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Pancreatic ductal adenocarcinoma: biomarker identification, exosome characterization, apoptosis and necroptosis induction by sulforaphane
Get PDFL'adenocarcinoma duttale pancreatico (PDAC) è un tumore aggressivo con tasso di sopravvivenza a
5 anni del 6%. La mancanza di sintomi precoci, l'assenza di specifici biomarcatori e la scarsa
efficacia dei trattamenti sono le principali ragioni di prognosi infausta.
Gli esosomi, nanovescicole secrete dalle cellule normali e tumorali, sono stati recentemente
considerati marcatori tumorali che potrebbero essere quantificati in modo non invasivo nei fluidi
corporei umani. Ho sviluppato un test ELISA adatto al rilevamento di proteine esosomiali in
campioni di plasma da pazienti con PDAC, al fine di valutare le correlazioni con la progressione
della malattia. I livelli delle proteine esosomali CD24, CXCR4, EpCAM, CD44v6 e Tspan8,
aumentavano con la progressione della malattia indicando che possano essere candidati
biomarcatori per il PDAC.
L'identificazione di potenziali biomarcatori diagnostici e prognostici può essere effettuata anche
attraverso la bioinformatica. La weighted gene co-expression network analysis (WGCNA) è un
nuovo metodo di systems biology che ho usato per dedurre le reti geniche da dati di espressione
basati su microarray ottenuti da campioni normali e PDAC. Sono stati identificati diversi geni e
miRNA cruciali per lo sviluppo del PDAC che potrebbero essere considerati potenziali biomarker
diagnostici e bersagli terapeutici.
Poiché vi è l'urgente necessità di identificare trattamenti più efficaci, studi recenti si sono
concentrati sulle proprietà anti-tumorali dei composti derivati dalle piante. Ho valutato se il
sulforafano, un composto fitochimico presente nei broccoli, potesse essere coinvolto
nell'induzione sia dell'apoptosi sia della necroptosi in linee cellulari di tumore al pancreas. I
risultati suggeriscono che questo composto induce apoptosi anche in una linea cellulare resistente
ai farmaci ma non innesca il pathway necroptotico quando le caspasi sono inibite. Lo studio
fornisce nuove informazioni sul meccanismo della morte indotta da sulforafano.Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with 5-years relative
survival rate of 6%. Lack of early symptoms, the absence of specific biomarkers and the low
treatment effectiveness are the principal reasons of this poor prognosis.
Exosomes, nanovesiscles secreted by normal and cancer cells, have been recently considered as
source of tumour markers that could be quantified non-invasively in human body fluids. I
developed an ELISA assay suitable for the detection of exosomal proteins in plasma samples from
PDAC patients, in order to evaluate correlations with the disease progression. I found that the
levels of the exosomal proteins Tspan8, EpCAM, CD24, CXCR4 and CD44v6 increased with the
disease progression indicating that they could be candidate biomarkers for pancreatic cancer.
The identification of potential diagnostic and prognostic biomarkers could be carried out also by
using bioinformatics tools. Weighted gene co-expression network analysis (WGCNA) is a new
system biology method that I used to deduce gene networks from microarray-based gene
expression datasets obtained from normal and PDAC samples. I identified several key genes and
miRNAs that could be crucial to PDAC development and therefore considered as potential
diagnostic biomarkers and therapeutic targets.
Since current standard therapies for PDAC have provided scarce survival advantage, there is the
urgent need to identify new treatment strategies. To this aim, recent studies have focused on the
anti-cancer properties of plant-derived compounds. I investigated if broccoli-derived sulforaphane
could be involved in induction of both apoptosis and necroptosis in pancreatic cancer cells. My
results suggest that this compound induces apoptosis even in a drug-resistant cell line but it does
not trigger the necroptotic pathway when the caspases are inhibited. The study provides new
insight into the mechanism of sulforaphane-induced death
Weighted gene co-expression network analysis reveals key genes involved in pancreatic ductal adenocarcinoma development
No full textIdentification of candidate miRNA biomarkers for pancreatic ductal adenocarcinoma by weighted gene co-expression network analysis
Get PDFPURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal prognosis which is, among others, due to a lack of suitable biomarkers and therapeutic targets. Previously, basic gene expression analysis methods have been used for their identification, but recently new algorithms have been developed allowing more comprehensive data analyses. Among them, weighted gene co-expression network analysis (WGCNA) has already been applied to several cancer types with promising results.
METHODS: We applied WGCNA to miRNA expression data from PDAC patients. Specifically, we processed microarray-based expression data of 2555 miRNAs in serum from 100 PDAC patients and 150 healthy subjects. We identified network modules of co-expressed miRNAs in the healthy subject dataset and verified their preservation in the PDAC dataset. In the non-preserved modules, we selected key miRNAs and carried out functional enrichment analyses of their experimentally known target genes. Finally, we tested their prognostic significance using overall survival analyses.
RESULTS: Through WGCNA we identified several miRNAs that discriminate healthy subjects from PDAC patients and that, therefore, may play critical roles in PDAC development. At a functional level, we found that they regulate p53, FoxO and ErbB associated cellular signalling pathways, as well as cell cycle progression and various genes known to be involved in PDAC development. Some miRNAs were also found to serve as novel prognostic biomarkers, whereas others have previously already been proposed as such, thereby validating the WGCNA approach. In addition, we found that these novel data may explain at least some of our previous PDAC gene expression analysis results.
CONCLUSIONS: We identified several miRNAs critical for PDAC development using WGCNA. These miRNAs may serve as biomarkers for PDAC diagnosis/prognosis and patient stratification, and as putative novel therapeutic targets
CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?
No full textCXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role. In particular, it seems to promote tumor invasion, proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in pancreatic cancer. Nevertheless, some evidence shows opposite functions; therefore research on CXCL12 is still ongoing. These discrepancies could be due to the presence of at least six CXCL12 splicing isoforms, each with different roles. Interestingly, three out of six variants have the highest levels of expression in the pancreas. Here, we report the current knowledge about the functions of this chemokine and then focus on pancreatic cancer. Moreover, we discuss the methods applied in recent studies in order to understand if they took into account the existence of the CXCL12 isoforms
The role of life-history traits, selective pressure and hydrographic boundaries in shaping the genetic structure of the transparent goby, Aphia minuta
No full textThe transparent goby (Aphia minuta) is a small progenetic goby that displays a short life cycle with early reproductive maturity and represents a valuable fishery resource harvested by artisanal fleets in most part of its distributional range. This study aimed to define the genetic variability in A. minuta at five sampling sites within the Mediterranean Sea and one in the Atlantic Ocean through the analysis of 11 nuclear microsatellite loci. The results revealed that several genetic diversity estimators (expected and observed heterozygosities, mean number of alleles and allelic richness) were lower in the Atlantic Ocean than in the Mediterranean Sea, suggesting the role of past or current demographic events in shaping this pattern. The genetic structure was investigated using both classical genetic differentiation descriptors and Bayesian approaches, and by defining the current and past migration rates. The results obtained revealed a pronounced genetic structure within the Mediterranean Sea and suggest a very low current migration rate. The pattern of historical migration suggests the possible role of hydrographic boundaries in shaping the genetic structure detected in this species. In addition, the identification of loci under selection suggests the possible implication of selective pressures that are acting on genes connected with the peculiar life cycle of this gobiid fish
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
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