PARP inhibition promotes endothelial-like traits in melanoma cells and modulates pericyte coverage dynamics during vasculogenic mimicry.

Vasculogenic mimicry (VM) describes the ability of highly aggressive tumor cells to develop pseudovascular structures without the participation of endothelial cells. PARP1 is implicated in the activation of hypoxia-inducible factors, which are crucial in tumor neovascularization. We have explored the role of hypoxia and PARP inhibition in VM. In uveal melanoma xenografts, the PARP inhibitor olaparib improved in vivo pericyte coverage specifically of VM channels. This was concomitant with reduced metastasis in olaparib-treated VM+ tumors. PARP inhibition and hypoxia modulated melanoma tube formation in vitro, inducing a more sparse and regular tubular architecture. Whole-transcriptome profiling revealed that olaparib treatment under hypoxic conditions modulated the expression of genes implicated in vasculogenesis during tube formation, enhancing the endothelial-like phenotype of VM+ uveal melanoma cells. PARP inhibition, especially during hypoxia, upregulated PDGFß, which is essential for pericyte recruitment. Our study indicates that PARP inhibitors may enhance the endothelial characteristics of VM+ cells, modulate pericyte coverage, and reduce metastatic spread in VM+ melanoma. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The importance of recognizing Buffer Zones to lands being developed, restored, or remediated: on planning for protection of ecological resources.

Environmental management relies on many types of information before making decisions regarding remediation, restoration, or other land use decisions, including ecological data, such as risks to species, populations, communities, and ecosystems. The aim of this investigation was to describe the ecological information required within the context of making environmental decisions and providing visual communication tools for regulators, conservationists, and the public to understand the risk to ecological resources on- and off-site. It is suggested that ecological information used in environmental decisions is required to be transparent throughout the planning and execution of a project, which needs to include: 1) ecological information and evaluations within development areas or units (in this case, watersheds), and 2) resources in adjacent areas (Buffer Zones) that might be affected. The Melton Valley administrative watershed (Oak Ridge Reservation, TN) is used as a case study because this site still has active facility development and environmental remediation, and there are important ecological resources on and off-site. Data indicate that although there are important resources on Melton Valley administrative watershed, there are also significant resources in the Buffer Zone around the watershed. Compared to the Melton Valley administrative watershed, the Buffer Zone contains more Interior (and Buffer) Forest and greater value resources. The point is made that when remediation, restoration, or development occurs, it is equally important to consider resources that are adjacent to the site in a Buffer Zone, particularly when remediation and development might continue for many years or decades.

Comparing land cover and interior forests on contaminated land and the surrounding region: Oak Ridge Reservation as a case study.

Pressure from expanding populations has resulted in a need for protection, reclamation, and restoration of damaged land to productive, beneficial health uses. The objective of this investigation was to 1) compare land cover on the Department of Energy (DOE) Oak Ridge Reservation (ORR) with the surrounding region, 2) select an indicator to evaluate ORR's protection of ecological resources, and 3) develop and implement a method to compare the amount of the indicator on ORR with the regions using National Land Cover Database (NLCD). Data demonstrated that ORR has a higher % of forests (deciduous, coniferous, mixed) than the 10 km and 30 km areas surrounding ORR, suggesting that obligations are being met to protect the ecology and environment. The findings also indicate that the interior forest at ORR is fragmented more than is the interior forest in the 30 km buffer zone, suggesting a need for DOE and managers of other lands to take into consideration the importance of intact interior forest when developing land or planning roads. The study describes the basis for specific ecological parameters such as interior forest that are important to consider when planning and executing remediation, restoration, and other management actions.

Assessment of Factors Influencing Personal Exposure to Air Pollution on Main Roads in Bogota: A Mixed-Method Study.

Background and Objectives: Particulate Matter (PM), particles of variable but small diameter can penetrate the respiratory system via inhalation, causing respiratory and/or cardiovascular diseases. This study aims to evaluate the association of environmental particulate matter (PM2.5) and black carbon (BC) with respiratory health in users of different transport modes in four roads in Bogotá. Materials and Methods: this was a mixed-method study (including a cross sectional study and a qualitative description of the air quality perception), in 300 healthy participants, based on an exploratory sequential design. The respiratory effect was measured comparing the changes between pre- and post-spirometry. The PM2.5 and black carbon (BC) concentrations were measured using portable devices. Inhaled doses were also calculated for each participant according to the mode and route. Perception was approached through semi-structured interviews. The analysis included multivariate models and concurrent triangulation. Results: The concentration of matter and black carbon were greater in bus users (median 50.67 µg m-3; interquartile range (-IR): 306.7). We found greater inhaled dosages of air pollutants among bike users (16.41 µg m-3). We did not find changes in the spirometry parameter associated with air pollutants or transport modes. The participants reported a major sensory influence at the visual and olfactory level as perception of bad air quality. Conclusions: We observed greater inhaled doses among active transport users. Nevertheless, no pathological changes were identified in the spirometry parameters. People's perceptions are a preponderant element in the assessment of air quality.

Vasculogenic mimicry signaling revisited: focus on non-vascular VE-cadherin.

Vasculogenic mimicry (VM) is a blood supply system independent of endothelial vessels in tumor cells from different origins. It reflects the plasticity of aggressive tumor cells that express vascular cell markers and line tumor vasculature. The presence of VM is associated with a high tumor grade, short survival, invasion and metastasis. Endothelial cells (ECs) express various members of the cadherin superfamily, in particular vascular endothelial (VE-) cadherin, which is the main adhesion receptor of endothelial adherent junctions. Aberrant extra-vascular expression of VE-cadherin has been observed in certain cancer types associated with VM. In this review we focus on non-endothelial VE-cadherin as a prominent factor involved in the acquisition of tubules-like structures by aggressive tumor cells and we summarize the specific signaling pathways, the association with trans-differentiation and stem-like phenotype and the therapeutic opportunities derived from the in-depth knowledge of the peculiarities of the biology of VE-cadherin and other key components of VM.

Effect of n-3 PUFA supplementation at different EPA:DHA ratios on the spontaneously hypertensive obese rat model of the metabolic syndrome.

The increasing incidence of the metabolic syndrome (MetS), a combination of risk factors before the onset of CVD and type 2 diabetes, encourages studies on the role of functional food components such as long-chain n-3 PUFA as preventive agents. In the present study, we explore the effect of EPA and DHA supplementation in different proportions on spontaneously hypertensive obese (SHROB) rats, a model for the MetS in a prediabetic state with mild oxidative stress. SHROB rats were randomised into four groups (n 7), each supplemented with EPA/DHA at ratios of 1:1, 2:1 and 1:2, or soyabean oil as the control for 13 weeks. The results showed that in all the proportions tested, EPA/DHA supplementation significantly lowered total and LDL-cholesterol concentrations, compared with those of the control group. EPA/DHA supplementation at the ratios of 1:1 and 2:1 significantly decreased inflammation (C-reactive protein levels) and lowered oxidative stress (decreased excretion of urinary isoprostanes), mainly at the ratio of 1:2. The activity of antioxidant enzymes increased in erythrocytes, abdominal fat and kidneys, with magnitudes depending on the EPA:DHA ratio. PUFA mixtures from fish affected different MetS markers of CVD risk factors in SHROB rats, depending on the ratios of EPA/DHA supplementation. The activation of endogenous defence systems may be related to the reduction of inflammation and oxidative stress.

Oxidative stress markers in predicting response to treatment with ferric carboxymaltose in nondialysis chronic kidney disease patients.

BACKGROUND: Nearly half of all non-dialysis chronic kidney disease (CKD) patients respond to iron therapy. Factors affecting anemia response to iron therapy are not well characterized. Oxidative stress (OS) is a recognized factor for anemia in CKD and promotes erythropoiesis stimulating agent (ESA) resistance; however, the influence in predicting response to intravenous (IV) iron has not been evaluated. METHODS: Patients (n = 47) with non-dialysis CKD stages 3 - 5 (mean eGFR: 26 ± 10.4 mL/min/1.73 m2) and iron-deficiency anemia (hemoglobin < 11 g/dL, transferrin saturation (TSAT) index < 20%, and/or ferritin < 100 ng/mL) received a single injection of 1,000 mg of ferric carboxymaltose (FCM) and were observed for 12 weeks. Based on erythropoietic response (defined as ≥ 1 g/dL increase in hemoglobin level), patients were classified as responders or non-responders. Baseline conventional markers of iron status (TSAT and ferritin), inflammatory markers (C-reactive protein and IL-6), OS markers (oxidized LDL, protein carbonyl groups, erythrocyte superoxide dismutase, and glutathione peroxidase (GPx)), and catalase activity were measured. RESULTS: FCM resulted in a significant increase in hemoglobin, TSAT, and ferritin (10 ± 0.7 vs. 11.4 ± 1.3 g/dL, p < 0.0001; 14.6 ± 6.4% vs. 28.9 ± 10%, p < 0.0001; 67.8 ± 61.7 vs. 502.5 ± 263.3 ng/dL, p < 0.0001, respectively). Responders and non-responders were 34 (72%) and 13 (28%), respectively. Age, baseline hemoglobin, estimated glomerular filtration rate, parathyroid hormone, and use of ESA or angiotensin-modulating agents were similar in both groups. Responders showed a tendency towards lower TSAT than non-responders (13.6 ± 6.5% vs. 17.2 ± 5.6%, p = 0.06) but similar ferritin levels. Inflammatory markers were similar in both groups. eGPx activity was lower in non-responders compared to responders (103.1 ± 50.9 vs. 144.9 ± 63.1 U/g Hb, p = 0.01, respectively), although the other proteins, lipid oxidation markers, and enzymatic antioxidants did not differ between the two groups. In the multivariate adjusted model, odds (95% CI) for achieving erythropoietic response to FCM were 10.53 (1.25 - 88.16) in the third tertile of eGPX activity and 3.20 (0.56 - 18.0) in the second tertile compared to those in the lowest tertiles (p = 0.02). CONCLUSIONS: Decreased eGPx activity has adverse influences on response to FCM, suggesting that impaired erythrocyte antioxidant defense may be involved in the response to iron therapy in CKD patients.

Eicosapentaenoic acid/docosahexaenoic acid 1:1 ratio improves histological alterations in obese rats with metabolic syndrome.

BACKGROUND: Marine polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been associated with improvement in the Metabolic Syndrome (MS). The aim of this study is to evaluate how three fish-oil diets with different eicosapentaenoic acid/docosahexaenoic acid ratios (EPA/DHA ratio) affect the histology of liver, kidney, adipose tissue and aorta in a preliminary morphological study. This work uses an animal model of metabolic syndrome in comparison with healthy animals in order to provide information about the best EPA:DHA ratio to prevent or to improve metabolic syndrome symptoms. METHODS: 35 Wistar rats, as a control, and 35 spontaneously hypertensive obese rats (SHROB) were fed for 13 weeks with 3 different supplementation of fish oil containing EPA and DHA ratios (1:1, 2:1 and 1:2, respectively). All samples were stained with haematoxylin/eosin stain, except aorta samples, which were stained also with Verhoeff and van Gieson's stain. A histological study was carried out to evaluate changes. These changes were statistically analyzed using SPSS IBM 19 software. The quantitative data were expressed by mean ± SD and were compared among groups and treatments using ANOVA with post-hoc tests for parametric data and the U-Mann-Whitney for non-parametric data. Qualitative data were expressed in frequencies, and compared with contingency tables using χ² statistics. RESULTS: EPA:DHA 1:1 treatment tended to improve the density and the wrinkling of elastic layers in SHROB rats. Only Wistar rats fed with EPA:DHA 1:1 treatment did not show mast cells in adipose tissue and has less kidney atrophy. In both strains EPA:DHA 1:1 treatment improved inflammation related parameters in liver and kidney. CONCLUSIONS: EPA:DHA 1:1 treatment was the most beneficial treatment since improved many histological parameters in both groups of rats.

Oxidative stress and other risk factors for white matter lesions in chronic hemodialysis patients.

BACKGROUND: Chronic kidney disease (CKD) is a risk factor for cardiovascular disease and promotes oxidative tress (OS), which has been implicated in the pathogenesis of white matter lesions (WML), a form of small-vessel cerebrovascular disease. The relationship between OS and WML in chronic hemodialysis (HD) patients has not yet been studied. METHODS: We studied 67 chronic HD patients, aged 40 - 65 years (average 54 years) without known cerebrovascular disease. All patients underwent brain magnetic resonance imaging and subcortical and periventricular WML were evaluated using semiquantitative measures. Patients were classified into two groups depending on the presence or absence of WML (Fazekas classification), and the WML were scored. Carotid ultrasonography was also performed to evaluate the presence of carotid artery plaques and/or stenosis. Markers of protein and lipid oxidation (protein carbonyl and oxLDL antibodies), the glutathione system, enzymatic antioxidants (superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase) and total antioxidant capacity (ORAC) were measured. OS markers were compared to those of a group of 36 healthy subjects. RESULTS: WML were present in 54% of the total population. Patients who had WML were older and had lower predialysis diastolic blood pressure than patients without WML. Other potential cardiovascular risk factors for WML, including obesity, hyperlipidemia, diabetes mellitus, presence of carotid artery plaques or stenosis, and duration and adequacy of HD were not related to the presence of WML. Compared to controls, HD patients had increased OS and decreased antioxidant capacity. However, OS did not differ between patients with WML and those without, and we found no association between OS markers and mean WML scores. After adjusting for several factors, only age and low predialysis diastolic blood pressure independently predicted an increased risk of WML. CONCLUSIONS: Our results confirm that chronic HD patients have increased OS, but this is not related to the presence or severity of WML.

Protective effect of the omega-3 polyunsaturated fatty acids: Eicosapentaenoic acid/Docosahexaenoic acid 1:1 ratio on cardiovascular disease risk markers in rats.

BACKGROUND: High consumption of fish carries a lower risk of cardiovascular disease as a consequence of dietary omega-3 long chain polyunsaturated fatty acid (n-3 PUFA; especially EPA and DHA) content. A controversy exists about the component/s responsible of these beneficial effects and, in consequence, which is the best proportion between both fatty acids. We sought to determine, in healthy Wistar rats, the proportions of EPA and DHA that would induce beneficial effects on biomarkers of oxidative stress, and cardiovascular disease risk. METHODS: Female Wistar rats were fed for 13 weeks with 5 different dietary supplements of oils; 3 derived from fish (EPA/DHA ratios of 1:1, 2:1, 1:2) plus soybean and linseed as controls. The activities of major antioxidant enzymes (SOD, CAT, GPX, and GR) were determined in erythrocytes and liver, and the ORAC test was used to determine the antioxidant capacity in plasma. Also measured were: C reactive protein (CRP), endothelial dysfunction (sVCAM and sICAM), prothrombotic activity (PAI-1), lipid profile (triglycerides, cholesterol, HDLc, LDLc, Apo-A1, and Apo-B100), glycated haemoglobin and lipid peroxidation (LDL-ox and MDA values). RESULTS: After three months of nutritional intervention, we observed statistically significant differences in the ApoB100/ApoA1 ratio, glycated haemoglobin, VCAM-1, SOD and GPx in erythrocytes, ORAC values and LDL-ox. Supplementation with fish oil derived omega-3 PUFA increased VCAM-1, LDL-ox and plasma antioxidant capacity (ORAC). Conversely, the ApoB100/ApoA1 ratio and percentage glycated haemoglobin decreased. CONCLUSIONS: Our results showed that a diet of a 1:1 ratio of EPA/DHA improved many of the oxidative stress parameters (SOD and GPx in erythrocytes), plasma antioxidant capacity (ORAC) and cardiovascular risk factors (glycated haemoglobin) relative to the other diets.

VE-Cadherin modulates ß-catenin/TCF-4 to enhance Vasculogenic Mimicry.

Vasculogenic Mimicry (VM) refers to the capacity to form a blood network from aggressive cancer cells in an independent way of endothelial cells, to provide nutrients and oxygen leading to enhanced microenvironment complexity and treatment failure. In a previous study, we demonstrated that VE-Cadherin and its phosphorylation at Y658 modulated kaiso-dependent gene expression (CCND1 and Wnt 11) through a pathway involving Focal Adhesion kinase (FAK). In the present research, using a proteomic approach, we have found that ß-catenin/TCF-4 is associated with nuclear VE-cadherin and enhances the capacity of malignant melanoma cells to undergo VM in cooperation with VE-Cadherin; in addition, preventing the phosphorylation of Y658 of VE-cadherin upon FAK disabling resulted in VE-Cadherin/ß-catenin complex dissociation, increased ß-catenin degradation while reducing TCF-4-dependent genes transcription (C-Myc and Twist-1). Uveal melanoma cells knockout for VE-Cadherin loses ß-catenin expression while the rescue of VE-Cadherin (but not of the phosphorylation defective VE-Cadherin Y658F mutant) permits stabilization of ß-catenin and tumor growth reduction in vivo experiments. In vivo, the concomitant treatment with the FAK inhibitor PF-271 and the anti-angiogenic agent bevacizumab leads to a strong reduction in tumor growth concerning the single treatment. In conclusion, the anomalous expression of VE-Cadherin in metastatic melanoma cells (from both uveal and cutaneous origins), together with its permanent phosphorylation at Y658, favors the induction of the aggressive VM phenotype through the cooperation of ß-catenin with VE-Cadherin and by enhancing TCF-4 genes-dependent transcription.

The evolution of nutrition intervention during the COVID-19 pandemic.

COVID-19 has challenged health professionals in widely divergent areas, including innovation of practice, communication, multidisciplinary activities, broader use of technology, and adaptability. The role of the dietitian and other health professionals in dealing with the evolving crisis might be considered essential in treating patients. Given the limited access to various food options, nutrition screening and assessment deserves a high priority to complete a comprehensive nutrition evaluation, identify nutrition risks, prioritize care, and provide early nutrition intervention and support to all patients with or who have had, COVID-19 and are experiencing ongoing symptoms. Such an intervention would benefit the patients and the health system by reducing the length of hospital stay, ameliorating further complications, limiting hospital readmission, enhancing recovery, and assisting in the management of comorbidities and their metabolic alterations. This brief overview outlines the essential role of nutrition intervention and support as part of an integrated, multidisciplinary treatment program for the care of COVID-19 patients during the pandemic. Restrictive movements have changed consultative approaches, and the importance of Telenutrition for the effective communication of health status and recommendations.

Implications of Hyperoxia over the Tumor Microenvironment: An Overview Highlighting the Importance of the Immune System.

Hyperoxia is used in order to counteract hypoxia effects in the TME (tumor microenvironment), which are described to boost the malignant tumor phenotype and poor prognosis. The reduction of tumor hypoxic state through the formation of a non-aberrant vasculature or an increase in the toxicity of the therapeutic agent improves the efficacy of therapies such as chemotherapy. Radiotherapy efficacy has also improved, where apoptotic mechanisms seem to be implicated. Moreover, hyperoxia increases the antitumor immunity through diverse pathways, leading to an immunopermissive TME. Although hyperoxia is an approved treatment for preventing and treating hypoxemia, it has harmful side-effects. Prolonged exposure to high oxygen levels may cause acute lung injury, characterized by an exacerbated immune response, and the destruction of the alveolar-capillary barrier. Furthermore, under this situation, the high concentration of ROS may cause toxicity that will lead not only to cell death but also to an increase in chemoattractant and proinflammatory cytokine secretion. This would end in a lung leukocyte recruitment and, therefore, lung damage. Moreover, unregulated inflammation causes different consequences promoting tumor development and metastasis. This process is known as protumor inflammation, where different cell types and molecules are implicated; for instance, IL-1ß has been described as a key cytokine. Although current results show benefits over cancer therapies using hyperoxia, further studies need to be conducted, not only to improve tumor regression, but also to prevent its collateral damage.

Prenatal and postnatal exposure to pesticides and school-age children's cognitive ability in rural Bogotá, Colombia.

Colombia is one of the largest pesticide consumers in South America. These products have a variety of negative consequences on the health of rural populations, especially neurocognitive disorders in children. In this work, the prenatal and postnatal exposure to pesticides was evaluated and the association between the cognitive capacity of school-age children in rural areas of the city of Bogotá, Colombia, investigated. Separate multiple linear regression models were used to evaluate associations of pesticide exposure measures and WISC-IV scales, adjusted for child sex, maternal educational attainment, growth retardation, and effect modification explored by sex, using a cross products term of 232 children between the ages of 7 and 10. It was found that among all children, pesticide exposure at school was associated with a worse working memory index (ß = -3.40; 95%CI; -6.6; -0.2) and a worst verbal comprehension index (ß = -3.2; 95%CI; -6.5; -0.2). Among girls, pesticide use at home was associated with a worse processing speed index (ß = -5.1; 95% CI; -10.1; -0.20) but not among boys (ß = 1.73; 95% CI; -2.6; 6.9). This revealed an association between the prenatal and postnatal exposure reported and some IQ sub-indices of children aged between 7 and 10 years residing in the rural areas of Usme and Sumapaz in the city of Bogotá, Colombia.

Spirometry parameter alterations due to exposure to indoor air pollutants in rural homes in Bogotá, Colombia.

The aim of this study was to determine the association between the concentrations of intradomiciliary PM2.5, CO, and BC and alterations in respiratory function parameters in a population living in rural dwellings in Bogotá, Colombia. For this cross-sectional study, people were recruited from the rural areas of the localities of Usme and Sumapaz in Bogotá. In total, 68 participants were recruited by means of nonrandom sampling. Indoor air monitoring of PM2.5, BC, and CO was carried out. Additionally, evaluations of pulmonary function were performed using spirometry. The variables of pulmonary function were included in a multiple linear regression by successive steps and adjusted by the main variables described as modifiers of spirometry parameters, which are age, height, sex, disability, and a history of tobacco use. Assumptions of multicollinearity and the randomization of variances in the residuals were evaluated. Negative associations were found between spirometry parameters and the concentrations of indoor air pollutants. For FEV1/FVC and theoretical FEV1, there was a statistically significant association with the concentration of carbon monoxide (p = 0.003 and 0.019, respectively). The environmental concentrations were higher in homes where biomass was used for cooking, but these differences were statistically significant only for BC and CO (p = 0.008 and 0.03, respectively). The concentrations of carbon monoxide in rural homes were associated with alterations in respiratory function parameters.

The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry.

In highly metastatic tumors, vasculogenic mimicry (VM) involves the acquisition by tumor cells of endothelial-like traits. Poly-(ADP-ribose) polymerase (PARP) inhibitors are currently used against tumors displaying BRCA1/2-dependent deficient homologous recombination, and they may have antimetastatic activity. Long non-coding RNAs (lncRNAs) are emerging as key species-specific regulators of cellular and disease processes. To evaluate the impact of olaparib treatment in the context of non-coding RNA, we have analyzed the expression of lncRNA after performing unbiased whole-transcriptome profiling of human uveal melanoma cells cultured to form VM. RNAseq revealed that the non-coding transcriptomic landscape differed between olaparib-treated and non-treated cells: olaparib significantly modulated the expression of 20 lncRNAs, 11 lncRNAs being upregulated, and 9 downregulated. We subjected the data to different bioinformatics tools and analysis in public databases. We found that copy-number variation alterations in some olaparib-modulated lncRNAs had a statistically significant correlation with alterations in some key tumor suppressor genes. Furthermore, the lncRNAs that were modulated by olaparib appeared to be regulated by common transcription factors: ETS1 had high-score binding sites in the promoters of all olaparib upregulated lncRNAs, while MZF1, RHOXF1 and NR2C2 had high-score binding sites in the promoters of all olaparib downregulated lncRNAs. Finally, we predicted that olaparib-modulated lncRNAs could further regulate several transcription factors and their subsequent target genes in melanoma, suggesting that olaparib may trigger a major shift in gene expression mediated by the regulation lncRNA. Globally, olaparib changed the lncRNA expression landscape during VM affecting angiogenesis-related genes.

The Multifactorial Role of PARP-1 in Tumor Microenvironment.

Poly(ADP-ribose) polymerases (PARPs), represent a family of 17 proteins implicated in a variety of cell functions; some of them possess the enzymatic ability to synthesize and attach poly (ADP-ribose) (also known as PAR) to different protein substrates by a post-translational modification; PARPs are key components in the cellular response to stress with consequences for different physiological and pathological events, especially during neoplasia. In recent years, using PARP inhibitors as antitumor agents has raised new challenges in understanding their role in tumor biology. Notably, the function of PARPs and PAR in the dynamic of tumor microenvironment is only starting to be understood. In this review, we summarized the conclusions arising from recent studies on the interaction between PARPs, PAR and key features of tumor microenvironment such as hypoxia, autophagy, tumor initiating cells, angiogenesis and cancer-associated immune response.

Vasculogenic Mimicry: Become an Endothelial Cell "But Not So Much".

Blood vessels supply all body tissues with nutrients and oxygen, take away waste products and allow the arrival of immune cells and other cells (pericytes, smooth muscle cells) that form part of these vessels around the principal endothelial cells. Vasculogenic mimicry (VM) is a tumor blood supply system that takes place independently of angiogenesis or endothelial cells, and is associated with poor survival in cancer patients. Aberrant expression of VE-cadherin has been strongly associated with VM. Even more, VE-cadherin has constitutively high phosphorylation levels on the residue of Y658 in human malignant melanoma cells. In this review we focus on non-endothelial VE-cadherin and its post-translational modifications as a crucial component in the development of tumor VM, highlighting the signaling pathways that lead to their pseudo-endothelial and stem-like phenotype and the role of tumor microenvironment. We discuss the importance of the tumor microenvironment in VM acquisition, and describe the most recent therapeutic targets that have been proposed for the repression of VM.

VE-cadherin promotes vasculogenic mimicry by modulating kaiso-dependent gene expression.

Aberrant extra-vascular expression of VE-cadherin (VEC) has been observed in metastasis associated with vasculogenic mimicry (VM); however, the ultimate reason why non-endothelial VEC favors the acquisition of this phenotype is not established. In this study, we show that human malignant melanoma cells have a constitutively high expression of phoshoVEC (pVEC) at Y658; pVEC is a target of focal adhesion kinase (FAK) and forms a complex with p120-catenin and the transcriptional repressor kaiso in the nucleus. FAK inhibition enabled kaiso to suppress the expression of its target genes and enhanced kaiso recruitment to KBS-containing promoters. Finally we have found that ablation of kaiso-repressed genes WNT11 and CCDN1 abolished VM. Thus, identification of pVEC as a component of the kaiso transcriptional complex establishes a molecular paradigm that links FAK-dependent phosphorylation of VEC as a major mechanism by which ectopical VEC expression exerts its function in VM.

Acute pesticide poisoning: Comparison of epidemiological characteristics between the rural and urban population

Objective: To analyze the behavior of pesticide poisoning associated with lethality in rural and urban populations in Colombia from 2007 to 2017. Methodology: Retrospective observational study that included a descriptive cross-sectional study and an ecological design that analyzed aggregate measures of morbidity, mortality, and risk attributable to the population in rural and urban areas. In the cross-sectional study, the relative risk was estimated to measure the factors associated with lethality among intoxications using Poisson regression with logarithmic function. For the time series, the trends were established with simple linear regression, and the seasonal decomposition was performed using the multiplicative model. Autocorrelations were tested using the Box-Ljung statistic. Results: Between 2007-2017; 89 490 cases were reported. The Morbidity due to poisoning showed a higher proportion in the rural population 36.03 cases per 100 000; this indicator was three times higher than in urban areas (12.33 cases per 100 000). The mortality rates in rural and urban areas were 1.00 and 0.13 cases per 100 000, respectively. The relative risk of fatality in case of intoxication was associated with the intention of suicide in the rural population Relative Risk (RR): 5.9 (95% CI: 5.0-6.9). Conclusion: A higher proportion of lethality associated with these events occurred in populations living in rural areas and reporting cases of suicidal intent. In addition, morbidity and mortality due to pesticide poisoning had the highest proportion in rural areas and a growing trend over time.

Objetivo: Analizar el comportamiento de las intoxicaciones por plaguicidas en poblaciones rurales y urbanas asociadas a la letalidad en Colombia durante 2007-2017. Metodología: Estudio observacional retrospectivo que incluyó: un estudio descriptivo transversal y un diseño ecológico que analizó medidas agregadas de morbilidad, mortalidad y riesgo atribuibles a la población en áreas rurales y urbanas. En el estudio transversal se estimó el riesgo relativo para medir los factores asociados a la letalidad entre las intoxicaciones mediante regresión de Poisson con función logarítmica. Para la serie de tiempo, las tendencias se establecieron con regresión lineal simple y la descomposición estacional se realizó mediante el modelo multiplicativo. Las autocorrelaciones se probaron mediante el estadístico Box-Ljung. Resultados: Entre 2007-2017; Se notificaron 89 490 casos. La Morbilidad por intoxicación presentó mayor proporción en la población rural 36,03 casos por 100 000; este indicador fue tres veces mayor que en las áreas urbanas (12,33 casos por 100 000). Las tasas de mortalidad en el área rural y urbana fueron de 1,00 y 0,13 casos por 100 000, respectivamente. El riesgo relativo de fatalidad en caso de intoxicación se asoció con la intención de suicidio en la población rural RR: 5,9 (IC 95%: 5,0-6,9). Conclusión: Una mayor proporción de letalidad asociada a estos eventos ocurrió en poblaciones que viven en áreas rurales y reportan casos de intención suicida. Además, la morbilidad y mortalidad por intoxicación por plaguicidas tuvo la mayor proporción en las zonas rurales y una tendencia creciente en el tiempo.

Objetivo: Analisar o comportamento das intoxicações por agrotóxicos em populações rurais e urbanas associadas à letalidade na Colômbia durante 2007-2017. Metodologia: Estudo observacional retrospectivo que incluiu: estudo transversal descritivo e delineamento ecológico que analisou medidas agregadas de morbidade, mortalidade e risco atribuíveis à população em áreas rurais e urbanas. No estudo transversal, o risco relativo foi estimado para medir os fatores associados à letalidade entre as intoxicações por meio da regressão de Poisson com função logarítmica. Para as séries temporais, as tendências foram estabelecidas com regressão linear simples e a decomposição sazonal foi realizada usando o modelo multiplicativo. As autocorrelações foram testadas usando a estatística Box-Ljung. Resultados: Entre 2007-2017; 89.490 casos foram notificados. A Morbidade por intoxicação apresentou maior proporção na população rural 36,03 casos por 100.000; este indicador foi três vezes superior ao das zonas urbanas (12,33 casos por 100 000). As taxas de mortalidade nas áreas rural e urbana foram de 1,00 e 0,13 casos por 100.000 habitantes, respectivamente. O risco relativo de fatalidade em caso de intoxicação associou-se à intenção de suicídio na população rural RR: 5,9 (IC 95%: 5,0-6,9). Conclusão: Maior proporção de letalidade associada a esses eventos ocorreu em populações residentes em áreas rurais e com relato de casos de intenção suicida. Além disso, a morbimortalidade por intoxicação por agrotóxicos teve maior proporção na zona rural e tendência crescente ao longo do tempo.