Epigenetic Biomarkers in Cardiovascular Diseases

Altres ajuts: Fundació La Marató de TV3 (201516-10, 201502-20)Cardiovascular diseases are the number one cause of death worldwide and greatly impact quality of life and medical costs. Enormous effort has been made in research to obtain new tools for efficient and quick diagnosis and predicting the prognosis of these diseases. Discoveries of epigenetic mechanisms have related several pathologies, including cardiovascular diseases, to epigenetic dysregulation. This has implications on disease progression and is the basis for new preventive strategies. Advances in methodology and big data analysis have identified novel mechanisms and targets involved in numerous diseases, allowing more individualized epigenetic maps for personalized diagnosis and treatment. This paves the way for what is called pharmacoepigenetics, which predicts the drug response and develops a tailored therapy based on differences in the epigenetic basis of each patient. Similarly, epigenetic biomarkers have emerged as a promising instrument for the consistent diagnosis and prognosis of cardiovascular diseases. Their good accessibility and feasible methods of detection make them suitable for use in clinical practice. However, multicenter studies with a large sample population are required to determine with certainty which epigenetic biomarkers are reliable for clinical routine. Therefore, this review focuses on current discoveries regarding epigenetic biomarkers and its controversy aiming to improve the diagnosis, prognosis, and therapy in cardiovascular patients

Mouse Models for Mycobacterium tuberculosis Pathogenesis : Show and Do Not Tell

Science has been taking profit from animal models since the first translational experiments back in ancient Greece. From there, and across all history, several remarkable findings have been obtained using animal models. One of the most popular models, especially for research in infectious diseases, is the mouse. Regarding research in tuberculosis, the mouse has provided useful information about host and bacterial traits related to susceptibility to the infection. The effect of aging, sexual dimorphisms, the route of infection, genetic differences between mice lineages and unbalanced immunity scenarios upon Mycobacterium tuberculosis infection and tuberculosis development has helped, helps and will help biomedical researchers in the design of new tools for diagnosis, treatment and prevention of tuberculosis, despite various discrepancies and the lack of deep study in some areas of these traits

Neurodegeneration in diabetic retinopathy : does it really matter?

Altres ajuts: RS is supported by the following grants: Ministerio de Economía y Competitividad and the Fundació Marató TV3 (201629-10). AWS is supported by the following grants: Fight for Sight, The Belfast Association for the Blind and The Jules Thorn Trust. TWG is supported by the following grants: R01EY20582, R24DK082841, Research to Prevent Blindness and The Taubman Medical Research Institute.The concept of diabetic retinopathy as a microvascular disease has evolved, in that it is now considered a more complex diabetic complication in which neurodegeneration plays a significant role. In this article we provide a critical overview of the role of microvascular abnormalities and neurodegeneration in the pathogenesis of diabetic retinopathy. A special emphasis is placed on the pathophysiology of the neurovascular unit (NVU), including the contributions of microvascular and neural elements. The potential mechanisms linking retinal neurodegeneration and early microvascular impairment, and the effects of neuroprotective drugs are summarised. Additionally, we discuss how the assessment of retinal neurodegeneration could be an important index of cognitive status, thus helping to identify individuals at risk of dementia, which will impact on current procedures for diabetes management. We conclude that glial, neural and microvascular dysfunction are interdependent and essential for the development of diabetic retinopathy. Despite this intricate relationship, retinal neurodegeneration is a critical endpoint and neuroprotection, itself, can be considered a therapeutic target, independently of its potential impact on microvascular disease. In addition, interventional studies targeting pathogenic pathways that impact the NVU are needed. Findings from these studies will be crucial, not only for increasing our understanding of diabetic retinopathy, but also to help to implement a timely and efficient personalised medicine approach for treating this diabetic complication

Neurodegeneration in diabetic retinopathy : does it really matter?

Altres ajuts: RS is supported by the following grants: Ministerio de Economía y Competitividad and the Fundació Marató TV3 (201629-10). AWS is supported by the following grants: Fight for Sight, The Belfast Association for the Blind and The Jules Thorn Trust. TWG is supported by the following grants: R01EY20582, R24DK082841, Research to Prevent Blindness and The Taubman Medical Research Institute.The concept of diabetic retinopathy as a microvascular disease has evolved, in that it is now considered a more complex diabetic complication in which neurodegeneration plays a significant role. In this article we provide a critical overview of the role of microvascular abnormalities and neurodegeneration in the pathogenesis of diabetic retinopathy. A special emphasis is placed on the pathophysiology of the neurovascular unit (NVU), including the contributions of microvascular and neural elements. The potential mechanisms linking retinal neurodegeneration and early microvascular impairment, and the effects of neuroprotective drugs are summarised. Additionally, we discuss how the assessment of retinal neurodegeneration could be an important index of cognitive status, thus helping to identify individuals at risk of dementia, which will impact on current procedures for diabetes management. We conclude that glial, neural and microvascular dysfunction are interdependent and essential for the development of diabetic retinopathy. Despite this intricate relationship, retinal neurodegeneration is a critical endpoint and neuroprotection, itself, can be considered a therapeutic target, independently of its potential impact on microvascular disease. In addition, interventional studies targeting pathogenic pathways that impact the NVU are needed. Findings from these studies will be crucial, not only for increasing our understanding of diabetic retinopathy, but also to help to implement a timely and efficient personalised medicine approach for treating this diabetic complication

First-in-human PeriCord cardiac bioimplant : scalability and GMP manufacturing of an allogeneic engineered tissue graft

Altres ajuts: La Marató de TV3 Foundation, Government of Catalonia, Catalan Society of Cardiology, "La Caixa" Banking Foundation, Spanish Ministry of Science, Innovation and Universities, Institute of Health Carlos III, and the European Regional Development Fund.Small cardiac tissue engineering constructs show promise for limiting post-infarct sequelae in animal models. This study sought to scale-up a 2-cm 2 preclinical construct into a human-size advanced therapy medicinal product (ATMP; PeriCord), and to test it in a first-in-human implantation. The PeriCord is a clinical-size (12-16 cm 2) decellularised pericardial matrix colonised with human viable Wharton's jelly-derived mesenchymal stromal cells (WJ-MSCs). WJ-MSCs expanded following good manufacturing practices (GMP) met safety and quality standards regarding the number of cumulative population doublings, genomic stability, and sterility. Human decellularised pericardial scaffolds were tested for DNA content, matrix stiffness, pore size, and absence of microbiological growth. PeriCord implantation was surgically performed on a large non-revascularisable scar in the inferior wall of a 63-year-old male patient. Coronary artery bypass grafting was concomitantly performed in the non-infarcted area. At implantation, the 16-cm 2 pericardial scaffold contained 12·5 × 10 6 viable WJ-MSCs (85·4% cell viability; <0·51 endotoxin units (EU)/mL). Intraoperative PeriCord delivery was expeditious, and secured with surgical glue. The post-operative course showed non-adverse reaction to the PeriCord, without requiring host immunosuppression. The three-month clinical follow-up was uneventful, and three-month cardiac magnetic resonance imaging showed ~9% reduction in scar mass in the treated area. This preliminary report describes the development of a scalable clinical-size allogeneic PeriCord cardiac bioimplant, and its first-in-human implantation. La Marató de TV3 Foundation, Government of Catalonia, Catalan Society of Cardiology, "La Caixa" Banking Foundation, Spanish Ministry of Science, Innovation and Universities, Institute of Health Carlos III, and the European Regional Development Fund

Neurocognitive Profile of the Post-COVID Condition in Adults in Catalonia-A Mixed Method Prospective Cohort and Nested Case-Control Study : Study Protocol

Altres ajuts: This study is also supported in part by grants from the CIBER-Consorcio Centro de Investigación Biomédica en Red-(CB 2021), Ministerio de Ciencia e Innovación and Unión Europea, NextGenerationEU.The diagnosis of the post-COVID condition is usually achieved by excluding other diseases; however, cognitive changes are often found in the post-COVID disorder. Therefore, monitoring and treating the recovery from the post-COVID condition is necessary to establish biomarkers to guide the diagnosis of symptoms, including cognitive impairment. Our study employs a prospected cohort and nested case-control design with mixed methods, including statistical analyses, interviews, and focus groups. Our main aim is to identify biomarkers (functional and structural neural changes, inflammatory and immune status, vascular and vestibular signs and symptoms) easily applied in primary care to detect cognitive changes in post-COVID cases. The results will open up a new line of research to inform diagnostic and therapeutic decisions with special considerations for cognitive impairment in the post-COVID condition

Ways Forward for Tolerance-Inducing Cellular Therapies- an AFACTT Perspective

Clinical studies with cellular therapies using tolerance-inducing cells, such as tolerogenic antigen-presenting cells (tolAPC) and regulatory T cells (Treg) for the prevention of transplant rejection and the treatment of autoimmune diseases have been expanding the last decade. In this perspective, we will summarize the current perspectives of the clinical application of both tolAPC and Treg, and will address future directions and the importance of immunomonitoring in clinical studies that will result in progress in the field

Mecanismes de control de la infecció tuberculosa latent a través de la teràpia amb la vacuna RUTI®

En el nostre grup, la Unitat de Tuberculosi Experimental, es va desenvolupar una vacuna terapèutica contra la ITBL (infecció tuberculosa latent) humana, anomenada RUTI. L'objectiu d'aquest treball va ser l'estudi del mecanisme d'acció de la RUTI®, l'avaluació de l'eficàcia terapèutica d'aquesta contra la ITBL, així com desenvolupar un model experimental que ens permetés demostrar la Hipòtesi Dinàmica de la ITBL i avaluar l'eficàcia i toxicitat de la vacuna. Per a l'assoliment d'aquest objectiu, en aquest projecte de Tesi Doctoral es va treballar amb diferents models experimentals d'ITBL com ratolins, cabres i porcs. Havent demostrat, en treballs anteriors, la seva eficàcia en models experimentals de volum petit com ratolins i cobais, en aquest treball es va treballar amb ratolins per tal d'entendre millor els mecanismes d'acció de la vacuna, en aquest model experimental d'ITBL. A més, es va plantejar provar la vacuna en models grans fisiològicament més semblants als humans. Així doncs, es va realitzar un estudi de camp amb cabres latentment infectades amb l'objectiu d'avaluar l'eficàcia i bioseguretat de la vacunació amb RUTI®. També es va treballar en el desenvolupament d'un model experimental d'ITBL en minipigs que ens ajudaria a estudiar la histopatologia de la ITBL humana i serviria d'eina d'estudi de diferents estratègies terapèutiques contra aquesta. En aquest model més humanitzat, es va assajar l'eficàcia i bioseguretat de la vacunació amb RUTI®, així com també es va estudiar la fisiologia bàsica de la ITBL.A therapeutic vaccine against human LTBI (latent tuberculous infection) was developed in our research group called "Unitat de Tuberculosi Experimentall". The name of this therapeutic vaccine was RUTI ®. The aim of this work was to study the mechanism of action of RUTI® as well as the evaluation of its therapeutic effectiveness against LTBI. Another objective was to develop a new experimental model of LTBI that would allow us to prove the Dynamic Hypothesis of LTBI and assess the effectiveness and toxicity of the vaccine in it. To achieve these objectives, we did some experiments with different experimental models of LTBI: mice, goats and pigs. Its effectiveness in small volume experimental models as mice and guinea pigs had been demonstrated in previous studies but in this work we did some experiments in mice in order to better understand the mechanisms of action of the vaccine, in this experimental model. In addition, vaccine testing was carried out in large models physiologically more similar to humans. Thus, a field study was carried out in LTBI goats in order to evaluate the efficacy and biosecurity of the RUTI® vaccination. We also worked on the development of an experimental model in minipigs that would allow us to study the histopathology of human LTBI and would be helpful to test some therapeutic strategies against LTBI in the future. In this humanized experimental model, the efficacy and and biosecurity of the RUTI ® vaccination was evaluated, as well as the physiology of the LTBI

First-in-human PeriCord cardiac bioimplant : scalability and GMP manufacturing of an allogeneic engineered tissue graft

Altres ajuts: La Marató de TV3 Foundation, Government of Catalonia, Catalan Society of Cardiology, "La Caixa" Banking Foundation, Spanish Ministry of Science, Innovation and Universities, Institute of Health Carlos III, and the European Regional Development Fund.Small cardiac tissue engineering constructs show promise for limiting post-infarct sequelae in animal models. This study sought to scale-up a 2-cm 2 preclinical construct into a human-size advanced therapy medicinal product (ATMP; PeriCord), and to test it in a first-in-human implantation. The PeriCord is a clinical-size (12-16 cm 2) decellularised pericardial matrix colonised with human viable Wharton's jelly-derived mesenchymal stromal cells (WJ-MSCs). WJ-MSCs expanded following good manufacturing practices (GMP) met safety and quality standards regarding the number of cumulative population doublings, genomic stability, and sterility. Human decellularised pericardial scaffolds were tested for DNA content, matrix stiffness, pore size, and absence of microbiological growth. PeriCord implantation was surgically performed on a large non-revascularisable scar in the inferior wall of a 63-year-old male patient. Coronary artery bypass grafting was concomitantly performed in the non-infarcted area. At implantation, the 16-cm 2 pericardial scaffold contained 12·5 × 10 6 viable WJ-MSCs (85·4% cell viability; <0·51 endotoxin units (EU)/mL). Intraoperative PeriCord delivery was expeditious, and secured with surgical glue. The post-operative course showed non-adverse reaction to the PeriCord, without requiring host immunosuppression. The three-month clinical follow-up was uneventful, and three-month cardiac magnetic resonance imaging showed ~9% reduction in scar mass in the treated area. This preliminary report describes the development of a scalable clinical-size allogeneic PeriCord cardiac bioimplant, and its first-in-human implantation. La Marató de TV3 Foundation, Government of Catalonia, Catalan Society of Cardiology, "La Caixa" Banking Foundation, Spanish Ministry of Science, Innovation and Universities, Institute of Health Carlos III, and the European Regional Development Fund