Omics approaches in pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal—around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients

Splicing regulator SLU7 is essential for maintaining liver homeostasis

A precise equilibrium between cellular differentiation and proliferation is fundamental for tissue homeostasis. Maintaining this balance is particularly important for the liver, a highly differentiated organ with systemic metabolic functions that is endowed with unparalleled regenerative potential. Carcinogenesis in the liver develops as the result of hepatocellular de-differentiation and uncontrolled proliferation. Here, we identified SLU7, which encodes a pre-mRNA splicing regulator that is inhibited in hepatocarcinoma, as a pivotal gene for hepatocellular homeostasis. SLU7 knockdown in human liver cells and mouse liver resulted in profound changes in pre-mRNA splicing and gene expression, leading to impaired glucose and lipid metabolism, refractoriness to key metabolic hormones, and reversion to a fetal-like gene expression pattern. Additionally, loss of SLU7 also increased hepatocellular proliferation and induced a switch to a tumor-like glycolytic phenotype. Slu7 governed the splicing and/or expression of multiple genes essential for hepatocellular differentiation, including serine/arginine-rich splicing factor 3 (Srsf3) and hepatocyte nuclear factor 4α (Hnf4α), and was critical for cAMP-regulated gene transcription. Together, out data indicate that SLU7 is central regulator of hepatocyte identity and quiescence

‘No hay más que un mundo’: Globalización y conexiones en los territorios ultramarinos de los Hasburgos españoles (1581-1640)

The study of the overseas empire of the Spanish Habsburgs during the period when the Crown of Portugal was incorporated to this politico-economic structure and the study of their encounters, exchanges and contributions at all levels are increasingly being perceived as a plausible and original alternative within the current historiographical debate evolving around the configuration of the new European political order produced during the Early Modern period and characterised by the so-called ‘crisis of the State’ and the economic ‘decadence’ of the territories of southern Europe. This article offers some observations concerning this interesting subject, as well as some insight into the implications that this process carried in the Spanish and Portuguese cases.Dentro del vigente debate historiográfico sobre la configuración del orden político europeo que se produjo durante la Edad Moderna, caracterizado por la llamada “crisis del Estado” y por la “decadencia” económica en los territorios del sur de Europa, el estudio de las posesiones de Ultramar de los Habsburgo españoles durante el momento de agregación de la Corona de Portugal a la Monarquía Hispánica (1581-1640), con sus encuentros, sus intercambios y sus mixturas a todos los niveles, se insinúa como una posible y original alternativa de trabajo y reflexión. En el presente artículo se ofrecen algunas consideraciones sobre esta interesante cuestión, destacando además las implicaciones que dicho proceso tuvo en los casos español y portugués

7th Drug hypersensitivity meeting: part two

No abstract availabl

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Función de la metaloproteasa de matriz 10 (MMP10) en la regeneración hepática y la carcinogénesis

Upon tissue injury, the liver mounts a potent reparative and regenerative response. This wound-healing response involves a transitory substitution of damaged hepatic parenchyma by extracellular matrix (ECM) that subsequently needs to be removed when liver tissue is regenerated. A role for proteases, including matrix metalloproteinases (MMPs), in this process is increasingly recognized, acting as regulatory molecules by the selective proteolytic activation of growth factors and cell surface receptors in addition to their ability to degrade ECM constituents. Moreover, MMPs also have been demonstrated to participate in cancer by promoting a protumorigenic microenvironment. We have evaluated the hepatic expression and function of MMP10 (stromelysin-2) in mouse models of liver wound-healing and regeneration, in human hepatocellular carcinoma (HCC) and in diethylnitrosamine (DEN)-induced mouse hepatocarcinogenesis. The role of MMP10 was evaluated by comparing the response of wild type (MMP10+/+) and MMP10-deficient (MMP10-/-) mice to the different experimental models. Mouse MMP10 hepatic expression was readily induced in different injury and regeneration models: two-thirds partial hepatectomy (PH), bile duct ligation (BDL) and carbon tetrachloride (CCl4) acute administration. MMP10 protein was detected in hepatocytes, cholangiocytes and macrophages. MMP10 was also induced in human and murine HCC tissues and cells. In cultured liver epithelial cells, MMP10 expression was additively induced by transforming growth factor-β and epidermal growth factor receptor ligands. TLR4 ligands also stimulated its expression in macrophages. Lack of MMP10 resulted in increased liver injury and fibrogenesis, impaired resolution of necrotic areas and defective turnover of fibrin(ogen) and fibronectin upon PH, BDL and CCl4 administration. On the other hand, in the DEN model, MMP10-/- mice showed less HCC incidence, smaller histological lesions, reduced tumor vascularization, and less lung metastases. Importantly, expression of the protumorigenic C-X-C chemokine receptor 4 (CXCR4) was reduced in those mice. A MMP10 overexpressing human HCC cell line was generated. These HCC cells had increased CXCR4 expression and showed enhanced migratory capacity, and the pharmacological inhibition of CXCR4 reduced MMP10-stimulated cell migration. MMP10 expression in HCC cells was induced by hypoxia and the CXCR4 ligand stroma-derived factor 1 (SDF1), through the ERK1/2 pathway, involving an activator protein 1 site in MMP10 gene promoter. Conclusions: MMP10 expression is induced during mouse liver injury and participates in the hepatic wound-healing response, where the profibrinolytic activity of MMP10 may be essential in this hepatoprotective role. In contrast, MMP10 contributes to HCC development, participating in tumor angiogenesis, growth, and dissemination. We identified a new reciprocal crosstalk between MMP10 and the CXCR4/SDF1 axis contributing to HCC progression and metastasis

Función de la metaloproteasa de matriz 10 (MMP10) en la regeneración hepática y la carcinogénesis

Upon tissue injury, the liver mounts a potent reparative and regenerative response. This wound-healing response involves a transitory substitution of damaged hepatic parenchyma by extracellular matrix (ECM) that subsequently needs to be removed when liver tissue is regenerated. A role for proteases, including matrix metalloproteinases (MMPs), in this process is increasingly recognized, acting as regulatory molecules by the selective proteolytic activation of growth factors and cell surface receptors in addition to their ability to degrade ECM constituents. Moreover, MMPs also have been demonstrated to participate in cancer by promoting a protumorigenic microenvironment. We have evaluated the hepatic expression and function of MMP10 (stromelysin-2) in mouse models of liver wound-healing and regeneration, in human hepatocellular carcinoma (HCC) and in diethylnitrosamine (DEN)-induced mouse hepatocarcinogenesis. The role of MMP10 was evaluated by comparing the response of wild type (MMP10+/+) and MMP10-deficient (MMP10-/-) mice to the different experimental models. Mouse MMP10 hepatic expression was readily induced in different injury and regeneration models: two-thirds partial hepatectomy (PH), bile duct ligation (BDL) and carbon tetrachloride (CCl4) acute administration. MMP10 protein was detected in hepatocytes, cholangiocytes and macrophages. MMP10 was also induced in human and murine HCC tissues and cells. In cultured liver epithelial cells, MMP10 expression was additively induced by transforming growth factor-β and epidermal growth factor receptor ligands. TLR4 ligands also stimulated its expression in macrophages. Lack of MMP10 resulted in increased liver injury and fibrogenesis, impaired resolution of necrotic areas and defective turnover of fibrin(ogen) and fibronectin upon PH, BDL and CCl4 administration. On the other hand, in the DEN model, MMP10-/- mice showed less HCC incidence, smaller histological lesions, reduced tumor vascularization, and less lung metastases. Importantly, expression of the protumorigenic C-X-C chemokine receptor 4 (CXCR4) was reduced in those mice. A MMP10 overexpressing human HCC cell line was generated. These HCC cells had increased CXCR4 expression and showed enhanced migratory capacity, and the pharmacological inhibition of CXCR4 reduced MMP10-stimulated cell migration. MMP10 expression in HCC cells was induced by hypoxia and the CXCR4 ligand stroma-derived factor 1 (SDF1), through the ERK1/2 pathway, involving an activator protein 1 site in MMP10 gene promoter. Conclusions: MMP10 expression is induced during mouse liver injury and participates in the hepatic wound-healing response, where the profibrinolytic activity of MMP10 may be essential in this hepatoprotective role. In contrast, MMP10 contributes to HCC development, participating in tumor angiogenesis, growth, and dissemination. We identified a new reciprocal crosstalk between MMP10 and the CXCR4/SDF1 axis contributing to HCC progression and metastasis

Splicing regulator SLU7 preserves survival of hepatocellular carcinoma cells and other solid tumors via oncogenic miR-17-92 cluster expression.

Resisting death is a central hallmark of cancer cells. Tumors rely on a number of genetic mechanisms to avoid apoptosis, and alterations in mRNA alternative splicing are increasingly recognized to have a role in tumorigenesis. In this study, we identify the splicing regulator SLU7 as an essential factor for the preservation of hepatocellular carcinoma (HCC) cells viability. Compared with hepatocytes, SLU7 expression is reduced in HCC cells; however, further SLU7 depletion triggered autophagy-related cellular apoptosis in association with the overproduction of reactive oxygen species. Remarkably, these responses were not observed in primary human hepatocytes or in the well-differentiated HepaRG cell line. Mechanistically, we demonstrate that SLU7 binds the C13orf25 primary transcript in which the polycistronic oncomir miR-17-92 cluster is encompassed, and is necessary for its processing and expression. SLU7 knockdown altered the splicing of the C13orf25 primary transcript, and markedly reduced the expression of its miR-17, miR-20 and miR-92a constituents. This led to the upregulation of CDKN1A (P21) and BCL2L11 (BIM) expression, two bona fide targets of the miR-17-92 cluster and recognized mediators of its pro-survival and tumorigenic activity. Interestingly, altered splicing of miR-17-92 and downregulation of miR-17 and miR-20 were not observed upon SLU7 knockdown in non-transformed hepatocytes, but was found in other (HeLa, H358) but not in all (Caco2) non-hepatic tumor cells. The functional relevance of miR-17-92 dysregulation upon SLU7 knockdown was established when oxidative stress, autophagy and apoptosis were reversed by co-transfection of HCC cells with a miR-17 mimic. Together, these findings indicate that SLU7 is co-opted by HCC cells and other tumor cell types to maintain survival, and identify this splicing regulator as a new determinant for the expression of the oncogenic miR-17-92 cluster. This novel mechanism may be exploited for the development of antitumoral strategies in cancers displaying such SLU7-miR-17-92 crosstalk