Targeting of the CD80/86 proinflammatory axis as a therapeutic strategy to prevent severe COVID-19

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Malalties inflamatòries; Identificació de l'objectiu; Infecció viralCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Enfermedades inflamatorias; Identificación del objetivo; Infección viralCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Inflammatory diseases; Target identification; Viral infectionAn excessive immune response known as cytokine storm is the hallmark of severe COVID-19. The cause of this cytokine rampage is yet not known. Based on recent epidemiological evidence, we hypothesized that CD80/86 signaling is essential for this hyperinflammation, and that blocking this proinflammatory axis could be an effective therapeutic approach to protect against severe COVID-19. Here we provide exploratory evidence that abatacept, a drug that blocks CD80/86 co-stimulation, produces changes at the systemic level that are highly antagonistic of the proinflammatory processes elicited by COVID-19. Using RNA-seq from blood samples from a longitudinal cohort of n = 38 rheumatic patients treated with abatacept, we determined the immunological processes that are significantly regulated by this treatment. We then analyzed available blood RNA-seq from two COVID19 patient cohorts, a very early cohort from the epicenter of the pandemic in China (n = 3 COVID-19 cases and n = 3 controls), and a recent and larger cohort from the USA (n = 49 severe and n = 51 mild COVD-19 patients). We found a highly significant antagonism between SARS-CoV-2 infection and COVID-19 severity with the systemic response to abatacept. Analysis of previous single-cell RNA-seq data from bronchoalveolar lavage fluid from mild and severe COVID-19 patients and controls, reinforce the implication of the CD80/86 proinflammatory axis. Our functional results further support abatacept as a candidate therapeutic approach to prevent severe COVID-19.The PACTABA project was funded Bristol-Myers Squibb. We thank all participants from the PACTABA study for their collaboration. AJ and SM are supported by the DoCTIS project funded by the European Union’s H2020 programme (Grant #848028). This work was supported by funds from the Vall d’Hebron Hospital Research Institute and from IMIDomics S.L. We thank Dr Ariel Jaitovich (Albany Medical Centre, USA) for providing additional clinical data on the late COVID-19 cohort

Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis

Epigenetics; Rheumatoid arthritis; Treatment responseEpigenètica; Artritis reumatoide; Resposta al tractamentEpigenética; Artritis reumatoide; Respuesta al tratamientoBackground Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease of the joints that has been associated with variation in the peripheral blood methylome. In this study, we aim to identify epigenetic variation that is associated with the response to tumor necrosis factor inhibitor (TNFi) therapy. Methods Peripheral blood genome-wide DNA methylation profiles were analyzed in a discovery cohort of 62 RA patients at baseline and at week 12 of TNFi therapy. DNA methylation of individual CpG sites and enrichment of biological pathways were evaluated for their association with drug response. Using a novel cell deconvolution approach, altered DNA methylation associated with TNFi response was also tested in the six main immune cell types in blood. Validation of the results was performed in an independent longitudinal cohort of 60 RA patients. Findings Treatment with TNFi was associated with significant longitudinal peripheral blood methylation changes in biological pathways related to RA (FDR<0.05). 139 biological functions were modified by therapy, with methylation levels changing systematically towards a signature similar to that of healthy controls. Differences in the methylation profile of T cell activation and differentiation, GTPase-mediated signaling, and actin filament organization pathways were associated with the clinical response to therapy. Cell type deconvolution analysis identified CpG sites in CD4+T, NK, neutrophils and monocytes that were significantly associated with the response to TNFi. Interpretation Our results show that treatment with TNFi restores homeostatic blood methylation in RA. The clinical response to TNFi is associated to methylation variation in specific biological pathways, and it involves cells from both the innate and adaptive immune systems.This study was funded by the Instituto de Salud Carlos III

Design and evaluation of a treatment programme for Spanish adolescents with overweight and obesity. The EVASYON Study

Background The prevalence of overweight and obesity (OW/OB) among adolescents worldwide has increased since the 60 s. Spain has reached one of the highest OW/OB prevalence rates among adolescents from European countries. The aim of this methodological paper is to describe the design and evaluation in the EVASYON study (Development, implementation and evaluation of the efficacy of a therapeutic programme for adolescents with OW/OB: integral education on nutrition and physical activity). Methods/Design The EVASYON was planned by a multidisciplinary team to treat OW/OB in Spanish adolescents. The EVASYON is a multi-centre study conducted in 5 hospitals in 5 Spanish cities (Granada, Madrid, Pamplona, Santander and Zaragoza) and two hundred and four OW/OB Spanish adolescents were recruited for this intervention. The treatment was implemented for approximately one-year follow-up. The adolescents were treated in groups of a maximum of 10 subjects; each group had 20 visits during the treatment period in two phases: intensive during the first 2 months (1st to 9th visits), and extensive during the last 11 months (10th to 20th visits). In order to assess the efficacy of the treatment, 8 dimensions were measured: diet; physical activity and fitness; eating behaviour; body composition; haematological profile; metabolic profile; minerals and vitamins; immuno-inflammatory markers. Moreover, genetic polymorphisms were also determined. Discussion The treatment programme developed in the EVASYON study was designed as a national pilot study to be implemented as an effective treatment for adolescents with OW/OB into the Spanish Health Care Service

Design of the nutritional therapy for overweight and obese Spanish adolescents conducted by registered dieticians: the EVASYON study

Background: Dietary treatment for obese adolescents should aim to ensure adequate growth and development, by reducing excessive fat mass accumulation, avoiding loss of lean body mass, improving well-being and selfesteem and preventing cyclical weight regain. The aim of this article is to describe the dietary intervention design and the methods used to evaluate nutritional knowledge and behavior in the EVASYON study (Development, implementation and evaluation of the efficacy of a therapeutic programme for overweight/obese adolescents). Methods/design: EVASYON is a multi-centre study conducted in 5 Spanish hospital settings (Granada, Madrid, Pamplona, Santander and Zaragoza), where 204 overweight/obese Spanish adolescents were treated in groups of 9 to 11 subjects over 20 visits. The study was implemented in two stages: an intensive, calorie-restricted period for the first 9 weeks, and an extensive body-weight follow-up period for the last 11 months. A moderate energy intake restriction was applied in the intensive period according to the degree of obesity, on the basis of a balanced diet supplying 50-55% of daily energy as carbohydrates; 30-35% as fats and 10-15% as proteins. In the intensive period, adolescents were prescribed both a fixed full-day meal plan for the first three weeks and a full day meal plan with different food-choices for 6 weeks. Later, adolescents received a flexible meal plan based on food exchanges for the follow-up period until the end of the trial. Data on food intake, dietary and meal-related habits and behavior were collected by means of dietary questionnaires. To analyse nutritional knowledge, adolescents were examined regarding nutrient concepts and food items for a healthy diet with the appropriate tools. Participants were given nutritional information with complementary teaching material, which was available on the EVASYON website (www.estudioevasyon.com). Discussion: The dietary intervention of the EVASYON programme with a moderate calorie restriction for a limi - ted period of time could be a good strategy in treating overweight and obese adolescents and that will be tested further. Moreover, combining fixed plan with free-choice menus may help adolescents and their families to make right decisions for every day meals

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors

Background: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. Methods: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. Findings: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. Conclusions: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. Funding: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen

Gene expression analyses determine two different subpopulations in KIT-negative GIST-like (KNGL) patients

Introduction: there are limited findings available on KIT-negative GIST-like (KNGL) population. Also, KIT expression may be post-transcriptionally regulated by miRNA221 and miRNA222. Hence, the aim of this study is to characterize KNGL population, by differential gene expression, and to analyze miRNA221/222 expression and their prognostic value in KNGL patients. Methods: KIT, PDGFRA, DOG1, IGF1R, MIR221 and MIR222 expression levels were determined by qRT-PCR. We also analyzed KIT and PDGFRA mutations, DOG1 expression, by immunohistochemistry, along with clinical and pathological data. Disease-free survival (DFS) and overall survival (OS) differences were calculated using Log-rank test. Results: hierarchical cluster analyses from gene expression data identified two groups: group I had KIT, DOG1 and PDGFRA overexpression and IGF1R underexpression and group II had overexpression of IGF1R and low expression of KIT, DOG1 and PDGFRA. Group II had a significant worse OS (p = 0.013) in all the series, and showed a tendency for worse OS (p = 0.11), when analyzed only the localized cases. MiRNA222 expression was significantly lower in a control subset of KIT-positive GIST (p < 0.001). OS was significantly worse in KNGL cases with higher expression of MIR221 (p = 0.028) or MIR222 (p = 0.014). Conclusions: we identified two distinct KNGL subsets, with a different prognostic value. Increased levels of miRNA221/222, which are associated with worse OS, could explain the absence of KIT protein expression of most KNGL tumors

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.

BACKGROUND Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. METHODS In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. FINDINGS When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. CONCLUSIONS We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. FUNDING This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen

Research advances in Risaralda. An overview of 8 experiences

I am honored to present to you this remarkable book, a testament to the invaluable research conducted in the fields of Health, Law, Engineering, and Administrative Sciences. Each chapter within these pages represents the culmination of extensive investigations carried out by dedicated scholars affiliated with the Red Universitaria de Risaralda (RUN), a network comprising 15 esteemed higher education institutions. Risaralda has emerged as a thriving hub for higher education, bolstered by its strategic geographical location, high quality of life, rich biodiversity, and competitive development. Today, Pereira ranks third in the index of university cities, with a student enrollment rate exceeding 63%. Close to 50,000 students pursue academic programs within the department. Notably, three institutions have achieved accreditation for their excellence in education, positioning Risaralda among the most competitive regions in terms of accredited academic programs. As we celebrate the 20th anniversary of the Red Universitaria de Risaralda in 2023, it is with great pride that we reflect on its pivotal role in fostering collaboration among public and private higher education institutions. Our mission has been twofold: attracting students to our region and supporting sustainable development and quality of life for our community. The mesa de investigación (research committee) has diligently coordinated the necessary actions to unite our researchers, facilitating an integrated approach to various disciplines and themes associated with the challenges faced in our region.CONTENT Introduction...................................................................................................................5 CHAPTER ONE. Tobacco Use and Social Skills in Children from Two Schools in Pereira, Colombia .......................................................................................................9 Angélica María Blanco Vanegas, Natalia Jeaneth Carmona Valencia and Ángela Liceth Pérez Rendón CHAPTER TWO. Lesbian visibility: between control and family silence.................................................35 Mireya Ospina Botero and Carolina Carmona Castilla CHAPTER THREE. New centralities in the city of Pereira, 1990-2019 .......................................................65 Cesar Augusto Castaño Galvis CHAPTER FOUR. Bibliometric analysis of scientific publications on the effect of roots on slope stability ...........................................................................................................95 Alejandro Alzate Buitrago, Raúl Alberto Gaviria Valencia, César Augusto Peñuela Meneses, Carlos Alberto Ospina Parra CHAPTER FIVE. Sustainability of local agri-food systems in a municipality of the Eje Cafetero, Colombia...............................................................................................131 Jaime Cardona Ocampo, Orlando Ospina Salazar and Julia Arredondo Botero CHAPTER SIX. Organizational strategies aimed at the Emberá Chamí unified indigenous reservation, Inamurcito community located in the municipality of Pueblo Rico, Risaralda............................................................................................................163 Carla Johana Martínez García and Yenny Marcela Vélez Herrera CHAPTER SEVEN. Psychomotor profile of children between 4 and 5 years old in the city of Pereira, Colombia ...................................................................................................199 Jhonatan Gonzalez-Santamaría and Claudia Jimena Lopez-Garcia CHAPTER EIGHT. Analysis of assembly tasks without the use of vision: an opportunity for the design of support technologies in manufacturing environments.....................217 Gustavo Adolfo Peña Marín, Carlos Andrés Quintero Diaztagle and Juan Diego Gallego Góme

Swiss public health measures associated with reduced SARS-CoV-2 transmission using genome data

Genome sequences from evolving infectious pathogens allow quantification of case introductions and local transmission dynamics. We sequenced 11,357 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from Switzerland in 2020 - the sixth largest effort globally. Using a representative subset of these data, we estimated viral introductions to Switzerland and their persistence over the course of 2020. We contrasted these estimates with simple null models representing the absence of certain public health measures. We show that Switzerland's border closures de-coupled case introductions from incidence in neighboring countries. Under a simple model, we estimate an 86-98% reduction in introductions during Switzerland's strictest border closures. Furthermore, the Swiss 2020 partial lockdown roughly halved the time for sampled introductions to die out. Last, we quantified local transmission dynamics once introductions into Switzerland occurred, using a phylodynamic model. We found that transmission slowed 35-63% upon outbreak detection in summer 2020, but not in fall. This finding may indicate successful contact tracing over summer before overburdening in fall. The study highlights the added value of genome sequencing data for understanding transmission dynamics

A three-generation study on the association of tobacco smoking with asthma

Background: Mothers' smoking during pregnancy increases asthma risk in their offspring. There is some evidence that grandmothers' smoking may have a similar effect, and biological plausibility that fathers' smoking during adolescence may influence offspring's health through transmittable epigenetic changes in sperm precursor cells. We evaluated the three-generation associations of tobacco smoking with asthma. Methods: Between 2010 and 2013, at the European Community Respiratory Health Survey III clinical interview, 2233 mothers and 1964 fathers from 26 centres reported whether their offspring (aged <= 51 years) had ever had asthma and whether it had coexisted with nasal allergies or not. Mothers and fathers also provided information on their parents' (grandparents) and their own asthma, education and smoking history. Multilevel mediation models within a multicentre three-generation framework were fitted separately within the maternal (4666 offspring) and paternal (4192 offspring) lines. Results: Fathers' smoking before they were 15 [relative risk ratio (RRR) = 1.43, 95% confidence interval (CI): 1.01-2.01] and mothers' smoking during pregnancy (RRR = 1.27, 95% CI: 1.01-1.59) were associated with asthma without nasal allergies in their offspring. Grandmothers' smoking during pregnancy was associated with asthma in their daughters [odds ratio (OR) = 1.55, 95% CI: 1.17-2.06] and with asthma with nasal allergies in their grandchildren within the maternal line (RRR = 1.25, 95% CI: 1.02-1.55). Conclusions: Fathers' smoking during early adolescence and grandmothers' and mothers' smoking during pregnancy may independently increase asthma risk in offspring. Thus, risk factors for asthma should be sought in both parents and before conception