Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell ...metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells.
Fibre metal laminates (FML) are significantly adopted in the aviation industry due to their convenient combination of specific strength, impact resistance and ductility. Drilling of such materials is ...a regular pre-requisite which enables assembly operations, typically through rivet joining. However, the hole-making operation is of increased complexity due to the dissimilarity of the involved materials, often resulting in defects (i.e., material interface delamination), which can significantly compromise the otherwise excellent fatigue strength. This work explores the potential of three different drill geometries, operating under variable cutting speeds and feeds on CFRP-AA laminates. In addition, the usage of sacrificial back support is investigated and cutting load, surface roughness and delamination extension are examined. In order to predict delamination occurrence, ADCB tests are performed, enabling the calculation of fracture energy threshold. Drill geometry presents a very significant influence on delamination occurrence. The usage of specific step-tools with secondary cutting edge showed superior performance. Despite its simplicity, the applied critical force threshold model was able to successfully predict interface delamination with good accuracy.
Despite substantial advances in the treatment of solid cancers, resistance to therapy remains a major obstacle to prolonged progression-free survival. Pancreatic ductal adenocarcinoma (PDAC) is one ...of the most aggressive cancers, with a high level of liver metastasis. Primary PDAC is highly hypoxic, and metastases are resistant to first-line treatment, including gemcitabine. Recent studies have indicated that endothelial cell (EC) focal adhesion kinase (FAK) regulates DNA-damaging therapy-induced angiocrine factors and chemosensitivity in primary tumor models. Here, we show that inducible loss of EC-FAK in both orthotopic and spontaneous mouse models of PDAC is not sufficient to affect primary tumor growth but reduces liver and lung metastasis load and improves survival rates in gemcitabine-treated, but not untreated, mice. EC-FAK loss did not affect primary tumor angiogenesis, tumor blood vessel leakage, or early events in metastasis, including the numbers of circulating tumor cells, tumor cell homing, or metastatic seeding. Phosphoproteomics analysis showed a downregulation of the MAPK, RAF, and PAK signaling pathways in gemcitabine-treated FAK-depleted ECs compared with gemcitabine-treated wild-type ECs. Moreover, low levels of EC-FAK correlated with increased survival and reduced relapse in gemcitabine-treated patients with PDAC, supporting the clinical relevance of these findings. Altogether, we have identified a new role of EC-FAK in regulating PDAC metastasis upon gemcitabine treatment that impacts outcome.
These findings establish the potential utility of combinatorial endothelial cell FAK targeting together with gemcitabine in future clinical applications to control metastasis in patients with pancreatic ductal adenocarcinoma.
A thorough control of the machining operations is essential to ensure the successful post-processing of additively manufactured components, which can be assessed through machinability tests endowed ...with numerical simulation of the metal cutting process. However, to accurately depict the complex metal cutting mechanism, it is not only necessary to develop robust numerical models but also to properly characterize the material behavior, which can be a long-winded process, especially for state-of-stress sensitive materials. In this paper, an efficient mechanical characterization methodology has been developed through the usage of both direct and inverse calibration procedures. Apart from the typical axisymmetric specimens (such as those used in compression and tensile tests), plane strain specimens have been applied in the constitutive law calibration accounting for plastic and damage behaviors. Orthogonal cutting experiments allowed the validation of the implemented numerical model for simulation of the metal cutting processes. Moreover, the numerical simulation of an industrial machining operation (longitudinal cylindrical turning) revealed a very reasonably prediction of cutting forces and chip morphology, which is crucial for the identification of favorable cutting scenarios for difficult-to-cut materials.
The present paper proposes a combined tribo-mechanical methodology for assessing friction under conditions representative of metal cutting, without resorting to machining process monitoring. The ...purpose is to withdraw the size effect’s contribution due to tool edge radius to the well-known overestimation of the friction coefficient. Comparative numerical analysis of several tribological tests led us to conclude that the ring compression test is one of the most suitable for reproducing the frictional conditions at the chip–tool interface. Two distinct metallic alloys were selected to demonstrate the application of the proposed methodology (UNS L51120 lead alloy and 18Ni300 maraging steel in conventional and additively manufactured conditions). The results help to better explain the influences of process parameters on the friction coefficient value under high temperature and high strain rate conditions. Results showed a typical increase in the coefficient of friction of up to 20% due to both temperature and strain rate parameters for 18Ni300. The results are of interest because they allow considering potential sources of error in the numerical simulation of metal cutting when the same friction coefficient value is considered for a wide range of cutting parameters.
The objective of this study was to evaluate Candida oral colonization in human immunodeficiency virus (HlV)-infected patients undergoing long-term highly active antiretroviral therapy (ARV). The ...cross-sectional study included 331 HIV patients, diagnosed from 1983 to 2003. Oral swabs were performed, and Candida species were determined using ID 32C. Isolates were tested for antifungal susceptibility. Clinical and laboratory data were collected to identify the association with Candida colonization. In total, 161 Candida isolates were detected among 147 of the 331 patients (44%), independently of the time when HIV infection was diagnosed. Candida albicans strains represented 137 (85%) of the isolates, and were susceptible to all of the tested antifungal drugs. Among the non-C. albicans strains, six isolates were dose-dependently susceptible to fluconazole, nine to itraconazole, and seven to ketoconazole. The isolation of Candida was significantly higher in patients with virological failure (83/147; p 0.0002) and CD4+ T-lymphocyte counts <200 cells/mm3 (30/83; p 0.0003). Recovery of Candida in the oral cavity was independent of protease inhibitor (PI) usage (p 0.60). Colonized patients typically underwent salvage therapy (p 0.003), and had more episodes of opportunistic fungal infections (p 0.046) and malignancies (p 0.004). Oral Candida colonization in patients under ARV therapy was associated with the immunosupressed status of HIV-infected patients, i.e. low number of CD4+ T-cells per cubic millimetre, failure of ARV therapy (salvage therapy), and higher number of opportunistic infections and malignancies. Despite the fact that Pls have in vitro antifungal activity, the use of this class of antiretroviral agent did not influence the presence of Candida in the oral cavity of AIDS patients.
The objective of this study was to evaluate the effects of corn hybrid and processing methods on intake and digestibility of nutrients, rumen fermentation and blood metabolites of steers fed ...no‐forage finishing diets. Four ruminally fistulated Nellore castrated steers (502 ± 15 kg initial body weight) were distributed in a 4 × 4 Latin square design with a 2 × 2 factorial arrangement consisting of two corn hybrids (semi‐dent and flint) and two processing methods (dry milled and high moisture grain). Interactions of hybrid and processing methods were observed on intake of dry matter (DM), organic matter (OM) and crude protein (CP), as well as on digestibility of DM and CP, rumen pH and ammonia nitrogen (N‐NH3). There was no interaction between hybrid and processing for the volatile fatty acids (VFA) total, acetate (C2), propionate (C3), isobutyric (iC4) and valeric (nC5) concentrations. VFA total concentration shown an average of 103.4 mmol/L. The C2 and C3 concentrations had no effect of the hybrid or processing with averages of 58.7 mmol/L for C2, and 31.3 mmol/l for C3. There was an effect of the processing method on starch consumption and fecal pH, the highest values were observed in grains with high moisture content. Starch digestibility was 0.89 g/g in dry milled and 0.96 g/g in high moisture corn. The greatest digestibility of starch in high moisture corn, irrespective of the corn hybrid, provided evidence of an increase in the energy supply, which may improve the feed efficiency and growth performance of cattle fed no‐roughage finishing diets.
Background and Aims
Chagas disease is a common cause of heart failure (HF) and death in developing countries. Although stroke is known to occur in these patients, an accurate estimate of stroke ...incidence is lacking. We aimed to determine the incidence of stroke and death in patients with HF, comparing Chagas and non-Chagas etiologies.
Methods
Cohort of stroke-free patients with HF (Framingham criteria) followed in a university-based outpatient clinic in Brazil. Baseline characteristics included sociodemographic, risk factor assessment, echocardiographic and electrocardiographic findings. Chagas disease was defined by appropriate serologic tests. Cause-specific Cox regression was used to search for predictors of stroke or death as separate outcomes.
Results
We studied 565 patients with HF between January 2003 and December 2018, mean age 54.3 ± 12.9 years, 305 (54.0%) females, 271/535 (50.7%) with Chagas disease. Chagas patients were older (55.5 vs. 53.1 years), more frequently women (60.5% vs. 47.3%), less frequently harbored coronary artery disease (14.5% vs. 34.1%) when compared to non-Chagas patients. Echocardiography showed more severe disease among non-Chagas patients median left ventricle ejection fraction (LVEF) 37.3% vs. 47.0%. Over a mean 42.9 (±34.4) months, we followed 404 (71.5%) patients, completing 1442 patient-years of follow-up. Stroke incidence was higher in Chagas when compared to non-Chagas patients (20.2 vs. 13.9 events per 1000 patient-years), while death rate was similar (41.6 vs. 43.1 deaths per 1000 patient-years). In the multivariable analysis for stroke outcome adjusted for LVEF and arrhythmias, cause-specific hazard ratio (CSHR) for Chagas was 2.54 (95% confidence interval 1.01–6.42, p = 0.048). Chagas disease was also associated with increased risk of death (CSHR 1.83; 95% confidence interval 1.04–3.24, p = 0.037).
Conclusion
Chagas disease is associated with increased risk of stroke and death when compared to other etiologies of HF, independently of HF severity or cardiac arrhythmias, suggesting other factors contribute to increased stroke risk and mortality in Chagas disease. Early prevention and treatment of Chagas disease is imperative to reduce a later risk of stroke in endemic areas.
Introducción: los objetivos del estudio fueron los siguientes: (1) analizar la influencia de los estilos de Liderazgo Transformacional (LT) y Laissez-faire (LLF) sobre el Síndrome de Quemarse por el ...Trabajo (SQT); (2) evaluar la influencia de las dimensiones de LT (Carisma o Influencia idealizada, Inspiración, Estimulación intelectual y Consideración individualizada) sobre las dimensiones de SQT Perfil 1 (Ilusión por el trabajo, Desgaste psíquico e Indolencia).Material y métodos: la muestra estuvo formada por 211 profesores portugueses de educación secundaria (28.9% hombres y 71.1% mujeres). LT (Carisma o Influencia idealizada, Inspiración, Estimulación intelectual y Consideración individualizada) y LLF fueron evaluados mediante una versión reducida de la Escala Multifactor Leadership Questionnaire (MLQ). Por su parte, el Perfil 1 de SQT (Ilusión por el trabajo, Desgaste psíquico e Indolencia) se evaluó mediante el Cuestionario para la Evaluación del Síndrome de Quemarse por el Trabajo (CESQT) en su versión para profesionales del sector educativo.Resultados: el análisis realizado permitió obtener los siguientes resultados: (1) influencia significativa y negativa entre LT y SQT globales; (2) influencia significativa y positiva entre LT e Ilusión por el trabajo; (3) influencia significativa y negativa entre Inspiración y SQT global; (4) influencia significativa y positiva entre Consideración individualizada e Ilusión por el trabajo.Discusión: en base a los resultados obtenidos se recomienda el impulso en los centros docentes de educación secundaria de políticas de recursos humanos orientadas a la formación de líderes transformacionales, como factor determinante en la mejora de los niveles de salud ocupacional, eficacia y rendimiento organizacional.
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