FOXF1 promotes tumor vessel normalization and prevents lung cancer progression through FZD4.

Cancer cells re-program normal lung endothelial cells (EC) into tumor-associated endothelial cells (TEC) that form leaky vessels supporting carcinogenesis. Transcriptional regulators that control the reprogramming of EC into TEC are poorly understood. We identified Forkhead box F1 (FOXF1) as a critical regulator of EC-to-TEC transition. FOXF1 was highly expressed in normal lung vasculature but was decreased in TEC within non-small cell lung cancers (NSCLC). Low FOXF1 correlated with poor overall survival of NSCLC patients. In mice, endothelial-specific deletion of FOXF1 decreased pericyte coverage, increased vessel permeability and hypoxia, and promoted lung tumor growth and metastasis. Endothelial-specific overexpression of FOXF1 normalized tumor vessels and inhibited the progression of lung cancer. FOXF1 deficiency decreased Wnt/ß-catenin signaling in TECs through direct transcriptional activation of Fzd4. Restoring FZD4 expression in FOXF1-deficient TECs through endothelial-specific nanoparticle delivery of Fzd4 cDNA rescued Wnt/ß-catenin signaling in TECs, normalized tumor vessels and inhibited the progression of lung cancer. Altogether, FOXF1 increases tumor vessel stability, and inhibits lung cancer progression by stimulating FZD4/Wnt/ß-catenin signaling in TECs. Nanoparticle delivery of FZD4 cDNA has promise for future therapies in NSCLC.

Leaving no-one behind in the workplace health promotion: towards regulatory equity in the Ecuadorian micro-enterprises.

The purpose of workplace public health programmes and regulations is to promote safety and health for the entire working population nationwide. Some countries limit the scope of such programmes to medium or big-sized companies, leaving out small and micro-enterprises, thus discriminating against many workers exposed to risks. This Viewpoint aims to identify inequalities in occupational health generated by the new Regulation for Workplace Health Promotion (WHP) in Ecuador. We showed how the regulation excludes all micro-enterprises and displayed the essential role of micro-enterprises in the business fabric and the Ecuadorian labour market. More than 93% of the registered companies are micro-enterprises and these include more than 25% of the employees in the formal economy. Integrating occupational health into the public health system will require deep analysis to improve protection for the working population.

OPTImized coronary interventions eXplaIn the bEst cliNical outcomEs (OPTI-XIENCE) study. Rationale and study design.

INTRODUCTION: Clinical events may occur after percutaneous coronary intervention (PCI), particularly in complex lesions and complex patients. The optimization of PCI result, using pressure guidewire and intracoronary imaging techniques, may reduce the risk of these events. The hypothesis of the present study is that the clinical outcome of patients with indication of PCI and coronary stent implantation that are at high risk of events can be improved with an unrestricted use of intracoronary tools that allow PCI optimization. METHODS AND ANALYSIS: Observational prospective multicenter international study, with a follow-up of 12 months, including 1064 patients treated with a cobalt­chromium everolimus-eluting stent. Inclusion criteria include any of the following: Lesion length > 28 mm; Reference vessel diameter < 2.5 mm or > 4.25 mm; Chronic total occlusion; Bifurcation with side branch ≥2.0 mm;Ostial lesion; Left main lesion; In-stent restenosis; >2 lesions stented in the same vessel; Treatment of >2 vessels; Acute myocardial infarction; Renal insufficiency; Left ventricular ejection fraction <30 %; Staged procedure. The control group will be comprised by a similar number of matched patients included in the "extended risk" cohort of the XIENCE V USA study. The primary endpoint will be the 1-year rate of target lesion failure (TLF) (composite of ischemia-driven TLR, myocardial infarction (MI) related to the target vessel, or cardiac death related to the target vessel). Secondary endpoints will include overall mortality, cardiovascular mortality, acute myocardial infarction, TVR, TLR, target vessel failure, and definitive or probable stent thrombosis at 1 year. IMPLICATIONS: The ongoing OPTI-XIENCE study will contribute to the growing evidence supporting the use of intra-coronary imaging techniques for stent optimization in patients with complex coronary lesions.

Host space, not energy or symbiont size, constrains feather mite abundance across passerine bird species.

Comprehending symbiont abundance among host species is a major ecological endeavour, and the metabolic theory of ecology has been proposed to understand what constrains symbiont populations. We parameterized metabolic theory equations to investigate how bird species' body size and the body size of their feather mites relate to mite abundance according to four potential energy (uropygial gland size) and space constraints (wing area, total length of barbs and number of feather barbs). Predictions were compared with the empirical scaling of feather mite abundance across 106 passerine bird species (26,604 individual birds sampled), using phylogenetic modelling and quantile regression. Feather mite abundance was strongly constrained by host space (number of feather barbs) but not by energy. Moreover, feather mite species' body size was unrelated to the body size of their host species. We discuss the implications of our results for our understanding of the bird-feather mite system and for symbiont abundance in general.

Spanish cardiac catheterization and coronary intervention registry. 32nd official report of the Interventional Cardiology Association of the Spanish Society of Cardiology (1990-2022).

INTRODUCTION AND OBJECTIVES: This article presents the annual activity report of the Interventional Cardiology Association of the Spanish Society of Cardiology (ACI-SEC) for the year 2022. METHODS: All Spanish centers with catheterization laboratories were invited to participate. Data were collected online and were analyzed by an external company in collaboration with the members of the board of the ACI-SEC. RESULTS: A total of 111 centers participated. The number of diagnostic studies increased by 4.8% compared with 2021, while that of percutaneous coronary interventions (PCI) remained stable. PCIs on the left main coronary artery increased by 22%. The radial approach continued to be preferred for PCI (94.9%). There was an upsurge in the use of drug-eluting balloons, as well as in intracoronary imaging techniques, which were used in 14.7% of PCIs. The use of pressure wires also increased (6.3% vs 2021) as did plaque modification techniques. Primary PCI continued to grow and was the most frequent treatment (97%) in ST-segment elevation myocardial infarction. Most noncoronary procedures maintained their upward trend, particularly percutaneous aortic valve implantation, atrial appendage closure, mitral/tricuspid edge-to-edge therapy, renal denervation, and percutaneous treatment of pulmonary arterial disease. CONCLUSIONS: The Spanish cardiac catheterization and coronary intervention registry for 2022 reveals a rise in the complexity of coronary disease, along with a notable growth in procedures for valvular and nonvalvular structural heart disease.

Trophic interactions shape the spatial organization of medium-chain carboxylic acid producing granular biofilm communities.

Granular biofilms producing medium-chain carboxylic acids (MCCA) from carbohydrate-rich industrial feedstocks harbor highly streamlined communities converting sugars to MCCA either directly or via lactic acid as intermediate. We investigated the spatial organization and growth activity patterns of MCCA producing granular biofilms grown on an industrial side stream to test (i) whether key functional guilds (lactic acid producing Olsenella and MCCA producing Oscillospiraceae) stratified in the biofilm based on substrate usage, and (ii) whether spatial patterns of growth activity shaped the unique, lenticular morphology of these biofilms. First, three novel isolates (one Olsenella and two Oscillospiraceae species) representing over half of the granular biofilm community were obtained and used to develop FISH probes, revealing that key functional guilds were not stratified. Instead, the outer 150-500 µm of the granular biofilm consisted of a well-mixed community of Olsenella and Oscillospiraceae, while deeper layers were made up of other bacteria with lower activities. Second, nanoSIMS analysis of 15N incorporation in biofilms grown in normal and lactic acid amended conditions suggested Oscillospiraceae switched from sugars to lactic acid as substrate. This suggests competitive-cooperative interactions may govern the spatial organization of these biofilms, and suggests that optimizing biofilm size may be a suitable process engineering strategy. Third, growth activities were similar in the polar and equatorial biofilm peripheries, leaving the mechanism behind the lenticular biofilm morphology unexplained. Physical processes (e.g., shear hydrodynamics, biofilm life cycles) may have contributed to lenticular biofilm development. Together, this study develops an ecological framework of MCCA-producing granular biofilms that informs bioprocess development.

Impacto de las exacerbaciones en la enfermedad pulmonar obstructiva crónica / Impact of Exacerbations on Chronic Obstructive Pulmonary Disease

La enfermedad pulmonar obstructiva crónica (EPOC) es la tercera causa de muerte en todo el mundo. Sin embargo, ante la falta de herramientas diagnósticas precisas en el primer nivel de atención médica, como la espirometría, es difícil determinar la prevalen-cia real de la EPOC.Por otro lado, la falta de una definición clara y precisa de las exacerbaciones de la EPOC hace que se subestime su impacto en la salud pública; habitualmente, los pacien-tes con EPOC que cursan una exacerbación retrasan la búsqueda de atención médica inmediata porque se acostumbran al deterioro asociado a la enfermedad o lo confun-den con cambios por la edad avanzada. Esto puede provocar un aumento de la mor-bilidad y la mortalidad, asimismo, mayor utilización de los recursos sanitarios y mayor carga económica. Por lo tanto, es importante sensibilizar sobre la importancia del diagnóstico temprano y el tratamiento adecuado de las exacerbaciones de la EPOC, del mismo modo que el mayor conocimiento público de los síntomas, las causas y los factores de riesgo de la EPOC. Con ello, se podrán aplicar estrategias de prevención, diagnóstico y tratamiento más eficaces que mejoren la calidad de vida de los pacientes y disminuyan la carga de la enfermedad para la sociedad.Esta revisión ofrece un análisis crítico de la definición más reciente y esboza las impli-caciones del comportamiento de las exacerbaciones, su impacto en los distintos ám-bitos del sistema sanitario, así como en las diferentes esferas de la vida de los pacien-tes con EPOC. (AU)

Chronic Obstructive Pulmonary Disease (COPD) is a common disease and the third leading cause of death worldwide. However, due to the lack of accurate diagnostic tools at the first level of care, such as spirometry, the true prevalence of COPD is difficult to determine.In addition, the lack of a clear definition of COPD exacerbations means that its pub-lic health impact is underestimated. Patients with COPD often do not seek immediate medical attention because they become used to the deterioration associated with the disease. This can lead to increased patient morbidity and mortality, as well as increased utilization of healthcare resources and higher economic costs. Therefore, it is important to promote greater awareness of the importance of early di-agnosis and proper management of COPD exacerbations, as well as increased public awareness of COPD symptoms, etiologic agents, and risk factors.By better understanding COPD exacerbations, more effective prevention, diagnosis and treatment strategies can be implemented to improve the quality of life of patients and reduce the burden of the disease on society.This review aims to provide a critical analysis of the most recent definition and to out-line the implications of the behavior of COPD exacerbations and their impact on the dif-ferent settings of the health care system, as well as on the different spheres of patients' lives. (AU)

El estadio del espejo y la psicopatología / The mirror stage and psychopathology

En este trabajo se muestra cómo Lacan añade a la experiencia con las imágenes, que se presentan en el estadio del espejo, un tercer elemento que porta el orden simbólico. Ello supone añadir la palabra a los fenómenos ya dados, pudiendo de este modo revisarlos y corregirlos; este suceso añadido permite reconducir los aspectos más siniestros del espejo. En este sentido, el gran Otro consigue consolidar las identificaciones logradas, apaciguar la agresividad y construir el ideal del yo. A partir de estas apreciaciones lacanianas ha sido posible estudiar ciertos aspectos de la psicopatología con una luz completamente nueva, observándose cómo existen puntos específicos en los que asientan las producciones sintomáticas. Del mismo modo, la psicopatología permite confirmar aspectos relativos al estadio del espejo formulados por Lacan. Se descubre entonces que las patologías más graves aparecen cuando no se llega a formar la imago unitaria o bien cuando esta se encuentra amenazada, falla el reconocimiento especular y, sobre todo, cuando decae la mediación simbólica. Cualquiera de estas posibilidades puede resultar enloquecedora para el ser humano. (AU)

In this paper, we show how Lacan adds a third element to the experience with the images that appear in the mirror: the holder of the symbolic order. This involves adding the effects of the word to the already given phenomena, allowing thus to review and correct them. This event gets to redirect the most sinister aspects of the mirror. In this sense, the great Other consolidates achieved identifications, placates aggression and builds the ego ideal. Starting from these Lacanian findings, it has been possible to study certain aspects of psychopathology in a whole new light, showing how there are specific points on which symptoms settle. Similarly, psychopathology can confirm aspects of the mirror stage as formulated by Lacan. We then discover that the most serious diseases appear when one does not get to form the image, or this unit is threatened, specular recognition fails, or, especially, when symbolic mediation decays. Any of these possibilities might produce disorders in humans. (AU)

Corrigendum: Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma via the combination therapy with FOXM1 inhibitor RCM1.

[This corrects the article DOI: 10.3389/fonc.2023.1112859.].

Fatal work accidents in Ecuador from 2014 to 2020: How the age of the deceased worker relates to the accidents' temporal and geographical characteristics.

This article analyzes the relationship between the age of male workers deceased in work accidents and temporal (year, month, day of the week, working shifts), geographic (provinces), and economic sector characteristics in which the accidents occurred in Ecuador between 2014 and 2020. Available data on fatal accidents from the Ecuadorian Social Security Institute (IESS) were collected. The results, which report both frequencies and proportions (rates), indicate that fatal accidents have decreased in the period, although the average age of deceased workers has increased. No significant differences were found regarding the month, day of the week, and work shift, nor in the frequency of accidents or the age of the deceased workers. However, differences were found in terms of geographical areas and sectors of economic activity. This study contributes to the literature as it is the first to analyze the temporal and geographical characteristics of fatal accidents about the age of the deceased worker.

Demonstration of Safety in Wild Type Mice of npFOXF1, a Novel Nanoparticle-Based Gene Therapy for Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins.

Introduction: Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins (ACDMPV) is a fatal congenital disease resulting from a pulmonary vascular endothelial deficiency of FOXF1, producing abnormal morphogenesis of alveolar capillaries, malpositioned pulmonary veins and disordered development of lung lobes. Affected neonates suffer from cyanosis, severe breathing insufficiency, pulmonary hypertension, and death typically within days to weeks after birth. Currently, no treatment exists for ACDMPV, although recent murine research in the Kalinichenko lab demonstrates nanoparticle delivery improves survival and reconstitutes normal alveolar-capillary architecture. The aim of the present study is to investigate the safety of intravenous administration of FOXF1-expressing PEI-PEG nanoparticles (npFOXF1), our pioneering treatment for ACDMPV. Methods: npFOXF1 was constructed, validated, and subsequently administered in a single dose to postnatal day 14 (P14) mice via retro-orbital injection. Biochemical, serologic, and histologic safety were monitored at postnatal day 16 (P16) and postnatal day 21 (P21). Results: With treatment we observed no lethality, and the general condition of mice revealed no obvious abnormalities. Serum chemistry, whole blood, and histologic toxicity was assayed on P16 and P21 and revealed no abnormality. Discussion: In conclusion, npFOXF1 has a very good safety profile and combined with preceding studies showing therapeutic efficacy, npFOXF1 can be considered as a good candidate therapy for ACDMPV in human neonates.

Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma via the combination therapy with FOXM1 inhibitor RCM1.

Rhabdomyosarcoma (RMS) is a highly metastatic soft-tissue sarcoma that often develops resistance to current therapies, including vincristine. Since the existing treatments have not significantly improved survival, there is a critical need for new therapeutic approaches for RMS patients. FOXM1, a known oncogene, is highly expressed in RMS, and is associated with the worst prognosis in RMS patients. In the present study, we found that the combination treatment with specific FOXM1 inhibitor RCM1 and low doses of vincristine is more effective in increasing apoptosis and decreasing RMS cell proliferation in vitro compared to single drugs alone. Since RCM1 is highly hydrophobic, we developed innovative nanoparticle delivery system containing poly-beta-amino-esters and folic acid (NPFA), which efficiently delivers RCM1 to mouse RMS tumors in vivo. The combination of low doses of vincristine together with intravenous administration of NPFA nanoparticles containing RCM1 effectively reduced RMS tumor volumes, increased tumor cell death and decreased tumor cell proliferation in RMS tumors compared to RCM1 or vincristine alone. The combination therapy was non-toxic as demonstrated by liver metabolic panels using peripheral blood serum. Using RNA-seq of dissected RMS tumors, we identified Chac1 as a uniquely downregulated gene after the combination treatment. Knockdown of Chac1 in RMS cells in vitro recapitulated the effects of the combination therapy. Altogether, combination treatment with low doses of vincristine and nanoparticle delivery of FOXM1 inhibitor RCM1 in a pre-clinical model of RMS has superior anti-tumor effects and decreases CHAC1 while reducing vincristine toxicity.

Changes in the Treatment Strategy Following Intracoronary Pressure Wire in a Contemporaneous Real-Life Cohort of Patients With Intermediate Coronary Stenosis. Results From a Nationwide Registry.

BACKGROUND: Intracoronary pressure wire is useful to guide revascularization in patients with coronary artery disease. AIMS: To evaluate changes in diagnosis (coronary artery disease extent), treatment strategy and clinical results after intracoronary pressure wire study in real-life patients with intermediate coronary artery stenosis. METHODS: Observational, prospective and multicenter registry of patients in whom pressure wire was performed. The extent of coronary artery disease and the treatment strategy based on clinical and angiographic criteria were recorded before and after intracoronary pressure wire guidance. 12-month incidence of MACE (cardiovascular death, non-fatal myocardial infarction or new revascularization of the target lesion) was assessed. RESULTS: 1414 patients with 1781 lesions were included. Complications related to the procedure were reported in 42 patients (3.0 %). The extent of coronary artery disease changed in 771 patients (54.5 %). There was a change in treatment strategy in 779 patients (55.1 %) (18.0 % if medical treatment; 68.8 % if PCI; 58.9 % if surgery (p < 0.001 for PCI vs medical treatment; p = 0.041 for PCI vs CABG; p < 0.001 for medical treatment vs CABG)). In patients with PCI as the initial strategy, the change in strategy was associated with a lower rate of MACE (4.6 % vs 8.2 %, p = 0.034). CONCLUSIONS: The use of intracoronary pressure wire was safe and led to the reclassification of the extent of coronary disease and change in the treatment strategy in more than half of the cases, especially in patients with PCI as initial treatment.

Feasibility and safety of zero-fluoroscopy left bundle branch pacing: An initial experience.

INTRODUCTION: Left bundle branch pacing (LBBP) has emerged in recent years as a new pacing modality, providing patients with a narrower paced QRS than conventional pacing and stable pacing parameters. At the same time, there is a growing concern about the use of fluoroscopy in pacemaker implantations, given its harmful effects on both patients and operators. However, there are no prior experiences of zero-fluoroscopy in LBBP procedure. METHODS: We conducted an observational prospective study recruiting consecutive patients that underwent zero-fluoroscopy LBBP pacemaker implantation. A 6-month follow-up visit was programmed for every patient. The main goal of our study was to assess the efficacy, feasibility, and safety of the procedure. RESULTS: From January 2021 to February 2022, we included 10 patients, 8 males. The average age was 63 ± 4 years. The procedure was successful in all patients. We observed a significant reduction in paced QRS width compared with basal QRS width (149 ± 31.9 vs. 116 ± 15.6 ms, p = .02). All device parameters remained stable at 6-month follow-up: no significant differences in mean impedance (700.5 ± 136.4 vs. 494 ± 72.7 Ohm, p = .09), capture threshold (0.67 ± 0.2 vs. 0.83 ± 0.2 V @ 0.4 ms, p = .27) or endocardial V-wave amplitude (10.6 ± 5.2 vs. 13.9 ± 6.3 mV, p = .19). No complications were reported in any case. CONCLUSION: Zero-fluoroscopy LBBP is feasible and safe, and it may be considered in cases where radiation exposure is contraindicated or especially undesirable. Future randomized clinical trials are needed for the widespread use of this new technique.

Relationship between alcohol consumption, stress, and depression in Ecuadorian workers: the moderating role of social support and sex.

This paper aims to analyze the association between alcohol consumption, work stress, and depression and the moderating effect of social support and sex in this relationship. In a sample of workers from an electric generation industry from Ecuador (N = 99), hierarchical linear regressions were conducted to test the direct and moderation effects. Results show that alcohol consumption is positively associated with work stress and depression; social support moderates alcohol consumption's impact on depression but not on stress. This interaction effect is different according to sex. Further, an increase in alcohol consumption is associated with higher stress in women but not in men, and it relates to higher depression in men but not in women. Finally, we discuss the role of sex and social support as key factors to cope with the adverse effects of alcohol on well-being at work.