We hereby present experimental and theoretical insights on the use of biomineralized magnetite nanoparticles, called magnetosomes, as heat nanoinductors in the magnetic hyperthermia technique. The ...heating efficiency or specific absorption rate of magnetosomes extracted from Magnetospirillum gryphiswaldense bacteria and immersed in water and agarose gel, was directly determined from the hysteresis loops obtained at different frequencies and magnetic field amplitudes. We demonstrate that heat production of magnetosomes can be predicted in the framework of the Stoner–Wohlfarth theory of uniaxial magnetic anisotropy subjected to significant dipolar interactions, which can be described in terms of an interaction anisotropy superimposed to that of each particle. Based on these findings, we propose optimal magnetic field amplitude and frequency values in order to maximize the heat production while keeping the undesired eddy current effects below safe and tolerable limits. The efficiency of magnetosomes as heat generators and their impact on cell viability has been checked in macrophage cells. Our results clearly indicate that the hyperthermia treatment causes both cell death and inhibition of cell proliferation. Specifically, only 36% of the treated macrophages remained alive 2 h after alternating magnetic field exposure, and 24 h later the percentage fell to 22%.
Cancer cells develop mechanisms that increase nutrient uptake, including key nutrient carriers, such as amino acid transporter 1 (LAT-1) and glucose transporter 1 (GLUT-1), regulated by the ...oxygen-sensing Von Hippel Lindau-hypoxia-inducible factor (VHL-HIF) transcriptional pathway. We aimed to analyze these metabolic players in gastroenteropancreatic neuroendocrine tumors (GEP-NET) and correlate them with tumor malignancy and progression. LAT-1, GLUT-1, and pVHL expression was analyzed in 116 GEP-NETs and 48 peritumoral tissue samples by immunohistochemistry. LAT-1 was stably silenced using specific shRNA in the human NET BON cell line. LAT-1 expression was significantly increased in tumor tissue compared to non-tumor tissue in both gastrointestinal (67% vs. 44%) and pancreatic NETs (54% vs. 31%). Similarly, GLUT-1 was substantially elevated in gastrointestinal (74% vs. 19%) and pancreatic (58% vs. 4%) NETs. In contrast, pVHL expression was decreased (85% vs. 58%) in pancreatic NETs. Tumors with metastases at diagnosis displayed increased LAT-1 and GLUT-1 and decreased pVHL expression (p < 0.001). In accordance with these data, silencing LAT-1 curtailed cell proliferation in BON cells. These findings suggest that specific mechanisms that increase nutrient uptake, such as LAT-1 and GLUT-1, are increased in GEP-NETs, whereas pVHL is decreased. These markers might be related to the proliferation and metastatic capacity of these tumors.
The distribution of the high concentrations of arsenic (As) and fluoride (F-) in groundwater on a Pan-European scale could be explained by the geological European context (lithology and structural ...faults). To test this hypothesis, seventeen countries and eighteen geological survey organizations (GSOs) have participated in the dataset. The methodology has used the HydroGeoToxicity (HGT) and the Baseline Concentration (BLC) index. The results prove that most of the waters considered in this study are in good conditions for drinking water consumption, in terms of As and/or F- content. A low proportion of the analysed samples present HGT≥ 1 levels (4% and 7% for As and F-, respectively). The spatial distribution of the highest As and/or F- concentrations (via BLC values) has been analysed using GIS tools. The highest values are identified associated with fissured hard rock outcrops (crystalline rocks) or Cenozoic sedimentary zones, where basement fractures seems to have an obvious control on the distribution of maximum concentrations of these elements in groundwaters.
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•Geological context is crucial in the spatial analysis of arsenic and fluoride.•HydroGeoToxicity (HGT) assesses quality of groundwater as drinking-water.•BaseLine Concentration (BLC) give the most significant geogenic anomalies.•Structural control is relevant in the distribution of arsenic in porous aquifers.•Lithology is pivotal in fluoride distribution (e.g. fissured hard rocks).
Purpose
Molecular subtyping based on gene expression profiling (i.e., PAM50 assay) aids in determining the prognosis and treatment of breast cancer (BC), particularly in hormone receptor ...(HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors, where luminal A and B subtypes have different prognoses and treatments. Several surrogate classifications have been proposed for distinguishing between the luminal A and B subtypes. This study determines the accuracy of local immunohistochemistry (IHC) techniques for classifying HR-positive/HER2-negative (HR+/HER2−) tumors according to intrinsic subtypes using the nCOUNTER PAM50 assay as reference and the HR status definition according the ASCO/CAP recommendations.
Methods
Molecular subtypes resulting from nCOUNTER PAM50 performed in our laboratory between 2014 and 2020 were correlated with three different proxy surrogates proposed in the literature based on ER, PR, HER2, and Ki67 expression with different cut-off values. Concordance was measured using the level of agreement and kappa statistics.
Results
From 1049 samples with the nCOUNTER test, 679 and 350 were luminal A and B subtypes, respectively. Only a poor-to-fair correlation was observed between the three proxy surrogates and real genomic subtypes as determined by nCOUNTER PAM50. Moreover, 5–11% and 18–36% of the nCOUNTER PAM50 luminal B and A tumors were classified as luminal A and B, respectively, by these surrogates.
Conclusion
The concordance between luminal subtypes determined by three different IHC-based classifiers and the nCOUNTER PAM50 assay was suboptimal. Thus, a significant proportion of luminal A and B tumors as determined by the surrogate classifiers could be undertreated or over-treated.
Severe asthma is a heterogeneous syndrome with several clinical variants and often represents a complex disease requiring a specialized and multidisciplinary approach, as well as the use of multiple ...drugs. The prevalence of severe asthma varies from one country to another, and it is estimated that 50% of these patients present a poor control of their disease. For the best management of the patient, it is necessary a correct diagnosis, an adequate follow-up and undoubtedly to offer the best available treatment, including biologic treatments with monoclonal antibodies. With this objective, this consensus process was born, which began in its first version in 2018, whose goal is to offer the patient the best possible management of their disease in order to minimize their symptomatology. For this 2020 consensus update, a literature review was conducted by the authors. Subsequently, through a two-round interactive Delphi process, a broad panel of asthma experts from SEPAR and the regional pulmonology societies proposed the recommendations and conclusions contained in this document.
Newborn Screening Programs (NSP) in Spain were born in the
city of Granada in 1968. Till the 1980s, they were developed around
the so-called “National Plan for Preventing Subnormality”, covering
up ...to 30% of the Spanish newborns. From 1982, when the health
system management was transferred to the different autonomous regions,
the NSP began to expand, and the bases to transform them into
an organized and multidisciplinary activity, integrated and coordinated
from the National Health System were settled. Despite this expansion,
it is not until the 1990s when their coverage reaches almost
100% newborns in Spain.
NSP grew up asymmetrically across the different autonomous
regions. In 2005 and 2006 the scientific societies SEQC (Spanish
Society of Clinical Chemistry) and AECNE (Spanish Society of
Newborn Screening), coordinated by the Health Promotion Area of
the General Directorate of Public Health, gathered together the necessary
information to elaborate a report on the NSP in Spain addressed
to the Interterritorial Council of the National Health System. In July
2013, that Council approved the seven diseases that should be part of
each region newborn screening panel, being the first step towards the
NSP harmonization in Spain. Currently, the NSP include between 8
and 29 diseases in their panels, thus more still more efforts are needed
in order to achieve a higher uniformity.
Los Programas de Cribado Neonatal (PCN) nacen en España en
Granada en el año 1968. Posteriormente, y hasta los años 80, se fueron
desarrollando en torno al llamado “Plan Nacional de Prevención
de la Subnormalidad” con una cobertura cercana al 30% de los recién
nacidos españoles. A partir de 1982, con el inicio de la gestión de
la sanidad a las comunidades autónomas (CCAA), los PCN se expandieron
y se comenzaron a sentar las bases para que éstos se convirtieran
en una actividad organizada y multidisciplinar, integrados y
coordinados desde el Sistema de Salud. A pesar de dicha expansión
no es hasta el inicio de la década de los 90 cuando se consigue una
cobertura próxima al 100% de los RN en España.
Los PCN fueron creciendo de forma muy asimétrica en las diferentes
CCAA y en los años 2005 y 2006 las Sociedades Científicas
SEQC (Sociedad Española de Química Clínica) y AECNE
(Asociación Española de Cribado Neonatal), con la coordinación
del Área de Promoción de la Salud de la Dirección General de Salud
Pública, recopilaron la información y elaboraron un informe, sobre
los PCN en España para el Consejo Interterritorial del sistema
Nacional de Salud (CISNS). En julio de 2013 este Consejo aprobó
las siete enfermedades que debían formar parte del panel de detección
de los PCN territoriales, primer paso hacia la armonización de
estos programas. Actualmente, los PCN incluyen entre 8 y 29 enfermedades
por lo que es necesario seguir trabajando para conseguir una
mayor uniformidad.
We aim to evaluate the adherence rate to an Antimicrobial Stewardship Program (ASP) in an Intensive Care Unit (ICU), and to assess its effect on the use of antibiotics, quality indicators and ...clinical outcomes.
Retrospective description of the interventions proposed by the ASP. We compared antimicrobial use, quality and safety indicators in an ASP versus a non-ASP period. The study was performed in a polyvalent ICU of a medium-size University Hospital (600 beds). We studied patients admitted to the ICU for any cause during the ASP period, provided that a microbiological sample aiming to diagnose a potential infection has been drawn, or antibiotics have been started. We elaborated and registered of non-mandatory recommendations to improve antimicrobial prescription (audit and feedback structure) and its registry during the ASP period (15 months, October 2018-December 2019). We compared indicators in a period with ASP (April-June 2019) and without ASP (April-June 2018).
We issued 241 recommendations on 117 patients, 67% of them classified as de-escalation type. The rate of adherence to the recommendations was high (96.3%). In the ASP period, the mean number of antibiotics per patient (3.3±4.1 vs 2.4±1.7, p=0.04) and the days of treatment (155 DOT/100 PD vs 94 DOT/100 PD, p <0.01) were reduced. The implementation of the ASP did not compromise patient safety or produce changes in clinical outcomes.
The implementation of an ASP is widely accepted in the ICU, reducing the consumption of antimicrobials, without compromising patient safety.
The immune checkpoint based therapy targeting the programmed death-1 (PD-1) receptor and its PD-L1 ligand has recently been approved for the therapy of different malignant conditions, but not yet for ...gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In this context, we evaluated the expression of PD-1 and PD-L1 in GEP-NETs and its potential correlations with clinical outcomes. Expression of PD-1/PD-L1 was analyzed by immunohistochemistry in 116 GEP-NETs and 48 samples of peritumoral tissue. In addition, the expression of these molecules was assessed by flow cytometry in peripheral blood mononuclear cells (PBMC) from patients with GEP-NETs (n = 32) and healthy controls (n = 32) and in intratumoral mononuclear cells (TMCs) (n = 3). Expression of PD-L1 and PD-1 was detected by immunohistochemistry in 6% and 1% of tumor tissue samples, respectively, and in 8% of peritumoral tissue samples, for both markers. We also observed that PD-1 expression by TMCs was associated with metastatic disease at diagnosis, and the levels of circulating PD-1+ PBMCs were associated with progressive disease upon follow-ups. In addition, circulating PD-1+ PBMCs were significantly correlated with PD-L1 expression by tumor cells. Our data suggest that PD-1/PD-L1 is expressed in 1 to 8% of GEP-NETs, and that this feature is significantly associated with disease evolution (p < 0.01).
Abstract Prolactin receptor (PRLr) is a member of the cytokine receptor superfamily 1 showing tissue specific structural diversity. Expression of PRLr isoforms in lymphoid tissues has been associated ...with immunomodulatory function of prolactin. Bovine tuberculosis (bTB) is characterized by chronic inflammation caused by the persistent infection of lymphoid tissues with Mycobacterium bovis . To test the hypothesis of the influence of PRLr in the pathogenesis of bTB, the aim of this study was to identify PRLr isoforms expressed during bTB in different tissues and to analyze their association with the pathogenesis of bTB. We examined lymphoid and non-lymphoid tissues ex vivo from experimentally and naturally infected cattle, as well as from bTB-free cattle, by Western blot (WB) and immunohistochemistry (IH). In vitro , monocytes from exposed, infected, and healthy cattle were stimulated with M. bovis antigens and then analyzed by WB. To detect transcriptional levels of PRLr in macrophages (MØ) exposed to M. bovis , real time PCR was performed. WB revealed diversity of PRLr isoforms in tissues from infected cattle but not in tissues from bTB-free cattle. PRLr isoforms 100 kDa 75, 50 and 40 were found expressed in tissues of animals infected with M. bovis , while only the short isoform of 40 kDa correlated with the immunopathology and ability to infect MØ. We confirmed the synthesis of PRLr mRNA in MØ after M. bovis exposure and propose that molecular pathogen patterns of M. bovis might modulate inflammation during bTB through expression of the PRLr isoform in MØ.
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