Macrophages present different Notch receptors and ligands on their surface. Following macrophage activation by LPS or other TLR ligands, Notch1 expression is upregulated. We report here that Notch ...signaling increases both basal and LPS-induced NF-κB activation, favoring the expression of genes implicated in the inflammatory response, such as the cytokines TNF-α and IL-6, or enzymes, such as iNOS. Delta4 seems to be the most effective ligand to induce Notch activation and increasing NF-κB transcriptional activity in macrophages. We show that Notch1 signaling promotes NF-κB translocation to the nucleus and DNA binding by increasing both phosphorylation of the IκB kinase α/β complex and the expression of some NF-κB family members. Treatment of macrophages with the γ-secretase inhibitor DAPT, which prevents the cleavage and activation of Notch receptors, inhibits all these processes, diminishing NF-κB activity following LPS stimulation. Additionally, we show that the active intracellular Notch fragment can directly interact with TNF-α and iNOS promoters. Our results suggest that Notch signaling results in an amplification of the macrophage-dependent inflammatory response by enhancing NF-κB signaling.
Conflicting evidence exists regarding the association between saturated fatty acids (SFAs) and type 2 diabetes. In this longitudinal case-cohort study, we aimed to investigate the prospective ...associations between objectively measured individual plasma phospholipid SFAs and incident type 2 diabetes in EPIC-InterAct participants.
The EPIC-InterAct case-cohort study includes 12 403 people with incident type 2 diabetes and a representative subcohort of 16 154 individuals who were selected from a cohort of 340 234 European participants with 3·99 million person-years of follow-up (the EPIC study). Incident type 2 diabetes was ascertained until Dec 31, 2007, by a review of several sources of evidence. Gas chromatography was used to measure the distribution of fatty acids in plasma phospholipids (mol%); samples from people with type 2 diabetes and subcohort participants were processed in a random order by centre, and laboratory staff were masked to participant characteristics. We estimated country-specific hazard ratios (HRs) for associations per SD of each SFA with incident type 2 diabetes using Prentice-weighted Cox regression, which is weighted for case-cohort sampling, and pooled our findings using random-effects meta-analysis.
SFAs accounted for 46% of total plasma phospholipid fatty acids. In adjusted analyses, different individual SFAs were associated with incident type 2 diabetes in opposing directions. Even-chain SFAs that were measured (14:0 myristic acid, 16:0 palmitic acid, and 18:0 stearic acid) were positively associated with incident type 2 diabetes (HR 95% CI per SD difference: myristic acid 1·15 95% CI 1·09–1·22, palmitic acid 1·26 1·15–1·37, and stearic acid 1·06 1·00–1·13). By contrast, measured odd-chain SFAs (15:0 pentadecanoic acid and 17:0 heptadecanoic acid) were inversely associated with incident type 2 diabetes (HR 95% CI per 1 SD difference: 0·79 0·73–0·85 for pentadecanoic acid and 0·67 0·63–0·71 for heptadecanoic acid), as were measured longer-chain SFAs (20:0 arachidic acid, 22:0 behenic acid, 23:0 tricosanoic acid, and 24:0 lignoceric acid), with HRs ranging from 0·72 to 0·81 (95% CIs ranging between 0·61 and 0·92). Our findings were robust to a range of sensitivity analyses.
Different individual plasma phospholipid SFAs were associated with incident type 2 diabetes in opposite directions, which suggests that SFAs are not homogeneous in their effects. Our findings emphasise the importance of the recognition of subtypes of these fatty acids. An improved understanding of differences in sources of individual SFAs from dietary intake versus endogenous metabolism is needed.
EU FP6 programme, Medical Research Council Epidemiology Unit, Medical Research Council Human Nutrition Research, and Cambridge Lipidomics Biomarker Research Initiative.
Purpose: This study aims to address the pressing need for accurate forecasting of healthcare resource demands during the COVID-19 pandemic. It presents a novel approach that combines a stochastic ...Markov model and a discrete event simulation model to dynamically predict hospital admissions and daily occupancy of hospital and ICU beds.Design/methodology/approach: The research builds upon existing work related to predicting COVID-19 spread and patient influx to hospital emergency departments. The proposed model was developed and validated at San Juan de Alicante University Hospital from July 10, 2020, to January 10, 2022, and externally validated at Hospital Vega Baja. The model involves an admissions generator based on a stochastic Markov model, feeding data into a discrete event simulation model in the R programming language. The probabilities of hospital admission were calculated based on age-stratified positive SARS-COV-2 results from the health department's catchment population. The discrete event simulation model simulates distinct patient pathways within the hospital to estimate bed occupancy for the upcoming week. The performance of the model was measured using the median absolute difference (MAD) between predicted and actual demand.Findings: When applied to data from San Juan hospital, the admissions generator demonstrated a MAD of 6 admissions/week (interquartile range IQR 2-11). The MAD between the model's predictions and actual bed occupancy was 20 beds/day (IQR 5-43), equivalent to 5% of total hospital beds. For ICU occupancy, the MAD was 4 beds/day (IQR 2-7), constituting 25% of ICU beds. Evaluation with data from Hospital Vega Baja showcased an admissions generator MAD of 2.42 admissions/week (IQR 1.02-7.41). The MAD between the model's predictions and actual bed occupancy was 18 beds/day (IQR 19.57-38.89), approximately 5.1% of hospital beds. The ICU occupancy MAD was 3 beds/day (IQR 1-5), making up 21.4% of ICU beds.Practical implications: The dynamic predictions of hospital admissions, ward beds, and ICU occupancy for COVID-19 patients proved highly valuable to hospital managers, facilitating early and informed planning of resource allocation. Additionally, this study underscores the importance of utilizing simulation techniques to predict and manage hospital occupancy levels, thereby enhancing decision-making in hospital bed management, not only during pandemics but also during regular periods.Originality/value: This study introduces a novel hybrid approach that combines stochastic modeling and discrete event simulation to forecast healthcare resource demands during the COVID-19 pandemic. The methodology's effectiveness in predicting admissions and bed occupancy contributes to improved resource planning and situational awareness.
Ovarian cancer (OC) is the fifth cancer death cause in women worldwide. The malignant nature of this disease stems from its unique dissemination pattern. Epithelial-to-mesenchymal transition (EMT) ...has been reported in OC and downregulation of Epithelial cadherin (E-cadherin) is a hallmark of this process. However, findings on the relationship between E-cadherin levels and OC progression, dissemination and aggressiveness are controversial. In this study, the evaluation of E-cadherin expression in an OC tissue microarray revealed its prognostic value to discriminate between advanced- and early-stage tumors, as well as serous tumors from other histologies. Moreover, E-cadherin, Neural cadherin (N-cadherin), cytokeratins and vimentin expression was assessed in TOV-112, SKOV-3, OAW-42 and OV-90 OC cell lines grown in monolayers and under anchorage-independent conditions to mimic ovarian tumor cell dissemination, and results were associated with cell aggressiveness. According to these EMT-related markers, cell lines were classified as mesenchymal (M; TOV-112), intermediate mesenchymal (IM; SKOV-3), intermediate epithelial (IE; OAW-42) and epithelial (E; OV-90). M- and IM-cells depicted the highest migration capacity when grown in monolayers, and aggregates derived from M- and IM-cell lines showed lower cell death, higher adhesion to extracellular matrices and higher invasion capacity than E- and IE-aggregates. The analysis of E-cadherin, N-cadherin, cytokeratin 19 and vimentin mRNA levels in 20 advanced-stage high-grade serous human OC ascites showed an IM phenotype in all cases, characterized by higher proportions of N- to E-cadherin and vimentin to cytokeratin 19. In particular, higher E-cadherin mRNA levels were associated with cancer antigen 125 levels more than 500 U/mL and platinum-free intervals less than 6 months. Altogether, E-cadherin expression levels were found relevant for the assessment of OC progression and aggressiveness.
The interactions between animals and their environment vary across species, regions, but also with gender. Sex‐specific relations between individuals and the ecosystem may entail different behavioral ...choices and be expressed through different patterns of habitat use. Regardless, only rarely sex‐specific traits are addressed in ecological modeling approaches. The European wildcat (Felis silvestris silvestris) is a species of conservation concern in Europe, with a highly fragmented and declining distribution across most of its range. We assessed sex‐specific habitat selection patterns for the European wildcat, at the landscape and home range levels, across its Iberian biogeographic distribution using a multipopulation approach. We developed resource selection functions in a use‐availability framework using radio‐telemetry data from five wildcat populations. At the landscape level, we observed that, while both genders preferentially established home ranges in areas close to broadleaf forests and far from humanized areas, females selected mid‐range elevation areas with some topographic complexity, whereas males used lowland areas. At the home range level, both females and males selected areas dominated by scrublands or broadleaf forests, but habitat features were less important at this level. The strength of association to habitat features was higher for females at both spatial levels, suggesting a tendency to select habitats with higher quality that can grant them enhanced access to shelter and feeding resources. Based on our results, we hypothesize that sex‐biased behavioral patterns may contribute to the resilience of wildcats’ genetic integrity through influencing the directionality of hybridization with domestic cats. Our study provides information about European wildcats’ habitat use in an Iberian context, relevant for the implementation of conservation plans, and highlights the ecological relevance of considering sex‐related differences in environmental preferences.
Sex‐specific relations between individuals and the ecosystem may entail different behavioral choices and be expressed through different patterns of habitat use. Using resource selection functions, we assessed sex‐specific habitat selection patterns for the European wildcat across its Iberian biogeographic distribution. Our results indicate that females selected higher quality habitats and that the strength of association to habitat features was higher for females than for males. Sex‐biased behavioural patterns may be decisive in the resilience of wildcats’ genetic integrity through influencing the directionality of hybridization with domestic cats and that conservation efforts should focus on conserving high‐quality habitats that may harbor a viable population of female wildcats.
Purpose
Dietary guidelines for egg consumption for general population differ among public health agencies. Our aim was to investigate the association between egg intake and both all-cause and ...specific-cause of mortality in a Mediterranean population.
Methods
The European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort included 40,621 men and women aged 29–69 years old in the nineties from 5 Spanish regions. After a mean of 18 years of follow-up, 3,561 deaths were recorded, of which 1,694 were from cancer, 761 from CVD, and 870 from other causes. Data on egg consumption was collected using a validated diet history at recruitment. Cox proportional hazards models, adjusted for confounders, were used in the analyses.
Results
The mean (standard deviation) egg consumption was 22.0 g/day (15.8) and 30.9 g/day (23.1) in women and men, respectively. No association was observed between egg consumption and all-cause mortality for the highest vs the lowest quartile (HR 1.01; 95% CI 0.91–1.11;
P
trend = 0.96). Likewise, no association was observed with cancer and cardiovascular diseases mortality. However, an inverse association was found between egg consumption and deaths for other causes (HR 0.76; 95% CI 0.63–0.93;
P
trend = 0.003), particularly for deaths from the nervous system (HR 0.59; 95% CI 0.35–1.00;
P
trend = 0.036). No interaction was detected with the adherence to Mediterranean diet.
Conclusions
This study shows no association between moderate egg consumption, up to 1 egg per day, and main causes of mortality in a large free-living Mediterranean population.
A total of 308,036 women were selected from the European Prospective Investigation into Cancer and Nutrition (EPIC) study to evaluate the association between tobacco smoking and the risk of cervical ...intraepithelial neoplasia of grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC). At baseline, participants completed a questionnaire and provided blood samples. During a mean follow‐up time of 9 years, 261 ICC cases and 804 CIN3/CIS cases were reported. In a nested case–control study, the baseline sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11, 16, 18, 31, 33, 35, 45, 52, 58, and antibodies against Chlamydia trachomatis (CT), and Human Herpes Virus 2 (HHV‐2). Cervical samples were not available for HPV‐DNA analysis in this study. Multivariate analyses were used to estimate associations between smoking and risk of CIN3/CIS and ICC in the cohort and the case–control studies. In the cohort analyses smoking status, duration and intensity showed a two‐fold increased risk of CIN3/CIS and ICC, while time since quitting was associated with a two‐fold reduced risk. In the nested case–control study, consistent associations were observed after adjustment for HPV, CT and HHV‐2 serostatus, in both HPV seronegative and seropositive women. Results from this large prospective study confirm the role of tobacco smoking as an important risk factor for both CIN3/CIS and ICC, even after taking into account HPV exposure as determined by HPV serology. The strong beneficial effect of quitting smoking is an important finding that will further support public health policies for smoking cessation.
What's new?
Tobacco smoking is a cited cause of cervical cancer, but whether it causes cervical malignancy independent of human papillomavirus (HPV) infection is unclear. Here, strong associations were found between most measures of tobacco smoking and the risk of cervical intraepithelial neoplasia of grade 3/carcinoma in situ and invasive cervical cancer, after taking into account past exposure to HPV infection. Quitting smoking was associated with a 2‐fold risk reduction. The findings confirm the role of tobacco smoking in cervical carcinogenesis and show that quitting the habit has important benefits for cancer protection.
Tin oxide is one of the most extensively studied semiconductor materials due to its broad field of applications. On the one hand, its high conductivity and its corrosion resistance are the most ...remarkable properties. Therefore, one of the most developed uses in the recent decades has been as ceramic electrode for electrooxidation process. On the other hand, its poor sinterability hinders a broader use. As a result, the use of advanced techniques or sintering aids for obtaining low-porosity specimens is necessary. So far, many additives have been studied, CaCO3, Co3O4, Nb2O5 or MnO2, among others. In the present work, the sintering behaviour of SnO2-based powder, containing Li2CO3 as a sintering aid, which generates a liquid phase, has been analysed, since it is one of the additives that has been studied to a lesser extent. The effect of the amount of sintering aid just like the thermal treatment parameters (maximum temperature, heating rate and soaking time) on volumetric contraction's evolution has been studied through a factorial experiment designs 2n. The results show that an amount of lithium carbonate greater than 1mol.% is unfavourable to densification. With regards to the thermal cycle's parameters, it is advisable to have thermal treatments at high temperatures (1300°C) with moderate soaking times (1h), as maximum temperatures have the biggest influence on the densification followed by soaking time while the heating rate has a lesser influence. Under these conditions, a microstructure of closed and rounded pores is obtained, in which a residual phase is enclosed, but the small proportion of which prevents its characterisation.
El óxido de estaño es uno de los materiales más estudiados, dado su extenso campo de aplicación. De entre sus propiedades, cabe destacar su alta conductividad eléctrica y su resistencia a la corrosión, de ahí que entre sus aplicaciones se encuentre la de electrodo cerámico. Sin embargo, su baja capacidad de densificación dificulta su uso. Como consecuencia, se requieren técnicas avanzadas o aditivos de sinterización que faciliten la obtención de piezas con baja porosidad. Hasta el momento han sido muchos los aditivos estudiados, CaCO3, Co3O4, Nb2O5 o MnO2, entre otros. En este trabajo se estudia el proceso de sinterización de piezas de SnO2 a las que se ha incorporado Li2CO3 como aditivo de sinterización, el cual genera una fase líquida, por ser uno de los aditivos en cuyo estudio se ha profundizado en menor medida. A través de diseños factoriales de experimentos 2n, se han determinado los efectos de los diferentes parámetros del ciclo de cocción (temperatura máxima, velocidad de calentamiento y tiempo de permanencia), así como la cantidad de aditivo de sinterización, sobre la evolución de la contracción volumétrica. Los resultados muestran que la incorporación del carbonato de litio, en porcentajes superiores al 1% molar, no es favorable para la densificación. Respecto a los parámetros de cocción, resultan recomendables tratamientos térmicos a elevada temperatura (1.300°C) con tiempos de permanencia moderados (1 hora), mientras que la velocidad de calentamiento ejerce una menor influencia. En estas condiciones se obtiene una microestructura de poros cerrados y redondeados, en la que queda encerrada una fase residual cuya reducida proporción impide su caracterización.
The consumption of processed meats (PMs) and red meats are linked to the likelihood of developing colorectal cancer. Various theories have been proposed to explain this connection, focusing on ...nitrosyl-heme and heme iron intake. We hypothesized that differences in nitrosyl-heme and heme iron intakes will be associated with various sociodemographic and lifestyle factors.
The study included 38,471 healthy volunteers (62% females) from five Spanish regions within the EPIC-Spain cohort. High-Performance Liquid Chromatography (HPLC) determined nitrosyl-heme and heme iron levels in the 39 most consumed PMs. Food intake was assessed using validated questionnaires in interviews. Nitrosyl-heme and heme iron intakes, adjusted for sex, age, body mass index (BMI), center, and energy intake, were expressed as geometric means due to their skewed distribution. Variance analysis identified foods explaining the variability of nitrosyl-heme and heme iron intakes.
The estimated intakes were 528.6 µg/day for nitrosyl-heme and 1676.2 µg/day for heme iron. Significant differences in nitrosyl-heme intake were found by sex, center, energy, and education level. Heme iron intake varied significantly by sex, center, energy, and smoking status. "
" and "
"
the highest intake values, while "
" and "
" were key sources of nitrosyl-heme and heme iron.
This is the first study to estimate levels of nitrosyl-heme intake directly in PMs for a large sample, revealing variations based on sex, BMI, smoking, and activity. Its data aids future exposure estimations in diverse populations.
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