Unidad de Investigación

Experts gathered at the Public University of Navarra (UPNA) have urged health and sports professionals to become ‘health agents’ by promoting physical activity among young people and pregnant women. Their goal is to improve the health and fitness of the population as a strategy to prevent non-communicable chronic diseases like obesity, heart disease or type 2 diabetes. A symposium was held by UPNA in Pamplona on Thursday 9 May to discuss exercise prescription as a way to improve health in all ages. Organised by the School of Medical Sciences and the Department of Medical Sciences, the event drew some 130 sports, health and biomedical experts.

Two UPNA researchers, who are also members of Navarrabiomed (the joint biomedical research centre of the Government of Navarra and the Public University of Navarra) and the Navarra Medical Research Institute (IdiSNA), delivered speeches: Mikel Izquierdo Redín, organiser the event, and Robinson Ramírez-Vélez. Mikel Izquierdo talked about strength training and the functions of the muscular system, ‘which a number of health professionals consider important for improving health and recovering from diseases linked with a sedentary lifestyle and population ageing, as well as for optimising sport performance after muscle injury.’ He debunked some of the myths created by pseudo-therapies in connection with strength training and improved muscle function. He said that muscle loss is not an inevitable outcome of ageing, as it can be prevented with proper training. He also observed that it is not true that children cannot do strength training exercises; on the contrary, they can, as long as they engage in controlled movements that are suitable for their age. He insisted that fitness ‘always’ offers benefits to patients who suffer from diseases such as type 2 diabetes and denied that the best muscle training is the one associated with extreme fatigue.

Finally, Izquierdo questioned the effectiveness and validity of the Kinesio Taping Method (which consists in applying elastic strips on muscles to treat pain), hypopressive techniques, electro stimulation suits and muscle roller sticks.

Health and pregnancy

Robinson Ramírez-Vélez said that, despite the efforts made to prevent non-communicable chronic disease, such as promoting healthy habits like physical exercise, a balanced diet, a good night’s sleep, quitting smoking and drinking, and so on, ‘we have failed to obtain the desired results.’ Studies reveal, he added, that ‘the mother’s state of health during pregnancy conditions to some extent the developing baby’s health later in life.’ He highlighted the importance of physical activity in children and adolescents – both aerobic exercise and resistance/strength training. Also, he insisted that health professionals should prescribe physical activity in all stages of life, even pregnancy.

The closing lecture was delivered by Antonio García-Hermoso, of Navarrabiomed and IdiSNA. He showed his disappointment in the fact that ‘Physical Education in school is not considered to be as important as subjects.’ He cited important international studies concluding that ‘exercise in youth is good for both physical and mental wellbeing.’ Finally, García-Hermoso recommended that ‘sports should be given the importance they deserve in primary, secondary and higher education.’

• 21 European institutions join forces to tackle end-stage liver disease and liver failure with a systems medicine approach
• Navarrabiomed-FMS takes part in the project through the Traslational Bioinformatics Unit.
   

Despite a vast array of available interventions and medications, more than 1 million people die of chronic liver disease (cirrhosis) per year worldwide, when the disease progresses to decompensated cirrhosis and acute-on-chronic liver failure (ACLF), a state in which the dysfunctional liver induces failure of other organs.

Following an acute decompensation of cirrhosis, 14% of the patients die of ACLF within 3 months. The reason why certain patients die and others survive is unknown, but huge differences between patients with regard to their individual genetics, medical history, precipitating events, clinical presentation and treatment response are suspected.

These individual differences call for personalised treatments based on a precise understanding of underlying mechanisms. Systems medicine and high-throughput technology nowadays allow for highly efficient analysis, integration, and predictive modelling of clinical data to develop the best fitted, most personalised treatment for each patient.

Over the next 5.5 years, the DECISION research consortium will analyse and integrate data from already existing clinical data and biological samples from 2,200 patients with cirrhosis at more than 8,600 time points to identify novel combinatorial therapies, validate them in animal models, and then test the most promising combinatorial therapy in a clinical trial.

The overall aim of the DECISION project is to prevent ACLF and to significantly reduce the mortality rate amongst patients with decompensated cirrhosis. The project receives 6 million € funding from the European Commission.
 

• Website: decision-for-liver.eu/
• David Gómez Cabrero. Head of the Traslational Bioinformatics Unit. 

The research has been conducted by PhD student Victoria Carr and co-led by Dr David Moyes, King´s College London and Dr David Gómez Cabrero, Navarrabiomed

The results have been published by Nature Communications journal

Dr David Gómez Cabrero, head of the Translational Bioinformatics Unit of Navarrabiomed, recently published with professionals at King's College London the results of an investigation that focuses on the characterization of antibiotic resistance within the oral cavity. The results of the study, carried out in 2017-2020, have recently been published in the journal Nature Communications and represent a significant advance in our understanding of antibiotic resistance and its relationship with the oral microbiome.
 
The generation of antibiotic resistance by certain microorganisms - including bacteria - is a global healthcare threat. To understand the process of antibiotic resistance acquisition, databases of the genes that drive this resistance have been generated (the profile of these genes is known as the “resistome”). Despite the high prevalence of microorganisms in the human oral cavity, until now, the study of the resistome in the mouth has been limited.
 
The research carried out at King's College London, and Navarrabiomed has thoroughly analyzed the oral resistome in 788 worldwide samples; furthermore, the oral resistome was also compared with the intestine resistome (derived from stool sample analysis). The combination of microbial DNA sequencing techniques and their bioinformatic analysis have allowed the identification of differences associated with the country of origin and their location within the oral cavity.
 
Specifically, differences in the prevalence of genes, classes and mechanisms of antibiotic resistance have been observed. For example, it has been shown that although there is a smaller range of different antibiotic resistance genes in the oral cavity, the prevalence of specific antibiotic resistance genes is higher than in the gut. Likewise, similarities in the resistome between saliva samples and faeces from the same individuals have been identified and shown to be less than similarities between the oral cavity of two separate individuals.
 
The study highlights the importance of characterizing the resistome in various regions of the human body to discover the potential for antibiotic resistance in each area and to what extent it affects the use of antibiotics in the clinical context.

• Abundance and diversity of resistomes differ between healthy human oral cavities and gut. Nature Communications. 
• Behind the paper: The oral resistome: A refreshing perspective on AMR. David Moyes.

   

• JAMA Pediatrics, the journal of the American Pediatrics Association, has published the study results.

A group of researchers from Navarrabiomed and the Department of Health Sciences at the Universidad Pública de Navarra (UPNA) specializing in prescribing physical exercise to improve health and quality of life has published an article on the effects of increasing the quality and quantity of physical education (PE) classes on improving the health-related physical fitness and fundamental motor skills of young people (ages 3 to 18). The article was recently published in JAMA Pediatrics (Journal of the American Medical Association).

The study analyzed data from approximately 50,000 young people and concluded that qualitative strategies such as including games and activities involving a high level of cardiovascular and muscular work, as well as better methodological session planning could provide young people with healthy benefits in terms of fitness and fundamental motor skills.

In addition to Antonio García-Hermoso, Robinson Ramírez-Vélez, Alicia María Alonso-Martínez and Mikel Izquierdo Redín (who form part of Navarrabiomed, Idisna and UPNA), the article authors also include Miguel Ángel Pérez-Sousa (Universidad de Huelva) and Rodrigo Ramírez-Campillo (Universidad de Los Lagos, Osorno, Chile).

Exercise is necessary to improve physical fitness

The study researchers also point out that it is not always possible to increase the number of hours spent per week on exercise or PE classes during school hours and therefore recommend improving the efficiency of these sessions by using strategies such as high-intensity interval training (HIIT), and muscle strength, jumping or circuit training. However, the authors mention that, despite the benefits of these strategies during school hours, young people should also participate in more out-of-school physical activities based on their age group (i.e., 60 minutes a day of moderate to intense physical activity).

They argue that PE classes also offer other benefits not specifically related to physical activity, such as helping young people develop socialization, teamwork and body language skills, and fostering healthy habits. Above all, the authors highlight the fact that improving physical fitness among school kids is a fundamental short- and long-term aspect of good health, given the high rates of obesity and physical inactivity among young people, which the authors refer to as “a public health problem that must be addressed by schools.”

Researchers from the Public University of Navarra (UPNA), Navarrabiomed and the Education Department of the Government of Navarra participated in a research project financed by the Navarra Education Department to create the first Physical Education Observatory for 3- to 6-year-old children in Navarra. They were Alicia Alonso, Mikel Izquierdo and Alazne Antón (UPNA), Antonio García-Hermoso and Robinson Ramírez-Vélez (Navarrabiomed), and Berta Villoslada and Berta Echavarri (CIP FP Lumbier-Education Department, Government of Navarra).

The Observatory is meant to promote physical activity in schoolchildren, reducing their screen time and adding relaxation time instead, as it has been shown that developing healthy habits in childhood is crucial to preventing cardiovascular disease in adult life. In order to achieve its goal, the Observatory will conduct a series of assessments in local schools, with children and their families, testing their fitness, measuring their sleep time and analysing all this information with them. The evaluation includes physical tests (jumping with both feet, speed/agility tests, etc.), body composition analysis (waist circumference, percentage of body fat and body mass index) and the use of personal electronic devices to measure the intensity of everyday activity and rest/sleep periods. In addition, the correlation will be established between fitness and school achievements.

The study is set to begin in Colegio Santa María la Real-Maristas Pamplona in October, then moving to Colegio Público San Juan de la Cadena. Finally, there will be a special teacher training module in CIP FP Lumbier, targeted at the students in the higher education training cycles (80), who will become assessors. This will be part of the module titled ‘Fitness testing and response to accidents’.

Throughout the process, school teachers will participate in measurements and evaluations, in an effort to introduce new trends, methods and formulas in children health assessment. According to the authors of the study, ‘the results might help understand why schoolchildren are gaining weight and their performance at school is worsening, with low levels of physical activity.’

Childhood as a critical period to develop healthy habits

‘Early childhood is a critical period for physical, social and cognitive development, to establish healthy behaviour patterns that can be kept into adulthood,’ the researchers say. Studies show that ‘regular participation in physical activities by pre-schoolers is essential for normal development and growth, with immediate and long-term benefits for physical and psychological wellbeing,’ they add. However, they explain, evidence for this age group is still relatively scarce as compared to the data available for children and adolescents aged 6 to 17.

Recently, the World Health Organisation (WHO) published new guidelines on physical activity, sedentary behaviour and sleep for children under 5 years of age. According to these recommendations, children 3-5 years of age should spend at least 180 minutes in a variety of types of physical activities, of which at least 60 minutes is moderate- to vigorous-intensity activity. ‘Despite the benefits for health of regular physical activity, many pre-schoolers fail to meet these standards,’ the authors of the study state. The Observatory is aimed at improving results in this area.

The European network APTITUDE - Acting for Trans-Pyrenees Prevention of Dependency in Seniors – is gathering in Pamplona on Wednesday, 3 July for a scientific seminar that is expected to draw more than 200 experts in active ageing and frailty. The seminar will take place at the Tres Reyes Hotel in Pamplona, starting at 8.15am. In addition, there will be side workshops organised with the Navarra Red Cross for the general public, at Rincón de la Aduana and Paseo del Doctor Arazuri, starting at 10am.

These events were introduced this morning at the biomedical research centre Navarrabiomed, the network’s leading institution in Navarra, along with the Public University of Navarre (UPNA), the Navarra Hospital Complex (CHN) and the Navarra Red Cross. At the press conference were Nicolás Martínez Velilla, APTITUDE Coordinator in Navarra and Head of the Geriatrics Unit at CHN, Juan José San Martín Baquedano, Coordinator of the Navarra Red Cross, and Jorge Marín Vidondo, Project Manager at Navarrabiomed.

Martínez Velilla said the seminar would be the third APTITUDE meeting – and the first to take place in Pamplona. It will gather primary health care professionals and representatives of hospitals and research centres, universities, nursing homes and businesses from Occitanie in France, Catalonia and Navarra in Spain, and Andorra.
At the seminar, experts will discuss the concept of intrinsic capacity in older individuals – that is, the set of physical and mental skills an individual can apply at any given moment, plus the functional capacity, which is the way in which an individual relates to and interacts with the environment – proposed by the World Health Organisation (WHO). Also, they will talk about the multi-component training offered by the project, targeted at health and social care practitioners working with frail seniors, so that they can prescribe the adequate physical activity routines, make cognitive stimulation interventions, give healthy diet guidelines, make psycho-social interventions, etc.

Keynote speakers include Norman Lazarus and Stephen Harridge, from King’s College London, who have broad experience in physical activity, anti-ageing and muscle deterioration in geriatric care and other sectors, like aerospace, where they have worked with NASA.

Open workshops

On Wednesday, between 10am and 2pm, there will be open workshops at Rincón de la Aduana and Paseo del Doctor Arazuri, Pamplona. Under the title ‘Active, healthy seniors/Tailerrak: Adineko aktibo eta osasuntsuak’, they are targeted at people over 65, but they can also be of interest to caretakers, relatives or volunteers. The workshops are free and no prior registration is required.

In addition, there will be APTITUDE-Red Cross Tents, hosting functional assessment, cognitive stimulation and adapted leisure activities for the elderly, giving information about support devices and healthy habits, and giving out supplementary material with workout routines.

Ageing and functional decline

According to INE data from 2018, the population of Navarra amounts to 647,219 people, 19.5 per cent are 65 or above. The region has one of the longest life expectancies in Europe: 86.6 years for women and 81 years for men. However, the quality of life varies: whereas women tend to live longer lives, they become more dependent than men after 65.

According to the World Health Organisation, the main causes of mild or severe disability in old age are sensory impairment, back or neck pain, chronic obstructive pulmonary disease (COPD), depression, falls, diabetes mellitus, dementia and osteoarthritis. Moreover, more than 50 per cent of the elderly suffer from a combination of illnesses and take three to five medicines together.

Initiatives like APTITUDE advocate a change of paradigm in elderly care. Caretakers should face the challenge of setting illness aside to focus on functional capacity and its maintenance or improvement. APTITUDE promotes healthy habits, physical activity and cross-generational, adapted leisure both in urban centres and rural environments, in an effort to combat loneliness, depopulation in rural areas and the stereotypes associated with ageing.

About APTITUDE

APTITUDE was established in 2018 as a three-year network to foster cross-border cooperation in four regions (Occitanie, Catalonia, Navarra and Andorra) by building its own local networks with a total budget of 2 million Euro.
The APTITUDE project, which includes the APTITUDE network in Navarra, gets 65 per cent of its funds from the European Regional Development Fund (ERDF), through the Interreg V-A Spain-France-Andorra (POCTEFA) cooperation programme, aimed at the development of cross-border economic, social and environmental action by means of joint strategies to promote sustainable territorial development.

APTITUDE partners:

Gérontopôle - Centre Hospitalier Universitaire (CHU) de Toulouse
Fundació Salut i Envelliment - Universitat Autònoma de Barcelona (UAB)
Servei Andorrà d’Atenció Sanitària
Complejo Hospitalario de Navarra (CHN) - Navarrabiomed

More information: www.aptitude-net.com

Photo: From left to right: Jorge Marín (Navarrabiomed), Nicolás Martínez (CHN-Navarrabiomed) and Juan José San Martín (Navarra Red Cross).

Professionals at the Navarra Hospital Complex (CHN) from the Public University of Navarra (UPNA) and Navarrabiomed are participating in the establishment of a European network for preventing old-age dependency and promoting active ageing. Hospitals and research centres from France, Spain (Navarra and Catalonia) and Andorra are part of this project, named APTITUDE (Acting for Trans-Pyrenees Prevention of Dependency in Seniors). As announced today, the network in Navarra is being coordinated by Navarrabiomed-Miguel Servet Foundation.

The three-year cross-border project will develop local networks in France, Navarra, Catalonia and Andorra. The project has been assigned a 2-million-Euro budget, with 1 million going to Spain (and 400,000 to Navarra). 65 per cent of the funds are being contributed by the European Regional Development Fund (ERDF) through the Interreg V-A Spain programme.

Through training programmes, awareness-raising activities and scientific evidence, the project is aimed at improving the quality of life of elderly people, encouraging the adoption of healthy habits and reducing the loss of functional autonomy, as explained by Antonio Merino Díaz de Cerio, CHN Managing Director, and Nicolás Martínez Velilla, Head of the Geriatrics Department, researcher at the Geriatrics Unit in Navarrabiomed and leader of APTITUDE in Navarra. In the words of Martínez Velilla, ‘the primary goal of the network is to prevent old-age dependency by trying to mitigate frailty in the elderly population.’

Antonio Merino stressed the importance of this type of European projects where protocols, good practices and procedures are shared for the benefit of all the participating institutions and society at large.

Specific actions by APTITUDE Navarra

Álvaro Casas Herrero, geriatrician at CHN and President of the Spanish Geriatrics Society, and Maite Soria Sarnago, Nursing Director at CHN, announced the actions to be undertaken in our community in the forthcoming months.

On Tuesday, 20 November, the project will be presented at a talk in the function room of the School of Medical Sciences, titled ‘Active and healthy seniors: Keys for adopting healthy habits’. The talk will start at 4pm and finish at 6.30pm. Admission is free, but there will be a limited number of seats available. It will also be streamed on the Navarrabiomed YouTube channel.

At the event, the leaders of the project will talk about healthy habits and good practices for improving the quality of life of old people. The President of Club Atlético Osasuna, Luis Sabalza Iriarte, will talk about ‘Working beyond retirement age’. He will share experiences from his career in the Club.

In addition, three strategic actions will take place in the upcoming months in Navarra. Firstly, a cross-border record will be established of people aged 65 and over who are interested in getting information or taking part in gerontechnology and clinical research programmes.

Simultaneously, Clinical and Innovation Research Travelling Teams will be established where professionals specialising in various medical fields will transfer clinical and research practice to urban and rural areas, thus ensuring broader penetration and larger participation for the population. The teams will be made of doctors, nurses, physiotherapists and occupational therapists.

Also, a database will be created with data provided voluntarily by frail old people and old adults with memory disorders, which will be used to design research projects involving all the centres participating in the project.

Lastly, the members of the project will participate in the validation of a new concept, ‘intrinsic capacity’, as defined by the World Health Organisation (WHO), which might be used in the clinical assessment of old people.

Recently published studies

The actions framed within the project are in line with the conclusions drawn in a study published recently in JAMA Internal Medicine, the peer-reviewed medical journal of the American Medical Association.

Professor Mikel Izquierdo Redín, Director of the Department of Medical Sciences at UPNA and senior researcher from the Physical Exercise and Frailty Research Unit at Navarrabiomed, presented a study that shows that a tailored physical activity plan for in-patients aged 75 or older reduces functional decline. The clinical trial consisted in a three-year follow-up of 370 patients in the Geriatrics Service of CHN.

The study reveals that preadmission health and functional status can indicate the risk of functional decline associated with hospitalisation. This clinical sign might be negatively affected by bed rest during hospitalisation.

Simultaneously, the team is participating in the DIABFRAIL LATAM European project, funded by the European Commission in the context of the Horizon 2020 European research project. DIABFRAIL LATAM focuses on pre-frail and frail old people with diabetes in Latin America. At present, 40 per cent of people aged 65 and older are affected by diabetes.

The project’s goal is to implement a treatment model in Colombia, Chile, Mexico, Peru and Argentina, consisting of physical exercise, education and a nutrition plan, plus blood sugar level and blood pressure goals adjusted to old adults with diabetes, who are particularly vulnerable as a result of their frailty. More than 1000 pre-frail and frail old people with type 2 diabetes are taking part in the clinical trial.

www.aptitude-net.com / aptitude@navarra.es

• Vanessa Arrieta Paniagua, predoctoral researcher at the Translational Cardiology Unit of Navarrabiomed - IdiSNA will present her doctoral thesis by the Public University of Navarra next Monday, November 28, at 12:00, in the Assembly Hall of Navarrabiomed. 

The doctoral work, entitled "Role of sST2 in myocardial fibrosis in severe aortic stenosis”, has been developed at the University Hospital of Navarra and Navarrabiomed under the direction of Natalia López Andrés, Principal investigator of the Translational Cardiology Unit.

Aortic stenosis is the most common valvular heart disease in Europe and North America affecting 2-7%, depending on the region, in population over 65 years of age. To date, there is no medical treatment that can slow down or reverse the evolution of the disease, so aortic valve replacement (surgical or percutaneous) is the only treatment when symptoms or ventricular dysfunction appear.

This disease produces an abnormal progressive narrowing of the aortic valve that, as a result of pressure overload, causes hypertrophy of the left ventricle. In this process, myocardial fibrosis has an important pathophysiological role, as well as a prognostic role. Initially, myocardial fibrosis is part of a compensatory mechanism, but in advanced stages a focal replacement fibrosis appears, leading to ventricular dysfunction and heart failure. The pathophysiological mechanisms underlying these processes are not fully understood. 

Focal replacement fibrosis can be detected and quantified by cardiac magnetic resonance imaging (MRI) with the delayed enhancement (DE) sequences. The presence of DE in patients with severe aortic stenosis has been shown to be an independent predictor of mortality and unfavourable clinical outcome in this group of patients. However, MRI is an expensive technique with limited availability, so it is not used in the follow-up of this group of patients in routine clinical practice.

The hypothesis of this thesis is that as the levels of soluble ST2 (sST2), a biomarker associated with the process of fibrosis and myocardial remodelling, are elevated in case of aortic stenosis, they may have a prognostic value. Specifically, this study addresses the role of sST2 in myocardial fibrosis in severe aortic stenosis. 
 

Research development 

The work is proposed from a translational point of view, and has a dual goal. First of all, to delve into the pathophysiological role of tSS2 in severe aortic stenosis. To this end, a proteomic study has been carried out to assess the proteins modulated by sST2 in human cardiac fibroblasts and the in vitro effects of sST2 on human cardiac fibroblasts have been investigated. The results have been validated in vitro in a rat model with pressure overload and in myocardial biopsies of patients with aortic stenosis that underwent surgery. 

Likewise, it has been demonstrated that sST2 exerts a deleterious role in human cardiac fibroblasts, on the one hand, affecting the mitochondrial function of the cell and thus increasing oxidative stress and the synthesis of proinflammatory molecules and on the other hand, promoting differentiation to myofibroblasts and increasing the synthesis of profibrotic molecules. These findings were validated in the animal model and in myocardial biopsies of patients with aortic stenosis.

Secondly, from the clinical point of view, a cohort of patients with severe aortic stenosis with surgical indication was analysed to check if the blood levels of sST2 are associated with the DE evaluated by MRI in patients with severe aortic stenosis. Thus, it is observed that patients with severe aortic stenosis with cardiac MRI DE have significantly higher blood levels of sST2 than those without RT. Blood sST2 levels are positively correlated with DE mass and with VI mass in patients with severe aortic stenosis. High levels of sST2 make it possible to identify patients with severe aortic stenosis with DE, without having to perform cardiac MRI, in a simple way that can be applied in routine clinical practice.
 

Dissemination of results 

The work carried out has led to several scientific publications: in 2019, in the journal Clinical Science, “Soluble ST2 promotes oxidative stress and inflammation in cardiac fibroblasts: an in vitro and in vivo study in aortic stenosis”, and in 2020 in the journal Cells, “Soluble St2 Induces Cardiac Fibroblast Activation and Collagen Synthesis via Neuropilin-1”.   

In addition, the results have been disclosed at several national and international congresses such as the SEC Congress in Bilbao (in 2015 and in 2017), at the 29th EACTS Annual Meeting in Amsterdam, in 2015 or at the Heart Failure Congress in Paris, in 2017.

Biochemist Jaime Ibarrola Ulzurrun (Pamplona, 1991) has shown for the first time that a hormone is involved in mitral valve prolapse, a heart valve disease that leads to heart failure, and that a series of drugs can have positive effects on this condition. ‘The drugs known as antimineralocorticoids or mineralocorticoid receptor antagonists (MCRAs) are a promising option to reduce mitral valve remodelling. The only existing solution to date was surgery,’ Ibarrola explains. This was the subject of his doctoral thesis at the Public University of Navarra (UPNA).

The mitral valve is the valve between the left atrium and the left ventricle of the heart. Mitral valve prolapse is a condition in which the two valve flaps of the mitral valve do not close smoothly or evenly, but instead bulge (prolapse) upward into the left atrium. Sometimes, the mitral valve does not close tightly, allowing blood to flow backward in the heart. This condition is known as mitral valve regurgitation or mitral insufficiency. Most people with mitral valve prolapse – one of the most common heart conditions, affecting 176 million people around the world – never have problems. They do not need treatment or lifestyle changes. Some, however, do need to be treated. ‘To date, no drugs have been developed for this condition, so the only viable solution is surgery,’ Ibarrola explains. His doctoral advisor was Natalia López Andrés, senior researcher at the Cardiovascular Translational Research Unit of Navarrabiomed, a joint centre of the Government of Navarra and the Public University of Navarra (UPNA).

New therapeutic targets

Ibarrola’s research responds to the need to study ‘new mechanisms and new therapeutic targets in order to find drug treatments for mitral valve prolapse.’ ‘Mineralocorticoids are a class of hormones produced by the human body. The primary mineralocorticoid is aldosterone. The aldosterone/mineralocorticoid receptor (Aldo/MR) pathway can cause cardiac fibrosis. In addition, a large number of studies have shown that the Aldo/MR pathway is involved in a number of heart conditions. MCRA drugs can block the effects of the Aldo/MR pathway. Moreover, significant clinical studies show that they can also improve cardiac function by reducing cardiac fibrosis,’ Ibarrola explains. He conducted his doctoral research project with financial aid from UPNA and a European programme.

Ibarrola worked on the hypothesis that the Aldo/MR pathway could play a role ‘in the development of mitral valve prolapse, modulating cell activation and cellular differentiation.’ ‘Furthermore, the Aldo/MR pathway could become a new therapeutic target in this disease, and blocking this pathway with MCRA drugs could prevent the alterations associated with mitral valve prolapse. For the first time, we were able to show that the Aldo/MR pathway is involved in the development of mitral valve prolapse and that the drugs could have a positive effect on this condition,’ Ibarrola concludes. His doctoral thesis got an A-grade cum laude.

Ibarrola’s résumé

Jaime Ibarrola holds a degree in Biochemistry and a master’s degree in Biomedical Research from the University of Navarra. At present, he is a postdoctoral researcher at the Molecular Cardiology Research Institute (MCRI) at Tufts University (Massachusetts, USA).

As a doctoral student, Ibarrola was twice a visiting scholar at the Cordeliers Research Centre, Sorbonne University, in Paris. He shared his results in eight international conferences in Germany, Spain, France and Ireland. Ibarrola is the author of about a dozen papers published in international scientific journals.

The predoctoral researcher of the Neuroepigenetics Unit of Navarrabiomed, Amaya Urdánoz Casado, will be sitting her viva from the Public University of Navarra next Tuesday, July 5th at 11:00 in the Assembly Hall of Navarrabiomed.

The doctoral work, entitled "Identification of circRNAs as candidate epigenetic biomarkers in Alzheimer's disease”, has been developed at Navarrabiomed under the direction of Maite Mendioroz Iriarte and Idoia Blanco Luquin.

This research focuses on Alzheimer's disease (AD), a neurodegenerative, chronic and, at the moment, irreversible disease that represents the first cause of age-related dementia. It is postulated that circular RNAs (circRNAs) play important roles in brain homeostasis, as well as in the development of neurodegenerative diseases. 
The objective of this doctoral thesis is to identify, in patients with AD compared to controls, circRNAs with differential expression in the human entorhinal cortex (CE), a brain region especially vulnerable to AD. To do this, the study of the expression of circRNAs is proposed using a candidate gene and a genome-wide approach.
In the former, candidate gene approach, 10 genes were selected, whose role in AD had already been described in the literature and from which circRNAs originated. 6 circRNAs derived from the APP, ADAM10, CDR1 and HOMER1 genes were identified, of which 4 showed a differential expression in EC between patients with AD and controls. In addition, three potential circRNAs derived from the TREM2 gene were identified for the first time in the EC.

In the second genome-wide approach, new circRNAs differentially expressed in the EC were identified that so far had not been associated with the development of the disease by transcriptome sequencing in patients with AD with respect to controls. In addition, several circRNA-miRNA-mRNA interaction networks (competitive endogenous RNA network, ceRNET) were predicted.
The results obtained show the deregulation of a series of circRNAs in the EC affected by AD with respect to controls, suggesting their potential involvement in the pathogenesis of the disease.

Disclosure of results and financing

The work carried out has resulted in a scientific publication in the International Journal of Molecular Sciences, “Gender-Dependent Deregulation of Linear and Circular RNA Variants of HOMER1 in the Entorhinal Cortex of Alzheimer's Disease”.
In addition, it has been disseminated at several national and international congresses, the Alzheimer's Association International virtual Conference Satellite Symposium, the 15th International virtual Conference on Alzheimer's and Parkinson's Diseases: Mechanisms, Clinical Strategies and promising Treatments of Neurodegenerative Diseases or at the BraYn Conference: Second brainstorming research assembly for young neuroscientists.

For the development of the thesis, Amaya Urdánoz has received several grants for the recruitment of doctoral students by companies and research and knowledge dissemination organizations: industrial doctoral students 2018-2020 and grants for the financing of a predoctoral contract in health sciences and technologies in the period 2019-2022, both funded by the Government of Navarra. She also received an Erasmus scholarship for her stay at Karolinska Intitutet and an aid for the mobility of doctoral students - UPNA Congresses (2021) to attend, with a communication of her research, the 15th International virtual Conference on Alzheimer's and Parkinson's Diseases: Mechanisms, Clinical Strategies and promising Treatments of Neurodegenerative Disease.

• The programme will offer support to the development of studies in digestive medicine, geriatrics, neuroscience and oncology that will bring advancement and excellence in these fields of research.
• ‘la Caixa’ Foundation and Caja Navarra Foundation are channelling 1.2 million Euro into this programme, to be run by the biomedical research centre Navarrabiomed, where four doctors from the Navarra Health System-Osasunbidea (SNS-O) will carry out quality biomedical research studies.
• Through this programme, ‘la Caixa’ Foundation and Caja Navarra Foundation will give support to the leading research centres in Navarra during the 2017-2021 period. Universities and research centres will thus get a total 6.4 million Euro.

Ana Díez Fontana, Regional Director of CaixaBank in Navarra; Javier Miranda, Chairman of Caja Navarra Foundation; and Iñigo Lasa, Director of Navarrabiomed, announced the research lines to be developed by doctors Eduardo Albéniz Arbizu, Nicolás Martínez Velilla, Maite Mendióroz Iriarte and Antonio Viudez Berral, who were selected by an external evaluation committee from 12 candidates.

The specialists in the programme will be relieved from part of their medical activity so that they can do research. They need time to develop their scientific projects and produce new knowledge in their medical specialties. The initiative enables the establishment of a critical mass of professionals that combine medical activity with research jobs, thus promoting translational medicine to the benefit of patients and society as a whole.

The four doctors selected to join the programme will soon start working at the labs of Navarrabiomed – the joint biomedical research centre of the Government of Navarra and the Public University of Navarra (UPNA). They will establish separate research units for the development of their projects, based on clinical practice at the Navarra Hospital Complex (CHN), with support from other Navarrabiomed units and platforms.

In addition to streamlining research activities in the respective units, they will encourage the participation of resident medical interns (MIRs) by getting them involved in biomedical research projects, trials and programmes.

Four excellent research projects in digestive medicine, geriatrics, neuroscience and oncology

Eduardo Albéniz Arbizu has worked in a number of hospitals across Spain. He received training in advanced endoscopy in France, Japan and China. Currently, he is working at the Gastrointestinal Endoscopy Unit of the CHN Digestive Medicine Service.

Dr Albéniz specialises in endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) for the removal of early-stage gastrointestinal tumours. These advanced procedures reduce the number of surgical and other more invasive interventions in the treatment of superficial neoplastic lesions. Resection of colorectal polyps, for example, is the procedure with the highest survival rates observed in screening studies for colorectal cancer carried out in Navarra.
The goal of the project led by Dr Albéniz is to provide evidence for the identification of predicting factors for the effectiveness of resection procedures and other factors associated with potential complications that might be minimised.

Nicolás Martínez Velilla has been the Head of the Geriatrics Unit at CHN since 2015. In 2013, he was appointed head of a team partnered with Navarrabiomed for the promotion of research into different aspects of geriatric medicine.

Dr Martínez Velilla’s proposal includes a thorough study for the prevention of old-age frailty and disability or dependency in hospitals and in the community at large. Furthermore, it includes the creation of a European cross-border network to deal with various aspects of ageing. The project is aimed at rethinking hospitalisation of older adults, prescribing exercise to older patients in hospitals so as to improve their quality of life and increasing the sustainability of the health system.

Maite Mendióroz Iriarte has built her professional career as a doctor and researcher in Pamplona, Barcelona, San Sebastián and New York. Since 2010, she has been a member of the Neurology Department at CHN. Over the past few years, she has received grants from ‘la Caixa’ Foundation, Caja Navarra Foundation and the Government of Navarra to boost activity in the Neuroepigenetics Unit at Navarrabiomed.

Between 2018 and 2021, Mendióroz Iriarte will develop a project whose goal is to identify a potential blood-based epigenetic biomarker for early detection and treatment of Alzheimer’s disease. Her study might become the first step towards the implementation of precision medicine in neurodegenerative diseases.

Antonio Viudez Berral has developed his professional career in Navarra, Catalonia and Baltimore, USA. In 2010, he joined the Medical Oncology Service at CHN. Since then, he has been a researcher at Navarrabiomed as well.

Dr Viudez’s project will study pancreatic neuroendocrine tumours to find accurate markers that predict the effectiveness of certain therapies.

In addition, the Medical Oncology Service will be able to strengthen its scientific activity, establishing new lines of research for the improvement of diagnosis, prognosis and prediction of treatment response and toxicity.

From left to right: Luis Gabilondo, Ana Díez, Maite Mendióroz, Eduardo Albéniz, Antonio Viudez, Nicolás Martínez, Javier Miranda and Iñigo Lasa.

The Navarra Hospital Complex (CHN) and the biomedical research centre Navarrabiomed have carried out an innovative study of the so-called ‘liquid biopsy’ in amyotrophic lateral sclerosis (ALS) diagnosis and follow-up. The results of this study were published in the international peer-reviewed journal Annals of Translational Medicine.

On the occasion of the Global ALS Awareness Day, members of the multidisciplinary team treating patients with ALS in Navarra shared the latest research and care developments in connection with this disease, including this innovative study of the use of liquid biopsy testing in ALS diagnosis and follow-up.

The leaders of the study were Maite Mendióroz and Ivonne Jericó, doctors from the CHN Neurology Department and researchers at Navarrabiomed. The project was part of the scientific activity done at the Navarra Medical Research Institute (IdiSNA), a public-private agency for the promotion of biomedical research in Navarra. The survey involved ALS patients and a control group (individuals without ALS), and professionals from the departments of Neurology and Anaesthesiology and the Nursing Team at CHN, and the Neuroepigenetics Unit at Navarrabiomed.

According to the study coordinators, one of the biggest weaknesses in research into neurodegenerative disease is the difficulty to access and study the nervous tissue of living patients. In order to address this difficulty, the study analyses the application of liquid biopsy testing, a technique recently developed in the field of cancer research, to ALS diagnosis.

Liquid biopsy is based on the fact that, when cells degenerate and die, their contents – including DNA – flow into the bloodstream. The released DNA molecules contain biochemical information about the original cells (hence the name ‘biopsy’) – in this case, diseased neurons. The original cell contents can be isolated and analysed in blood samples (hence the name ‘liquid’). The researchers have successfully used this technique with ALS patients to identify a new gene, RHBDF2, as a biomarker for ALS diagnosis in the future.

‘To the best of our knowledge, this is the first time ever liquid biopsy has been used to diagnose neurodegenerative diseases. The results have been encouraging so far. Now we are planning to extend the technique to other neurodegenerative diseases, such as Alzheimer’s disease,’ the doctors said, adding that the survey was made possible by the generous participation of patients and their families, and the volunteers in the control group.

A multidisciplinary team, 11 years and more than 200 patients

The team treating ALS patients in Navarra have striven to promote ALS research right from the start. Currently, two researchers at the Navarrabiomed Neuromuscular Disease and Motor Neuron Disease Group (headed by Dr Jericó) are working on ALS for their PhD projects, and other four projects address this neurodegenerative disease – specifically, the identification of biomarkers for diagnosis and follow-up, the role of neuroinflammation, the underlying mechanisms, the analysis of genetic factors, and the study of epidemiological aspects and disability.
The Group coordinates both research and care activities, and collaborates with the Navarrabiomed Proteomics and Biobank platforms, the Neuroepigenetics Research Unit (headed by Dr Mendióroz) and the Navarra Public and Occupational Health Service (Rare Disease Registry).

Amyotrophic lateral sclerosis is a progressive nervous system disease with a heterogeneous clinical presentation but common symptoms like muscle weakness and progressive muscular atrophy. Prognosis is variable among patients. About 5 to 10 per cent of ALS is familial, which means it arises in families in which there is a history of ALS. The other 90 to 95 per cent of ALS is sporadic, meaning it occurs without a family history, its causes still being unknown. Every year, 1 to 2 people every 100,000 are diagnosed with ALS. Despite being a rare disease, it has a deep social and family impact. Currently, there is no cure for ALS, but this does not mean there is no treatment.

ALS care involves multiple disciplines. On the occasion of the Global ALS Awareness Day the multidisciplinary team at CHN shared an informative brochure with patients and their families, highlighting the importance of coordinated social and health care through multidisciplinary units or teams. Active for 11 years now, the CHN team have treated over 200 patients to date.

Navarra has been one of the first Spanish regions to implement a multidisciplinary care model for ALS patients. Since 2007, the region has been offering comprehensive, coordinated care to them and their families, through a multi- and interdisciplinary team whose members include a neurologist, (Dr Ivonne Jericó), a nutritionist (Dr Ana Zugasti), two pulmonologists (Dr Joan Boldú and Dr Begoña Fernandez), a neurophysiologist (Dr Asun Ibiricu), an intensive care physician (Dr Juan Pedro Tirapu), a social worker (Rakel Suescun), neurology nurses, dieticians, a palliative care service and members of the Psychological and Social Support Service at San Juan de Dios Hospital (Yolanda Santesteban and Ana Baños).

From the beginning, the team set out to offer adequate, tailored, patient-centred social and health care, while promoting research as the key to finding an effective treatment for ALS.
 

Image: Members of the multidisciplinary team treating patients with ALS in Navarra.