Unidad de Investigación

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.

• 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 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.

•    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).

• Since 2015 the associations annual investment in research has been increased by 65%

On October 27th, 2019 Breast Cancer Association of Navarre SARAY collected 75,000 euros in the solidarity race celebrated in Pamplona. 49,970 euros will fund two studies developed by Navarrabiomed on metastatic breast cancer.

One of the projects is focused on liquid biopsy in this type of cancer, and it is led by Natalia Ramírez Huerto, the head of the Hematological Oncology Unit of Navarrabiomed. SARAY´s contribution for the second year of the project development raises to 24,970 euros. Other study lead by Cancer Signaling Unit head Imanol Arozarena Martinicorena will receive 22,000 euros. His project aims to develop new adjuvant therapies to treat brain and bone metastases from these tumors. The additional funds will be donated to the Chronos Hope Project from Solti Foundation.

On the 25th of June SARAY decided to allocate the incomes in a face-to-face and online assembly among 725 associates (event delayed three months later due to the COVID-19 crisis). During the last years, the organization shows a strong commitment with biomedical research performed in Navarre. Therefore, it is relevant to highlight that since 2015 SARAY has increased by 65% its annual investment in oncology research.

Imanol Arozarena, senior researcher from the Cancer Signalling Unit at the Navarrabiomed biomedical research centre and a member of Instituto de Investigación Sanitaria de Navarra (IdiSNA), has recently published a melanoma review with University of Manchester Professor Claudia Wellbrock.

The two scientists were asked by the renowned scientific journal Nature Reviews: Cancer to write an article on the latest findings in melanoma cell distinct phenotypes and their relevance for melanoma development and response to therapy.

As many as 4000 new melanoma cases are diagnosed in Spain every year. Malignant melanoma is a serious type of skin cancer that is usually metastatic. It is notorious for its intra- and inter-tumour heterogeneity.

Such variability results from the ability of melanoma cells (melanocytes) to adjust to changing environmental conditions by reprogramming their genetic expression. Thus, melanocytes develop resistance to both targeted therapy and immunotherapy, and their plasticity plays a role in metastasis development.

In their article, the authors reveal the importance of combining recent developments in genomic technologies and the availability of large gene expression datasets for a precise definition of the gene signatures that characterise changes in each patient’s tumours and the prognostic relevance for tumour development and response to therapy.

According to Arozarena, ‘By understanding the molecular mechanisms that adapt melanoma cells to anti-tumour drugs, we will be able to prevent both therapy resistance and the progression of metastatic melanoma.

• www.navarra.es
• Review Article - Phenotype plasticity as enabler of melanoma progression and therapy resistance

• The Carlos III Health Institute finances two projects in Navarre through Spain's COVID-19 Fund and grants the full amount applied for in both cases. 

The Spanish Ministry of Science and Innovation, through the Carlos III Health Institute (ISCIII), has awarded €232,000 to develop two public research projects within the context of the Navarre Health Research Institute (IdiSNA). David Escors Murugarren, a researcher at Navarrabiomed, and Jesús Castilla Catalán, a researcher at the Institute of Public and Occupational Health of Navarre (ISPLN), have received 100% of the amounts they applied for from the COVID-19 Fund, a mechanism approved by Royal Decree-Law 8 of 17 March 2020 on urgent extraordinary measures for dealing with the economic and social impact of COVID-19.

David Escors, the principal investigator at the Navarrabiomed Oncoimmunology Research Unit, began his scientific career working on coronaviruses at the Spanish National Biotechnology Center (CNB-CSIC), along with researcher Luis Enjuanes. He then continued his work at University College London (UCL) by applying lentiviral vectors and gene therapy in immunotherapy. He is a coronavirus specialist and the positive evaluation received from the ISCIII will enable him to obtain the €115,000 he applied for to develop the project “Platforms for developing biosafe SARS-CoV-2 vaccines.”

The aim of the initiative is to develop a platform for engineering biosafe vaccines for the virus that causes COVID-19 disease. The focus will be on the expression of viral proteins that may activate immunity. This line of research was started up specifically for COVID-19, given the current health emergency, but is based on the European ISOLDA Project - Horizon 2020 for generating more effective and safer virus vaccines (yellow fever, influenza and coronavirus) for adults over 65. Navarrabiomed has worked on this project since 2019 in coordination with professionals from the Spanish National Research Council (CSIC) and with Dutch, German and Italian collaborators.

Institute of Public and Occupational Health of Navarre

At the Institute of Public and Occupational Health of Navarre’s Group of Infectious Diseases and Vaccines, Jesús Castilla will lead the study “Infection, Hospitalization, ICU Admissions and Deaths Caused by SARS-CoV-2 in a Population Cohort.” To carry out the study, he will also receive the total amount applied for from the ISCIII: €117,000.

His proposal focuses on estimating the effect of sociodemographic characteristics, chronic diseases and other conditioning health factors on the risk of infection, hospitalization and severe forms of COVID-19. This will involve calculating the incidence of suspected cases, infections confirmed using PCR, hospitalizations, ICU admissions, assisted ventilation and mortality. The mortality rate will also be calculated in confirmed cases and hospitalizations. Antibody seroprevalence will also be evaluated in a sample of patients from the sentinel physician network and/or donors.

This is the second SARS-CoV-2 initiative for Jesús Castilla, given the ISPLN’s participation in the European project I-MOVE-COVID-19, with the involvement of 11 countries and 20 organizations. It is one of the European projects funded through the fast-track call of Horizon 2020, the European Union’s research and innovation program to promote research of different aspects of the SARS-CoV-2 virus.

Both research projects financed by the ISCIII will form part of the scientific activity of the IdiSNA, a public-private partnership for promoting biomedical research in Navarre. Both the ISPLN and Navarrabiomed are partnership members.

El Dr. Hugo Arasanz, oncólogo del Complejo Hospitalario de Navarra e investigador de la Unidad de Inmunomodulación de Navarrabiomed - IdiSNA, recibió ayer en Madrid la Ayuda Clínico Junior de la Asociación Española Contra el Cáncer (AECC). La financiación recibida (120.000 €) se destinará al proyecto "Subpoblaciones linfocitarias como biomarcador predictivo de respuesta a inmunoterapia anti-PD1/PDL1 en carcinoma no-microcítico de pulmón avanzado en 1º línea de tratamiento". Este estudio se desarrollará durante los próximos cuatro años y contará con la dirección del Dr. David Escors. 

El Museo Reina Sofía acogió ayer la entrega de las ayudas anuales de la AECC, dentro de los actos programados en el Día Mundial de la Investigación en Cáncer (WCRD en sus siglas en inglés), que se comemora cada año el 24 de septiembre. En total, la AECC ha entregado casi 21 millones de euros para financiar 171 proyectos que se suman a los 56M€ con los que hoy se están financiando 380 proyectos de investigación en desarrollo.

Asimismo, la asociación ha puesto de manifiesto la necesidad de elaborar un Plan Nacional de Investigación en Cáncer para alcanzar el 70% de supervivencia media a cinco años en el año 2030, en la actualidad se sitúa en un 53%.

Más información sobre el proyecto

La inmunoterapia antiPD1/PDL1 ha supuesto una revolución en el tratamiento del cáncer no-microcítico de pulmón, ya que ha mejorado los resultados de la quimioterapia, asociando además menor toxicidad. Por desgracia la proporción de pacientes que responden al tratamiento es reducida, son menos todavía los que mantienen la enfermedad controlada durante un periodo de tiempo prolongado, y no se dispone de biomarcadores predictivos que permitan identificar a estos pacientes con precisión.

El equipo del Dr. David Escors ha desarrollado un sistema de monitorización de poblaciones linfocitarias por citometría de flujo a partir de sangre periférica en pacientes en progresión a quimioterapia que permite predecir aquellos que van a responder a la inmunoterapia. Dada la reciente aprobación de la inmunoterapia en pacientes en primera línea, este proyecto pretende correlacionar los perfiles linfocitarios de los pacientes y su dinámica con la eficacia del tratamiento en este contexto, incorporando además el estudio de las citosinas proinmunogénicas en plasma y la posible influencia del daño genotóxico en las células inmunitarias producido por las diferentes terapias como causa de menor eficacia en segunda línea.

El proyecto del Dr. Hugo Arasanz se completará con estudios mecanísticos in vitro que permitan conocer los elementos que condicionan la respuesta al tratamiento y plantear combinaciones que puedan revertir la resistencia primaria a estas terapias.