Unidad de Investigación

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

• Four Catalan institutions are also participating in this project to develop molecules with coronavirus-neutralizing properties

The Supera COVID-19 Fund launched by Banco Santander through Santander Universities, in collaboration with Crue Spanish Universities and the Spanish National Research Council (CSIC), has granted €160,000 in funding to a research project on COVID-19 designed by a consortium made up of Navarrabiomed researchers and four Catalan institutions coordinated by the Universidad Pública de Navarra (UPNA). This project seeks to develop molecules with SARS-CoV-2-neutralizing properties for the treatment of patients requiring hospitalization and clinical supervision due to the infection’s severity.

These molecules are based on peptides specific to the ACE2 receptor that can reduce or halt the ability of SARS-CoV-2 to cause infection. “These molecules reproduce the human receptor region the virus attaches to,” explained project leader Jacinto López Sagaseta, from the Protein Crystallography Unit at the Navarrabiomed Biomedical Research Center. “We are trying to create molecules from this region that have a greater capacity to bind to the viral particle, which would hinder the virus’s ability to attach to the natural receptor and thus slow down infection.” According to López, these molecules may “help chemists design drugs that can mitigate the process and speed of infection and thereby facilitate patients’ clinical recovery”.

In order to implement the 12-month project, a consortium was set up of researchers from different disciplines, including chemical synthesis, protein engineering, structural analysis and cell biology, as well as specialists in the conditions of biosafety level three (BSL3, for laboratories, on a scale of one to four), to test the potential of these molecules. Specifically, besides Navarrabiomed and the UPNA, four Barcelona research institutions are also participating in the project: IRB Barcelona (Institute for Research in Biomedicine), IQAC-CSIC (Institute for Advanced Chemistry of Catalonia), CIBER-BBN (Bioengineering, Biomaterials and Nanomedicine Subject Area of the CIBER Biomedical Research Center), and IRTA (Institute of Agrifood Research and Technology). Besides Jacinto López Sagaseta, other Navarrabiomed researchers taking part in this research project include Gilda Dichiara Rodríguez, Elena Erausquin Arrondo and Ane Ochoa Echevarría, who are members of the Protein Crystallography Unit.
The consortium members hope that “the availability of molecules with a strong inhibitory effect will significantly mitigate the socioeconomic impact of the pandemic due to the persistence of current and/or future SARS-CoV-2 outbreaks, as well as outbreaks of other potentially harmful coronaviruses with similar entry routes,” said López.

€8.5 million fund

The €8.5 million Supera COVID-19 Fund has been earmarked for projects of different organizations that are based on the fund’s three-pronged strategic approach against COVID-19: research on the virus and its prevention, research on its social impact, and strengthening universities’ technological capacity and reducing the digital divide. A total of 700 grant applications were submitted, of which 35 were selected and received funding to the tune of €5 million to carry out applied research against the virus. Nearly €1 million was also distributed to twelve projects on the social impact of the virus. Finally, €2.5 million will be allocated to supply young university students in unfavorable socioeconomic situations throughout Spain with nearly 5,000 computers and 15,000 Internet connectivity solutions and webcams.

• The Government of Navarre provided €1.1 million in funding for eight research projects and has now added two more Navarre initiatives to the list of recipients of funding from the Carlos III Health Institute

María Chivite, the President of the Government of Navarre, recognized “the good work” being done at research centers and institutes in the Region of Navarre to find alternatives that help alleviate the effects of COVID-19. She spoke in the context of a meeting she attended this morning with ten researchers in charge of their own publicly funded studies on this disease, which has caused 515 deaths in Navarre and more than 27,000 in all of Spain.

The meeting was also attended by Santos Induráin, the Minister of Health, and Juan Cruz Cigudosa, the Minister of University, Innovation and Digital Transformation, and provided a firsthand opportunity to learn about the research purpose of the projects that have received grants from the Navarre COVI+D Fund. Created by the Government of Navarre to promote research on this topic, the fund paid out €1.1 million in May to eight projects that had received a favorable assessment from the Carlos III Health Institute. The Carlos III Health Institute has also provided direct funding of €232,000 for two other Navarre research projects.

Chivite took advantage of the forum to remind the participants of the Government of Navarre’s commitment to innovation and research “as a model of economic and social development,” not just through these grants, but also by means of the R&D&i Emergency Plan, presented last week, and the Reactivate Navarre Plan / Nafarroa Suspertu 2020-2023. The Government is also committed to improving technological infrastructure and promoting supra-regional cooperation. “We want Navarre to lead the way in biomedicine because we have the talent and skills to do just that. It’s one of the strategic areas we’re working on. We have to be able to transfer knowledge and research to favor industrial and technological development,” she said, before expressing her confidence that Navarre will become “a key stop on the R&D&i map.”

Chivite confirmed that the goal of the Government of Navarre is “to keep increasing investment and setting up strong pillars for the model of growth.” Navarre will thus be prepared for future challenges of the likes of COVID-19.

Chivite informed the researchers of the public support of their research work, though “people are aware of the pressure you’re under when you’re studying this coronavirus, because of the high expectations about finding a vaccine, treatments and other aspects that could alleviate the effects of a virus that has had a major impact on our society.” She asked for respect “for the time frames, rigor and meticulousness” of the researcher’s work, and also expressed hope that this work would promote “true and instructive information” that avoids fake news and disinformation in society as a whole.
 

Ten projects

In addition to President Chivite, the meeting was attended by Rosario Martínez, the Director General for Innovation. Also attending were the researchers from the ten projects that received public funding: Luis Martínez de Morentin, Fermín Mallor Giménez, Borja Sáez Ochoa, Natalia Ramírez Huerto, Jacinto López Sagaseta, Pablo Sarobe Ugarriza, Patricia Fanlo Mateo, David Escors Murugarren, Jesús Castilla Catalán and Leyre Ruete Ibarrola, who attended in representation of Beatriz Lacruz Escalada. They were joined by the heads of the different research centers where the projects are being carried out. This group included María Rosario Luquin, the Scientific Director of  the Navarre Health Research Institute (IdiSNA), Claudio Fernández, the Director of the Lurederra Foundation, and Íñigo Lasa Uzcudun, the Director of Navarrabiomed.

The directors of the ten research projects presented their lines of research, which include the study of possible vaccines, the use of specific drugs, resource management, the development of preventive measures and products, and the analysis of incidence bearing in mind sociodemographic characteristics and other conditioning factors.

The Government of Navarre aims to promote Navarre innovation and national prominence through the COVI+D Fund grants. But the goal is also to attract scientific talent, given the fact that these grants include staff payroll expenses.

• 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.

High-cholesterol levels, or hypercholesterolemia, affects nearly 1500-2500 people in Navarra, and less than 20 per cent of them are not aware that they suffer from this condition. Hypercholesterolemia is considered to cause 22 per cent of coronary events, most of which could be prevented with early diagnosis and treatment. The biomedical research centre Navarrabiomed has launched NAGENCOL, a project to address this issue using whole-genome sequencing as a diagnostic tool to offer personalised treatment to patients who suffer from hypercholesterolemia. The project is framed within NAGEN, a global strategy aimed at applying genomic medicine in the Navarra Health System-Osasunbidea (SNS-O).

Currently, hypercholesterolemia poses a real challenge to the public health system, because the life expectancy of untreated patients can decrease by 25 years, and 50 per cent of them are more likely to have a heart attack before the age of 55. NAGENCOL addresses this problem, offering a new model that uses genomic information, together with other clinical and demographic data, to bring precision medicine to individual patients.

This ambitious public health project has a budget of 2 million Euro, contributed by the Department of Economic Development at the Directorate-General for Industry, Energy and Innovation of the Government of Navarra, within the framework of the Genomics and Advanced Medicine project (GEMA) and the Intelligent Specialisation Strategy S3.

The NAGENCOL activities are managed by five strategic partners specialising in clinical practice, scientific and technical services, and research. They include the Navarra Hospital Complex (CHN), Nasertic, Tracasa Instrumental SL and Navarrabiomed as the leader of the study. The project is headed by Dr Ander Ernaga and Dr Juan Pablo Martínez from the Endocrinology Service at CHN.

NAGEN Strategy

Since 2016, Navarrabiomed has been leading the Genomic Medicine Strategy (NAGEN) of the Navarra Health System-Osasunbidea. With the support of the Government of Navarra, Navarrabiomed has since coordinated two strategic projects: NAGEN 1000 (best precision medicine project award winner in 2018) and Pharmanagen.

The two initiatives, along with NAGENCOL, are being used to set up, in the SNS-O patient care units, the infrastructure required for using genomic data as a powerful diagnostic tool and to determine the best personalised treatment for each patient.

Navarrabiomed has led the NAGEN: Navarra Genome 1000 project since 2016. The project focuses on whole genome sequencing for a new approach to rare genetic disorders in the Navarra Health System-Osasunbidea (SNS-O). So far, thanks to collaboration with doctors from 18 medical specialties at the Navarra Hospital Complex (CHN), the study includes data about 400 patients and their relatives, precise diagnoses for 25 per cent patients and identification of possible causes for another 25 per cent.

The patients that are part of the study had not been accurately diagnosed, despite having been treated by several specialists and having taken a large number of traditional tests. Angel Alonso, the coordinator of the project, highlighted the project’s relevance to healthcare services: ‘Making genomic analysis available to the public health system is revolutionary. It means a significant change in the clinical approach to patients with rare genetic disorders.’

Impact on the patient and their family

On the occasion of Rare Disease Day on the last day of February, it is worth mentioning that about 6 per cent of the global population are individuals with rare diseases. In Navarra, their number amounts to 38,000. At present, there are 7000 types of rare diseases, most of them of genetic origin.

In many cases, genetic testing enables the patient and their family to get a deeper knowledge of their condition and its progression, to understand how a genetic disease is inherited and to learn about the risks for other family members. The emotional significance of finding answers to the questions posed by the symptoms – which sometimes have remained unanswered for too long – means putting an end to uncertainty and isolation for most patients with rare diseases.

NAGEN 1000: a pioneering project in Spain

NAGEN 1000 is a ground-breaking project at the national level, placing Navarra at the forefront of genomic analysis and technology. The project was introduced last year at the Senate Presentation of Genomic Studies, whose conclusions were approved in 2019, thus green-lighting the development of a national strategy for personalised medicine.

Currently, the project’s methods, procedures and infrastructure are being transferred to daily clinical practice in SNS-O, to the benefit of the people of Navarra.

NAGEN 1000 is financed by the Economic Development Department at the Directorate-General for Industry, Energy and Innovation within the framework of the Intelligent Specialisation Strategy S3. It is being developed by a consortium made of CHN, Nasertic (a company run by the Government of Navarra), Avantia and Navarrabiomed, leader and coordinator of the project, with the support of the Directorate-General for Information Technology, Telecommunications and Public Information (DIGITIP), and the cooperation of the Centro Nacional de Análisis Genómico (CNAG-CRG) and the Clinical Bioinformatics Research Area into Rare Diseases (CIBERER) of Instituto de Salud Carlos III (ISCIII).

• 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.

• 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.

   

•    A consortium made of more than 600 professionals from 50 countries highlights the importance of confirming the diagnosis of people presenting with alterations in their capacity to smell and taste
 

Navarrabiomed is participating in an international research project that has confirmed that most people suffering from COVID-19 experience a loss of their sense of smell and/or taste. This initiative is part of an international consortium made up of more than 600 professionals from 50 countries.

Enrique Santamaría Martínez PhD, Head of the Navarrabiomed Clinical Neuroproteomics Unit, is responsible for leading the center’s participation in an international consortium that has confirmed the direct relationship between COVID-19 and anosmia (loss of the sense of smell) and the reduction in taste capacity in early stages of the disease. More than 600 professionals from 50 countries are collaborating on this study, whose findings may determine who is given diagnostic tests in new outbreaks.

On 7 April 2020, the Global Consortium for Chemosensory Research (GCCR) launched a massive survey with the aim of gathering sensory information on the ability to smell and taste of participants, people diagnosed with an objective test such as PCR or after clinical assessment no more than 15 days prior to responding to the survey. Among other variables, participants were asked to quantify their smell, taste and chemesthesis function (their capacity to smell, taste and perceive cooling, tingling and burning sensations in the mouth) before and while suffering from COVID-19 disease. They were also asked to mention any kind of nasal obstruction that had occurred.

The consortium obtained preliminary results 11 days later, on 18 April, and published the findings on 8 May in the free-access repository medrxiv.org. A total of 4,039 people from more than 40 countries filled out the survey and an analysis of the results indicates that smell, taste and chemesthesis were significantly reduced in patients diagnosed with COVID-19 disease. It is important to point out that nasal obstruction does not seem to be associated with these losses, which suggests that it may be an indicator for differentiating infection from SARS-CoV-2 from other viral infections such as cold and flu (which do produce nasal obstruction).

The reduction in the capacity to smell and taste may be taken as a distinctive characteristic of possible cases of COVID-19 arriving at hospitals and health centers and that require confirmation by means of a diagnostic test.

The project is different from previous studies on chemosensory abilities and COVID-19 because it proposes a massive international approach within a collaborative open-science framework. The study is led by Valentina Parma (Temple University, Philadephia, USA), John Hayes (Penn State, USA), Thomas Hummel (Technische Universität Dresden, Alemania), Steve Munger (Universidad de Florida, USA) and Danielle Reed (Monell Chemical Senses Center, USA). 

Research in progress

The consortium has now received more than 37,000 responses and the survey is still active. Navarrabiomed encourages anyone who has recently suffered from a respiratory disease, including COVID-19, to go online to https://gcchemosensr.org/ and fill out the survey in one of the 29 languages available. “Patient participation is key for determining the symptomatology of SARS-CoV-2. Consortium committees are currently organizing specific research projects that will make use of all the information compiled in the GCCR initiative,” said Dr. Santamaría.

The Navarrabiomed Clinical Neuroproteomics Unit is interested in determining why COVID-19 patients lose their sense of smell. To answer this question, the Unit is collaborating with the group of Dr. David Escors (Head of the Oncoimmunology Unit, Navarrabiomed) in order to untangle the molecular mechanisms that are altered at the olfactory level by the SARS-CoV-2 virus.

“One of the coronavirus’s access routes is through the nasal cavity, which is why analysis of the “nose-brain” route could provide information on why strokes, seizures and encephalitis have been observed in some COVID-19 patients”.

Furthermore, according to preliminary results from the seroprevalence study carried out by the Spanish Ministry of Health and the Carlos III Health Institute, the loss of smell should not merely be considered an early symptom of COVID-19 disease, but also a predictor of immune response,” Dr. Santamaría said.

The Navarrabiomed Neuroproteomics Unit, in collaboration with public and private health institutions in Navarre, is currently working on the development and deployment of precision olfactory medicine, which, together with immunological analysis, will lead to more effective diagnosing and monitoring of the many diseases involving loss of smell, one of which is COVID-19.
 

LEnrique Santamaría and Joaquín Fernández-Irigoyen, researchers at the Proteomics Unit of the biomedical research centre Navarrabiomed, were the coordinators of Current Proteomic Approaches Applied to Brain Function, released by the academic publishing company Springer Nature as part of its Neuromethods collection.

The book introduces 20 standard protocols to deepen the knowledge of proteins and their role in neurodegenerative and psychiatric disorders.

In this book, Santamaría and Fernández-Irigoyen, who are also professionally related to the Navarra Medical Research Institute (IdiSNA) and the ProteoRed-ISCIII national platform, offer a compendium of methods for brain proteome quantification, post-translational modification monitoring, neuronal organelle identification and characterisation, and bioinformatics tool implementation for omics data integration. It is meant to be an essential guidebook for students a valuable resource for graduate students and postdoctoral fellows interested in neuroproteomics, as well as for researchers looking for further insight into the growing field of mass spectrometry in neuroscience.

Book contributors included as many as 75 researchers from labs in Spain, Switzerland, France, Denmark, Portugal, Germany, India, the USA and Brazil. Many of them are regular participants in The Human Brain Proteome Project (HBPP).

HBPP is an international initiative sponsored by the Human Proteome Organisation (HUPO) promoting proteomic studies on the human brain and follow-up projects to decipher the role of proteins in brain development, health and disease.

 

Saioa Mendaza Lainez, investigadora predoctoral en la Unidad de Patología Molecular del Cáncer de Navarrabiomed, realizará la lectura de su tesis doctoral por la Universidad Pública de Navarra el martes 30 de junio, a las 11:30, a través de videoconferencia en Navarrabiomed (solamente podrán acudir aquellas personas autorizadas previamente). 

La tesis, titulada Approaching the epigenome of triple-negative breast cancer to identify new biomarkers, ha sido desarrollada en Navarrabiomed bajo la dirección del Dr. David Guerrero Setas y la Dra. Esperanza Martín Sánchez.

El cáncer de mama es la neoplasia más frecuente en mujeres a nivel mundial y la primera causa de muerte por cáncer en este mismo sexo. La investigación aborda el cáncer de mama triple negativo (CMTN), un subtipo que a diferencia del resto carece de tratamiento dirigido, lo que conlleva consecuencias más agresivas en las personas que lo padecen. Esto hace que a día de hoy, la búsqueda de nuevos biomarcadores y dianas terapéuticas para esta enfermedad sea imprescindible.

Dado que las alteraciones epigenéticas están involucradas en la tumorigénesis, el objetivo de esta tesis ha sido caracterizar la metilación del DNA y la acetilación de histonas de este tipo de cáncer. Con ello se ha buscado identificar nuevas firmas potencialmente diagnósticas y pronósticas, así como alteraciones destinatarias de fármacos dirigidos.

Los resultados de esta caracterización han permitido concluir que el patrón epigenético está alterado en CMTN respecto a tejido mamario no neoplásico. Más importante aún, la investigación ha desvelado dos alteraciones epigenéticas específicas como potenciales biomarcadores de peor pronóstico: la acetilación de la histona H4K5 y la hipometilación del gen ADAM12, el cual se presenta también como posible diana terapéutica frente a este cáncer.

Asimismo, se ha identificado una nueva firma basada en metilación de DNA con utilidad diagnóstica. Por último, se han descrito los procesos biológicos de los distintos genes regulados por la acetilación de H4K6 en líneas celulares no neoplásicas y CMTN.

El trabajo realizado ha dado lugar a tres publicaciones científicas y ha sido difundido en dos congresos consecutivos de European Association for Cancer Research; uno celebrado en Manchester en el año 2017 y en Amsterdam en el 2018.

Para el desarrollo de la tesis Saioa Mendaza ha sido beneficiaria de dos becas: Ayudas para la formación de Personal Investigador de la Univesidad Pública de Navarra  para la realización de tesis doctorales y Beca a la excelencia de la Funcación Caja Navarra para la realización de una estancia en University of Massachussets Medical School (EEUU).