29 research outputs found

    Successful development of vitrified embryonic kidney after laparoscopy transplantation into non-immunosuppressed hosts

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    [EN] Transplantation from living or deceased donors has been limited by donor availability that is opposed to the increasing demand and by the risk of allograft loss rejection and immunosuppressive therapy toxicity. In recent years, xenotransplantation of metanephroi has offered a novel solution for the unlimited supply of human donor organs. However, even if in a most favourable and idyllic situation the organ availability and its demand could be balanced using transplantation of animal embryonic organs, the future of this treatment would still be compromised without proper long-term storage procedure. Thus, based on the ongoing long-term storage necessities, this study was designed to investigate the effect of two specific time window of the metanephroi development (15 days-old and 16 days-old) on the in vivo developmental capacity and the developed morphologically normal glomeruli of vitrified metanephroi in non-immunosuppressive rabbits. Metanephroi originating from 15 and 16 days old rabbit embryos were vitrified using M22 solution and Cryotop® as a device. After three months of storage in liquid nitrogen, metanephroi were transplanted into non-immunosuppressed adult hosts by laparoscopy surgery. Twenty-one days after allotransplantation, 6 (32%) and 7 (35%) new kidneys were recovered. All the new kidneys recovered exhibited significant growth and mature glomeruli. However, histomorphometry analysis revealed that new kidneys developed from 16 days-old metanephroi exhibit a greater degree of maturity compared with 15 days-old metanephroi. Results obtained in the present study point out that, in rabbit model, vitrified 16 days-old metanephroi could be stored in liquid nitrogen, achieving good in vivo developmental capacity and the developed morphologically normal glomeruli after laparoscopy transplantation into non-immunosuppressed hosts.This work was supported by funds from the Generalitat Valenciana Research Programme (PrometeoII 2014/036), ALCER-TURIA foundation and PRECIPITA CROWDFUNDING. English text version was revised by N. Macowan English Language Service.Garcia-Dominguez, X.; Vicente Antón, JS.; Vera Donoso, CD.; Marco-Jiménez, F. (2017). Successful development of vitrified embryonic kidney after laparoscopy transplantation into non-immunosuppressed hosts. Transplantation open. 2(2):1-5. https://doi.org/10.15761/JTO.1000125S152

    PSMA-Targeted Mesoporous Silica Nanoparticles for Selective Intracellular Delivery of Docetaxel in Prostate Cancer Cells

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    [EN] Although docetaxel is currently broadly used in prostate cancer treatment, poor water solubility and systemic toxicity limit the dose and duration of therapy. In this context, although different nanoplatforms have been proposed to overcome these issues, selective therapy needs developing methodologies to target malignant cells and minimizing the impact on healthy tissue. We here present a novel drug delivery system obtained by covalent conjugation of docetaxel and an anti-prostate specific membrane antigen (PSMA) molecule (anti-FOLH1 monoclonal antibody, clone C803N) over mesoporous silica nanoparticles. This conjugate remains stable in physiological medium and shows high selectivity for LNCaP, a specific cell line that overexpresses PSMA. As a consequence, cell internalization is increased by 25%. Furthermore, cytotoxic activity of the targeted system increases by 2-fold with regard to nontargeted nanoparticles and by 2 orders with regard to the naked drug. Conversely, no targeting effect is observed over PC3, a nonbearing PSMA cell line. We expect that this therapeutic system shows strong potential for treating nonmetastatic prostate cancer, mostly through intraprostatic administration.Financial support from the Spanish Ministry of Economy and Competitiveness (projects MAT2015-66666-C3-2-R, TEC2016-80976-R, and SEV-2016-0683) and the Generalitat Valenciana (project PROMETEO/2017/060) is gratefully acknowledged. We appreciate the assistance of the Electron Microscopy Service of the Universitat Politecnica de Valencia.Rivero-Buceta, EM.; Vidaurre Agut, CM.; Vera Donoso, CD.; Benlloch Baviera, JM.; Moreno Manzano, V.; Botella Asuncion, P. (2019). PSMA-Targeted Mesoporous Silica Nanoparticles for Selective Intracellular Delivery of Docetaxel in Prostate Cancer Cells. ACS Omega. 4(1):1281-1291. https://doi.org/10.1021/acsomega.8b02909S128112914

    Protein Corona over Mesoporous Silica Nanoparticles: Influence of the Pore Diameter on Competitive Adsorption and Application to Prostate Cancer Diagnostics

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    [EN] Diagnostic tests based on proteomics analysis can have significant advantages over more traditional biochemical tests. However, low molecular weight (MW) protein biomarkers are difficult to identify by standard mass spectrometric analysis, as they are usually present at low concentrations and are masked by more abundant resident proteins. We have previously shown that mesoporous silica nanoparticles are able to capture a predominantly low MW protein fraction from the serum, as compared to the protein corona (PC) adsorbed onto dense silica nanoparticles. In this study, we begin by further investigating this effect using liquid chromatography-mass spectrometry (LC-MS)/MS and thermogravimetric analysis (TGA) to compare the MW of the proteins in the coronas of mesoporous silica nanoparticles with the same particle size but different pore diameters. Next, we examine the process by which two proteins, one small and one large, adsorb onto these mesoporous silica nanoparticles to establish a theory of why the corona becomes enriched in low MW proteins. Finally, we use this information to develop a novel system for the diagnosis of prostate cancer. An elastic net statistical model was applied to LC-MS/MS protein coronas from the serum of 22 cancer patients, identifying proteins specific to each patient group. These studies help to explain why low MW proteins predominate in the coronas of mesoporous silica nanoparticles, and they illustrate the ability of this information to supplement more traditional diagnostic tests.Financial support from the University of Vermont, the Spanish Ministry of Economy and Competitiveness (projects TEC2016-80976-R and SEV-2016-0683), and the Generalitat Valenciana (project PROMETEO/2017/060), is gratefully acknowledged. We thank Dr. Jaime Font de Mora for his assistance in the clinical sample collection and Dr. David Herva ' s for the statistical study supervision. We also appreciate the assistance of the electron microscopy service of the Universitat Politecnica de Valencia.Vidaurre Agut, CM.; Rivero-Buceta, EM.; RomanĂ­-Cubells, E.; Clemments, AM.; Vera Donoso, CD.; Landry, C.; Botella Asuncion, P. (2019). Protein Corona over Mesoporous Silica Nanoparticles: Influence of the Pore Diameter on Competitive Adsorption and Application to Prostate Cancer Diagnostics. ACS Omega. 4(5):8852-8861. https://doi.org/10.1021/acsomega.9b00460S885288614

    Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

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    © The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups

    Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

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    Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

    Repositioning of the global epicentre of non-optimal cholesterol

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    High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.Peer reviewe

    Rising rural body-mass index is the main driver of the global obesity epidemic in adults