ISPA - Instituto de Investigación Sanitaria del Principado de Asturias (Asturias)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16990

El 5 de abril de 2016 el Principado de Asturias, el Servicio de Salud del Principado de Asturias (SESPA), la Universidad de Oviedo y la FINBA, como órgano gestor que además provee personalidad jurídica y financiación público-privada al Instituto, suscribieron un Convenio de colaboración para la creación del Instituto de Investigación Sanitaria del Principado de Asturias (ISPA). De forma casi simultánea a la firma del convenio se inauguró en la inmediata vecindad del HUCA un edificio de 4.000 m2 con espacios dedicados a laboratorios de investigación, servicios comunes y plataformas de investigación. Este Convenio se amplió según Resolución de 21 de marzo de 2019 (BOE: 17/05/2019) para asociar el CSIC al mismo. Es un objetivo nuclear del ISPA desarrollar actividades de investigación e innovación de alta cualificación, fruto de la colaboración interdisciplinar no solo dentro de las ciencias de la salud sino con sectores tecnológicos, de manera que se pueda acortar el tiempo de transferencia de los hallazgos del laboratorio a la aplicación a los pacientes o al desarrollo de productos susceptibles de comercialización. Para ello, el ISPA cuenta con grupos que se proyectan a escala internacional en su área de conocimiento. Acreditado por el Instituto de Salud Carlos III como Instituto de Investigación Sanitaria en 2021, y renovando esta acreditación cada 5 años, forma parte así del total de 34 Institutos de Investigación Sanitaria acreditados existentes en la actualidad.

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A genome-wide association meta-analysis of all-cause and vascular dementia
(Wiley, 2024-09) Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium; Calero, Miguel; NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos); NIH - National Institute on Aging (NIA) (Estados Unidos); NIH - National Institute of Neurological Disorders and Stroke (NINDS) (Estados Unidos)
Introduction: Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. Methods: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors. Results: For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). Discussion: Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD. Highlights: We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). Known genetic variants associated with AD were replicated for ACD and VaD. Functional analyses identified novel loci for ACD and VaD. Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.
Health-Related Quality of Life in Long-Term Colorectal Cancer Survivors
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-09-25) Marcos-Delgado, Alba; Martín-Sánchez, Vicente; Molina-Barceló, Ana; Alonso-Molero, Jéssica; Perez-Gomez, Beatriz; Pollán, Marina; Aragones, Nuria; Ederra-Sanz, María; Fernández-Tardón, Guillermo; Binefa, Gemma; Moreno, Victor; Barrios-Rodríguez, Rocío; Amiano, Pilar; Huerta, José María; Teso, Enrique Pastor; Alguacil, Juan; Castaño-Vinyals, Gemma; Kogevinas, Manolis; Molina de la Torre, Antonio José; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Junta de Castilla y León (España); Regional Government of Andalusia (España)
The aim of our study is to evaluate the relationship between sociodemographic and clinical characteristics of individuals with Colorectal Cancer (CRC), tumour-intrinsic characteristics and treatment received with health-related quality of life (HRQoL). Methods: Cross-sectional analysis of data from 805 survivors from the MCC study was conducted. HRQoL was assessed through a general and specific questionnaire, SF-12 and FCSI (Colorectal Symptom Index). Statistical analyses were performed with linear regression with adjustment for sociodemographic variables, stage at diagnosis and histological grade. Results: Participants had survived a median of 7.9 years from diagnosis (IQR 7.1-8.5 years). Age at diagnosis, sex and area showed a clear association with HRQoL in both physical and mental dimensions of the SF-12 questionnaire. A direct association between CRC recurrence was also found in the PCS-12 and MCS-12 dimensions and radical surgery in the PCS-12. Regarding the scores in FCSI questionnaire, statistically significant differences were observed by sex, age and area, with older women being the most impaired (p < 0.001). Conclusions: Age, sex and area was associated with lower scores of HRQoL among CRC survivors. Knowing the determinants related to HRQoL would allow us to lay the groundwork to develop strategies that help reduce morbidity and mortality, relapses and increase HRQoL.
Burden of postmenopausal breast cancer attributable to excess body weight: comparative study of body mass index and CUN-BAE in MCC-Spain study
(BMJ Publishing Group, 2024-12-10) Cubelos-Fernández, Naiara; Dávila-Batista, Verónica; Fernández-Villa, Tania; Castaño-Vinyals, Gemma; Perez-Gomez, Beatriz; Amiano, Pilar; Ardanaz, Eva; Delgado Sillero, Irene; Llorca, Javier; Tardón, Guillermo Fernández; Alguacil, Juan; Vanaclocha-Espi, Mercedes; Marcos-Gragera, Rafael; Moreno, Victor; Aragones, Nuria; Dorronsoro, Ane; Guevara, Marcela; Reguero Celada, Sofía; Pollan-Santamaria, Marina; Kogevinas, Manolis; Martín, Vicente; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Ciencia e Innovación (España); Fundación Marqués de Valdecilla; International Cancer Genome Consortium; Ministerio de Economía y Competitividad (España); Red Temática de Investigación Cooperativa en Cáncer (RTICC) (España); Junta de Castilla y León (España); Regional Government of Andalusia (España); Generalitat Valenciana (España); Fundación La Caixa; Basque Government (España); Gobierno de la Región de Murcia (España); Unión Europea. Comisión Europea; Asociación Española Contra el Cáncer; Agència de Gestió d´Ajuts Universitaris i de Recerca (AGAUR); Government of Catalonia (España); Fundación Caja de Ahorros de Asturias; University of Oviedo (España); Unión Europea. Fondo Social Europeo (ESF/FSE)
Background: 10% of postmenopausal breast cancer cases are attributed to a high body mass index (BMI). BMI underestimates body fat, particularly in older women, and therefore the cancer burden attributable to obesity may be even higher. However, this is not clear. CUN-BAE (Clínica Universidad de Navarra-Body Adiposity Estimator) is an accurate validated estimator of body fat, taking into account sex and age. The objective of this study was to compare the burden of postmenopausal breast cancer attributable to excess body fat calculated using BMI and CUN-BAE. Methods: This case-control study included 1033 cases of breast cancer and 1143 postmenopausal population controls from the multicase-control MCC-Spain study. Logistic regression models were used to calculate odds ratios (ORs). The population attributable fraction (PAF) of excess weight related to breast cancer was estimated with both anthropometric measures. Stratified analyses were carried out for hormone receptor type. Results: Excess body weight attributable to the risk of breast cancer was 23.0% when assessed using a BMI value ≥30 kg/m2 and 38.0% when assessed using a CUN-BAE value of ≥40% body fat. Hormone receptor stratification showed that these differences in PAFs were only observed in hormone receptor positive cases, with an estimated burden of 19.9% for BMI and 41.9% for CUN-BAE. Conclusion: These findings suggest that the significance of excess body fat in postmenopausal hormone receptor positive breast cancer could be underestimated when assessed using only BMI. Accurate estimation of the cancer burden attributable to obesity is crucial for planning effective prevention initiatives.
Lung Function and Symptoms of Exposure to the Volcanic Eruption in the Canary Islands: First Follow-Up of the ASHES Study
(Elsevier, 2024-08) Candal-Pedreira, Cristina; Díaz-Pérez, David; Velasco, Valle; Casanova, Ciro; Acosta, Orlando; Peces-Barba, Germán; Barreiro, Esther; Castaño, Argelia; Cañas Portilla, Ana Isabel; Cruz Carmona, María Jesús; Diego, Carmen; Garcia-Aymerich, Judith; Martínez, Cristina; Molina-Molina, María; Muñoz, Xavier; Sanchez Iñigo, Francisco Javier; Ruano-Ravina, Alberto; Sociedad Española de Neumología y Cirugía Torácica
Introduction: Exposure to gases and particulate matter released during volcanic eruptions can prove harmful to population health. This paper reports the preliminary results of the ASHES study, aimed at ascertaining the respiratory health effects of the 2021 volcanic eruption in La Palma Island (Spain) on the adult population without previous respiratory disease. Methods: Ambispective cohort study on the healthy adult population. Three exposure groups were considered: Group 1, high exposure; Group 2, moderate exposure; and Group 3, minor or no exposure. We carried out a descriptive analysis of symptoms during and after the eruption, as well as measure lung function after the eruption (through forced spirometry and diffusing capacity of carbon monoxide). Results: The analysis included 474 subjects: 54 in Group 1, 335 in Group 2, and 85 in Group 3. A significant increase in most symptoms was observed for subjects in the groups exposed during the eruption. After the eruption, this increase remained for some symptoms. There seems to be a dose-response relationship, such that the higher the exposure, the higher the odds ratio. A prebronchodilator FEV1/FVC ratio<70% was observed in 13.0% of subjects in Group 1, 8.6% of subjects in Group 2, and 7.1% of subjects in Group 3. Conclusions: This study is the first to report a dose-response relationship between exposure to volcanic eruptions and the presence of symptoms in adults. Furthermore, there is a tendency toward obstructive impairment in individuals with higher exposure.
Trends in Adherence to the Mediterranean Diet in Spanish Children and Adolescents across Two Decades
(Multidisciplinary Digital Publishing Institute (MDPI), 2023-05-17) Herrera-Ramos, Estefania; Tomaino, Laura; Sanchez-Villegas, Almudena; Ribas-Barba, Lourdes; Gómez, Santiago F; Wärnberg, Julia; Osés, Maddi; González-Gross, Marcela; Gusi, Narcis; Aznar, Susana; Marín-Cascales, Elena; González-Valeiro, Miguel Ángel; Terrados, Nicolás; Tur, Josep A; Segu, Marta; Fito, Montserrat; Homs, Clara; Benavente-Marín, Juan Carlos; Labayen, Idoia; Zapico, Augusto Garcia; Sánchez-Gómez, Jesús; Jiménez-Zazo, Fabio; Alcaraz-Ramón, Pedro Emilio; Sevilla-Sanchez, Marta; Pulgar-Muñoz, Susana; Bouzas, Cristina; Sistac-Sorigué, Clara; Schröder, Helmut; Serra-Majem, Lluis
Unhealthy dietary habits determined during childhood may represent a risk factor to many of the chronic non-communicable diseases (NCDs) in adulthood. Mediterranean Diet (MD) adherence in children and adolescents (8-16 years) living in Spain was investigated using the KIDMED questionnaire in a comparative analysis of two cross-sectional nationwide representative studies: enKid (1998-2000, n = 1001) and PASOS (2019-2020, n = 3540). Taking into account the educational level of pupils, as well as the characteristics of the place of living, a significant association was found between a KIDMED score ≥ 8 (optimal MD adherence) and primary education as well as residency in an area of <50,000 inhabitants, while living in the southern regions was associated with non-optimal MD adherence (p < 0.001). Participants of the 2019-2020 study showed an increase in the consumption of dairy products (31.1% increase), pasta/rice (15.4% increase), olive oil (16.9% increase), and nuts (9.7% increase), as well as a decreased sweets and candies intake (12.6% reduction). In contrast, a significantly lower MD adherence was found when comparing the 2019-2020 (mean ± SE: 6.9 ± 0.04) and the 1998-2000 study (7.37 ± 0.08); p < 0.001), due to less consumption of fish (20.3% reduction), pulse (19.4% reduction), and fruits (14.9% reduction), and an increased intake of commercial goods/pastries or fast-food intake (both 19.4% increase). The lowest adherence was recorded for adolescents also in the most recent study, where 10.9% of them presented a KIDMED score ≤ 3. This study shows that eating habits are deteriorating among Spanish children and adolescents. Such findings point out the urgency of undertaking strong measures to promote the consumption of healthy, sustainable, and non-ultra-processed food, such as those available in an MD, not only at a scientific and academic level, but also at a governmental one.
Independent and Joined Association between Socioeconomic Indicators and Pediatric Obesity in Spain: The PASOS Study
(Multidisciplinary Digital Publishing Institute (MDPI), 2023-04-20) Homs, Clara; Berruezo, Paula; Arcarons, Albert; Wärnberg, Julia; Osés, Maddi; González-Gross, Marcela; Gusi, Narcis; Aznar, Susana; Marín-Cascales, Elena; González-Valeiro, Miguel Ángel; Serra-Majem, Lluis; Terrados, Nicolás; Tur, Josep A; Segu, Marta; Fito, Montserrat; Benavente-Marín, Juan Carlos; Labayen, Idoia; Zapico, Augusto Garcia; Sánchez-Gómez, Jesús; Jiménez-Zazo, Fabio; Alcaraz, Pedro E; Sevilla-Sanchez, Marta; Herrera-Ramos, Estefania; Pulgar-Muñoz, Susana; Bouzas, Cristina; Milà, Raimon; Schröder, Helmut; Gómez, Santiago F
Childhood obesity is a public health problem worldwide. An important determinant of child and adolescent obesity is socioeconomic status (SES). However, the magnitude of the impact of different SES indicators on pediatric obesity on the Spanish population scale is unclear. The aim of this study was to assess the association between three SES indicators and obesity in a nationwide, representative sample of Spanish children and adolescents. A total of 2791 boys and girls aged 8 to 16 years old were included. Their weight, height, and waist circumference were measured. SES was assessed using two parent/legal guardian self-reported indicators (educational level -University/non-University- and labor market status -Employed/Unemployed-). As a third SES indicator, the annual mean income per person was obtained from the census section where the participating schools were located (≥12.731€/<12.731€). The prevalence of obesity, severe obesity, and abdominal obesity was 11.5%, 1.4%, and 22.3%, respectively. Logistic regression models showed an inverse association of both education and labor market status with obesity, severe obesity, and abdominal obesity (all p < 0.001). Income was also inversely associated with obesity (p < 0.01) and abdominal obesity (p < 0.001). Finally, the highest composite SES category (University/Employed/≥12.731€ n = 517) showed a robust and inverse association with obesity (OR = 0.28; 95% CI: 0.16-0.48), severe obesity (OR = 0.20; 95% CI: 0.05-0.81), and abdominal obesity (OR = 0.36; 95% CI: 0.23-0.54) in comparison with the lowest composite SES category (Less than University/Unemployed/<12.731€; n = 164). No significant interaction between composite SES categories and age and gender was found. SES is strongly associated with pediatric obesity in Spain.
Omega-3 Fatty Acid Intake during Pregnancy and Child Neuropsychological Development: A Multi-Centre Population-Based Birth Cohort Study in Spain
(Multidisciplinary Digital Publishing Institute (MDPI), 2022-02) Tahaei, Hana; Gignac, Florence; Pinar, Ariadna; Fernandez-Barres, Silvia; Romaguera, Dora; Vioque, Jesus; Santa-Marina, Loreto; Subiza-Perez, Mikel; Llop, Sabrina; Soler-Blasco, Raquel; Arija, Victoria; Salas-Salvado, Jordi; Tardon, Adonina; Riano-Galan, Isolina; Sunyer, Jordi; Guxens, Monica; Julvez, Jordi
Background: There are few studies that look at the intake of all types of omega-3 polyunsaturated fatty acids (n-3 PUFAs) during the different stages of pregnancy along with a long-term neuropsychological follow-up of the child. This study aims to explore the association between maternal n-3 PUFA intake during two periods of pregnancy and the child's neuropsychological scores at different ages. Methods: Prospective data were obtained for 2644 pregnant women recruited between 2004 and 2008 in population-based birth cohorts in Spain. Maternal n-3 PUFA intake during the first and third trimester of pregnancy was estimated using validated food frequency questionnaires. Child neuropsychological functions were assessed using Bayley Scales of Infant Development version one (BSID) at 1 year old, the McCarthy Scale of Children's Abilities (MSCA) at 4 years old, and the Attention Network Test (ANT) at 7 years old. Data were analysed using multivariate linear regression models and adjusted for potential covariates, such as maternal social class, education, cohort location, alcohol consumption, smoking, breastfeeding duration, and energy intake. Results: Compared to participants in the lowest quartile (<1.262 g/day) of n-3 PUFA consumption during the first trimester, those in the highest quartile (>1.657 g/day) had a 2.26 points (95% confidence interval (CI): 0.41, 4.11) higher MSCA general cognitive score, a 2.48 points (95% CI: 0.53, 4.43) higher MSCA verbal score, and a 2.06 points (95% CI: 0.166, 3.95) higher MSCA executive function score, and a 11.52 milliseconds (95% CI: -22.95, -0.09) lower ANT hit reaction time standard error. In the third pregnancy trimester, the associations were weaker. Conclusions: Positive associations between n-3 PUFA intake during early pregnancy and child neuropsychological functions at 4 and 7 years of age were found, and further clinical research is needed to confirm these findings.
Defining a Methylation Signature Associated With Operational Tolerance in Kidney Transplant Recipients
(Frontiers Media, 2021-08-20) Rodriguez, Ramon M; Hernandez-Fuentes, Maria P; Corte-Iglesias, Viviana; Saiz, Maria Laura; Lozano, Juan Jose; Cortazar, Ana R; Mendizabal, Isabel; Suarez-Fernandez, Maria Luisa; Coto, Eliecer; Lopez-Vazquez, Antonio; Diaz-Corte, Carmen; Aransay, Ana M; Lopez-Larrea, Carlos; Suarez-Alvarez, Beatriz
Operational tolerance after kidney transplantation is defined as stable graft acceptance without the need for immunosuppression therapy. However, it is not clear which cellular and molecular pathways are driving tolerance in these patients. We performed genome-wide analysis of DNA methylation in peripheral blood mononuclear cells from kidney transplant recipients with chronic rejection and operational tolerance from the Genetic Analysis of Molecular Biomarkers of Immunological Tolerance (GAMBIT) study. Our results showed that both clinical stages diverge in 2737 genes, indicating that each one has a specific methylation signature associated with transplant outcome. We also observed that tolerance is associated with demethylation in genes involved in immune function, including B and T cell activation and Th17 differentiation, while in chronic rejection it is associated with intracellular signaling and ubiquitination pathways. Using co-expression network analysis, we selected 12 genomic regions that are specifically hypomethylated or hypermethylated in tolerant patients. Analysis of these genes in transplanted patients with low dose of steroids showed that these have a similar methylation signature to that of tolerant recipients. Overall, these results demonstrate that methylation analysis can mirror the immune status associated with transplant outcome and provides a starting point for understanding the epigenetic mechanisms associated with tolerance.
Comparison of the 2022 and 2017 European LeukemiaNet risk classifications in a real-life cohort of the PETHEMA group
(Nature Publishing Group, 2023-05-12) Sargas, Claudia; Ayala, Rosa; Larráyoz, María J; Chillón, María C; Rodriguez-Arboli, Eduardo; Bilbao, Cristina; Prados de la Torre, Esther; Martínez-Cuadrón, David; Rodríguez-Veiga, Rebeca; Boluda, Blanca; Gil, Cristina; Bernal, Teresa; Bergua, Juan; Algarra, Lorenzo; Tormo, Mar; Martínez-Sánchez, Pilar; Soria, Elena; Serrano, Josefina; Alonso-Dominguez, Juan M; García, Raimundo; Amigo, María Luz; Herrera-Puente, Pilar; Sayas, María J; Lavilla-Rubira, Esperanza; Martinez-Lopez, Joaquin; Calasanz, María J; García-Sanz, Ramón; Pérez-Simón, José A; Gómez Casares, María T; Sánchez-García, Joaquín; Barragán, Eva; Montesinos, Pau; PETHEMA cooperative study group; Ministerio de Ciencia, Innovación y Universidades (España); Instituto de Salud Carlos III
Next-Generation Sequencing is needed for the accurate genetic risk stratification of acute myeloid leukemia according to European LeukemiaNet (ELN) guidelines. We validated and compared the 2022 ELN risk classification in a real-life cohort of 546 intensively and 379 non-intensively treated patients. Among fit patients, those aged ?65 years old showed worse OS than younger regardless risk classification. Compared with the 2017 classification, 14.5% of fit patients changed the risk with the 2022 classification, increasing the high-risk group from 44.3% to 51.8%. 3.7% and 0.9% FLT3-ITD mutated patients were removed from the favorable and adverse 2017 categories respectively to 2022 intermediate risk group. We suggest that midostaurin therapy could be a predictor for 3 years OS (85.2% with vs. 54.8% without midostaurin, P = 0.04). Forty-seven (8.6%) patients from the 2017 intermediate group were assigned to the 2022 adverse-risk group as they harbored myelodysplasia (MDS)-related mutations. Patients with one MDS-related mutation did not reach median OS, while patients with ?2 mutations had 13.6 months median OS (P = 0.002). Patients with TP53 � complex karyotype or inv(3) had a dismal prognosis (7.1 months median OS). We validate the prognostic utility of the 2022 ELN classification in a real-life setting providing supportive evidences to improve risk stratification guidelines.
Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin
(Nature Publishing Group, 2023-05-23) Capdevila, J; Hernando, J; Teule, A; Lopez, C; Garcia-Carbonero, R; Benavent, M; Custodio, A; Garcia-Alvarez, A; Cubillo, A; Alonso, V; Carmona-Bayonas, A; Alonso-Gordoa, T; Crespo, G; Jimenez-Fonseca, P; Blanco, M; Viudez, A; La Casta, A; Sevilla, I; Segura, A; Llanos, M; Landolfi, S; Nuciforo, P; Manzano, J L; García-Carbonero, Rocio; Grupo Espanol de Tumores Neuroendocrinos y Endocrinos (GETNE); AstraZeneca
Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.
Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights
(Elsevier, 2023-07) Koutros, Stella; Kiemeney, Lambertus A; Pal Choudhury, Parichoy; Milne, Roger L; Lopez de Maturana, Evangelina; Ye, Yuanqing; Joseph, Vijai; Florez-Vargas, Oscar; Dyrskjøt, Lars; Figueroa, Jonine; Dutta, Diptavo; Giles, Graham G; Hildebrandt, Michelle A T; Offit, Kenneth; Kogevinas, Manolis; Weiderpass, Elisabete; McCullough, Marjorie L; Freedman, Neal D; Albanes, Demetrius; Kooperberg, Charles; Cortessis, Victoria K; Karagas, Margaret R; Johnson, Alison; Schwenn, Molly R; Baris, Dalsu; Furberg, Helena; Bajorin, Dean F; Cussenot, Olivier; Cancel-Tassin, Geraldine; Benhamou, Simone; Kraft, Peter; Porru, Stefano; Carta, Angela; Bishop, Timothy; Southey, Melissa C; Matullo, Giuseppe; Fletcher, Tony; Kumar, Rajiv; Taylor, Jack A; Lamy, Philippe; Prip, Frederik; Kalisz, Mark; Weinstein, Stephanie J; Hengstler, Jan G; Selinski, Silvia; Harland, Mark; Teo, Mark; Kiltie, Anne E; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Lloreta, Josep; Schned, Alan; Lenz, Petra; Riboli, Elio; Brennan, Paul; Tjønneland, Anne; Otto, Thomas; Ovsiannikov, Daniel; Volkert, Frank; Vermeulen, Sita H; Aben, Katja K; Galesloot, Tessel E; Turman, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J; Hohensee, Chancellor; Hunt, Rebecca; Patel, Alpa V; Huang, Wen-Yi; Thorleifsson, Gudmar; Gago-Dominguez, Manuela; Amiano, Pilar; Golka, Klaus; Stern, Mariana C; Yan, Wusheng; Liu, Jia; Li, Shengchao Alfred; Katta, Shilpa; Hutchinson, Amy; Hicks, Belynda; Wheeler, William A; Purdue, Mark P; McGlynn, Katherine A; Kitahara, Cari M; Haiman, Christopher A; Greene, Mark H; Rafnar, Thorunn; Chatterjee, Nilanjan; Chanock, Stephen J; Wu, Xifeng; Real, Francisco X; Silverman, Debra T; Garcia-Closas, Montserrat; Stefansson, Kari; Prokunina-Olsson, Ludmila; Malats, Nuria; Rothman, Nathaniel; NIH - National Cancer Institute (NCI) (Estados Unidos); Radboud University Medical Center; Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Canadian Institutes of Health Research (CIHR) Cancer Council Victoria; National Health and Medical Research Council (Australia)
Background: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. Objective: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. Design, setting, and participants: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis. Outcome measurements and statistical analyses: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking. Results and limitations: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10-8) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2; multiplicative p value for interaction [pM-I] = 0.004), 8q21.13 (PAG1; pM-I = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; pM-I = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44-1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers. Conclusions: We report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer. Patient summary: We identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer.
Immune Landscape in Tumor Microenvironment: Implications for Biomarker Development and Immunotherapy
(Multidisciplinary Digital Publishing Institute (MDPI), 2020-08) Pérez-Romero, Karim; Rodriguez, Ramon M; Amedei, Amedeo; Barcelo-Coblijn, Gwendolyn; Lopez, Daniel H
Integration of the tumor microenvironment as a fundamental part of the tumorigenic process has undoubtedly revolutionized our understanding of cancer biology. Increasing evidence indicates that neoplastic cells establish a dependency relationship with normal resident cells in the affected tissue and, furthermore, develop the ability to recruit new accessory cells that aid tumor development. In addition to normal stromal and tumor cells, this tumor ecosystem includes an infiltrated immune component that establishes complex interactions that have a critical effect during the natural history of the tumor. The process by which immune cells modulate tumor progression is known as immunoediting, a dynamic process that creates a selective pressure that finally leads to the generation of immune-resistant cells and the inability of the immune system to eradicate the tumor. In this context, the cellular and functional characterization of the immune compartment within the tumor microenvironment will help to understand tumor progression and, ultimately, will serve to create novel prognostic tools and improve patient stratification for cancer treatment. Here we review the impact of the immune system on tumor development, focusing particularly on its clinical implications and the current technologies used to analyze immune cell diversity within the tumor.
EpidemIBD: rationale and design of a large-scale epidemiological study of inflammatory bowel disease in Spain
(SAGE Publishing, 2019-05) Chaparro, Maria; Barreiro-de Acosta, Manuel; Benitez, Jose Manuel; Cabriada, Jose Luis; Casanova, Maria Jose; Ceballos, Daniel; Esteve, Maria; Fernandez, Hipolito; Ginard Vicens, Daniel; Gomollon, Fernando; Lorente, Rufo; Nos, Pilar; Riestra, Sabino; Rivero, Montserrat; Robledo, Pilar; Rodriguez, Cristina; Sicilia, Beatriz; Torrella, Emilio; Garre, Ana; Garcia-Esquinas, Esther; Rodríguez-Artalejo, Fernando; Gisbert, Javier P; EpidemIBD study group of GETECCU
Background: Inflammatory bowel disease (IBD) is associated with a considerable burden to the patient and society. However, current data on IBD incidence and burden are limited because of the paucity of nationwide epidemiological studies, heterogeneous designs, and a low number of participating centers and sample size. The EpidemIBD study is a large-scale investigation to provide an accurate assessment of the incidence of IBD in Spain, as well as treatment patterns and outcomes. Methods: This multicenter, population-based incidence cohort study included patients aged >18 years with IBD (Crohn's disease, ulcerative colitis, or unclassified IBD) diagnosed during 2017 in 108 hospitals in Spain, covering 50% of the Spanish population. Each participating patient will attend 10 clinic visits during 5 years of follow up. Demographic data, IBD characteristics and family history, complications, treatments, surgeries, and hospital admissions will be recorded. Results: The EpidemIBD study is the first large-scale nationwide study to investigate the incidence of IBD in Spain. Enrollment is now completed and 3627 patients are currently being followed up. Conclusions: The study has been designed to overcome many of the limitations of previous European studies into IBD incidence by prospectively recruiting a large number of patients from all regions of Spain. In addition to epidemiological information about the burden of IBD, the 5-year follow-up period will also provide information on treatment patterns, and the natural history and financial burden of IBD.
Maternal circulating Vitamin D-3 levels during pregnancy and behaviour across childhood
(Nature Publishing Group, 2019-10-15) Lopez-Vicente, Monica; Sunyer, Jordi; Lertxundi, Nerea; Gonzalez, Llucia; Rodriguez-Dehli, Cristina; Espada Saenz-Torre, Mercedes; Vrijheid, Martine; Tardon, Adonina; Llop, Sabrina; Torrent Quetglas, Maties; Ibarluzea, Jesus; Guxens, Monica
Vitamin D deficiency during critical periods of development could lead to persistent brain alterations. We aimed to assess the association between maternal vitamin D-3, the major circulatory form of vitamin D, at pregnancy and neurodevelopmental outcomes during childhood, namely: behavioural problems, Attention Deficit and Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) symptoms, and social competence. This study included 2,107 mother-child pairs of a Spanish population-based birth cohort. Maternal plasma vitamin D-3 was measured in pregnancy. The outcomes were measured through questionnaires at 5, 8, 14, and 18 years old. We ran multivariate regression models adjusted for potential confounding variables. We found that per each 10 ng/mL increment of maternal vitamin D-3, children obtained higher social competence scores (coefficient =0.77; 95% CI=0.19, 1.35) at 5 years old. However, we observed null associations between maternal vitamin D-3 and total behavioural problems and ADHD and ASD symptoms in children from 5 to 18 years old. Further studies carried out in countries where the population is exposed to lower vitamin D levels are needed.
Ratio índice/anular (proxy de exposición hormonal intraútero) y riesgo de cáncer de próstata (MCC-Spain)
(Elsevier, 2023) Carbajo-Ariza, Manuel; Castaño-Vinyals, Gemma; Dierssen-Sotos, Trinidad; Jimenez-Moleon, Jose J.; Tardón, Adonina; Molina-Barcceló, Ana; Kogevinas, Manolis; Pollan-Santamaria, Marina; Perez-Gomez, Beatriz; Centro de Investigación Biomédica en Red - CIBERESP (Epidemiología y Salud Pública); Instituto de Salud Carlos III
Antecedentes/Objetivos: La hipótesis de la programación fetal plantea que las exposiciones durante el periodo prenatal afectan la salud del adulto. En esta línea, la exposición hormonal intrauterina (EHI) podría relacionarse con el riesgo de cáncer de próstata (CP). Un marcador propuesto para estudiar esta exposición es la ratio índice/anular de la mano (2D:4D), que presenta dimorfismo sexual y, experimentalmente experimentalmente, se ha asociado con la razón estrógenos/andrógenos intraútero. Nuestro objetivo es estudiar si la EHI, estimada con 2D:4D, influye en el riesgo de CP, globalmente o según su agresividad, y si el riesgo genético de tener CP modula la asociación. Métodos: Se dispuso de información de 944 casos incidentes de CP, con confirmación anatomopatológica, y 1174 controles de base poblacional del estudio multicéntrico MCC-Spain en 7 provincias. Se midió los dedos con calibre. Se categorizaron los participantes por quintiles de 2D:4D en controles. Para testar asociación entre ratio y CP se ajustó un modelo mixto de regresión logística con las variables edad, estudios y BMI como factores fijos, y la persona que tomó la medida como variable de efecto aleatorio, para todos y estratificados por edad (menores y mayores de 65 años). Para explorar diferencias por agresividad, los tumores se clasificaron con escalas ISUP (1-2 vs. 3-5) y AJCC8 (< = “” td = “”>. Resultados: Las ratios mayores, proxy de ambiente fetal más estrogénico, se asocian a menor riesgo de CP (OR Q5vsQ1 = 0.78; IC95%: 0,56-1,09; p-tend:0,04), aunque la relación no parece lineal. El efecto es más claro en mayores de 65 años (OR Q5 vs. Q1 = 0,71; IC95%: 0,46-1,09; p-tend = 0,04) y en CP más avanzado (ISUP 1-2 RRR Q5 vs. Q1 = 0,86; IC95%: 0,60-1,23) vs. (ISUP 3-5 RRR Q5 vs. Q1 = 0,56; IC95%: 0,34-0,95). La susceptibilidad genética no modifica el efecto de 2D:4D en el riesgo de CP. Conclusiones/Recomendaciones: Los resultados apoyan la hipótesis de relación entre EHI y riesgo de CP en el adulto, reforzando el interés de prestar atención al entorno prenatal en la etiología de enfermedades crónicas. Por otro lado, este parámetro antropométrico podría considerarse en modelos que buscan identificar personas con mayor probabilidad de enfermar de CP.
Impact of Chronic Disease Self-Management Program on the Self-Perceived Health of People in Areas of Social Vulnerability in Asturias, Spain
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-04-09) García-Ovejero, Ester; Pisano-González, Marta; Salcedo-Diego, Isabel; Serrano-Gallardo, Pilar; Unión Europea
The Chronic Disease Self-Management Program (CDSMP) focuses on a health promotion perspective with a salutogenic approach, reinforcing the pillars of self-efficacy. The aim of this study was to assess the impact of the CDSMP on Self-perceived Health (SPH) in disadvantaged areas of Asturias, España. The study included vulnerable adults with experience of chronic diseases for over six months, along with their caregivers. The intervention consisted of a six-session workshop led by two trained peers. SPH was evaluated by administering the initial item of the SF-12 questionnaire at both baseline and six months post-intervention. To evaluate the variable "Change in SPH" [improvement; remained well; worsening/no improvement (reference category)], global and disaggregated by sex multivariate multinomial logistic regression models were applied. There were 332 participants (mean = 60.5 years; 33.6% were at risk of social vulnerability; 66.8% had low incomes). Among the participants, 22.9% reported an improvement in their SPH, without statistically significant sex-based differences, while 38.9% remained in good health. The global model showed age was linked to decreased "improvement" probability (RRRa = 0.96), and the "remaining well" likelihood drops with social risk (RRRa = 0.42). In men, the probability of "remaining well" decreased by having secondary/higher education (RRRa = 0.25) and increased by cohabitation (RRRa = 5.11). Women at social risk were less likely to report "remaining well" (RRRa = 0.36). In conclusion, six months after the intervention, 22.9% of the participants had improved SPH. Age consistently decreased the improvement in the different models.
Peripheral Neutrophil-to-Lymphocyte Ratio in Bronchiectasis: A Marker of Disease Severity.
(2022-09-30) Martinez-García, Miguel Ángel; Olveira, Casilda; Girón, Rosa; García-Clemente, Marta; Máiz-Carro, Luis; Sibila, Oriol; Golpe, Rafael; Méndez, Raúl; Rodríguez Hermosa, Juan Luis; Barreiro, Esther; Prados, Concepción; Rodríguez López, Juan; de la Rosa, David
Most patients with bronchiectasis have a predominantly neutrophilic inflammatory profile, although other cells such as lymphocytes (as controllers of bronchial inflammation) and eosinophils also play a significant pathophysiological role. Easy-to-interpret blood biomarkers with a discriminative capacity for severity or prognosis are needed. The objective of this study was to assess whether the peripheral neutrophil-to-lymphocyte ratio (NLR) is associated with different outcomes of severity in bronchiectasis. A total of 1369 patients with bronchiectasis from the Spanish Registry of Bronchiectasis were included. To compare groups, the sample was divided into increasing quartiles of NLR ratio. Correlations between quantitative variables were established using Pearson's P test. A simple linear regression (with the value of exacerbations as a quantitative variable) was used to determine the independent relationship between the number and severity of exacerbations and the NLR ratio. The area under the curve (AUC)-ROC was used to determine the predictive capacity of the NLR for severe bronchiectasis, according to the different multidimensional scores. Mean age: 69 (15) years (66.3% of women). The mean NLR was 2.92 (2.03). A higher NLR was associated with more severe bronchiectasis (with an especially significant discriminative power for severe forms) according to the commonly used scores (FACED, E-FACED and BSI), as well as with poorer quality of life (SGRQ), more comorbidities (Charlson index), infection by pathogenic microorganisms, and greater application of treatment. Furthermore, the NLR correlated better with severity scores than other parameters of systemic inflammation. Finally, it was an independent predictor of the incident number and severity of exacerbations. In conclusion, the NLR is an inexpensive and easy-to-measure marker of systemic inflammation for determining severity and predicting exacerbations (especially the most severe) in patients with bronchiectasis.
Low Percentage of Vegetable Fat in Red Blood Cells Is Associated with Worse Glucose Metabolism and Incidence of Type 2 Diabetes.
(2022-03-25) Chiva-Blanch, Gemma; Giró, Oriol; Cofán, Montserrat; Calle-Pascual, Alfonso L; Delgado, Elías; Gomis, Ramon; Jiménez, Amanda; Franch-Nadal, Josep; Rojo Martínez, Gemma; Ortega, Emilio
The identification of nutritional patterns associated with the development of type 2 diabetes (T2D) might help lead the way to a more efficient and personalized nutritional intervention. Our study is aimed at evaluating the association between fatty acids (FA) in red blood cell (RBC) membranes, as a quantitative biomarker of regular dietary fat intake, and incident type 2 diabetes in a Spanish population. We included 1032 adult Spaniards (57% women, age 49 ± 15 years, 18% prediabetes), without diabetes at study entry, from the Di@bet.es cohort. Incident diabetes was diagnosed at the end of the study follow-up. The FA percentage in RBC was determined at baseline by gas chromatography. Participants were followed on average 7.5 ± 0.6 years. Lower percentages of linoleic acid (LA), α-linolenic (ALA), and eicosapentaenoic acid (EPA), and higher percentages of docosahexaenoic acid (DHA) in RBC membranes were associated, independently of classical risk factors, with worse glucose metabolism at the end of the study follow-up. In addition, higher percentages of ALA and EPA, and moderate percentages of DHA, were associated with lower risk of diabetes. No significant associations were found for LA and diabetes risk. Dietary patterns rich in vegetables are independently associated with lower risk of both deterioration of glucose regulation and incident diabetes, and should be reinforced for the prevention of diabetes.
Serum vascular endothelial growth factor b and metabolic syndrome incidence in the population based cohort Di@bet.es study.
(2022-08-20) Lago-Sampedro, Ana; Lhamyani, Said; Valdés, Sergio; Colomo, Natalia; Maldonado-Araque, Cristina; González-Molero, Inmaculada; Doulatram-Gamgaram, Viyey; Delgado, Elias; Chaves, Felipe J; Castaño, Luis; Calle-Pascual, Alfonso; Franch-Nadal, Josep; Rojo-Martínez, Gemma; García-Serrano, Sara; García-Escobar, Eva
Although vascular endothelial growth factor b (VEGFb) might have an impact on the development of obesity, diabetes and related disorders, the possible relationship between VEGFb serum levels and the incidence of these metabolic complications in humans is still unknown. The aim of our study was to evaluate the association between VEGFb serum levels and the new-onset of metabolic syndrome (MS) and its components in the Spanish adult population after 7.5 years of follow-up. A total of 908 subjects from the Di@bet.es cohort study without MS at cross-sectional stage according to International Diabetes Federation (IDF) or Adult Treatment Panel III (ATP-III) criteria were included. Additionally, five sub-populations were grouped according to the absence of each MS component at baseline. Socio-demographic, anthropometric and clinical data were recorded. The Short Form of International Physical Activity Questionnaire (SF-IPAQ) was used to estimate physical activity. A fasting blood extraction and an oral glucose tolerance test were performed. Serum determinations of glucose, lipids, hsCRP and insulin were made. VEGFb levels were determined and categorized according to the 75th percentile of the variable. New cases of MS and its components were defined according to ATPIII and IDF criteria. A total of 181 or 146 people developed MS defined by IDF or ATP-III criteria respectively. Serum triglyceride levels, hs-CRP and systolic blood pressure at the baseline study were significantly different according to the VEGFb categories. Adjusted logistic regression analysis showed that the likelihood of developing MS and abdominal obesity was statistically reduced in subjects included in the higher VEGFb category. Low serum levels of VEGFb may be considered as early indicators of incident MS and abdominal obesity in the Spanish adult population free of MS, independently of other important predictor variables.
Ambient air pollution and thyroid function in Spanish adults. A nationwide population-based study (Di@bet.es study).
(2022-08-17) Valdés, Sergio; Doulatram-Gamgaram, Viyey; Maldonado-Araque, Cristina; Lago-Sampedro, Ana; García-Escobar, Eva; García-Serrano, Sara; García-Vivanco, Marta; Garrido Juan, Luis; Theobald, Mark Richard; Gil, Victoria; Martín-Llorente, Fernando; Ocon, Pilar; Calle-Pascual, Alfonso; Castaño, Luis; Delgado, Elías; Menendez, Edelmiro; Franch-Nadal, Josep; Gaztambide, Sonia; Girbés, Joan; Chaves, F Javier; Galán-García, José L; Aguilera-Venegas, Gabriel; Gutierrez-Repiso, Carolina; Fernández-García, José Carlos; Colomo, Natalia; Soriguer, Federico; García-Fuentes, Eduardo; Rojo-Martínez, Gemma
Recent reports have suggested that air pollution may impact thyroid function, although the evidence is still scarce and inconclusive. In this study we evaluated the association of exposure to air pollutants to thyroid function parameters in a nationwide sample representative of the adult population of Spain. The Di@bet.es study is a national, cross-sectional, population-based survey which was conducted in 2008-2010 using a random cluster sampling of the Spanish population. The present analyses included 3859 individuals, without a previous thyroid disease diagnosis, and with negative thyroid peroxidase antibodies (TPO Abs) and thyroid-stimulating hormone (TSH) levels of 0.1-20 mIU/L. Participants were assigned air pollution concentrations for particulate matter In multivariate linear regression models, there was a highly significant negative correlation between PM2.5 concentrations and both FT4 (p Exposures to PM2.5 in the general population were associated with mild alterations in thyroid function.

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