors are largely unknown, viral ligands have been identified. We investigated the ability of an activating NK receptor ligand derived from the mumps virus, haemagglutinin-neuraminidase (HN) to enhance NK activation against tumor cells. HN-expressing B16.OVA tumor cells induced stronger activation of NK cells compared with B16.OVA cells and also promoted dendritic cell (DC) activation toward a DC1 phenotype, in vitro. Moreover, incubation of DCs, NK cells and HN-expressing B16-OVA cells further enhanced NK cell activation through the NK-DC crosstalk, in a cell-to-cell contact- and IL-12-dependent fashion. Immunization of mice with HN-expressing B16-OVA cells resulted in > 85% survival rate after subsequent challenge with parental B16 or B16.OVA tumor cells. Tumor rejection was dependent on both NK and CD8+ T cells but not on CD4+ T cells, demonstrating induction of an effective adaptive immune response through innate immune cell activation. Our data indicate the potential of using robust NK cell activation, which through the NK-DC crosstalk stimulates effective antitumor responses, providing an alternate vaccine strategy
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
The role of systemic inflammatory and nutritional blood-borne markers in predicting response to neoadjuvant chemotherapy and survival in oesophagogastric cancer
No full textThe aim of this study was to interrogate whether blood-borne inflammatory and nutritional markers predict long-term survival and response to neoadjuvant chemotherapy in radically treated oesophagogastric cancer patients. This retrospective study included 246 patients who underwent oesophageal resection for high-grade dysplasia or carcinoma between 2005 and 2010. The predictive value of routine preoperative immunonutritional blood tests was assessed for their association with survival and response to chemotherapy. On multivariate analysis, higher neutrophil–lymphocyte ratio (NLR) (p < 0.0001), N stage (p < 0.0001) and perineural invasion (p < 0.0001) were associated with poor overall survival. Regarding disease-free survival, multivariate analysis showed reduced serum albumin (p = 0.034), N stage (p < 0.0001), M stage (p = 0.037), vascular invasion (p < 0.0001) and presence of R1 resection (p = 0.003) to correlate with earlier recurrence. In those who received neoadjuvant chemotherapy, analysis of prechemotherapy characteristics showed only serum albumin (p = 0.037) to predict pathological response to chemotherapy. Preoperative immunonutritional markers, NLR and albumin, were independent prognostic markers for overall survival and disease-free survival, respectively, after oesophageal cancer resection. Prospective studies evaluating the role of immunonutritional modulation to improve response to chemotherapy and long-term outcome are required
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
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