Integrated Surface-Groundwater Modelling of Nitrate Concentration in Mediterranean Rivers, the Júcar River Basin District, Spain

[EN] High nutrient discharge from groundwater (GW) into surface water (SW) have multiple undesirable effects on river water quality. With the aim to estimate the impact of anthropic pressures and river-aquifer interactions on nitrate status in SW, this study integrates two hydrological simulation and water quality models. PATRICAL models SW-GW interactions and RREA models streamflow changes due to human activity. The models were applied to the Jucar River Basin District (RBD), where 33% of the aquifers have a concentration above 50 mg NO3-/L. As a result, there is a direct linear correlation between the nitrate concentration in rivers and aquifers (Jucar r(2) = 0.9, and Turia r(2) = 0.8), since in these Mediterranean basins, the main amount of river flows comes from groundwater discharge. The concentration of nitrates in rivers and GW tends to increase downstream of the district, where artificial surfaces and agriculture are concentrated. The total NO3- load to Jucar RBD rivers was estimated at 10,202 tN/year (239 kg/km(2)/year), from which 99% is generated by diffuse pollution, and 3378 tN/year (79 kg/km(2)/year) is discharged into the Mediterranean Sea. Changes in nitrate concentration in the RBD rivers are strongly related to the source of irrigation water, river-aquifer interactions, and flow regulation. The models used in this paper allow the identification of pollution sources, the forecasting of nitrate concentration in surface and groundwater, and the evaluation of the efficiency of measures to prevent water degradation, among other applications.The first author's research is partially funded by a PhD scholarship from the food research stream of the program "Colombia Cientifica-Pasaporte a la Ciencia", granted by the Colombian Institute for Educational Technical Studies Abroad (Instituto Colombiano de Credito Educativo y Estudios Tecnicos en el Exterior, ICETEX). The authors thank the Spanish Research Agency (AEI) for the financial support to RESPHIRA project (PID2019-106322RB-100)/AEI/10.13039/501100011033.Dorado-Guerra, DY.; Paredes Arquiola, J.; Pérez-Martín, MÁ.; Tafur Hermann, H. (2021). Integrated Surface-Groundwater Modelling of Nitrate Concentration in Mediterranean Rivers, the Júcar River Basin District, Spain. Sustainability. 13(22):1-21. https://doi.org/10.3390/su132212835S121132

Effect of climate change on the water quality of Mediterranean rivers and alternatives to improve its status

[EN] Surface water (SW) quality is particularly vulnerable to increased concentrations of nutrients, and this issue may be exacerbated by climate change. Knowledge of the effects of temperature and rainfall on SW quality is required to take the necessary measures to achieve good SW status in the future. To address this, the aims of this study were threefold: (1) to assess how a changing climate may alter the nitrate, ammonium, phosphorus and biological oxygen demand status (BOD5) of SW; (2) assess the relationship between water quality and flow; and (3) simulate diffuse and point source pollution reduction scenarios in the Júcar River Basin District in the Mediterranean region. A regionalised long-term climate scenario was used following one Representative Concentration Pathway (RCP8.5) with the data incorporated into the coupling of hydrological and water quality models. According to these climate change scenarios, SW with poor nitrate, ammonium, phosphorus and BOD5 status are expected to increase in the future by factors of 1.3, 1.9, 4 and 4, respectively. Furthermore, median ammonium and phosphorus concentration may be doubled in months with low flows. Additional measures are required to maintain current status in the water bodies, and it is necessary to reduce at least 25% of diffuse nitrate pollution, and 50% of point loads of ammonium, phosphorus, and BOD5.We appreciate the help provided by the Jacar River Basin District Authority (CHJ) , who gathered field data. The first author's research was partially funded by a PhD scholarship from the food research stream of the programme "Colombia Cientifica-Pasaporte a la Ciencia", granted by the Colombian Institute for Educational Technical Studies Abroad (Instituto Colombiano de Credito Educativo y Estudios Tecnicos en el Exterior, ICETEX) . The authors thank the Spanish Research Agency (AEI) for the financial support to RESPHIRA project (PID 2019- 106322RB-100) /AEI/10.13039/501100011033. The contributors gratefully acknowledge funding for open access charge: CRUE-Universitat Politecnica de Valencia.Dorado-Guerra, DY.; Paredes Arquiola, J.; Pérez-Martín, MÁ.; Corzo-Pérez, G.; Ríos-Rojas, L. (2023). Effect of climate change on the water quality of Mediterranean rivers and alternatives to improve its status. Journal of Environmental Management. 348. https://doi.org/10.1016/j.jenvman.2023.11906934

JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia

Chronic myelogenous leukemia (CML) is a hematological malignancy that highly depends on the BCR-ABL1/STAT5 signaling pathway for cell survival. First-line treatments for CML consist of tyrosine kinase inhibitors that efficiently target BCR-ABL1 activity. However, drug resistance and intolerance are still therapeutic limitations in Ph+ cells. Therefore, the development of new anti-CML drugs that exhibit alternative mechanisms to overcome these limitations is a desirable goal. In this work, the antitumoral activity of JKST6, a naphthoquinone-pyrone hybrid, was assessed in imatinib-sensitive and imatinib-resistant human CML cells. Live-cell imaging analysis revealed JKST6 potent antiproliferative activity in 2D and 3D CML cultures. JKST6 provoked cell increase in the subG1 phase along with a reduction in the G0/G1 phase and altered the expression of key proteins involved in the control of mitosis and DNA damage. Rapid increases in Annexin V staining and activation/cleavage of caspases 8, 9 and 3 were observed after JKST6 treatment in CML cells. Of interest, JKST6 inhibited BCR-ABL1/STAT5 signaling through oncokinase downregulation that was preceded by rapid polyubiquitination. In addition, JKST6 caused a transient increase in JNK and AKT phosphorylation, whereas the phosphorylation of P38-MAPK and Src was reduced. Combinatory treatment unveiled synergistic effects between imatinib and JKST6. Notably, JKST6 maintained its antitumor efficacy in BCR-ABL1-T315I-positive cells and CML cells that overexpress BCR-ABL and even restored imatinib efficacy after a short exposure time. These findings, together with the observed low toxicity of JKST6, reveal a novel multikinase modulator that might overcome the limitations of BCR-ABL1 inhibitors in CML therapy.This research has been funded by Spanish Ministry of Economy and Competitiveness - MINECO - (SAF 2015–65113-C2–1-R and RTI2018–094356-B-C21 to AEB, SAF2015–65113-C2–2 to LFP, SAF2017–88026-R to JL) with the co-funding of European Regional Development Fund (EU-ERDF), Canary Islands Government (CEI2018–23/ACIISI to BG, CEI2019–08/ACIISI to BG and LFP, ProID2021010037 to AEB, LFP and BG) and "Juan de la Cierva Incorporacion" Grant Program from the Ministry of Science, Innovation and Universities (IJC2018-035193-I to CR). This project has been also supported by Alfredo Martin-Reyes Foundation (Arehucas)-Canary Islands Foundation for Cancer Research (FICIC). HAT is recipient of a predoctoral program grant from ULPGC (2016). JCM was funded by the Instituto de Salud Carlos III through a Miguel Servet program (CPII17/ 00015)

Differing contributions of the gut microbiota to the blood pressure lowering effects induced by first-line antihypertensive drugs

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.16410This work was supported by Grants from Agencia Estatal de Investigación (AEI), Ministerio de Ciencia e Innovación (MCIN) (PID2020-116347RB-I00 funded by MCIN/AEI/10.13039/501100011033) and Junta de Andalucía (CTS 164, P20_00193 and A-CTS-318-UGR20) with funds from the European Union and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV), Spain. M.T. and I.R.-V. are postdoctoral fellow of Spanish Ministerio de Ciencia e Innovación (Juan de la Cierva Incorporación Program, IJC2020-044581-I, and Juan de la Cierva Formación Program, respectively). J. M. is a predoctoral fellow of MCIN, and C. G.-C. and S. M. are predoctoral fellow of Junta de Andalucía. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, ‘FEDER una manera de hacer Europa’).Background and Purpose: This study analyses whether first-line antihypertensive drugs ameliorate the dysbiosis state in hypertension, and to test if this modification contributes to their blood pressure (BP) lowering properties in a genetic model of neurogenic hypertension. Experimental Approach: Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were untreated or treated with captopril, amlodipine or hydrochlorothiazide. A faecal microbiota transplantation (FMT) experiment was also performed by gavage of faecal content from donor SHR-treated groups to SHR recipients for 3 weeks. Key results: Faeces from SHR showed gut dysbiosis, characterized by lower acetate- and higher lactate-producing bacteria and lower strict anaerobic bacteria. All three drugs increased the anaerobic bacteria proportion, captopril and amlodipine restored the proportion of acetate-producing bacterial populations to WKY levels, whereas hydrochlorothiazide decreased butyrate-producing bacteria. Captopril and amlodipine decreased gut pathology and permeability and attenuated sympathetic drive in the gut. Both drugs decreased neuroinflammation and oxidative stress in the hypothalamic paraventricular nuclei. Hydrochlorothiazide was unable to reduce neuroinflammation, gut sympathetic tone and gut integrity. FMT from SHR-amlodipine to SHR decreased BP, ameliorated aortic endothelium-dependent relaxation to acetylcholine, lowered NADPH oxidase activity, aortic Th17 infiltration and reduced neuroinflammation, whereas FMT from SHR-hydrochlorothiazide did not have these effects. Conclusions and Implications: First-line antihypertensive drugs induced different modifications of gut integrity and gut dysbiosis in SHR, which result in no contribution of microbiota in the BP lowering effects of hydrochlorothiazide, whereas the vasculo-protective effect induced by amlodipine involves gut microbiota reshaping and gut-immune system communication.Universidad de GranadaMCIN/AEI/10.13039/501100011033 PID2020-116347RB-I00Junta de Andalucía (CTS 164, P20_00193 and A-CTS-318-UGR20)European UnionMinisterio de Economía y Competitividad, Instituto de Salud Carlos III (CIBER-CV)Spanish Ministerio de Ciencia e Innovación IJC2020-044581-IJunta de AndalucíaFondo Europeo de Desarrollo Regional, FEDE

Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: A longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects

[Background and Aim] Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic-associated fatty liver disease (MAFLD).[Methods] Spanish multicenter study including 1893 biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow-up (4.7 ± 3.8 years).[Results] Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). More than 70% of non-NASH patients showed some inflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these.[Conclusions] The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death.This project has been partially funded by the ‘Consejería de Salud de la Junta de Andalucía’ (PI-0075-2014) and the ‘Spanish Ministry of Economy, Innovation and Competition, Instituto de Salud Carlos III’ (PI19/01404, PI16/01842, PI17/00535 and GLD19/00100).Peer reviewe

Estrategias de uso racional de medicamentos en personas mayores como mejora de la calidad de vida y de promoción del bienestar

El proyecto “Estrategias de uso racional de medicamentos en personas mayores como mejora de la calidad de vida y de promoción del bienestar” se basa en la elaboración y diseño de estrategias de prevención y mejora en torno al cumplimiento terapéutico, el uso racional del medicamento, y la identificación temprana de reacciones adversas a medicamentos, entre otros problemas relacionados con el medicamento. Este proyecto es una continuación del anterior ApS UCM 2019 “Identificación de problemas relacionados con el medicamento y estrategias de mejora en personas mayores”. En esta ocasión, y por la pandemia por COVID-19, este ApS será virtual, desarrollándose diversos talleres en formato de vídeo para dar formación a las personas mayores en materia de medicamento y que se centrarán en el tratamiento de las distintas patologías de la meta 3.4. de los ODS 2030, con el fin de aumentar la calidad de vida y el bienestar social de este colectivo. Esta actividad se integra en la docencia de las asignaturas de Farmacología General, y Farmacología y Farmacoterapia del Grado en Farmacia y del Doble Grado de Farmacia y Nutrición como estrategia de aprendizaje para consolidar y profundizar lo aprendido en estas materias

Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI-1805 TOT-HER3 trial and biological determinants of early response

Patritumab deruxtecan (HER3-DXd) exhibits promising efficacy in breast cancer, with its activity not directly correlated to baseline ERBB3/HER3 levels. This research investigates the genetic factors affecting HER3-DXd's response in women with early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B). The CelTIL score, measuring tumor cellularity and infiltrating lymphocytes from baseline to day 21, was used to assess drug activity. Part A demonstrated increased CelTIL score after one dose of HER3-DXd. Here we report CelTIL score and safety for Part B. In addition, the exploratory analyses of part A involve a comprehensive study of gene expression, somatic mutations, copy-number segments, and DNA-based subtypes, while Part B focuses on validating gene expression. RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3). Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer. Patritumab deruxtecan (HER3-DXd) is a promising therapy for breast cancer, targeting HER3. Here, the authors analyse the genomic factors that affect the response to HER3-DXd in patients with early-stage HER2-negative breast cancer as part of the SOLTI-1805 TOT-HER3 clinical trial and report outcomes for Part B of the trial using lower HER3-DXd dose in patients with HER2-negative breast cancer

Relationship between IGF-1 and body weight in inflammatory bowel diseases: Cellular and molecular mechanisms involved

Inflammatory bowel diseases (IBD), represented by ulcerative colitis (UC) and Crohn''s disease (CD), are characterized by chronic inflammation of the gastrointestinal tract, what leads to diarrhea, malnutrition, and weight loss. Depression of the growth hormone-insulin-like growth factor-1 axis (GH-IGF-1 axis) could be responsible of these symptoms. We demonstrate that long-term treatment (54 weeks) of adult CD patients with adalimumab (ADA) results in a decrease in serum IGF-1 without changes in serum IGF-1 binding protein (IGF1BP4). These results prompted us to conduct a preclinical study to test the efficiency of IGF-1 in the medication for experimental colitis. IGF-1 treatment of rats with DSS-induced colitis has a beneficial effect on the following circulating biochemical parameters: glucose, albumin, and total protein levels. In this experimental group we also observed healthy maintenance of colon size, body weight, and lean mass in comparison with the DSS-only group. Histological analysis revealed restoration of the mucosal barrier with the IGF-1 treatment, which was characterized by healthy quantities of mucin production, structural maintenance of adherers junctions (AJs), recuperation of E-cadherin and ß-catenin levels and decrease in infiltrating immune cells and in metalloproteinase-2 levels. The experimentally induced colitis caused activation of apoptosis markers, including cleaved caspase 3, caspase 8, and PARP and decreases cell-cycle checkpoint activators including phosphorylated Rb, cyclin E, and E2F1. The IGF-1 treatment inhibited cyclin E depletion and partially protects PARP levels. The beneficial effects of IGF-1 in experimental colitis could be explained by a re-sensitization of the IGF-1/IRS-1/AKT cascade to exogenous IGF-1. Given these results, we postulate that IGF-1 treatment of IBD patients could prove to be successful in reducing disease pathology. © 2021 The Author

Oportunistic diagnosis based on age and hepatitis C virus clearance: an essential step to improve the overall health of the liver

© Copyright 2023 y Creative Commons (CC-BY-NC-ND). Sociedad Española de Patología Digestiva (SEPD) y © Arán Ediciones S.L.Back in January 2022, an EASL-Lancet Commission on the impact of liver disorders in the European region commissioned by the WHO demonstrated that this condition is, actually, the second leading cause of loss of labor years in Europe after ischemic heart disease (1). This is a very relevant piece of information since this is something that is going to impact the new generations of Europeans unless a significant change is made in public health policies. Despite the advances made over the last few years in hepatitis C virus clearance—understood as a significant reduction of morbidity and mortality associated with Hepatitis B and C viruses—there are still challenges ahead to improve liver health due to the high use of alcohol, and the inseparable triad obesity / diabetes mellitus / metabolic associated fatty liver disease. Also, access to healthcare for several population groups at risk of presenting higher rates of liver disease has become a problem.This article was supported by the Spanish Association for the Study of the Liver (AEEH), the Alliance for the Clearance of Viral Hepatitis in Spain (AEHVE), the Viral Hepatitis Working Group (GEHEP) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Digestive Pathology (SEPD), and the Spanish Society of Family and Community Medicine (SEMFyC).Peer reviewe

The new degree in pharmacy. Is it enough for the formative needs in the nutrition area?

La importancia de la alimentación en la consecución de la salud y en la prevención de la enfermedad y la necesidad de un buen control de la dieta para alcanzar resultados satisfactorios en la reducción del riesgo, tratamiento y control de muchas de las enfermedades crónicas, es un hecho documentado científicamente y de gran relevancia en la sociedad actual. La Orden CIN/2137/2008, de 3 de julio establece los requisitos para la verificación de los títulos universitarios oficiales que habiliten para el ejercicio de la profesión farmacéutica, abarcando diversas competencias que aluden directamente a la formación del farmacéutico en el campo de la nutrición. Entre ellas se incluyen 1) Prestar consejo terapéutico en farmacoterapia y dietoterapia, así como consejo nutricional y alimentario a los usuarios de los establecimientos en los que presten servicio. 2) Conocer la relación existente entre la alimentación y salud, y la importancia de la dieta en el tratamiento y prevención de las enfermedades. 3) Desarrollar análisis higiénico-sanitarios (bioquímico, bromatológico, microbiológicos, parasitológicos) relacionados con la salud en general y con los alimentos y medio ambiente en particular. 4) Conocer las técnicas analíticas relacionadas con el diagnóstico de laboratorio de tóxicos, alimentos y medioambiente. En este sentido, el nuevo Grado en Farmacia aprobado por el Consejo de Gobierno de la Universidad de Granada incluye la asignatura troncal “Nutrición y Bromatología” de 6 créditos. Sin embargo los créditos obligatorios aprobados por la ANECA para esta materia en 8 Universidades Españolas oscilan entre 7,5 para Sevilla y 12 créditos para Madrid con una media de 9,4 créditos. De esta forma ¿Es posible cubrir con los 6 créditos asignados a esta materia una formación mínima para que el farmacéutico pueda realizar adecuadamente las competencias que se le han asignado?The importance of nutrition on human health and on illness prevention, and the need for a good control of the diet to reach satisfactory results in the reduction of the risk, treatment and control of many of the chronic diseases, is a scientifically documented fact quite relevant in the current society. The Disposition CIN