Acid ceramidase (AC) catalyzes the hydrolysis of ceramide into sphingosine, in turn a substrate of sphingosine kinases that catalyze its conversion into the mitogenic sphingosine-1-phosphate. AC is ...expressed at high levels in several tumor types and has been proposed as a cancer therapeutic target. Using a model derived from PC-3 prostate cancer cells, the highly tumorigenic, metastatic, and chemoresistant clone PC-3/Mc expressed higher levels of the AC ASAH1 than the nonmetastatic clone PC-3/S. Stable knockdown of ASAH1 in PC-3/Mc cells caused an accumulation of ceramides, inhibition of clonogenic potential, increased requirement for growth factors, and inhibition of tumorigenesis and lung metastases. We developed de novo ASAH1 inhibitors, which also caused a dose-dependent accumulation of ceramides in PC-3/Mc cells and inhibited their growth and clonogenicity. Finally, immunohistochemical analysis of primary prostate cancer samples showed that higher levels of ASAH1 were associated with more advanced stages of this neoplasia. These observations confirm ASAH1 as a therapeutic target in advanced and chemoresistant forms of prostate cancer and suggest that our new potent and specific AC inhibitors could act by counteracting critical growth properties of these highly aggressive tumor cells.
Increasing evidence has pointed to the important function of T cells in controlling immune homeostasis and pathogenesis after myocardial infarction (MI), although the underlying molecular mechanisms ...remain elusive. In this study, a broad analysis of immune markers in 283 patients revealed significant CD69 overexpression on Tregs after MI. Our results in mice showed that CD69 expression on Tregs increased survival after left anterior descending (LAD) coronary artery ligation. Cd69.sup.-/- mice developed strong IL-17.sup.+ gammadeltaT cell responses after ischemia that increased myocardial inflammation and, consequently, worsened cardiac function. CD69.sup.+ Tregs, by induction of AhR-dependent CD39 ectonucleotidase activity, induced apoptosis and decreased IL-17A production in gammadeltaT cells. Adoptive transfer of CD69.sup.+ Tregs into Cd69.sup.-/- mice after LAD ligation reduced IL-17.sup.+ gammaST cell recruitment, thus increasing survival. Consistently, clinical data from 2 independent cohorts of patients indicated that increased CD69 expression in peripheral blood cells after acute MI was associated with a lower risk of rehospitalization for heart failure (HF) after 2.5 years of follow-up. This result remained significant after adjustment for age, sex, and traditional cardiac damage biomarkers. Our data highlight CD69 expression on Tregs as a potential prognostic factor and a therapeutic option to prevent HF after MI.
Blocking of the Tumor Necrosis Factor (TNF) activity is a successful therapeutic approach for 50-60% of rheumatoid arthritis (RA) patients. However, there are yet no biomarkers to stratify patients ...for anti-TNF therapy. Rheumatoid factor (RF) and anti-cyclic-citrullinated antibodies (anti-CCP) have been evaluated as biomarkers of response but the results have shown limited consistency. Anti-carbamylated protein (anti-CarP) and anti-peptidylarginine deiminase type 4 (anti-PAD4) antibodies have been much less studied. Despite being linked to common immune processes, the interaction between these markers has not been evaluated yet. Our aim was to analyze the interaction between these four antibodies in relation to the response to anti-TNF therapy.
For this objective, a prospective cohort of n = 80 RA patients starting anti-TNF therapy was recruited. Serum determinations at baseline were performed for RF, anti-CCP, anti-CarP and anti-PAD4 antibodies using enzyme-linked immunosorbent assays (ELISA). The clinical response to anti-TNF therapy was determined at week 12 using the change in DAS28 score. Association was performed using multivariate linear regression adjusting for baseline DAS28, sex and age.
The interaction between pairs of antibodies was tested by the addition of an interaction term. We found two highly significant antibody interactions associated with treatment response: anti-CarP with anti-PAD4 (p = 0.0062), and anti-CCP with RF (p = 0.00068). The latter antibody interaction was replicated in an independent retrospective cohort of RA patients (n = 199, p = 0.04).
The results of this study suggest that antibody interaction effects are important factors in the response to anti-TNF therapy in RA.
Aims Dehesas are agroforestry systems characterized by scattered trees among pastures, crops and/or fallows. A study at a Spanish dehesa has been carried out to estimate the spatial distribution of ...the soil organic carbon stock and to assess the influence of the tree cover. Methods The soil organic carbon stock was estimated from the five uppermost cm of the mineral soil with high spatial resolution at two plots with different grazing intensities. The Universal Kriging technique was used to assess the spatial distribution of the soil organic carbon stocks, using tree coverage within a buffering area as an auxiliary variable. Results A significant positive correlation between tree presence and soil organic carbon stocks up to distances of around 8 m from the trees was found. The tree crown cover within a buffer up to a distance similar to the crown radius around the point absorbed 30 % of the variance in the model for both grazing intensities, but residual variance showed stronger spatial autocorrelation under regular grazing conditions. Conclusions Tree cover increases soil organic carbon stocks, and can be satisfactorily estimated by means of crown parameters. However, other factors are involved in the spatial pattern of the soil organic carbon distribution. Livestock plays an interactive role together with tree presence in soil organic carbon distribution.
The prevention of a complex phenomenon, such as suicide, requires an interdisciplinary approach that provides a comprehensive response to the care needs of people with suicidal behavior (SB). The aim ...of this study is to investigate the clinical and healthcare features of people presenting thoughts and/or attempts of suicide to define risk factors for recurrence.
Over 79,000 confirmed cases of mpox were notified worldwide between May and November 2022, most of them in men who have sex with men. Cases in women, for whom mpox might pose different risks, are ...rare, and Spain has reported more than one third of those in Europe. Using surveillance data, our study found similar time trends, but differences in delay of diagnosis, sexual transmission and signs and symptoms between men and women.
Over 79,000 confirmed cases of mpox were notified worldwide between May and November 2022, most of them in men who have sex with men. Cases in women, for whom mpox might pose different risks, are ...rare, and Spain has reported more than one third of those in Europe. Using surveillance data, our study found similar time trends, but differences in delay of diagnosis, sexual transmission and signs and symptoms between men and women.
5G for Construction: Use Cases and Solutions Mendoza, Jessica; de-la-Bandera, Isabel; Álvarez-Merino, Carlos Simón ...
Electronics (Basel),
07/2021, Letnik:
10, Številka:
14
Journal Article
Recenzirano
Odprti dostop
The world is currently undergoing a new industrial revolution characterized by the digitization and automation of industry through the use of Information and Communication Technologies (ICTs). The ...construction sector is one of the largest sectors of the industry. Most of the tasks associated with this sector are carried out at worksites that are defined by their dynamism, decentralization, temporality, and the intervention of a large number of workers, subcontractors, machinery, equipment, and materials. These characteristics make this sector a great challenge for the implementation of ICTs. In this paper, the benefits of the use of the Fifth-Generation (5G) of mobile networks in the construction industry are presented. To that end, first, the digitization and automation needs of the sector are jointly analyzed, establishing different use cases and identifying the requirements of each one. Second, the main characteristics of 5G that address these use cases are identified. Third, a global framework for the application of 5G technology to the construction industry is proposed. Finally, an overview of some directions for future work are provided.
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