1,720,975 research outputs found
A role for microRNAs/Notch2R network in pediatric High-Grade Gliomas (pHGGs)
Get PDFGliomas represent a very heterogeneous group of tumors that affect the cellular components of the glial system. Pediatric High Grade Gliomas (pHGGs) are a rare, malignant and diffusively infiltrating neoplasms. They show an extremely broad range of clinical behaviour with only few patients achieving long-term survival.
Notch signaling is an evolutionarily conserved pathway that regulates many cellular and developmental processes. Its dysregulation has been reported in many pathological contexts, including brain tumours, but little is known about the relevance of Notch signaling in pHGGs. The study of epigenetic mechanism engaged in its regulation could allow a better understanding of mechanisms at the basis of its deregulation.
MicroRNAs are small molecules of 21-24 nucleotides in length and are emerging as major regulators of cancer-related gene expression. The identification of specific microRNAs signature is one of the latest hallmarks of scientific efforts. High-throughput microRNA profiling of pHGGs showing that several dysregulated microRNAs characterized these tumors.
The present project intends to investigate the functional role of the Notch signalling unveiling epigenetic networks between dysregulated microRNAs and the Notch pathways.
For the purpose, immunohistochemistry (IHC) on pHGG patients’ derived tissues and immunofluorescence (IF) on a patient derived pHGG cell line (KNS42) were performed to assess Notch receptors expression level. RT-qPCR was used to validate microRNAs levels in pHGG tissues and cells in respect to healthy brain tissues. Cell growth and viability were evaluated on KNS42 cells after microRNAs re-expression or pharmacological (GSI IX) and genetic (siRNA N2) treatments with by trypan blue exclusion assays. Luciferase reporter assay was performed to validate the binding of miR-29a-3p to the 3’-UTR of Notch2.
IHC and IF analysis have demonstrated that Notch2 is highly expressed in pHGG tissues and cells. Pharmacologic and genetic treatments have highlighted its pivotal role in the control of pHGGs cell growth. Studies on patients’ derived pHGG tissues and pHGG cell line, KNS42, revealed down-regulation of three miRNAs, specifically miR-107, miR-181c and miR-29a-3p. Their re-expression in KNS42 cell line has effect on Notch2 protein levels and cell proliferation. The same effect was obtained after pharmacological inhibition of Notch signaling pathway with GSI IX for 96 h. Functional luciferase assay provides the evidence that miR-29a-3p is a direct negative regulator of Notch2 expression.
The study reported suggests that Notch2 pathway activation plays a critical role in pHGGs growth and reveals a direct epigenetic mechanism that controls Notch2 expression. These findings identify new molecular targets for more effective treatment of these devastating pediatric brain tumors
Mitochondrial-DAMPs released after lung transplantation promote primary graft dysfunction
Get PDFLung transplantation (LTx) often results in primary graft dysfunction (PGD), a form of acute lung injury (ALI) that is responsible for poor short and long-term outcomes. Although the underlying mechanisms that promote PGD are undefined recent evidence has pointed to the involvement of danger associated molecular patterns (DAMPs). Mitochondrial DAMPs (Mt-DAMPS) share the potent immunostimulatory qualities of bacterial pathogen-associated molecular patterns (PAMPs) since they can activate the necrotactic formyl peptide receptor 1 (FPR1) regulating neutrophil migration to injured areas. However, the contribution of the Mt-DAMPs-FPR1 axis to organ transplant injury remains unclear.
In a murine orthotopic LTx model of PGD, we detected the release of donor-derived Mt-DAMPs into the injured airways. We also demonstrate that FPR1 expression in the recipient regulates neutrophil intragraft distribution by promoting airways neutrophilia. This effect seems to be specifically associated with the activation of the Mt-DAMPs-FPR1 axis which leads to neutrophil upregulation of adhesion molecules and increased extravascular neutrophil cluster stability. As a consequence of FPR1 expression, we demonstrated prolonged neutrophil retention into the injured airways and exacerbation of the ALI. In a prospective study of 62 human lung recipients, circulating Mt-DAMPs, in the form of mitochondria DNA (Mt-DNA), were increased after LTx and the higher perioperative levels were predictive of severe late PGD.
In conclusion, this thesis proposes that the early release of graft-derived Mt-DAMPs after LTx contributes to exacerbating ALI through an FPR1 dependent regulation of neutrophil intragraft trafficking and activation. Moreover, higher perioperative circulating levels of Mt- DNA in human LTx recipients appear to be a possible biomarker for the early detection of severe PGD
Specific role for p300/CREB-binding protein-associated factor activity in E2F1 stabilization in response to DNA damage
No full textE2F1, a member of the E2F family of transcription factors, plays a pivotal role in controlling both physiological cell-cycle progression and apoptotic cell death in response to DNA damage and oncogene activation. In response to genotoxic stresses, E2F1 is stabilized by signals that include ATM-dependent phosphorylation. We recently demonstrated that DNA damage induces also E2F1 acetylation, which is required for its recruitment onto apoptotic gene promoters. Here we show that E2F1 is stabilized in response to doxorubicin and cisplatin treatments even in the absence of either ATM-dependent phosphorylation or p53 and cAbl, two major transducers of DNA damage signaling. We found that acetylation of E2F1 is, instead, required to stabilize the protein in response to doxorubicin. Finally, we report that the formation of E2F1-p300/CREB-binding protein-associated factor (P/CAF) complexes is preferentially induced in doxorubicin-treated cells, and that P/CAF acetyltransferase (HAT), but not p300 HAT activity, is required for a significant E2F1 stabilization and accumulation. Our results unveil a differential role of P/CAF and p300 in acetylation-induced stabilization of E2F1, thus supporting a specific role for P/CAF HAT activity in E2F1-dependent apoptosis in response to DNA damage
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
Radiological evaluation of biomarkers for renal cell carcinoma
Get PDFRole of MRI DWI sequences in the evaluation of early response to neo- angiogenesis inhibitors in metastatic renal cell carcinoma
Purpose: Angiogenesis inhibitors have a potential role in treating metastatic renal cell carcinoma, but it is still not clear why some patients don't respond. Our objective was to look for DWI parameters able to identify patients with metastatic renal cell carcinoma who would not benefit from target therapy. RECIST1.1 was considered as Reference Standard.
Methods & Materials: We prospectively enrolled 43 patients candidate to start angiogenesis inhibitors with at least one target lesion and who underwent 1,5T MRI examination with multiple bvalues DWI sequences (0,40,200,300,600): one week before (t0), 2 weeks after (t2) and 8 weeks (t8) after treatment beginning. ADC value was calculated drawing ROIs on 3 different planes.
33 patients with 38 lesions had suitable data for comparative evaluation.
Results: At T8 follow-up 9 patients had partial response (PR), 20 table disease (SD), 4 progression disease (PD); average progression free survival was 272 days. PD group, as compared to DC or to PR showed significantly lower ADC values at b40 at t0 (p<0.05): we can assess that more vascularised lesions are more responsive to treatment. PD group have significantly lower ADC values then both other groups, at t0, t2 and t8, for all b-values (p<0.05).
PFS and OS correlates well with ADC, in particular OS with ADC b40 at t0 (r=0,69).
Coclusions: Results show that PD group has significantly lower ADC values than PR or DC everytime (t0, t2, t8)
At t0 there is a better correlation between PFS or OS & ADC than PFS & dimensional criteria.
ADC at t0 may help selecting patients with promising good response to angiogenesis inhibitors.
Moreover at t0 and at t2 ADC has the potential to select patients who wouldn't benefit from angiogenesis inhibitors
Nowadays, in the era of target therapy, it is crucial to select patients potentially responders. We have to look at cost/benefit ratio and at increasing costs of treatment options.
DWI has the potential role to identify patients whose's tumor wouldn't benefit from target therapy, adding a value (ADC) to other imaging (e.g. DCE-MRI, texture imaging) and clinical parameters (e.g. miRNA) in a hypothetic multiparametric analysis.CT Texture Analysis in Clear Cell Renal Cell Carcinoma: a Radiogenomics Prospective
Purpose: The aim of this study was to investigate whether quantitative parameters obtained from CT Texture Analysis (CTTA) correlate with expression of miRNA in clear cell Renal Cell Carcinoma (ccRCC).
Methods and Materials: In a retrospective single centre study, multiphasic CT examination (with arterial, portal, equilibrium and urographic phases) was performed on 20 patients with clear cell renal carcinomas (14 men and 6 women; mean age 65 years ± 13). Measures of heterogeneity were obtained in post-processing by placing a ROI on the entire tumour and CTTA parameters such as entropy, kurtosis, skewness, mean, mean of positive pixels, and SD of pixel distribution histogram were measured using multiple filter settings. Quantitative data were correlated with the expression of miRNAs obtained from the same cohort of patients: 8 fresh frozen samples and 12 formalin-fixed paraffin-embedded samples (miR-21-5p, miR-210-3p, miR-185-5p, miR-221-3p, miR-145-5p). Both evaluations (miRNAs and CTTA) were performed on tumour tissues as well as on normal cortico-medullar tissues. Analysis of Variance with linear multiple regression model methods were obtained with SPSS statistic software. For all comparisons, statistical significance was assumed p<0.05
Results: We evidenced that CTTA has robust parameters (e.g. entropy, mean, sd) to distinguish normal from pathological tissues. Moreover, a higher coefficient of determination between entropy and miR-21-5p expression (R2 =0,25) was evidenced in tumour tissues as compared to normal tissues (R2 =0,15).
Interestingly, excluding four patients with extreme over-expression of miR-21-5p, excellent relation between entropy and miR21-5p levels was found specifically in tumour samples (R2= 0,64; p<0.05).
Conclusion: Entropy and miRNA-21-5p show promising correlation in ccRCC; in addiction CTTA features, in particular mean and entropy show a statistically significant increase in ccRCC as compared with normal renal parenchyma
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
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