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- ItemRestricted1,25-Dihydroxyvitamin D3 regulates VEGF production through a vitamin D response element in the VEGF promoter(Elsevier, 2009) Cardús i Figueras, Anna; Panizo García, Sara; Encinas Martín, Mario; Dolcet Roca, Xavier; Gallego, Carme; Aldea, Martí; Fernández i Giráldez, Elvira ; Valdivielso Revilla, José ManuelIn previous studies we have demonstrated that the active form of vitamin D (1,25(OH)2D3) increases vascular endothelial growth factor (VEGF) expression and release in vascular smooth muscle cells (VSMC) in vitro. However, the mechanism by which 1,25(OH)2D3 increases VEGF production is currently unknown. In this work, we demonstrated binding of vitamin D receptor to two response elements in the VEGF promoter. We performed promoter transactivation analysis and we observed that, in 293T cells, VEGF promoter was activated after vitamin D treatment. Using site-directed mutagenesis we have shown that both response elements are important for VEGF promoter activity. Therefore, the increase in VEGF expression and secretion induced by 1,25(OH)2D3 in VSMC in vitro could be explained by direct binding of the vitamin D receptor, as a transcription factor, to VEGF promoter. These results could explain part of the beneficial effects of vitamin D treatment in renal patients by a possible VEGF-mediated improvement of the endothelial dysfunction.
- ItemOpen Access2-phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53(Elsevier, 2014) Mattiolo, Paolo; Barbero-Farran A.; Yuste Mateos, Víctor J. (Víctor José); Boix Torras, Jacint; Ribas i Fortuny, Judit2-Phenylethynesulfonamide (PES) or pifithrin-μ is a promising anticancer agent with preferential toxicity for cancer cells. The type of cell death and the molecular cascades activated by this compound are controversial. Here, we demonstrate PES elicits a caspase- and BAX/BAK-independent non-necroptotic necrotic cell death, since it is not inhibited by necrostatin-1. This process is characterized by an early generation of reactive oxygen species (ROS) resulting in p53 up-regulation. Accordingly, thiolic antioxidants protect cells from PES-induced death. Furthermore, inhibiting the natural sources of glutathione with l-buthionine-sulfoximine (BSO) strongly cooperates with PES in triggering cytotoxicity. Genetically modified p53-null or p53 knocked-down cells show resistance to PES-driven necrosis. The predominant localization of p53 in chromatin-enriched fractions added to the up-regulation of the p53-responsive gene p21, strongly suggest the involvement of a transcription-dependent p53 program. On the other hand, we report an augmented production of ROS in p53-positive cells that, added to the increased p53 content in response to PES-elicited ROS, suggests that p53 and ROS are mutually regulated in response to PES. In sum, p53 up-regulation by ROS triggers a positive feedback loop responsible of further increasing ROS production and reinforcing PES-driven non-necroptotic necrosis.
- ItemRestricted2-phenylethynesulphonamide (PFT-μ) enhances the anticancer effect of the novel hsp90 inhibitor NVP-AUY922 in melanoma, by reducing GSH levels(Wiley online library, 2016) Yeramian Hakim, Andree; Veà Jódar, Àlvar; Benítez, Sandra; Ribera i Calvet, Joan; Domingo, Mónica; Santacana Espasa, Maria; Martínez Alonso, Montserrat; Maiques Carlos, Oscar; Valls Marsal, Joan; Dolcet Roca, Xavier; Vilella, Ramón; Cabiscol Català, Elisa; Matias-Guiu, Xavier; Martí Laborda, Rosa Ma.Heat shock proteins (HSPs), are molecular chaperones that assist the proper folding of nascent proteins. This study aims to evaluate the antitumour effects of the hsp90 inhibitor NVP-AUY922 in melanoma, both in vitro and in vivo. Our results show that NVP-AUY922 inhibits melanoma cell growth in vitro, with down regulation of multiple signalling pathways involved in melanoma progression such as NF-KB and MAPK/ERK. However, NVP-AUY922 was unable to limit tumour growth in vivo. Cotreatment of A375M xenografts with NVP-AUY922 and PFT-l, a dual inhibitor of both hsp70 and autophagy, induced a synergistic increase of cell death in vitro, and delayed tumour formation in A375M xenografts. PFT-l depleted cells from the reduced form of glutathione (GSH) and increased oxidative stress. The oxidative stress induced by PFT-l further enhanced NVP-AUY922-induced cytotoxic effects. These data suggest a potential therapeutic role for NVP-AUY922 used in combination with PFT-l, in melanoma.
- ItemOpen Access2018 consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary(Springer, 2018) Losa, F.; Iglesias, L.; Pané, M.; Sanz, J.; Nieto, B.; Fusté, V.; de la Cruz‑Merino, L.; Concha, Ángel; Balañá, Carme; Matias-Guiu, XavierCancer of unknown primary (CUP) is defned as a heterogeneous group of tumours that present with metastasis, and in which attempts to identify the original site have failed. They difer from other primary tumours in their biological features and how they spread, which means that they can be considered a separate entity. There are several hypotheses regarding their origin, but the most plausible explanation for their aggressiveness and chemoresistance seems to involve chromosomal instability. Depending on the type of study done, CUP can account for 2–9% of all cancer patients, mostly 60–75 years old. This article reviews the main clinical, pathological, and molecular studies conducted to analyse and determine the origin of CUP.The main strategies for patient management and treatment, by both clinicians and pathologists, are also addressed.
- ItemOpen Access7-Bromoindirubin-3'-oxime induces caspase-independent cell death(Nature Publishing Group, 2006) Ribas i Fortuny, Judit; Bettayeb, Karima; Ferandin, Yoan; Knockaert, Marie; Garrofé Ochoa, Xènia; Totzke, Frank; Schächtele, Christoph; Mester, Jan; Polychronopoulos, Panagiotis; Magiatis, Prokopios; Skaltsounis, Alexios-Leandros; Boix Torras, Jacint; Meijer, LaurentIndirubin, an isomer of indigo, is a reported inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) as well as an agonist of the aryl hydrocarbon receptor (AhR). Indirubin is the active ingredient of a traditional Chinese medicinal recipe used against chronic myelocytic leukemia. Numerous indirubin analogs have been synthesized to optimize this promising kinase inhibitor scaffold. We report here on the cellular effects of 7-bromoindirubin-3'-oxime (7BIO). In contrast to its 5-bromo- and 6-bromo- isomers, and to indirubin-3'-oxime, 7BIO has only a marginal inhibitory activity towards CDKs and GSK-3. Unexpectedly, 7BIO triggers a rapid cell death process distinct from apoptosis. 7-Bromoindirubin-3'-oxime induces the appearance of large pycnotic nuclei, without classical features of apoptosis such as chromatin condensation and nuclear fragmentation. 7-Bromoindirubin-3'-oxime-induced cell death is not accompanied by cytochrome c release neither by any measurable effector caspase activation. Furthermore, the death process is not altered either by the presence of Q-VD-OPh, a broad-spectrum caspase inhibitor, or the overexpression of Bcl-2 and Bcl-XL proteins. Neither AhR nor p53 is required during 7BIO-induced cell death. Thus, in contrast to previously described indirubins, 7BIO triggers the activation of non-apoptotic cell death, possibly through necroptosis or autophagy. Although their molecular targets remain to be identified, 7-substituted indirubins may constitute a new class of potential antitumor compounds that would retain their activity in cells refractory to apoptosis.
- ItemOpen Access7-Bromoindirubin-3'-oxime uncovers a serine protease-mediated paradigm of necrotic cell death(Elsevier, 2008) Ribas i Fortuny, Judit; Yuste Mateos, Víctor J. (Víctor José); Garrofé Ochoa, Xènia; Meijer, Laurent; Esquerda Colell, Josep; Boix Torras, JacintThe new 7-bromoindirubin-3′-oxime (7BIO) compound induces caspase-independent cell death in all cell lines tested to date. Irrespective of the cell line, a 25 μM treatment for 24 h is lethal for the entire cell population. In SH-SY5Y and Jurkat cells, 7BIO (25 μM) was found to collapse the mitochondrial transmembrane potential (ΔΨm) at only 2-3 h of treatment. Concomitantly mitochondria swelled, cristae disrupted and, after 9 h, external cell membranes ruptured. In addition, endoplasmic reticulum dilated and, unexpectedly, the acute cytoplasmic destruction yielded isolated nuclei with preserved morphology and DNA integrity. Furthermore, the process was independent of both Bax and Bak, since cell viability and ΔΨm decayed indistinguishably in double Bax−/−Bak−/− mouse embryonic fibroblasts (MEFs) and their wild type counterparts. Pharmacological inhibition of the mitochondrial permeability transition pore (MPTP) did not prevent 7BIO-induced ΔΨm loss in none of the aforementioned cell lines. Caspase-independent inducers of cell death like AIF (Apoptosis Inducing Factor), cathepsins and calpains were not involved. Only the chemical inhibitors of serine proteases and, particularly, AEBSF afforded a significant protection thus suggesting a process regulated by this type of enzymes. As far as we know, these features are quite unique once taken together. Therefore, we propose 7BIO is triggering a specific type of necrotic cell death. Finally, the cytotoxicity of 7BIO on apoptosis-resistant cells like double Bax−/−Bak−/− MEFs seems of great interest envisaging cancer therapy.
- ItemOpen Access7-dehydrocholesterol efficiently supports Ret signaling in a mouse model of Smith-Opitz-Lemli syndrome(Nature Publishing Group, 2016) Gou Fàbregas, Myriam; Macià Armengol, Anna; Anerillas Aljama, Carlos; Vaquero, Marta; Jové Font, Mariona; Jain, Sanjay; Ribera i Calvet, Joan; Encinas Martín, MarioSmith-Lemli-Opitz syndrome (SLOS) is a rare disorder of cholesterol synthesis. Affected individuals exhibit growth failure, intellectual disability and a broad spectrum of developmental malformations. Among them, renal agenesis or hypoplasia, decreased innervation of the gut, and ptosis are consistent with impaired Ret signaling. Ret is a receptor tyrosine kinase that achieves full activity when recruited to lipid rafts. Mice mutant for Ret are born with no kidneys and enteric neurons, and display sympathetic nervous system defects causing ptosis. Since cholesterol is a critical component of lipid rafts, here we tested the hypothesis of whether the cause of the above malformations found in SLOS is defective Ret signaling owing to improper lipid raft composition or function. No defects consistent with decreased Ret signaling were found in newborn Dhcr7−/− mice, or in Dhcr7−/− mice lacking one copy of Ret. Although kidneys from Dhcr7−/− mice showed a mild branching defect in vitro, GDNF was able to support survival and downstream signaling of sympathetic neurons. Consistently, GFRα1 correctly partitioned to lipid rafts in brain tissue. Finally, replacement experiments demonstrated that 7-DHC efficiently supports Ret signaling in vitro. Taken together, our findings do not support a role of Ret signaling in the pathogenesis of SLOS.
- ItemOpen AccessA 3D MRI‐based atlas of a lizard brain(Wiley, 2018) Hoops, Daniel; Desfilis, Ester; Ullmann, Jeremy F.P.; Janke, Andrew L.; Stait‐Gardner, Timothy; Devenyi, Gabriel A.; Price, William S.; Medina Hernández, Loreta Mª; Whiting, Martin J.; Keogh, J. ScottMagnetic resonance imaging (MRI) is an established technique for neuroanatomical analysis, being particularly useful in the medical sciences. However, the application of MRI to evolutionary neuroscience is still in its infancy. Few magnetic resonance brain atlases exist outside the standard model organisms in neuroscience and no magnetic resonance atlas has been produced for any reptile brain. A detailed understanding of reptilian brain anatomy is necessary to elucidate the evolutionary origin of enigmatic brain structures such as the cerebral cortex. Here, we present a magnetic resonance atlas for the brain of a representative squamate reptile, the Australian tawny dragon (Agamidae: Ctenophorus decresii), which has been the subject of numerous ecological and behavioral studies. We used a high-field 11.74T magnet, a paramagnetic contrasting-enhancing agent and minimum-deformation modeling of the brains of thirteen adult male individuals. From this, we created a high-resolution three-dimensional model of a lizard brain. The 3D-MRI model can be freely downloaded and allows a better comprehension of brain areas, nuclei, and fiber tracts, facilitating comparison with other species and setting the basis for future comparative evolution imaging studies. The MRI model and atlas of a tawny dragon brain (Ctenophorus decresii) can be viewed online and downloaded using the Wiley Biolucida Server at wiley.biolucida.net.
- ItemOpen AccessA blood microRNA classifier for the prediction of ICU mortality in COVID-19 patients: a multicenter validation study(BMJ, 2023) de Gonzalo Calvo, David; Molinero, Marta; Benítez, Iván; Perez-Pons, Manel; García Mateo, Nadia; Ortega, Alicia; Postigo, Tamara; García Hidalgo, María Coronada; Belmonte, Thalía; Rodríguez Muñoz, Carlos; González, Jessica; Torres, Gerard; Gort Paniello, Clara; Moncusí Moix, Anna; Estella, Ángel; Tamayo Lomas, Luis; Martínez de la Gándara, Amalia; Socias, Lorenzo; Peñasco, Yhivian; de la Torre, Maria del Carmen; Bustamante Munguira, Elena; Gallego, Elena; Martínez Varela, Ignacio; Martin Delgado, María Cruz; Vidal Cortés, Pablo; López Messa, Juan; Pérez García, Felipe; Caballero, Jesús; Añón, José M.; Loza Vázquez, Ana; Carbonell, Nieves; Marin Corral, Judith; Jorge García, Ruth Noemí; Barberà, Carme; Ceccato, Adrián; Fernández Barat, Laia; Ferrer, Ricard; García Gasulla, Darío; Lorente-Balanza, Jose Ángel; Menéndez, Rosario; Motos, Anna; Peñuelas, Oscar; Riera, Jordi; Bermejo Martin, Jesús F.; Torres, Antoni; Barbé Illa, FerranBackground: The identification of critically ill COVID-19 patients at risk of fatal outcomes remains a challenge. Here, we first validated candidate microRNAs (miRNAs) as biomarkers for clinical decision-making in critically ill patients. Second, we constructed a blood miRNA classifier for the early prediction of adverse outcomes in the ICU. Methods: This was a multicenter, observational and retrospective/prospective study including 503 critically ill patients admitted to the ICU from 19 hospitals. qPCR assays were performed in plasma samples collected within the first 48 h upon admission. A 16-miRNA panel was designed based on recently published data from our group. Results: Nine miRNAs were validated as biomarkers of all-cause in-ICU mortality in the independent cohort of critically ill patients (FDR < 0.05). Cox regression analysis revealed that low expression levels of eight miRNAs were associated with a higher risk of death (HR from 1.56 to 2.61). LASSO regression for variable selection was used to construct a miRNA classifier. A 4-blood miRNA signature composed of miR-16-5p, miR-192-5p, miR-323a-3p and miR-451a predicts the risk of all-cause in-ICU mortality (HR 2.5). Kaplan‒Meier analysis confirmed these findings. The miRNA signature provides a significant increase in the prognostic capacity of conventional scores, APACHE-II (C-index 0.71, DeLong test p-value 0.055) and SOFA (C-index 0.67, DeLong test p-value 0.001), and a risk model based on clinical predictors (C-index 0.74, DeLong test-p-value 0.035). For 28-day and 90-day mortality, the classifier also improved the prognostic value of APACHE-II, SOFA and the clinical model. The association between the classifier and mortality persisted even after multivariable adjustment. The functional analysis reported biological pathways involved in SARS-CoV infection and inflammatory, fibrotic and transcriptional pathways.
- ItemOpen AccessA Clinical-Genetic Score for Predicting Weight Loss after Bariatric Surgery: The OBEGEN Study(MDPI, 2021) Ciudin, Andreea; Fidilio, Enzamaria; Gutiérrez Carrasquilla, Liliana; Caixàs, Assumpta; Vilarrasa, Núria; Pellitero, Silvia; Simó-Servat, Andreu; Vilallonga, Ramón; Ruiz, Amador; de la Fuente, Maricruz; Luna, Alexis; Sánchez, Enric; Rigla, Mercedes; Hernández, Cristina; Salas, Eduardo; Simó, Rafael; Lecube Torelló, AlbertAround 30% of the patients that undergo bariatric surgery (BS) do not reach an appropriate weight loss. The OBEGEN study aimed to assess the added value of genetic testing to clinical variables in predicting weight loss after BS. A multicenter, retrospective, longitudinal, and observational study including 416 patients who underwent BS was conducted (Clinical.Trials.gov- NCT02405949). 50 single nucleotide polymorphisms (SNPs) from 39 genes were examined. Receiver Operating Characteristic (ROC) curve analysis were used to calculate sensitivity and specificity. Satisfactory response to BS was defined as at nadir excess weight loss >50%. A good predictive model of response [area under ROC of 0.845 (95% CI 0.805–0.880), p < 0.001; sensitivity 90.1%, specificity 65.5%] was obtained by combining three clinical variables (age, type of surgery, presence diabetes) and nine SNPs located in ADIPOQ, MC4R, IL6, PPARG, INSIG2, CNR1, ELOVL6, PLIN1 and BDNF genes. This predictive model showed a significant higher area under ROC than the clinical score (p = 0.0186). The OBEGEN study shows the key role of combining clinical variables with genetic testing to increase the predictability of the weight loss response after BS. This finding will permit us to implement a personalized medicine which will be associated with a more cost-effective clinical practice.
- ItemOpen AccessA common copy-number variant within SIRPB1 correlates with human Out-of-Africa migration after genetic drift correction(Public Library of Science, 2018) Royo Sánchez-Palencia, José Luis; Valls Marsal, Joan; Acemel, Rafael D.; Gómez-Marin, Carlos; Pascual Pons, Mariona; Lupiañez, Arantxa; Gomez-Skarmeta, Jose Luis; Fibla Palazón, JoanPrevious reports have proposed that personality may have played a role on human Out-Of- Africa migration, pinpointing some genetic variants that were positively selected in the migrating populations. In this work, we discuss the role of a common copy-number variant within the SIRPB1 gene, recently associated with impulsive behavior, in the human Out-Of-Africa migration. With the analysis of the variant distribution across forty-two different populations, we found that the SIRPB1 haplotype containing duplicated allele significantly correlated with human migratory distance, being one of the few examples of positively selected loci found across the human world colonization. Circular Chromosome Conformation Capture (4C-seq) experiments from the SIRPB1 promoter revealed important 3D modifications in the locus depending on the presence or absence of the duplication variant. In addition, a 3' enhancer showed neural activity in transgenic models, suggesting that the presence of the CNV may compromise the expression of SIRPB1 in the central nervous system, paving the way to construct a molecular explanation of the SIRPB1 variants role in human migration.
- ItemOpen AccessA comparison of emotional wellbeing and burnout of primary care professionals in 2014 and 2021(Frontiers Media, 2023) Abad, Alejandro; Fuentes Botargues, Araceli; Paredes, Eugeni; Godoy, Sofía; Perera, Sara; Yuguero Torres, OriolBackground: Due to the pandemic that started in February–March 2020 and after many years of economic restrictions suffered by our health system, the levels of stress, exhaustion and suffering among health workers has increased. Objective: Our study aims to perform a comparative analysis of the degree of burnout and emotional wellbeing among health professionals between 2014 and 2021. Methods: This is a comparative descriptive study of two cohorts of primary care professionals of the Lleida health region (SPAIN). We have one cohort from 2014 and another from 2021 with the same selection criteria. Burnout was assessed using the Maslach Burnout Inventory (MBI-HSS) test. Gender, age, professional category and work environment were also evaluated. Results: We obtained a response rate in 2014 of 52.7% (n = 267) and of 41.4% (n = 217) in 2021 with similar sociodemographic characteristics. There are significant differences (p < 0.001) in the three categories of burnout. The high scores for emotional exhaustion and depersonalization have increased, rising between 2014 and 2021 from 23.2 to 60.8% and from 12.4 to 42.4%, respectively. However, there is also a significant increase in high personal accomplishment, rising from 9.0% in 2014 to 26.7%. We have also detected differences depending on age and professional role. Conclusion: This study shows worsening burnout levels of primary care professionals in our region, specifically emotional exhaustion and depersonalization. However, it also shows that during the pandemic, personal accomplishment was reinforced.
- ItemOpen AccessA Contemporary Picture of Enterococcal Endocarditis(Elsevier, 2020-02) Pericàs, Juan M.; Llopis Pérez, Jaime; Muñoz, Patricia; Gálvez Acebal, Juan; Kestler, Martha; Valerio, Maricela; Hernández Meneses, Marta; Goneaga, Miguel A.; Cobo Belaustegui, Manuel; Montejo, Miguel; Ojeda Burgos, Guillermo; Sousa Regueiro, M. Dolores; Alarcón, Aristides de; Ramos Martínez, Antonio; Miró Meda, José M.; GAMES InvestigatorsBackground Enterococcal endocarditis (EE) is a growing entity in Western countries. However, quality data from large studies is lacking. Objectives The purpose of this study was to describe the characteristics and analyze the prognostic factors of EE in the GAMES cohort. Methods This was a post hoc analysis of a prospectively collected cohort of patients from 35 Spanish centers from 2008 to 2016. Characteristics and outcomes of 516 cases of EE were compared with those of 3,308 cases of nonenterococcal endocarditis (NEE). Logistic regression and Cox proportional hazards regression analysis were performed to investigate risk factors for in-hospital and 1-year mortality, as well as relapses. Results Patients with EE were significantly older; more frequently presented chronic lung disease, chronic heart failure, prior endocarditis, and degenerative valve disease; and had higher median age-adjusted Charlson score. EE more frequently involved the aortic valve and prosthesis (64.3% vs. 46.7%; p < 0.001; and 35.9% vs. 28.9%; p = 0.002, respectively) but less frequently pacemakers/defibrillators (1.5% vs. 10.5%; p < 0.001), and showed higher rates of acute heart failure (45% vs. 38.3%; p = 0.005). Cardiac surgery was less frequently performed in EE (40.7% vs. 45.9%; p = 0.024). No differences in in-hospital and 1-year mortality were found, whereas relapses were significantly higher in EE (3.5% vs. 1.7%; p = 0.035). Increasing Charlson score, LogEuroSCORE, acute heart failure, septic shock, and paravalvular complications were risk factors for mortality, whereas prior endocarditis was protective and persistent bacteremia constituted the sole risk factor for relapse. Conclusions Besides other baseline and clinical differences, EE more frequently affects prosthetic valves and less frequently pacemakers/defibrillators. EE presents higher rates of relapse than NEE.
- ItemOpen AccessA cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe(Elsevier, 2020-01) Lazarus, Jeffrey V.; Ekstedt, Mattias; Marchesini, Giulio; Mullen, Jillian; Novak, Katja; Pericàs, Juan M.; Roel, Elena; Romero-Gómez, Manuel; Ratziu, Vlad; Tacke, Frank; Cortez-Pinto, Helena; Anstee, Quentin M.; EASL International Liver Foundation NAFLD Policy Review CollaboratorsBackground & Aims: Non-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and has become an important field of biomedical inquiry. We aimed to determine whether European countries have mounted an adequate public health response to NAFLD and non-alcoholic steatohepatitis (NASH). Methods: In 2018 and 2019, NAFLD experts in 29 European countries completed an English-language survey on policies, guidelines, awareness, monitoring, diagnosis and clinical assessment in their country. The data were compiled, quality checked against existing official documents and reported descriptively. Results: None of the 29 participating countries had written strategies or action plans for NAFLD. Two countries (7%) had mentions of NAFLD or NASH in related existing strategies (obesity and alcohol). Ten (34%) reported having national clinical guidelines specifically addressing NAFLD and, upon diagnosis, all included recommendations for the assessment of diabetes and liver cirrhosis. Eleven countries (38%) recommended screening for NAFLD in all patients with either diabetes, obesity and/or metabolic syndrome. Five countries (17%) had referral algorithms for follow-up and specialist referral in primary care, and 7 (24%) reported structured lifestyle programmes aimed at NAFLD. Seven (24%) had funded awareness campaigns that specifically included prevention of liver disease. Four countries (14%) reported having civil society groups which address NAFLD and 3 countries (10%) had national registries that include NAFLD. Conclusions: We found that a comprehensive public health response to NAFLD is lacking in the surveyed European countries. This includes policy in the form of a strategy, clinical guidelines, awareness campaigns, civil society involvement, and health systems organisation, including registries. Lay summary: We conducted a survey on non-alcoholic fatty liver disease with experts in European countries, coupled with data extracted from official documents on policies, clinical guidelines, awareness, and monitoring. We found a general lack of national policies, awareness campaigns and civil society involvement, and few epidemiological registries.
- ItemOpen AccessA Custom Target Next-Generation Sequencing 70-Gene Panel and Replication Study to Identify Genetic Markers of Diabetic Kidney Disease(MDPI, 2021) Mota Zamorano, Sonia; González, Luz María; Robles, Nicolás Roberto; Valdivielso Revilla, José Manuel; Cancho, Bárbara; López Gómez, Juan; Gervasini, GuillermoDiabetic kidney disease (DKD) has been pointed out as a prominent cause of chronic andend-stage renal disease (ESRD). There is a genetic predisposition to DKD, although clinically relevantloci are yet to be identified. We utilized a custom target next-generation sequencing 70-gene panelto screen a discovery cohort of 150 controls, DKD and DKD-ESRD patients. Relevant SNPs for thesusceptibility and clinical evolution of DKD were replicated in an independent validation cohortof 824 controls and patients. A network analysis aiming to assess the impact of variability alongspecific pathways was also conducted. Forty-eight SNPs displayed significantly different frequenciesin the study groups. Of these, 28 withp-values lower than 0.01 were selected for replication.MYH9rs710181 was inversely associated with the risk of DKD (OR = 0.52 (0.28–0.97),p= 0.033), whilstSOWAHBrs13140552 andCNDP1rs4891564 were not carried by cases or controls, respectively(p= 0.044 and 0.023). In addition, theRGMArs1969589 CC genotype was significantly correlatedwith lower albumin-to-creatinine ratios in the DKD patients (711.8±113.0 vs. 1375.9±474.1 mg/gfor TC/TT; mean difference = 823.5 (84.46–1563.0);p= 0.030). No biological pathway stood out asmore significantly affected by genetic variability. Our findings reveal new variants that could beuseful as biomarkers of DKD onset and/or evolution.
- ItemOpen AccessA detailed review on the phytochemical profiles and anti-diabetic mechanisms of Momordica charantia(Elsevier, 2022) Faith Oyelere, Sunday; Hezekiah Ajayi, Oluwatobi; Eunice Ayoade, Titilayo; Santana Pereira, George; Dayo Owoyemi, Bolaji Charles; Olaoluwa Ilesanmi, Ajibola; Amos Akinyemi, OlalekanDiabetes mellitus is the most well-known endocrine dilemma suffered by hundreds of million people globally, with an annual mortality of more than one million people. This high mortality rate highlights the need for in-depth study of anti-diabetic agents. This review explores the phytochemical contents and anti-diabetic mechanisms of M. charantia (cucurbitaceae). Studies show that M. charantia contains several phytochemicals that have hypoglycemic effects, thus, the plant may be effective in the treatment/management of diabetes mellitus. Also, the biochemical and physiological basis of M. charantia anti-diabetic actions is explained. M. charantia exhibits its anti-diabetic effects via the suppression of MAPKs and NF-κβin pancreatic cells, promoting glucose and fatty acids catabolism, stimulating fatty acids absorption, inducing insulin production, ameliorating insulin resistance, activating AMPK pathway, and inhibiting glucose metabolism enzymes (fructose-1,6-bisphosphate and glucose-6-phosphatase). Reviewed literature was obtained from credible sources such as PubMed, Scopus, and Web of Science.
- ItemOpen AccessA Free App for Diagnosing Burnout (BurnOut App): Development Study(JMIR Publications, 2022) Gòdia Manonelles, Jordi; Pifarré Montalà, Marc; Vilaplana Mayoral, Jordi; Solsona Tehàs, Francesc; Abella i Pons, Francesc; Calvo, Antoni; Mitjans, Anna; Gonzalez Olmedo, Maria PauBackground: Health specialists take care of us, but who takes care of them? These professionals are the most vulnerable to the increasingly common syndrome known as burnout. Burnout is a syndrome conceptualized as a result of chronic workplace stress that has not been successfully managed. Objective: This study aims to develop a useful app providing burnout self-diagnosis and tracking of burnout through a simple, intuitive, and user-friendly interface. Methods: We present the BurnOut app, an Android app developed using the Xamarin and MVVMCross platforms, which allows users to detect critical cases of psychological discomfort by implementing the Goldberg and Copenhagen Burnout Inventory tests. Results: The BurnOut app is robust, user-friendly, and efficient. The good performance of the app was demonstrated by comparing its features with those of similar apps in the literature. Conclusions: The BurnOut app is very useful for health specialists or users, in general, to detect burnout early and track its evolution.
- ItemOpen AccessA genome-wide transcriptional study reveals that iron deficiency inhibits the yeast TORC1 pathway(Elsevier, 2019-09) Romero, Antonia María; Ramos-Alonso, Lucía; Montellá-Manuel, Sandra; García-Martínez, José; Torre Ruiz, M. A. de la; Pérez-Ortín, José E.; Martínez-Pastor, María Teresa; Puig, SergiIron is an essential micronutrient that participates as a cofactor in a broad range of metabolic processes including mitochondrial respiration, DNA replication, protein translation and lipid biosynthesis. Adaptation to iron deficiency requires the global reorganization of cellular metabolism directed to optimize iron utilization. The budding yeast Saccharomyces cerevisiae has been widely used to characterize the responses of eukaryotic microorganisms to iron depletion. In this report, we used a genomic approach to investigate the contribution of transcription rates to the modulation of mRNA levels during adaptation of yeast cells to iron starvation. We reveal that a decrease in the activity of all RNA polymerases contributes to the down-regulation of many mRNAs, tRNAs and rRNAs. Opposite to the general expression pattern, many genes including components of the iron deficiency response, the mitochondrial retrograde pathway and the general stress response display a remarkable increase in both transcription rates and mRNA levels upon iron limitation, whereas genes encoding ribosomal proteins or implicated in ribosome biogenesis exhibit a pronounced fall. This expression profile is consistent with an activation of the environmental stress response. The phosphorylation stage of multiple regulatory factors strongly suggests that the conserved nutrient signaling pathway TORC1 is inhibited during the progress of iron deficiency. These results suggest an intricate crosstalk between iron metabolism and the TORC1 pathway that should be considered in many disorders.
- ItemOpen AccessA low fractional excretion of Phosphate/Fgf23 ratio is associated with severe abdominal Aortic calcification in stage 3 and 4 kidney disease patients(BioMed Central, 2013) Craver Hospital, Lourdes; Dusso Rosso, Adriana; Martínez Alonso, Montserrat; Sarró, Felipe; Valdivielso Revilla, José Manuel; Fernández i Giráldez, ElviraBackground: Vascular calcification (VC) contributes to high mortality rates in chronic kidney disease (CKD). High serum phosphate and FGF23 levels and impaired phosphaturic response to FGF23 may affect VC. Therefore, their relative contribution to abdominal aortic calcification (AAC) was examined in patients CKD stages 3–4. Methods: Potential risk factors for AAC, measured by the Kauppila Index (KI), were studied in 178 patients. Results: In multivariate linear analysis, AAC associated positively with age, male gender, CKD-stage, presence of carotid plaques (CP) and also with FGF23, but negatively with fractional excretion of phosphate (FEP). Intriguingly, FEP increased with similar slopes with elevations in PTH, with reductions in GFR, and also with elevations in FGF23 but the latter only in patients with none (KI = 0) or mild (KI = 1-5) AAC. Lack of a FEP-FGF23 correlation in patients with severe AAC (KI > 5) suggested a role for an impaired phosphaturic response to FGF23 but not to PTH in AAC. Logistic and zero-inflated analysis confirmed the independent association of age, CKD stage, male gender and CP with AAC, and also identified a threshold FEP/FGF23 ratio of 1/3.9, below which the chances for a patient of presenting severe AAC increased by 3-fold. Accordingly, KI remained unchanged as FEP/FGF23 ratios decreased from 1/1 to 1/3.9 but markedly increased in parallel with further reductions in FEP/FGF23 < 1/3.9. Conclusions: In CKD 3–4, an impaired phosphaturic response to FGF23 with FEP/FGF23 < 1/3.9 associates with severe AAC independently of age, gender or CP.
- ItemOpen AccessA Machine-Learning Model for Lung Age Forecasting by Analyzing Exhalations(MDPI, 2022) Pifarré Montalà, Marc; Tena del Pozo, Alberto; Clarià Sancho, Francisco; Solsona Tehàs, Francesc; Vilaplana Mayoral, Jordi; Benavides, Arnau; Mas, Lluis; Abella i Pons, FrancescSpirometers are important devices for following up patients with respiratory diseases. These are mainly located only at hospitals, with all the disadvantages that this can entail. This limits their use and consequently, the supervision of patients. Research efforts focus on providing digital alternatives to spirometers. Although less accurate, the authors claim they are cheaper and usable by many more people worldwide at any given time and place. In order to further popularize the use of spirometers even more, we are interested in also providing user-friendly lung-capacity metrics instead of the traditional-spirometry ones. The main objective, which is also the main contribution of this research, is to obtain a person’s lung age by analyzing the properties of their exhalation by means of a machine-learning method. To perform this study, 188 samples of blowing sounds were used. These were taken from 91 males (48.4%) and 97 females (51.6%) aged between 17 and 67. A total of 42 spirometer and frequency-like features, including gender, were used. Traditional machine-learning algorithms used in voice recognition applied to the most significant features were used. We found that the best classification algorithm was the Quadratic Linear Discriminant algorithm when no distinction was made between gender. By splitting the corpus into age groups of 5 consecutive years, accuracy, sensitivity and specificity of, respectively, 94.69%, 94.45% and 99.45% were found. Features in the audio of users’ expiration that allowed them to be classified by their corresponding lung age group of 5 years were successfully detected. Our methodology can become a reliable tool for use with mobile devices to detect lung abnormalities or diseases.