Publications by authors named "Marta Bueno"

69 Publications

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Athletes' Psychological Adaptation to Confinement Due to COVID-19: A Longitudinal Study.

Front Psychol 2020 14;11:613495. Epub 2021 Jan 14.

Sport Psychology Unit, Center for Applied Psychology, Universidad Autónoma de Madrid, Madrid, Spain.

Studies of individuals under conditions of confinement or severe social and physical restrictions have consistently shown deleterious mental health effects but also high levels of adaptability when dealing with such conditions. Considering the role of physical activity and sport in psychological adaptation, this paper describes a longitudinal study to explore to what extent the imposed restrictions due to the outbreak of SARS-CoV-2 may have affected athletes' mental health outcomes and how far the process of adaptation to confinement conditions is differentially affected depending on whether the sports activity was practiced individually or in a group, and outdoors, indoors, or both. Two hundred and seventy-four athletes were assessed over 7 weeks using the GHQ-28 and an survey exploring the practice of physical activity. A mixed-model fixed effects ANCOVA was used to analyze the effects of time, place, and company in which the sport was practiced, with an index of the amount of physical activity expended as a covariate. Results show a significant effect of time in three out of four of the GHQ-28 subscales, in all cases showing a consistent adaptation to conditions over time. Results also show that playing sport indoors, outdoors, or both, and practicing alone vs. with others differentially affect the somatic symptoms exhibited during confinement: Athletes who practiced sport with others showed higher levels of somatic symptoms at the beginning of the set of data but a quicker rate of adaptation. Differences arising from practicing sport alone or with others were more pronounced in the case of indoor sports, which could be related to the fact that physical activity that can be practiced during confinement is more similar to that practiced indoors alone. Implications relating to what sport psychologists and other health professionals may offer to athletes in stressful situations are discussed.
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http://dx.doi.org/10.3389/fpsyg.2020.613495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873871PMC
January 2021

The SEEN comprehensive clinical survey of adult obesity: Executive summary.

Endocrinol Diabetes Nutr (Engl Ed) 2021 Feb 12;68(2):130-136. Epub 2020 Sep 12.

Servicio de Endocrinología y Nutrición, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Gregorio Marañón, Madrid, España.

Obesity is one of the great challenges in healthcare nowadays with important implications for health so requiring comprehensive management. This document aims to establish practical and evidence-based recommendations for the diagnosis and management of in Spain, from the perspective of the clinical endocrinologist. A position statement has been made that can be consulted at www.seen.es, and that has been agreed by the Obesity Group of the Spanish Society of Endocrinology and Nutrition (GOSEEN), together with the Nutrition Area (NutriSEEN) and the Working Group of Endocrinology, Nutrition and Physical Exercise (GENEFSEEN).
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http://dx.doi.org/10.1016/j.endinu.2020.05.003DOI Listing
February 2021

Lost in Translation: Endoplasmic Reticulum-Mitochondria Crosstalk in Idiopathic Pulmonary Fibrosis.

Am J Respir Cell Mol Biol 2020 10;63(4):408-409

The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.1165/rcmb.2020-0273EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528920PMC
October 2020

Impact of bariatric surgery on subclinical atherosclerosis in patients with morbid obesity.

Surg Obes Relat Dis 2020 Oct 10;16(10):1419-1428. Epub 2020 Jun 10.

Department of Biochemistry and Molecular Biomedicine, Biology Faculty, University of Barcelona, Barcelona, Spain.

Background: The main cause of death in obese individuals is cardiovascular disease precipitated by atherosclerosis. Endothelial dysfunction and inflammation are considered early events in the development of the disease.

Objectives: The aim of this study was to identify biomarkers of subclinical atherosclerosis in patients with morbid obesity by comparing clinical, vascular, and biochemical parameters indicative of endothelial dysfunction in patients with and without atheromatous plaque and monitoring changes after bariatric surgery.

Settings: Multicenter collaboration between Biochemistry and Biomedicine Department in Barcelona University and University Hospital Arnau de Vilanova in Lleida.

Methods: Plasma samples from 66 patients with morbid obesity were obtained before bariatric surgery and at 6 and 12 months after. Patients were divided into 2 groups based on the presence of atheromatous plaque. We used contrast-enhanced carotid ultrasound, enzyme-linked immunosorbent assay, Griess, and EndoPAT-2000 methods.

Results: Patients with plaque showed the worst profile of cardiovascular risk factors. Carotid intima-media thickness and plasminogen activator inhibitor-1 were higher in plaque group (P < .0001). After bariatric surgery, vasa vasorum, oxidized low-density lipoprotein, and plasminogen activator inhibitor-1 decreased (P < .0001 in all cases).

Conclusions: Obesity promotes atherogenesis, leading to vascular endothelial damage. Bariatric surgery reduces cardiovascular risk and the prognosis is better for patients without plaque. The increase in plasminogen activator inhibitor-1, carotid intima-media thickness, and vasa vasorum proliferation might be the first alterations in the atheromatous process in obesity and could serve as good biomarkers of subclinical atherosclerosis.
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http://dx.doi.org/10.1016/j.soard.2020.05.035DOI Listing
October 2020

Mitochondria, Aging, and Cellular Senescence: Implications for Scleroderma.

Curr Rheumatol Rep 2020 06 19;22(8):37. Epub 2020 Jun 19.

Department of Medicine, Aging Institute, University of Pittsburgh, 560 Bridgeside Point 1 Bldg.100 Technology Drive, Pittsburgh, PA, 15219, USA.

Purpose Of Review: The etiology of systemic sclerosis (SSc), which is a rare immune-mediated inflammatory disease characterized by vascular damage and fibrosis, is still unknown. However, different intrinsic (genetics) and extrinsic (environmental) factors play a part in the progression of the disease. This review focuses on the role of aging, mitochondrial dysfunction, and senescence in SSc.

Recent Findings: Mitochondrial dysfunction and senescence have been linked to the age-related susceptibility to other interstitial lung diseases (ILD) such as idiopathic pulmonary fibrosis (IPF). SSc is not regarded as an age-related disease but does show a higher incidence of cardiac events, fibrosis, and mortality at older age. We provide an overview of the current status of the role of aging, mitochondrial dysfunction, and senescence in SSc. Further work is needed to validate some of these pathways in SSc and may allow for new therapeutic interventions focused on restoring mitochondrial homeostasis and the targeted removal of chronic-senescent cells.
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http://dx.doi.org/10.1007/s11926-020-00920-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008485PMC
June 2020

Dynamics of Anthropometric Indices in a Large Paired Cohort With 10 Years of Follow-Up: Paving the Way to Sarcopenic Obesity.

Front Endocrinol (Lausanne) 2020 17;11:209. Epub 2020 Apr 17.

Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova de Lleida, Obesity, Diabetes and Metabolism (ODIM) Research Group, IRBLleida, University of Lleida, Lleida, Spain.

Paired cohort investigations assessing the evolution of anthropometric indices are scarce. Here we assessed the 10-year evolution of BMI, total body fat, and lean body mass in 50,019 participants aged 18-90 years at the time of first assessment. A retrospective cohort study using an electronic database that contains anonymized, longitudinal data from Primary Care medical records covering the 2007-2008 and 2017-2018 periods. Total body fat was estimated using the Clínica Universidad de Navarra-Body Adiposity Estimator formula, and the Hume formula was applied to estimate lean body mass. The mean BMI of participants <60 years old in the 2007-2008 period increased significantly, from 27.5 to 28.3 kg/m ( < 0.001). However, the BMI of older subjects decreased during the next decade, from 28.9 to 28.3 kg/m ( < 0.001). The estimated total body fat showed a continuous progressive increase over all ages. Finally, lean body mass showed a progressive increase until the 40s, with a plateau between 40-45 years old and an uninterrupted decrease until older ages. Also, subjects who increased their BMI by 2 kg/m during the 10-year period were mainly women and younger at baseline, with a lower initial BMI and total body fat in comparison with those who experienced a BMI decrease of ≥2.0 kg/m. The evolutions of BMI and the estimated body compositions reported here confirm that the adverse decrease in lean body mass begins in middle age. The proportion of older subjects is important when evaluating overweight and obesity prevalence in cross-sectional studies.
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http://dx.doi.org/10.3389/fendo.2020.00209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212464PMC
May 2021

New Metrics to Assess Type 2 Diabetes After Bariatric Surgery: The "Time-Within-Remission Range".

J Clin Med 2020 Apr 9;9(4). Epub 2020 Apr 9.

Hospital Universitario San Cecilio, 18016 Granada, Spain.

Almost one third of patients do not achieve type 2 diabetes remission after bariatric surgery or are unable to sustain this effect long term. Our objective was to delve further into the dynamic responses of diabetes after bariatric surgery and to evaluate the "time-within-remission range" as a variable of metabolic control. A descriptive cohort study was done using a computerised multicentre and multidisciplinary registry. All data were adjusted by propensity score. A total of 1186 subjects with a follow-up of 4.5 ± 2.5 years were included. Type of surgery, diabetes remission, recurrence of diabetes, "time-within-remission range" and key predictors of diabetes outcomes were assessed. All patients (70% women, 51.4 ± 9.2 years old, body mass index (BMI) 46.3 ± 6.9 kg/m) underwent primary bariatric procedures. "Time-within-remission range" were 83.3% (33.3-91.6) after gastric bypass, 68.7% (7.1-87.5) after sleeve gastrectomy and 90% (83.3-92.8) after malabsorptive techniques ( < 0.001 for all). Duration of diabetes, baseline HbA1c and insulin treatment were significantly negatively correlated with the "time-within-remission range". The association of bariatric techniques with "time-within-remission range", using gastric bypass as a reference, were: odds ratio (OR) 3.70 (2.34-5.84), < 0.001 for malabsorptive techniques and OR 0.55 (0.40-0.75), < 0.001 for sleeve gastrectomy. Characteristics of type 2 diabetes powerfully influence the outcomes of bariatric surgery. The "time-within-remission range" unveils a superiority of gastric bypass compared to sleeve gastrectomy.
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http://dx.doi.org/10.3390/jcm9041070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230819PMC
April 2020

Mitochondria dysfunction and metabolic reprogramming as drivers of idiopathic pulmonary fibrosis.

Redox Biol 2020 06 19;33:101509. Epub 2020 Mar 19.

Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. It is characterized by deposition of extracellular matrix proteins, like collagen and fibronectin in the lung interstitium leading to respiratory failure. Our understanding of the pathobiology underlying IPF is still incomplete; however, it is accepted that aging is a major risk factor in the disease while growing evidence suggests that the mitochondria plays an important role in the initiation and progression of pulmonary fibrosis. Mitochondria dysfunction and metabolic reprogramming had been identified in different IPF lung cells (alveolar epithelial cells, fibroblasts, and macrophages) promoting low resilience and increasing susceptibility to activation of profibrotic responses. Here we summarize changes in mitochondrial numbers, biogenesis, turnover and associated metabolic adaptations that promote disrepair and fibrosis in the lung. Finally, we highlight new possible therapeutic approaches focused on ameliorate mitochondrial dysfunction.
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http://dx.doi.org/10.1016/j.redox.2020.101509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251240PMC
June 2020

Are Obesity Indices Useful for Detecting Subclinical Atheromatosis in a Middle-Aged Population?

Obes Facts 2020 22;13(1):29-39. Epub 2020 Jan 22.

Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova, Obesity, Diabetes and Metabolism (ODIM) Research Group, IRBLleida, University of Lleida, Lleida, Spain,

Objective: There is a close relationship between excess adiposity and cardiovascular disease. Although body mass index (BMI) is the most used approach to estimate excess weight, other anthropometric indices have been developed to measure total body and abdominal adiposity. Here, our objective was to assess the usefulness of these anthropometric indices to detect subclinical atheromatous disease.

Methods: A cross-sectional study with 6,809 middle-aged subjects (mean age, 57 [53-63] years) with low to moderate cardiovascular risk from the ILERVAS project. Measures of total body fat (BMI, Clínica Universidad de Navarra - Body Adiposity Estimator [CUN-BAE], and Deurenberg's formula) and central adiposity (waist and neck circumferences, conicity index, waist-to-height ratio, Bonora's equation, the A body adiposity index, and body roundness index) were performed in all participants. Bilateral carotid and femoral ultrasound vascular studies allowed the identification of subjects with plaque. -Results: All measured indices were significantly higher in males with subclinical carotid or femoral plaques (p ≤ 0.021 for all). Also, a positive and significant correlation between all indices and the number of affected territories was found (p ≤ 0.013 for all). From the ROC analysis, all measurements identified patients with asymptomatic atheromatosis but none of them helped make clinical decisions. Regarding females, the results were less conclusive.

Conclusion: Obesity indices are related to subclinical atheromatosis, especially in men, in a large cohort of middle-aged subjects. However, the indices could not detect the presence of arterial plaque, so, when used in isolation, are unlikely to be decisive.
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http://dx.doi.org/10.1159/000502696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098313PMC
September 2020

Senotherapeutics: Targeting senescence in idiopathic pulmonary fibrosis.

Semin Cell Dev Biol 2020 05 24;101:104-110. Epub 2019 Dec 24.

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Medicine, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Fibrosis Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease characterized by progressive scarring of the lung tissue, leading to respiratory failure. There is no cure for IPF, and current anti-fibrotic treatments modestly arrest its further progression. IPF prevalence and incidence increase with age, which is a recognized risk factor. Intense clinical and basic research over the last fifteen years has shown that hallmarks of accelerated aging are present in the lungs of patients with IPF. Different cell types in IPF lungs exhibit premature hallmarks of aging, including telomere attrition and cellular senescence. In this Review, we discuss recent insights into the mechanisms behind these age-related alterations and their contribution to the development of lung fibrosis. We focus on the genetic and molecular basis of telomere attrition in alveolar type II epithelial cells, which promote cellular senescence and lung fibrosis. Mechanistically, senescent cells secrete pro-fibrotic factors that activate scar-forming myofibroblasts. Ultimately, senescent alveolar epithelial cells lose their regenerative capacity, impeding fibrosis resolution. In addition, mitochondrial dysfunction is strongly associated with the appearance of senescent epithelial cells and senescent myofibroblasts in IPF, which persist in the fibrotic tissue by adapting their metabolic pathways and becoming resistant to apoptosis. We discuss emerging novel therapeutic strategies to treat IPF by targeting cellular senescence with the so-called senotherapeutics.
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http://dx.doi.org/10.1016/j.semcdb.2019.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913053PMC
May 2020

Assessment of Radio-Induced Damage in Endothelial Cells Irradiated with 40 kVp, 220 kVp, and 4 MV X-rays by Means of Micro and Nanodosimetric Calculations.

Int J Mol Sci 2019 Dec 9;20(24). Epub 2019 Dec 9.

IRSN, Institut de Radioprotection et de Sûreté Nucléaire, BP17, 92262 Fontenay aux Roses, France.

The objective of this work was to study the differences in terms of early biological effects that might exist between different X-rays energies by using a mechanistic approach. To this end, radiobiological experiments exposing cell monolayers to three X-ray energies were performed in order to assess the yields of early DNA damage, in particular of double-strand breaks (DSBs). The simulation of these irradiations was set in order to understand the differences in the obtained experimental results. Hence, simulated results in terms of microdosimetric spectra and early DSB induction were analyzed and compared to the experimental data. Human umbilical vein endothelial cells (HUVECs) were irradiated with 40, 220 kVp, and 4 MV X-rays. The Geant4 Monte Carlo simulation toolkit and its extension Geant4-DNA were used for the simulations. Microdosimetric calculations aiming to determine possible differences in the variability of the energy absorbed by the irradiated cell population for those photon spectra were performed on 10,000 endothelial cell nuclei representing a cell monolayer. Nanodosimetric simulations were also carried out using a computation chain that allowed the simulation of physical, physico-chemical, and chemical stages on a single realistic endothelial cell nucleus model including both heterochromatin and euchromatin. DNA damage was scored in terms of yields of prompt DSBs per Gray (Gy) and per giga (10) base pair (Gbp) and DSB complexity was derived in order to be compared to experimental data expressed as numbers of histone variant H2AX (γ-H2AX) foci per cell. The calculated microdosimetric spread in the irradiated cell population was similar when comparing between 40 and 220 kVp X-rays and higher when comparing with 4 MV X-rays. Simulated yields of induced DSB/Gy/Gbp were found to be equivalent to those for 40 and 220 kVp but larger than those for 4 MV, resulting in a relative biological effectiveness (RBE) of 1.3. Additionally, DSB complexity was similar between the considered photon spectra. Simulated results were in good agreement with experimental data obtained by IRSN (Institut de radioprotection et de sûreté nucléaire) radiobiologists. Despite differences in photon energy, few differences were observed when comparing between 40 and 220 kVp X-rays in microdosimetric and nanodosimetric calculations. Nevertheless, variations were observed when comparing between 40/220 kVp and 4 MV X-rays. Thanks to the simulation results, these variations were able to be explained by the differences in the production of secondary electrons with energies below 10 keV.
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http://dx.doi.org/10.3390/ijms20246204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940891PMC
December 2019

Assessing Motivational Stages and Processes of Change for Weight Management Around Bariatric Surgery: a Multicenter Study.

Obes Surg 2019 10;29(10):3348-3356

Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.

Introduction/purpose: The assessment of the patients' motivation as a predictor of behavioral change via five stages (pre-contemplation, contemplation, preparation, action, and maintenance) and four processes (emotional re-evaluation, weight management actions, environmental restructuring, and weight consequences evaluation) of change.

Materials/methods: A total of 542 participants (251 waiting for bariatric surgery (BS), 90 undergoing BS, and 201 controls) completed the Stages (S-Weight) and Processes (P-Weight) of Change in Overweight and Obese People questionnaires in a multicenter cross-sectional study.

Results: A higher percentage of subjects seeking BS (31.7%) were in the action stage (16.7% of post-BS patients, p < 0.001; 14.9% of controls, p < 0.001). The referred body mass index (BMI) reduction was higher in subjects in active stages (3.6 ± 4.4 kg/m in maintenance versus 1.4 ± 1.4 kg/m in contemplation, p < 0.001). In the P-Weight questionnaire, patients looking for BS scored significant higher in the four processes of change than controls. In addition, a positive and significantly correlation between BMI and the four processes was observed. In the stepwise multivariate analysis, BMI and the S-Weight allocation were constantly associated with the four processes of change.

Conclusion: Obesity is accompanied by a modifying behavioral stage, suggesting that subjects before BS are seriously thinking about overcoming excess weight. To identify subjects on the waiting list for BS who will be more receptive to weight lost interventions remains a challenge.
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http://dx.doi.org/10.1007/s11695-019-04001-4DOI Listing
October 2019

PINK1 attenuates mtDNA release in alveolar epithelial cells and TLR9 mediated profibrotic responses.

PLoS One 2019 6;14(6):e0218003. Epub 2019 Jun 6.

Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

We have previously shown that endoplasmic reticulum stress (ER stress) represses the PTEN inducible kinase 1 (PINK1) in lung type II alveolar epithelial cells (AECII) reducing mitophagy and increasing the susceptibility to lung fibrosis. Although increased circulating mitochondrial DNA (mtDNA) has been reported in chronic lung diseases, the contribution of mitophagy in the modulation of mitochondrial DAMP release and activation of profibrotic responses is unknown. In this study, we show that ER stress and PINK1 deficiency in AECII led to mitochondrial stress with significant oxidation and damage of mtDNA and subsequent extracellular release. Extracellular mtDNA was recognized by TLR9 in AECII by an endocytic-dependent pathway. PINK1 deficiency-dependent mtDNA release promoted activation of TLR9 and triggered secretion of the profibrotic factor TGF-β which was rescued by PINK1 overexpression. Enhanced mtDNA oxidation and damage were found in aging and IPF human lungs and, in concordance, levels of circulating mtDNA were significantly elevated in plasma and bronchoalveolar lavage (BAL) from patients with IPF. Free mtDNA was found elevated in other ILDs with low expression of PINK1 including hypersensitivity pneumonitis and autoimmune interstitial lung diseases. These results support a role for PINK1 mediated mitophagy in the attenuation of mitochondrial damage associated molecular patterns (DAMP) release and control of TGF-β mediated profibrotic responses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218003PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553779PMC
February 2020

From Energy Deposition of Ionizing Radiation to Cell Damage Signaling: Benchmarking Simulations by Measured Yields of Initial DNA Damage after Ion Microbeam Irradiation.

Radiat Res 2019 06 25;191(6):566-584. Epub 2019 Apr 25.

a Radiobiology of Accidental Exposure Laboratory.

Advances in accelerator technology, which have enabled conforming radiotherapy with charged hadronic species, have brought benefits as well as potential new risks to patients. To better understand the effects of ionizing radiation on tumor and surrounding tissue, it is important to investigate and quantify the relationship between energy deposition at the nanometric scale and the initial biological events. Monte Carlo track structure simulation codes provide a powerful tool for investigating this relationship; however, their success and reliability are dependent on their improvement and development accordingly to the dedicated biological data to which they are challenged. For this aim, a microbeam facility that allows for fluence control, down to one ion per cell nucleus, was used to evaluate relative frequencies of DNA damage after interaction between the incoming ion and DNA according to radiation quality. Primary human cells were exposed to alpha particles of three different energies with respective linear energy transfers (LETs) of approximately 36, 85 or 170 keV·µm at the cells' center position, or to protons (19 keV·µm). Statistical evaluation of nuclear foci formation (53BP1/γ-H2AX), observed using immunofluorescence and related to a particle traversal, was undertaken in a large population of cell nuclei. The biological results were adjusted to consider the factors that drive the experimental uncertainties, then challenged with results using Geant4-DNA code modeling of the ionizing particle interactions on a virtual phantom of the cell nucleus with the same mean geometry and DNA density as the cells used in our experiments. Both results showed an increase of relative frequencies of foci (or simulated DNA damage) in cell nuclei as a function of increasing LET of the traversing particles, reaching a quasi-plateau when the LET exceeded 80-90 keV·µm. For the LET of an alpha particle ranging from 80-90 to 170 keV·µm, 10-30% of the particle hits did not lead to DNA damage inducing 53BP1 or γ-H2AX foci formation.
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http://dx.doi.org/10.1667/RR15312.1DOI Listing
June 2019

Home parenteral nutrition provision modalities for chronic intestinal failure in adult patients: An international survey.

Clin Nutr 2020 02 25;39(2):585-591. Epub 2019 Mar 25.

Auckland City Hospital, Auckland, New Zealand.

Background & Aims: The safety and effectiveness of a home parenteral nutrition (HPN) program depends both on the expertise and the management approach of the HPN center. We aimed to evaluate both the approaches of different international HPN-centers in their provision of HPN and the types of intravenous supplementation (IVS)-admixtures prescribed to patients with chronic intestinal failure (CIF).

Methods: In March 2015, 65 centers from 22 countries enrolled 3239 patients (benign disease 90.1%, malignant disease 9.9%), recording the patient, CIF and HPN characteristics in a structured database. The HPN-provider was categorized as health care system local pharmacy (LP) or independent home care company (HCC). The IVS-admixture was categorized as fluids and electrolytes alone (FE) or parenteral nutrition, either commercially premixed (PA) or customized to the individual patient (CA), alone or plus extra FE (PAFE or CAFE). Doctors of HPN centers were responsible for the IVS prescriptions.

Results: HCC (66%) was the most common HPN provider, with no difference noted between benign-CIF and malignant-CIF. LP was the main modality in 11 countries; HCC prevailed in 4 European countries: Israel, USA, South America and Oceania (p < 0.001). IVS-admixture comprised: FE 10%, PA 17%, PAFE 17%, CA 38%, CAFE 18%. PA and PAFE prevailed in malignant-CIF while CA and CAFE use was greater in benign-CIF (p < 0.001). PA + PAFE prevailed in those countries where LP was the main HPN-provider and CA + CAFE prevailed where the main HPN-provider was HCC (p < 0.001).

Conclusions: This is the first study to demonstrate that HPN provision and the IVS-admixture differ greatly among countries, among HPN centers and between benign-CIF and cancer-CIF. As both HPN provider and IVS-admixture types may play a role in the safety and effectiveness of HPN therapy, criteria to homogenize HPN programs are needed so that patients can have equal access to optimal CIF care.
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http://dx.doi.org/10.1016/j.clnu.2019.03.010DOI Listing
February 2020

The influence of sleep apnea syndrome and intermittent hypoxia in carotid adventitial vasa vasorum.

PLoS One 2019 5;14(2):e0211742. Epub 2019 Feb 5.

Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova, Obesity, Diabetes and Metabolism (ODIM) research group, IRBLleida, University of Lleida, Lleida, Catalonia, Spain.

Subjects with sleep apnea-hypopnea syndrome (SAHS) show an increased carotid intima-media thickness. However, no data exist about earlier markers of atheromatous disease, such as the proliferation and expansion of the adventitial vasa vasorum (VV) to the avascular intima in this setting. Our aim was to assess carotid VV density and its relationship with sleep parameters in a cohort of obese patients without prior vascular events. A total of 55 subjects evaluated for bariatric surgery were prospectively recruited. A non-attended respiratory polygraphy was performed. The apnea-hypopnea index (AHI) and the cumulative percentage of time spent with oxygen saturation below 90% (CT90) were assessed. Serum concentrations of soluble intercellular adhesion molecule 1, P-selectin, lipocalin-2 and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured. Contrast-enhanced carotid ultrasound was used to assess the VV density. Patients with SAHS (80%) showed a higher adventitial VV density (0.801±0.125 vs. 0.697±0.082, p = 0.005) and higher levels of sVCAM-1 (745.2±137.8 vs. 643.3±122.7 ng/ml, p = 0.035) than subjects with an AHI lower than 10 events/hour. In addition, a positive association exist between mean VV density and AHI (r = 0.445, p = 0.001) and CT90 (r = 0.399, p = 0.005). Finally, in the multiple linear regression analysis, female sex, fasting plasma glucose and AHI (but not CT90) were the only variables independently associated with the mean adventitial VV density (R2 = 0.327). In conclusion, a high VV density is present in obese subjects with SAHS, and chronic intermittent hypoxia is pointed as an independent risk factor for the development of this early step of atheromatous disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211742PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363284PMC
November 2019

SIMULATION OF EARLY RADIATION-INDUCED DNA DAMAGE ON DIFFERENT TYPES OF CELL NUCLEI.

Radiat Prot Dosimetry 2019 May;183(1-2):26-31

IRSN, Institut de Radioprotection et de Sûreté Nucléaire, Fontenay aux Roses, France.

This work presents a comparison of simulated early radiation-induced DNA damage represented by yields of double-strand breaks (DSB) in three different human cell nuclei geometries representing fibroblasts, lymphocytes and endothelial cells for protons and alpha particles of different energies and for different irradiation configurations. Each cell nucleus model includes a multi-scale description of the DNA target from the molecular level to the whole human genome representation (6 Gbp) in the G0/G1 phase of the cell cycle and was generated with the DnaFabric software. The three nuclei differ in shape, volume, and therefore DNA density. A calculation chain based on Geant4-DNA that takes into account the physical, physico-chemical and chemical stages was used to simulate the irradiation of the different cell nuclei. Results show an increase of DSB/primary/μm with an increase of DNA density and an increase of DSB/Gy/Gbp with an increase of the cell nucleus volume which indicates that the cell nucleus shape and size have an impact on early DNA damage, which may play a role in latter effects.
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http://dx.doi.org/10.1093/rpd/ncy237DOI Listing
May 2019

Dosimetric impact of Acuros XB dose-to-water and dose-to-medium reporting modes on VMAT planning for head and neck cancer.

Phys Med 2018 Nov 15;55:107-115. Epub 2018 Nov 15.

Department of Medical Sciences, University of Girona, C/Emili Grahit 77, 17003 Girona, Spain; Department of Radiology, Clínica Girona, Institut de Diagnòstic per la Imatge, C/Lorenzana 36, 17002 Girona, Spain. Electronic address:

Purpose: To assess the dosimetric impact of switching from the Analytical Anisotropic Algorithm (AAA) to Acuros XB (AXB) for both dose-to-medium (Dm) and dose-to-water (Dw) in VMAT for H&N patients. To study whether it should be linked to a change in the dose prescriptions to the PTVs and in the constraints to the OARs.

Methods: 110H&N patients treated with VMAT were included. Calculations were performed with AAA and AXB. PTV54, PTV60, PTV70, spinal cord, brainstem, brain, larynx, oral cavity, cochleas, parotid glands and mandible were delineated. Clinically-relevant dose-volume parameters were compared. Paired t-tests were used to analyze the differences in mean values. The Pitman-Morgan dispersion test was computed to evaluate inter-patient variability of these differences.

Results: AAA overestimated all dose-volume parameters compared to AXB Dm (0.2 Gy to 2.4 Gy). No systematic trend was observed in the differences between AAA and AXB Dw (-5.3 Gy to 0.6 Gy). Dose-volume parameters were significantly higher for AXB Dw compared to AXB Dm (0.1 Gy to 6.6 Gy). In all cases, the largest absolute differences (4%-14%) were found for maximum absorbed doses to the cochleas and the mandible. The number of parameters with significant inter-patient variability was greater when switching from AAA to AXB Dw than from AAA to AXB Dm.

Conclusions: There are important differences between AXB and AAA in VMAT planning for H&N cancer. The systematic differences and their inter-patient variability identified may help to facilitate decision-making about the dose prescriptions to the PTVs and the constraints to the OAR.
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http://dx.doi.org/10.1016/j.ejmp.2018.10.024DOI Listing
November 2018

Outcomes of Bariatric Surgery in Patients with Cirrhosis.

Obes Surg 2019 02;29(2):585-592

Department of Endocrinology and Nutrition, Parc Taulí University Hospital, UAB, Sabadell, Spain.

Context: Information concerning the risk-benefit profile of bariatric surgery in subjects with liver cirrhosis is scarce. Our aim was to describe the long-term outcomes of bariatric surgery in a cohort of patients with liver cirrhosis submitted to bariatric surgery.

Methods: This was a multicenter, retrospective observational study performed by the Obesity Group of the Spanish Society of Endocrinology and Nutrition (GOSEEN), with a review of patients with cirrhosis who had undergone bariatric surgery during the period from April 2004 to March 2017 in ten public reference hospitals in Spain.

Results: Data on 41 patients with cirrhosis submitted to obesity surgery were collected (mean age 53.8 ± 7.9 years, 46.3% women, presurgical BMI 45 ± 8.3 kg/m). All but one patient belonged to Child-Pugh class A, and sleeve gastrectomy was conducted in 68.3% of cases. Percentage of total weight loss (%TWL) was 26.33 ± 8.3% and 21.16 ± 15.32% at 1 and 5 years after surgery, respectively. This was accompanied by a significant reduction of type 2 diabetes, high blood pressure, and dyslipidemia and by an improvement of liver enzymes over time. Model for End-Stage Liver Disease (MELD) index increased from 7.2 ± 1.9 to 9.8 ± 4.6 after 5 years. Seven patients (17%) developed early postsurgical complications. No postsurgical mortality was observed. During follow-up, only five patients developed liver decompensation.

Conclusions: Bariatric surgery in selected patients with liver cirrhosis has metabolic benefits that could have a positive impact on liver prognosis.

Trial Registration: Controlledtrials.com Identifier: 10.1186/ISRCTN15009106.
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http://dx.doi.org/10.1007/s11695-018-3562-8DOI Listing
February 2019

Autosomal dominant hypercholesterolemia in Catalonia: Correspondence between clinical-biochemical and genetic diagnostics in 967 patients studied in a multicenter clinical setting.

J Clin Lipidol 2018 Nov - Dec;12(6):1452-1462. Epub 2018 Sep 7.

Institut de Recerca - Hospital de la Santa Creu i Sant Pau, Serveis de Bioquímica, i d'Endocrinologia i Nutrició, IIB Sant Pau, CIBERDEM, Universitat Autònoma de Barcelona, Departaments de Bioquímica i Biologia Molecular, i Medicina, Barcelona, Spain. Electronic address:

Background: Autosomal dominant hypercholesterolemia (ADH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes, and it is estimated to be greatly underdiagnosed. The most cost-effective strategy for increasing ADH diagnosis is a cascade screening from mutation-positive probands.

Objective: The objective of this study was to evaluate the results from 2008 to 2016 of ADH genetic analysis performed in our clinical laboratory, serving most lipid units of Catalonia, a Spanish region with approximately 7.5 million inhabitants.

Methods: After the application of the Dutch Lipid Clinic Network (DLCN) clinical diagnostic score for ADH, this information and blood or saliva from 23 different lipid clinic units were investigated in our laboratory. DNA was screened for mutations in LDLR, APOB, and PCSK9, using the DNA-array LIPOchip, the next-generation sequencing SEQPRO LIPO RS platform, and multiplex ligation-dependent probe amplification (MLPA). The Simon Broome Register Group (SBRG) criteria was calculated and analyzed for comparative purposes.

Results: A total of 967 unrelated samples were analyzed. From this, 158 pathogenic variants were detected in 356 patients. The main components of the DLCN criteria associated with the presence of mutation were plasma LDL cholesterol (LDLc), age, and the presence of tendinous xanthomata. The contribution of family history to the diagnosis was lower than in other studies. DLCN and SBRG were similarly useful for predicting the presence of mutation.

Conclusion: In a real clinical practice, multicenter setting in Catalonia, the percentage of positive genetic diagnosis in patients potentially affected by ADH was 38.6%. The DLCN showed a relatively low capacity to predict mutation detection but a higher one for ruling out mutation.
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http://dx.doi.org/10.1016/j.jacl.2018.09.002DOI Listing
October 2019

Senescence of bone marrow-derived mesenchymal stem cells from patients with idiopathic pulmonary fibrosis.

Stem Cell Res Ther 2018 09 26;9(1):257. Epub 2018 Sep 26.

Dorothy P. & Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh School of Medicine, W1244 BST Tower 200 Lothrop Street, Pittsburgh, PA, 15261, USA.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease for which age is the most important risk factor. Different mechanisms associated with aging, including stem cell dysfunction, have been described to participate in the pathophysiology of IPF. We observed an extrapulmonary effect associated with IPF: increase in cell senescence of bone marrow-derived mesenchymal stem cells (B-MSCs).

Methods: B-MSCs were obtained from vertebral bodies procured from IPF patients and age-matched normal controls. Cell senescence was determined by cell proliferation and expression of markers of cell senescence p16, p21, and β-galactosidase activity. Mitochondrial function and DNA damage were measured. Paracrine induction of senescence and profibrotic responses were analyzed in vitro using human lung fibroblasts. The reparative capacity of B-MSCs was examined in vivo using the bleomycin-induced lung fibrosis model.

Results: In our study, we demonstrate for the first time that B-MSCs from IPF patients are senescent with significant differences in mitochondrial function, with accumulation of DNA damage resulting in defects in critical cell functions when compared with age-matched controls. Senescent IPF B-MSCs have the capability of paracrine senescence by inducing senescence in normal-aged fibroblasts, suggesting a possible link between senescent B-MSCs and the late onset of the disease. IPF B-MSCs also showed a diminished capacity to migrate and were less effective in preventing fibrotic changes observed in mice after bleomycin-induced injury, increasing illness severity and proinflammatory responses.

Conclusions: We describe extrapulmonary alterations in B-MSCs from IPF patients. The consequences of having senescent B-MSCs are not completely understood, but the decrease in their ability to respond to normal activation and the risk of having a negative impact on the local niche by inducing inflammation and senescence in the neighboring cells suggests a new link between B-MSC and the onset of the disease.
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http://dx.doi.org/10.1186/s13287-018-0970-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158816PMC
September 2018

Influence of Morbid Obesity and Bariatric Surgery Impact on the Carotid Adventitial Vasa Vasorum Signal.

Obes Surg 2018 12;28(12):3935-3942

Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova, Obesity, Diabetes and Metabolism Research Group (ODIM), IRBLleida, University of Lleida, Av. Rovira Roure 80, 25198, Lleida, Spain.

Introduction/purpose: Adventitial vasa vasorum (VV) expansion to the avascular intima precedes an increase in carotid intima-media thickness. However, factors involved in the development of the atherosclerotic process and its reversibility remain unclear. We aimed to evaluate the VV signal in both morbid obesity and after bariatric surgery (BS).

Materials/methods: We conducted a case-control study to examine the VV signal in the carotid of 40 morbidly obese patients and 40 non-obese controls. The effect of BS was evaluated in 33 patients. Contrast-enhanced carotid ultrasound was used to assess the VV signal.

Results: The mean VV density was higher in obese than in non-obese subjects (0.739 ± 0.117 vs. 0.570 ± 0.111, p < 0.001). The VV signal positively correlated with BMI (p < 0.001) and waist circumference (p = 0.001) but was not related to cIMT. The stepwise multivariate regression analysis revealed that waist circumference (beta = 0.507, p < 0.001) together with fasting plasma glucose (beta = 0.229, p = 0.024) were independently associated with the VV signal (R = 0.382). Before BS, the median VV signal correlated with soluble intercellular adhesion molecule 1 (p = 0.022). After a 12-month follow-up, a 12.0% decrease in VV (0.731 ± 0.126 vs. 0.643 ± 0.115, p = 0.003) was observed. In the univariate analysis, the decrease in VV was associated with the baseline VV density (p < 0.001), baseline systolic blood pressure (p = 0.019) and a decrease in sICAM (p = 0.005). However, only baseline systolic pressure (beta = 0.417, p = 0.024) independently predicted the absolute change in VV signal (R = 0.174).

Conclusions: Morbidly obesity is associated with increased VV density. In addition, BS appears to reduce the earlier expansion of the adventitial vasa vasorum.
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http://dx.doi.org/10.1007/s11695-018-3410-xDOI Listing
December 2018

Idiopathic Pulmonary Fibrosis: Aging, Mitochondrial Dysfunction, and Cellular Bioenergetics.

Front Med (Lausanne) 2018 5;5:10. Epub 2018 Feb 5.

Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.

At present, the etiology of idiopathic pulmonary fibrosis (IPF) remains elusive. Over the past two decades, however, researchers have identified and described the underlying processes that result in metabolic dysregulation, metabolic reprogramming, and mitochondrial dysfunction observed in the cells of IPF lungs. Metabolic changes and mitochondrial dysfunction in IPF include decreased efficiency of electron transport chain function with increasing production of reactive oxygen species, decreased mitochondrial biogenesis, and impaired mitochondrial macroautophagy, a key pathway for the removal of dysfunctional mitochondria. Metabolic changes in IPF have potential impact on lung cell function, differentiation, and activation of fibrotic responses. These alterations result in activation of TGF-β and predispose to the development of pulmonary fibrosis. IPF is a disease of the aged, and many of these same bioenergetic changes are present to a lesser extent with normal aging, raising the possibility that these anticipated alterations in metabolic processes play important roles in creating susceptibility to the development of IPF. This review explores what is known regarding the cellular metabolic and mitochondrial changes that are found in IPF, and examines this body of literature to identify future research direction and potential points of intervention in the pathogenesis of IPF.
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http://dx.doi.org/10.3389/fmed.2018.00010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807592PMC
February 2018

ATF3 represses PINK1 gene transcription in lung epithelial cells to control mitochondrial homeostasis.

Aging Cell 2018 04 24;17(2). Epub 2018 Jan 24.

Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

PINK1 (PTEN-induced putative kinase 1) is a key regulator of mitochondrial homeostasis that is relatively depleted in aging lungs and in lung epithelial cells from patients with idiopathic pulmonary fibrosis (IPF), a disease linked with aging. Impaired PINK1 expression and accumulation of damaged mitochondria in lung epithelial cells from fibrotic lungs were associated with the presence of ER stress. Here, we show that ATF3 (activating transcription factor 3), a member of the integrated stress response (ISR), negatively regulates transcription of the PINK1 gene. An ATF3 binding site within the human PINK1 promoter is located in the first 150 bp upstream of the transcription start site. Induction of ER stress or overexpression of ATF3 inhibited the activity of the PINK1 promoter. Importantly, overexpression of ATF3 causes accumulation of depolarized mitochondria, increased production of mitochondrial ROS, and loss of cell viability. Furthermore, conditional deletion of ATF3 in type II lung epithelial cells protects mice from bleomycin-induced lung fibrosis. Finally, we observed that ATF3 expression increases in the lung with age and, specially, in lung epithelial cells from IPF lungs. These data provide a unique link between ATF3 and PINK1 expression suggesting that persistent stress, driven by ATF3, can dysregulate mitochondrial homeostasis by repression of PINK1 mRNA synthesis.
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http://dx.doi.org/10.1111/acel.12720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847866PMC
April 2018

Nitric Oxide-Independent Soluble Guanylate Cyclase Activation Improves Vascular Function and Cardiac Remodeling in Sickle Cell Disease.

Am J Respir Cell Mol Biol 2018 05;58(5):636-647

2 Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine.

Sickle cell disease (SCD) is associated with intravascular hemolysis and oxidative inhibition of nitric oxide (NO) signaling. BAY 54-6544 is a small-molecule activator of oxidized soluble guanylate cyclase (sGC), which, unlike endogenous NO and the sGC stimulator, BAY 41-8543, preferentially binds and activates heme-free, NO-insensitive sGC to restore enzymatic cGMP production. We tested orally delivered sGC activator, BAY 54-6544 (17 mg/kg/d), sGC stimulator, BAY 41-8543, sildenafil, and placebo for 4-12 weeks in the Berkeley transgenic mouse model of SCD (BERK-SCD) and their hemizygous (Hemi) littermate controls (BERK-Hemi). Right ventricular (RV) maximum systolic pressure (RVmaxSP) was measured using micro right-heart catheterization. RV hypertrophy (RVH) was determined using Fulton's index and RV corrected weight (ratio of RV to tibia). Pulmonary artery vasoreactivity was tested for endothelium-dependent and -independent vessel relaxation. Right-heart catheterization revealed higher RVmaxSP and RVH in BERK-SCD versus BERK-Hemi, which worsened with age. Treatment with the sGC activator more effectively lowered RVmaxSP and RVH, with 90-day treatment delivering superior results, when compared with other treatments and placebo groups. In myography experiments, acetylcholine-induced (endothelium-dependent) and sodium-nitroprusside-induced (endothelium-independent NO donor) relaxation of the pulmonary artery harvested from placebo-treated BERK-SCD was impaired relative to BERK-Hemi but improved after therapy with sGC activator. By contrast, no significant effect for sGC stimulator or sildenafil was observed in BERK-SCD. These findings suggest that sGC is oxidized in the pulmonary arteries of transgenic SCD mice, leading to blunted responses to NO, and that the sGC activator, BAY 54-6544, may represent a novel therapy for SCD-associated pulmonary arterial hypertension and cardiac remodeling.
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http://dx.doi.org/10.1165/rcmb.2017-0292OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946331PMC
May 2018

Simulation of early DNA damage after the irradiation of a fibroblast cell nucleus using Geant4-DNA.

Sci Rep 2017 09 20;7(1):11923. Epub 2017 Sep 20.

IRSN, Institut de Radioprotection et de Sûreté Nucléaire, BP17, 92962, Fontenay-aux-Roses, France.

In order to improve the understanding of the mechanisms involved in the generation of early DNA damage, a new calculation chain based on the Geant4-DNA toolkit was developed. This work presents for the first time the simulation of the physical, physicochemical and chemical stages of early radiation damage at the scale of an entire human genome (fibroblast, male) and using Geant4-DNA models. The DnaFabric software was extended to generate and export this nucleus model to a text file with a specific format that can be read by Geant4 user applications. This calculation chain was used to simulate the irradiation of the nucleus by primary protons of different energies (0,5; 0,7; 0,8; 1; 1,5; 2; 3; 4; 5; 10; 20 MeV) and the results, in terms of DNA double strand breaks, agree with experimental data found in the literature (pulsed field electrophoresis technique). These results show that the simulation is consistent and that its parameters are well balanced. Among the different parameters that can be adjusted, our results demonstrate that the criterion used to select direct strand break appears to have a very significant role on the final number of simulated double strand breaks.
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http://dx.doi.org/10.1038/s41598-017-11851-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607336PMC
September 2017

IPF lung fibroblasts have a senescent phenotype.

Am J Physiol Lung Cell Mol Physiol 2017 Dec 31;313(6):L1164-L1173. Epub 2017 Aug 31.

The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, Pittsburgh, Pennsylvania;

The mechanisms of aging that are involved in the development of idiopathic pulmonary fibrosis (IPF) are still unclear. Although it has been hypothesized that the proliferation and activation of human lung fibroblasts (hLFs) are essential in IPF, no studies have assessed how this process works in an aging lung. Our goal was to elucidate if there were age-related changes on primary hLFs isolated from IPF lungs compared with age-matched controls. We investigated several hallmarks of aging in hLFs from IPF patients and age-matched controls. IPF hLFs have increased cellular senescence with higher expression of β-galactosidase, p21, p16, p53, and cytokines related to the senescence-associated secretory phenotype (SASP) as well as decreased proliferation/apoptosis compared with age-matched controls. Additionally, we observed shorter telomeres, mitochondrial dysfunction, and upon transforming growth factor-β stimulation, increased markers of endoplasmic reticulum stress. Our data suggest that IPF hLFs develop senescence resulting in a decreased apoptosis and that the development of SASP may be an important contributor to the fibrotic process observed in IPF. These results might change the existing paradigm, which describes fibroblasts as aberrantly activated cells, to a cell with a senescence phenotype.
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http://dx.doi.org/10.1152/ajplung.00220.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148001PMC
December 2017

Pediatric imaging in DICER1 syndrome.

Pediatr Radiol 2017 Sep 4;47(10):1292-1301. Epub 2017 May 4.

Department of Diagnostic Imaging, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, M5G 1X8, Canada.

Background: DICER1 syndrome, arising from a mutation in the DICER1 gene mapped to chromosome 14q32, is associated with an increased risk of a range of benign and malignant neoplasms.

Objective: To determine the spectrum of abnormalities and imaging characteristics in patients with DICER1 syndrome at a tertiary pediatric hospital.

Materials And Methods: This retrospective analysis evaluated imaging in patients ≤18 years with DICER1 germline variants between January 2004 and July 2016. An imaging database search including keywords pleuropulmonary blastoma, cystic nephroma, pineoblastoma, embryonal rhabdomyosarcoma, ovarian sex cord-stromal tumor, ovarian Sertoli-Leydig cell tumor and DICER1 syndrome, was cross-referenced against the institutional Cancer Genetics Program database, excluding patients with negative/unknown DICER1 gene testing.

Results: Sixteen patients were included (12 females; mean age at presentation: 4.2 years, range: 14 days to 17 years), with surveillance imaging encompassing the following modalities: chest X-ray and CT; abdominal, pelvic and neck US; and brain and whole-body MRI. Malignant lesions (68.8% of patients) included pleuropulmonary blastoma (5), pineoblastoma (3), ovarian Sertoli-Leydig cell tumor (1), embryonal rhabdomyosarcoma (1) and renal sarcoma (1); benign lesions (37.5% of patients) included thyroid cysts (2), thyroid nodules (2), cystic nephroma (2), renal cysts (1) and pineal cyst (1). A common lesional appearance observed across modalities and organs was defined as the "cracked windshield" sign.

Conclusion: The spectrum of DICER1-related tumors and the young age at presentation suggest early surveillance of at-risk patients is critical, while minimizing exposure to ionizing radiation.
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http://dx.doi.org/10.1007/s00247-017-3875-0DOI Listing
September 2017

Advanced glycation end-products in morbid obesity and after bariatric surgery: When glycemic memory starts to fail.

Endocrinol Diabetes Nutr 2017 01 18;64(1):4-10. Epub 2017 Jan 18.

Servicio de Endocrinología y Nutrición, Hospital Universitario Arnau de Vilanova, Institut de Recerca Biomèdica (IRB) de Lleida, Universitat de Lleida, Lleida, España; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, España. Electronic address:

Background And Objective: Advanced glycation end-products (AGEs) are a marker of metabolic memory. Their levels increases when oxidative stress, inflammation, or chronic hyperglycemia exists. The role of morbid obesity in AGE levels, and the impact of bariatric surgery on them are unknown.

Patients And Method: An observational study with three sex- and age-matched cohorts: 52 patients with obesity, 46 patients undergoing bariatric surgery in the last 5 years, and 46 control subjects. AGE were measured using skin autofluorescence (SAF) in the forearm with an AGE Reader™ (DiagnOptics Technologies, Groningen, The Netherlands). Presence of metabolic syndrome was assessed.

Results: Patients with morbid obesity had higher SAF levels (2.14±0.65AU) than non-obese subjects (1.81±0.22AU; P<.001), which was mainly attributed to obese subjects with metabolic syndrome (2.44±0.67 vs. 1.86±0.51AU; P<.001). After bariatric surgery, SAF continued to be high (2.18±0.40AU), and greater as compared to the non-obese population (P<.001). A multivariate analysis showed that age and presence of metabolic syndrome (but not sex or body mass index) were independently associated to SAF (R=0.320).

Conclusion: SAF is increased in patients with morbid obesity and metabolic syndrome, mainly because of the existence of type 2 diabetes mellitus. In the first 5 years following bariatric surgery, weight loss and metabolic improvement are not associated with a parallel decrease in subcutaneous AGE levels.
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http://dx.doi.org/10.1016/j.endinu.2016.09.009DOI Listing
January 2017