Short-term effect of eucalyptus leachates on green food webs in headwaters

Despite the reported allelopathic nature of the Eucalyptus genus, eucalypt leachates have unknown effects on the trophic base of stream green food webs. Eucalypt plantations have increased worldwide, including riparian ecosystems. We aimed to test whether short-term eucalypt leachates might alter water chemistry, periphytic algal biomass and diatoms, and herbivorous invertebrates’ (i.e., scrapers). We studied two oligotrophic and well-preserved headwaters from NW Spain. The experiment followed a before-after control-impact paired (BACIp) design, with weekly sampling before and after eucalypt leaves addition to streams. In the stream with lower discharge, the eucalypt treatments seemed to affect increases in biomass accrual (Chl-a) and diatom assemblages, disfavouring sensitive species (e.g., Eunotia minor and Achnanthidium pyrenaicum). Therefore, the ecological status was reduced from high to good. In the stream with higher discharge, invertebrate assemblages changed with scrapers having their abundances modified in comparison with the control (e.g., Habrophlebia sp. and Elmidae). Results suggest that eucalypt leaves leachates exert toxic effects on periphyton and on diatom and invertebrate assemblages, and this effect might be mediated by discharge. Alterations at the base of stream food webs may compromise their good ecological status. Further studies are necessary to identify whether this toxicity is due to allelopathic processes

Imbalance between endothelial damage and repair capacity in chronic obstructive pulmonary disease

Background: Circulating endothelial microparticles (EMPs) and progenitor cells (PCs) are biological markers of endothelial function and endogenous repair capacity. The study was aimed to investigate whether COPD patients have an imbalance between EMPs to PCs compared to controls and to evaluate the effect of cigarette smoke on these circulating markers. Methods: Circulating EMPs and PCs were determined by flow cytometry in 27 nonsmokers, 20 smokers and 61 COPD patients with moderate to severe airflow obstruction. We compared total EMPs (CD31+CD42b-), apoptotic if they co-expressed Annexin-V+ or activated if they co-expressed CD62E+, circulating PCs (CD34+CD133+CD45+) and the EMPs/PCs ratio between groups. Results: COPD patients presented increased levels of total and apoptotic circulating EMPs, and an increased EMPs/PCs ratio, compared with nonsmokers. Women had less circulating PCs than men through all groups and those with COPD showed lower levels of PCs than both control groups. In smokers, circulating EMPs and PCs did not differ from nonsmokers, being the EMPs/PCs ratio in an intermediate position between COPD and nonsmokers. Conclusions: We conclude that COPD patients present an imbalance between endothelial damage and repair capacity that might explain the frequent concurrence of cardiovascular disorders. Factors related to the disease itself and gender, rather than cigarette smoking, may account for this imbalance

Germline Mutations in FAF1 Are Associated With Hereditary Colorectal Cancer

Background & aims: A significant proportion of colorectal cancer (CRC) cases have familial aggregation but little is known about the genetic factors that contribute to these cases. We performed an exhaustive functional characterization of genetic variants associated with familial CRC. Methods: We performed whole-exome sequencing analyses of 75 patients from 40 families with a history of CRC (including early-onset cases) of an unknown germline basis (discovery cohort). We also sequenced specific genes in DNA from an external replication cohort of 473 families, including 488 patients with colorectal tumors that had normal expression of mismatch repair proteins (validation cohort). We disrupted the Fas-associated factor 1 gene (FAF1) in DLD-1 CRC cells using CRISPR/Cas9 gene editing; some cells were transfected with plasmids that express FAF1 missense variants. Cells were analyzed by immunoblots, quantitative real-time polymerase chain reaction, and functional assays monitoring apoptosis, proliferation, and assays for Wnt signaling or nuclear factor (NF)-kappa-B activity. Results: We identified predicted pathogenic variant in the FAF1 gene (c.1111G>A; p.Asp371Asn) in the discovery cohort; it was present in 4 patients of the same family. We identified a second variant in FAF1 in the validation cohort (c.254G>C; p.Arg85Pro). Both variants encoded unstable FAF1 proteins. Expression of these variants in CRC cells caused them to become resistant to apoptosis, accumulate beta-catenin in the cytoplasm, and translocate NF-kappa-B to the nucleus. Conclusions: In whole-exome sequencing analyses of patients from families with a history of CRC, we identified variants in FAF1 that associate with development of CRC. These variants encode unstable forms of FAF1 that increase resistance of CRC cells to apoptosis and increase activity of beta-catenin and NF-kappa-B

Evaluating the Potential of Polygenic Risk Score to Improve Colorectal Cancer Screening

Background: Colorectal cancer has high incidence and associ-ated mortality worldwide. Screening programs are recommended for men and women over 50. Intermediate screens such as fecal immunochemical testing (FIT) select patients for colonoscopy with suboptimal sensitivity. Additional biomarkers could improve the current scenario. Methods: We included 2,893 individuals with a positive FIT test. They were classified as cases when a high-risk lesion for colorectal cancer was detected after colonoscopy, whereas the control group comprised individuals with low-risk or no lesions. 65 colorectal cancer risk genetic variants were geno-typed. Polygenic risk score (PRS) and additive models for risk prediction incorporating sex, age, FIT value, and PRS were generated. Results: Risk score was higher in cases compared with controls [per allele OR = 1.04; 95% confidence interval (CI), 1.02-1.06; P = 65), compared with those in the first decile (<= 54; OR = 2.22; 95% CI, 1.59-3.12; P < 0.0001). The model combining sex, age, FIT value, and PRS reached the highest accuracy for identifying patients with a high-risk lesion [cross-validated area under the ROC curve (AUROC): 0.64; 95% CI, 0.62-0.66]. Conclusions: This is the first investigation analyzing PRS in a two-step colorectal cancer screening program. PRS could improve current colorectal cancer screening, most likely for higher at-risk subgroups. However, its capacity is limited to predict colorectal cancer risk status and should be complemented by additional biomarkers.Impact: PRS has capacity for risk stratification of colorectal cancer suggesting its potential for optimizing screening strategies alongside with other biomarkers

Progenitor cell mobilisation and recruitment in pulmonary arteries in chronic obstructive pulmonary disease

BACKGROUND: Pulmonary vascular abnormalities are a characteristic feature of chronic obstructive pulmonary disease (COPD). Cigarette smoking is the most important risk factor for COPD. It is believed that its constant exposure triggers endothelial cell damage and vascular remodelling. Under pathological conditions, progenitor cells (PCs) are mobilized from the bone marrow and recruited to sites of vascular injury. The aim of the study was to investigate whether in COPD the number of circulating PCs is related to the presence of bone marrow-derived cells in pulmonary arteries and the association of these phenomena to both systemic and pulmonary endothelial dysfunction. METHODS: Thirty-nine subjects, 25 with COPD, undergoing pulmonary resection because of a localized carcinoma, were included. The number of circulating PCs was assessed by flow cytometry using a triple combination of antibodies against CD45, CD133 and CD34. Infiltrating CD45+ cells were identified by immunohistochemistry in pulmonary arteries. Endothelial function in systemic and pulmonary arteries was measured by flow-mediated dilation and adenosine diphosphate-induced vasodilation, respectively. RESULTS: COPD patients had reduced numbers of circulating PCs (p < 0.05) and increased numbers of CD45+ cells (< 0.05) in the pulmonary arterial wall than non-COPD subjects, being both findings inversely correlated (r = - 0.35, p < 0.05). In pulmonary arteries, the number of CD45+ cells correlated with the severity of vascular remodelling (r = 0.4, p = 0.01) and the endothelium-dependent vasodilation (r = - 0.3, p = 0.05). Systemic endothelial function was unrelated to the number of circulating PCs and changes in pulmonary vessels. CONCLUSION: In COPD, the decrease of circulating PCs is associated with their recruitment in pulmonary arteries, which in turn is associated with endothelial dysfunction and vessel remodelling, suggesting a mechanistic link between these phenomena. Our findings are consistent with the notion of an imbalance between endothelial damage and repair capacity in the pathogenesis of pulmonary vascular abnormalities in COPD

Gene expression profile of angiogenic factors in pulmonary arteries in COPD: Relationship with vascular remodeling

Pulmonary vessel remodeling in chronic obstructive pulmonary disease (COPD) involves changes in smooth muscle cell proliferation, which are highly dependent on the coordinated interaction of angiogenicrelated growth factors. The purpose of the study was to investigate, in isolated pulmonary arteries (PA) from patients with COPD, the gene expression of 46 genes known to be modulators of the angiogenic process and/or involved in smooth muscle cell proliferation and to relate it to vascular remodeling. PA segments were isolated from 29 patients and classified into tertiles, according to intimal thickness. After RNA extraction, the gene expression was assessed by RT-PCR using TaqMan low-density arrays. The univariate analysis only showed upregulation of angiopoietin-2 (ANGPT-2) in remodeled PA (P < 0.05). The immunohistochemical expression of ANGPT-2 correlated with intimal enlargement (r = 0.42, P < 0.05). However, a combination of 10 factors in a multivariate discriminant analysis model explained up to 96% of the classification of the arteries. A network analysis of 46 genes showed major decentralization. In this network, the metalloproteinase-2 (MMP-2) was shown to be the bridge between intimal enlargement and fibrogenic factors. In COPD patients, plasma levels of ANGPT-2 were higher in current smokers or those with pulmonary hypertension. We conclude that an imbalance in ANGPT-2, combined with related factors such as VEGF, β-catenin, and MMP-2, may partially explain the structural derangements of the arterial wall. MMP-2 may act as a bridge channeling actions from the main fibrogenic factors.Fil: Garcia-Lucio, Jessica. Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer ; EspañaFil: Argemi, Gemma. Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer ; EspañaFil: Tura Ceide O. Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer ; España. Universidad de Barcelona; EspañaFil: Diez, Marta. Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer ; EspañaFil: Paul, Tanja. Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer ; EspañaFil: Bonjoch, Cristina. Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer ; EspañaFil: Coll-Bonfill, Nuria. Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer ; EspañaFil: Blanco, Isabel. Universidad de Barcelona; España. Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer ; EspañaFil: Barberá, Joan A.. Universidad de Barcelona; España. Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer ; EspañaFil: Musri, Melina Mara. Universidad de Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Peinado Víctor I.. Universidad de Barcelona; España. Department Of Pulmonary Medicine, Hospital Clinic, Idib; Españ

Imbalance between endothelial damage and repair capacity in chronic obstructive pulmonary disease

<div><p>Background</p><p>Circulating endothelial microparticles (EMPs) and progenitor cells (PCs) are biological markers of endothelial function and endogenous repair capacity. The study was aimed to investigate whether COPD patients have an imbalance between EMPs to PCs compared to controls and to evaluate the effect of cigarette smoke on these circulating markers.</p><p>Methods</p><p>Circulating EMPs and PCs were determined by flow cytometry in 27 nonsmokers, 20 smokers and 61 COPD patients with moderate to severe airflow obstruction. We compared total EMPs (CD31⁺CD42b^-), apoptotic if they co-expressed Annexin-V⁺ or activated if they co-expressed CD62E⁺, circulating PCs (CD34⁺CD133⁺CD45⁺) and the EMPs/PCs ratio between groups.</p><p>Results</p><p>COPD patients presented increased levels of total and apoptotic circulating EMPs, and an increased EMPs/PCs ratio, compared with nonsmokers. Women had less circulating PCs than men through all groups and those with COPD showed lower levels of PCs than both control groups. In smokers, circulating EMPs and PCs did not differ from nonsmokers, being the EMPs/PCs ratio in an intermediate position between COPD and nonsmokers.</p><p>Conclusions</p><p>We conclude that COPD patients present an imbalance between endothelial damage and repair capacity that might explain the frequent concurrence of cardiovascular disorders. Factors related to the disease itself and gender, rather than cigarette smoking, may account for this imbalance.</p></div