TNF-α/IL-1/NF-κB transduction pathway in human cancer prostate

TNFα exerts apoptosis throughout an intracellular transduction pathway that involves the kinase proteins TRAF-2 (integration point of apoptotic and survival signals), ASK1 (pro-apoptotic protein), MEK-4 (p38 activator and metastasis suppressor gene), JNK (stress mitogen activated protein kinase) and the transcription factor AP-1. TNFα also exerts proliferation by p38 activation, or when TRAF-2 simultaneously induces the transcription factor NF-κB by NIK. NIK and p38 may also be activated by IL-1. P38 activated several transcription factors such as Elk-1, ATF-2 and NF-κB. NIK also may activate NF-κB. The aim of the present article was to evaluate the different components of this TNFα/IL-1 transduction pathway in human prostate carcinoma (PC) in comparison with normal human prostate. In prostate cancer, pro-apoptotic TNFα/AP-1 pathway is probably inactivated by different factors such as p21 (at ASK-1 level) and bcl-2 (at JNK level), or diverted towards p38 or NIK activation. IL-1α enhances proliferation through IL-1RI that activates either NIK or p38 transduction pathway. P38 and NIK activate different transcription factors related with cell proliferation and survival such as ATF-2, Elk-1 or NF-κB. In order to search a possible target to cancer prostate treatment we proposed that inhibition of several proinflamatory cytokines such as IL-1 and TNFα might be a possible target for PC treatment, because decrease the activity of all transduction pathway members that activate transcription factors as NF-κB, Elk-1 or ATF-2.Ministerio de Educación y Cienci

Understanding HAT1: A Comprehensive Review of Noncanonical Roles and Connection with Disease

Histone acetylation plays a vital role in organizing chromatin, regulating gene expression and controlling the cell cycle. The first histone acetyltransferase to be identified was histone acetyltransferase 1 (HAT1), but it remains one of the least understood acetyltransferases. HAT1 catalyzes the acetylation of newly synthesized H4 and, to a lesser extent, H2A in the cytoplasm. However, 20 min after assembly, histones lose acetylation marks. Moreover, new noncanonical functions have been described for HAT1, revealing its complexity and complicating the understanding of its functions. Recently discovered roles include facilitating the translocation of the H3H4 dimer into the nucleus, increasing the stability of the DNA replication fork, replication-coupled chromatin assembly, coordination of histone production, DNA damage repair, telomeric silencing, epigenetic regulation of nuclear lamina-associated heterochromatin, regulation of the NF-kappa B response, succinyl transferase activity and mitochondrial protein acetylation. In addition, the functions and expression levels of HAT1 have been linked to many diseases, such as many types of cancer, viral infections (hepatitis B virus, human immunodeficiency virus and viperin synthesis) and inflammatory diseases (chronic obstructive pulmonary disease, atherosclerosis and ischemic stroke). The collective data reveal that HAT1 is a promising therapeutic target, and novel therapeutic approaches, such as RNA interference and the use of aptamers, bisubstrate inhibitors and small-molecule inhibitors, are being evaluated at the preclinical level

Prognostic value of inhibitors of apoptosis proteins (IAPs) and caspases in prostate cancer: caspase-3 forms and XIAP predict biochemical progression after radical prostatectomy

Background: The expression status of apoptotic regulators, such as caspases and inhibitors of apoptosis proteins (IAPs), could reflect the aggressiveness of tumors and, therefore, could be useful as prognostic markers. We explored the associations between tumor expression of caspases and IAPs and clinicopathological features of prostate cancer – clinical and pathological T stage, Gleason score, preoperative serum PSA levels, perineural invasion, lymph node involvement, surgical margin status and overall survival – and evaluated its capability to predict biochemical progression after radical prostatectomy. Methods: Protein expression of caspases (procaspase-8, cleaved caspase-8, procaspase-3, cleaved caspase-3, caspase-7 and procaspase-9) and IAPs (cIAP1/2, cIAP2, NAIP, Survivin and XIAP) was analyzed by immunohistochemistry in radical prostatectomy samples from 84 prostate cancer patients. Spearman’s test, Kaplan-Meier curves, and univariate and multivariate Cox proportional hazard regression analysis were performed. Results: cIAP1/2, cIAP2, Survivin, procaspase-8, cleaved caspase-8, procaspase-3 and caspase-7 expression correlated with at least one clinicopathological feature of the disease. Patients negative for XIAP, procaspase-3 or cleaved caspase-3 had a significantly worse prognosis. Of note, XIAP, procaspase-3 and cleaved caspase-3 were predictors of biochemical progression independent of Gleason score and pathological T stage. Conclusions: Our results indicate that alterations in the expression of IAPs and caspases contribute to the malignant behavior of prostate tumors and suggest that tumor expression of XIAP, procaspase-3 and cleaved caspase-3 may help to identify prostate cancer patients at risk of progression

Interleukin-2 and its receptor complex (alpha, beta and gamma chains) in in situ and infiltrative human breast cancer: an immunohistochemical comparative study

The presence and distribution of interleukin-2 (IL-2) and its receptor complex (Ralpha, Rbeta, Rgamma) were studied in 52 women who were clinically and histopathologically diagnosed with breast tumours ( 17 in situ and 35 infiltrating), and in 13 women with benign fibrocystic lesions in the breast. Methods. Immunohistochemistry with antibodies against IL-2, IL-2Ralpha, IL-2Rbeta and IL-2Rgamma was used. A comparative semiquantitative immunohistochemical study between the three breast groups ( fibrocystic lesions, in situ tumours and infiltrating tumours) was performed. Results. IL-2 and its three receptor chains were immunodetected in the cytoplasm of epithelial cells. The three receptor chains were also detected on the cell surface. In fibrocystic lesions, immunoreactions to IL-2 (38.5% of cases), IL-2Ralpha (53.8%) and IL-2Rbeta (30.8%) were very weak, whereas immunoreaction to IL-2Rgamma (46.1%) was somewhat more intense. In in situ tumours, the percentages of cases that immunostained positively for IL-2 and its three receptor chains were similar to those observed in fibrocystic lesions, but immunostainings of the four antibodies were more intense. In infiltrative tumours, the percentages of positively stained cases and also immunostaining intensities were approximately twice that found for in situ tumours. Within infiltrating tumours, the percentage of cases showing immunoreaction to IL-2 and their three receptor chains was higher in the patients with lymph node infiltration at the time of surgery. Conclusion. The development of breast tumour is associated with an increased expression of IL-2 and its three receptor chains, and this expression also seems to be associated with the malignancy of the tumour.Universidad de Alcal

Pizarra Digital Interactiva y enciclopedias audiovisuales

Se desarrolla un proyecto de innovación educativa que pretende generalizar y sistematizar el uso de la Pizarra Digital Interactiva (PDI) y las enciclopedias audiovisuales en el quehacer educativo cotidiano con contenidos curriculares, induciendo una renovación de las metodologías docentes y de los procesos de enseñanza y aprendizaje, basados en la idea del centro de educar a los alumnos y alumnas con los medio propios de la época en que se vive. El proyecto pretende llevar la PDI a los alumnos y alumnas de Educación Infantil y Educación Primaria con el fin de mejorar el proceso de enseñanza aprendizaje. La metodología de trabajo se ha desarrollado en tres fases. La primera se ocupa de la formación y la preparación de las ponencias para el grupo del profesorado. La segunda fase se centra en la elaboración de los contenidos y los grupos de trabajo específicos para trabajar las distintas aplicaciones. En la tercera fase se produce la experimentación en el aula con el alumnado. El objetivo se ha cumplido ampliamente, utilizándose la PDI incluso para otros fines como conferencias para las familias y el desarrollo cotidiano de las clases. Se confirma la idea de que la PDI es una poderosa herramienta educativa y que su introducción en las aulas no podrá hacerse sin reformar antes a las personas e instituciones. Los componentes del grupo están satisfechos de haber adquirido los conocimientos necesarios para utilizar la PDI y sus aplicaciones didácticas en el aula.Castilla y LeónConsejería de Educación. Dirección General de Universidades e Investigación; Monasterio de Nuestra Señora de Prado, Autovía Puente Colgante s. n.; 47071 Valladolid; +34983411881; +34983411939ES

Chronic Venous Disease during Pregnancy Is Related to Inflammation of the Umbilical Cord: Role of Allograft Inflammatory Factor 1 (AIF-1) and Interleukins 10 (IL-10), IL-12 and IL-18

Chronic venous disease (CVD) is a common condition that affects the veins in the lower limbs, resulting in a variety of symptoms, such as swelling, pain, and varicose veins (VVs). The plenty hormonal, hemodynamic and mechanical changes occurred in pregnancy make women especially vulnerable to suffer from this condition in this period. Previous works have identified that CVD is associated with an increased inflammatory milieu and significant damage in maternofetal tissues, such as the umbilical cord. However, the inflammatory status of this structure in these patients has not been studied yet. Thus, the aim of the present study was to examine gene and protein expression of a set of inflammatory markers—Allograft inflammatory factor 1 (AIF-1), the proinflammatory cytokines interleukin 12A (IL-12A) and IL-18 and the anti-inflammatory product IL-10—in the umbilical cord of women with CVD during pregnancy (N = 62) and healthy pregnant women (HC; N = 52) by the use of real time qPCR and immunohistochemistry (IHC). Our results demonstrate that the umbilical cord tissue from CVD women exhibit an increased expression of AIF-1, IL-12A and IL-18 along with a decrease in IL-10. Therefore, our study suggests an inflammatory status of this structure related to CVD. Further studies should be conducted to evaluate the expression of other inflammatory markers, as well as to analyze the maternofetal impact of these findings

Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure.

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) α-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of "extra-target" RAS suggests the need for RAS screening in all three DAA target regions