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Our previous work on the optimization of a new class of small molecule PCSK9 mRNA translation inhibitors focused on empirical optimization of the amide tail region of the lead PF-06446846 (1). This work resulted in compound 3 that showed an improved safety profile. We hypothesized that this improvement was related to diminished binding of 3 to non-translating ribosomes and an apparent improvement in transcript selectivity. Herein, we describe our efforts to further optimize this series of inhibitors through modulation of the heterocyclic head group and the amine fragment. Some of the effort was guided by an emerging cryo electron microscopy structure of the binding mode of 1 in the ribosome. These efforts led to the identification of 15 that was deemed suitable for evaluation in a humanized PCSK9 mouse model and a rat toxicology study. Compound 15 demonstrated a dose dependent reduction of plasma PCSK9 levels. The rat toxicological profile was not improved over that of 1, which precluded 15 from further consideration as a clinical candidate.
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The purpose of this study was to examine the effects and correlations of the perceived religious affiliation on a fictitious terrorism case. Participants were 402 French adults who completed a questionnaire after reading a scenario involving the arrest of a person (French vs. North African; man vs. woman) wearing an explosive belt. They indicated the level of the perpetrator's religious affiliation and judged her/him and the act. The participants' level of social dominance orientation (SDO) was measured and studied along in its two dimensions. The results showed an effect of ethnicity on perceived religious affiliation, which was correlated with judgment and mediated the effect of social dominance on judgment. The implications of this study are discussed in terms of intergroup interactions and religious prejudice.
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We report a copper-catalyzed strategy for arylboronic ester synthesis that exploits photoinduced ligand-to-metal charge transfer (LMCT) to convert (hetero)aryl acids into aryl radicals amenable to ambient-temperature borylation. This near-UV process occurs under mild conditions, requires no prefunctionalization of the native acid, and operates broadly across diverse aryl, heteroaryl, and pharmaceutical substrates. We also report a one-pot procedure for decarboxylative cross-coupling that merges catalytic LMCT borylation and palladium-catalyzed Suzuki-Miyaura arylation, vinylation, or alkylation with organobromides to access a range of value-added products. The utility of these protocols is highlighted through the development of a heteroselective double-decarboxylative C(sp2)-C(sp2) coupling sequence, pairing copper-catalyzed LMCT borylation and halogenation processes of two distinct acids (including pharmaceutical substrates) with subsequent Suzuki-Miyaura cross-coupling.
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Cobre , Paladio , Catálisis , Preparaciones FarmacéuticasRESUMEN
Aryl halides are a fundamental motif in synthetic chemistry, playing a critical role in metal-mediated cross-coupling reactions and serving as important scaffolds in drug discovery. Although thermal decarboxylative functionalization of aryl carboxylic acids has been extensively explored, the scope of existing halodecarboxylation methods remains limited, and there currently exists no unified strategy that provides access to any type of aryl halide from an aryl carboxylic acid precursor. Herein, we report a general catalytic method for direct decarboxylative halogenation of (hetero)aryl carboxylic acids via ligand-to-metal charge transfer. This strategy accommodates an exceptionally broad scope of substrates. We leverage an aryl radical intermediate toward divergent functionalization pathways: (1) atom transfer to access bromo- or iodo(hetero)arenes or (2) radical capture by copper and subsequent reductive elimination to generate chloro- or fluoro(hetero)arenes. The proposed ligand-to-metal charge transfer mechanism is supported through an array of spectroscopic studies.
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Ácidos Carboxílicos , Halogenación , Ácidos Carboxílicos/química , Catálisis , Cobre/química , LigandosRESUMEN
In this paper is described an easily synthesized chiral diazaborolidine that is inexpensive, stable, and provides excellent stereoselection across a number of reaction classes. These versatile compounds possess utility in four different classes of cycloaddition reactions, offering good yield and stereoselectivity. X-ray structure analysis provides insight about the origin of stereocontrol.
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KEY MESSAGE: Individual stem rust resistance genes could be directly mapped within self-incompatible rye populations. Genetic resources of rye (Secale cereale L.) are cross-pollinating populations that can be highly diverse and are naturally segregating. In this study, we show that this segregation could be used for mapping stem rust resistance. Populations of pre-selected donors from the Russian Federation, the USA and Austria were tested on a single-plant basis for stem rust resistance by a leaf-segment test with three rust isolates. Seventy-four plants per population were genotyped with a 10 K-SNP chip. Using cumulative logit models, significant associations between the ordinal infection score and the marker alleles could be found. Three different loci (Pgs1, Pgs2, Pgs3) in three populations were highly significant, and resistance-linked markers could be validated with field experiments of an independent seed sample from the original population and were used to fix two populations for resistance. We showed that it is possible to map monogenically inherited seedling resistance genes directly in genetic resources, thus providing a competitive alternative to linkage mapping approaches that require a tedious and time-consuming inbreeding over several generations.
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Basidiomycota/patogenicidad , Mapeo Cromosómico , Resistencia a la Enfermedad/genética , Enfermedades de las Plantas/genética , Secale/genética , Alelos , Ligamiento Genético , Genotipo , Enfermedades de las Plantas/microbiología , Polimorfismo de Nucleótido Simple , Secale/microbiologíaRESUMEN
OBJECTIVES: We examined whether providing a quantitative report (QReport) of regional brain volumes improves radiologists' accuracy and confidence in detecting volume loss, and in differentiating Alzheimer's disease (AD) and frontotemporal dementia (FTD), compared with visual assessment alone. METHODS: Our forced-choice multi-rater clinical accuracy study used MRI from 16 AD patients, 14 FTD patients, and 15 healthy controls; age range 52-81. Our QReport was presented to raters with regional grey matter volumes plotted as percentiles against data from a normative population (n = 461). Nine raters with varying radiological experience (3 each: consultants, registrars, 'non-clinical image analysts') assessed each case twice (with and without the QReport). Raters were blinded to clinical and demographic information; they classified scans as 'normal' or 'abnormal' and if 'abnormal' as 'AD' or 'FTD'. RESULTS: The QReport improved sensitivity for detecting volume loss and AD across all raters combined (p = 0.015* and p = 0.002*, respectively). Only the consultant group's accuracy increased significantly when using the QReport (p = 0.02*). Overall, raters' agreement (Cohen's κ) with the 'gold standard' was not significantly affected by the QReport; only the consultant group improved significantly (κs 0.41â0.55, p = 0.04*). Cronbach's alpha for interrater agreement improved from 0.886 to 0.925, corresponding to an improvement from 'good' to 'excellent'. CONCLUSION: Our QReport referencing single-subject results to normative data alongside visual assessment improved sensitivity, accuracy, and interrater agreement for detecting volume loss. The QReport was most effective in the consultants, suggesting that experience is needed to fully benefit from the additional information provided by quantitative analyses. KEY POINTS: ⢠The use of quantitative report alongside routine visual MRI assessment improves sensitivity and accuracy for detecting volume loss and AD vs visual assessment alone. ⢠Consultant neuroradiologists' assessment accuracy and agreement (kappa scores) significantly improved with the use of quantitative atrophy reports. ⢠First multi-rater radiological clinical evaluation of visual quantitative MRI atrophy report for use as a diagnostic aid in dementia.
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Enfermedad de Alzheimer , Demencia Frontotemporal , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Atrofia , Demencia Frontotemporal/diagnóstico por imagen , Sustancia Gris , Humanos , Imagen por Resonancia Magnética , Persona de Mediana EdadRESUMEN
BACKGROUND: Tissue-resident memory T (Trm) cells are detrimental in patients with numerous chronic inflammatory diseases, including allergic contact dermatitis (ACD). OBJECTIVES: We sought to analyze the contribution of Trm cells to the chronicity and severity of ACD and to define the local parameters regulating their development and functions. METHODS: We used an experimental model of ACD (ie, contact hypersensitivity to 2,4-dinitrofluorobenzene) that is mediated by CD8+ T cells. RESULTS: Our data show that early effector T cells accumulated in the skin during the acute contact hypersensitivity reaction and gave rise to epidermal CD8+ Trm cells expressing a specific set of inhibitory checkpoint receptors (ICRs), such as programmed cell death protein 1 (PD-1) and T cell immunoglobulin and mucin domain 3 (TIM-3). Those Trm cells remained in the epidermis for several weeks and mediated the eczema exacerbations, which developed on allergen re-exposure without the contribution of circulating specific T cells. Furthermore, allergen-induced Trm cell reactivation was constrained because treatment with ICR antagonists dramatically enhanced the magnitude and severity of eczema exacerbations. Finally, we show that the persistence of the allergen in the epidermis for long periods of time was responsible for both the development and maintenance of epidermal Trm cells, as well as the sustained expression of ICRs. CONCLUSION: Although CD8+ Trm cells are key for the pathophysiology of ACD, intrinsic mechanisms control their reactivation to prevent damaging immunopathology. Developing strategies targeting the reactivation of skin Trm cells in situ through their ICRs should open new perspectives for the treatment of ACD.
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Linfocitos T CD8-positivos/inmunología , Dermatitis Alérgica por Contacto/inmunología , Receptor 2 Celular del Virus de la Hepatitis A/inmunología , Memoria Inmunológica , Receptor de Muerte Celular Programada 1/inmunología , Piel/inmunología , Alérgenos , Animales , Células Cultivadas , Dinitrofluorobenceno , Femenino , Ratones Endogámicos C57BL , Oxazolona , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Describe the course and outcomes in a UK national cohort of neonates with vein of Galen malformation identified before 28 days of life. METHODS: Neonates with angiographically confirmed vein of Galen malformation presenting to 1 of 2 UK treatment centers (2006-2016) were included; those surviving were invited to participate in neurocognitive assessment. Results in each domain were dichotomized into "good" and "poor" categories. Cross-sectional and angiographic brain imaging studies were systematically interrogated. Logistic regression was used to explore potential outcome predictors. RESULTS: Of 85 children with neonatal vein of Galen malformation, 51 had survived. Thirty-four participated in neurocognitive assessment. Outcomes were approximately evenly split between "good" and "poor" categories across all domains, namely, neurological status, general cognition, neuromotor skills, adaptive behavior, and emotional and behavioral development. Important predictors of poor cognitive outcome were initial Bicêtre score ≤ 12 and presence of brain injury, specifically white matter injury, on initial imaging; in multivariate analysis, only Bicêtre score ≤ 12 remained significant. INTERPRETATION: Despite modern supportive and endovascular treatment, more than one-third of unselected newborns with vein of Galen malformation did not survive. Outcome was good in around half of survivors. The importance of white matter injury suggests that abnormalities of venous as well as arterial circulation are important in the pathophysiology of brain injury. Ann Neurol 2018;84:547-555.
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Malformaciones de la Vena de Galeno/diagnóstico por imagen , Malformaciones de la Vena de Galeno/epidemiología , Niño , Preescolar , Estudios de Cohortes , Estudios Transversales , Procedimientos Endovasculares/métodos , Procedimientos Endovasculares/tendencias , Femenino , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/tendencias , Masculino , Pruebas de Estado Mental y Demencia , Estudios Retrospectivos , Reino Unido/epidemiología , Malformaciones de la Vena de Galeno/psicología , Malformaciones de la Vena de Galeno/cirugíaRESUMEN
BACKGROUND: Skin aging is a complex biological process mixing intrinsic and extrinsic factors, such as sun exposure. At the molecular level, skin aging affects in particular the extracellular matrix proteins. MATERIALS AND METHODS: Using Raman imaging, which is a nondestructive approach appropriate for studying biological samples, we analyzed how aging modifies the matrix proteins of the papillary and reticular dermis. Biopsies from the buttock and dorsal forearm of volunteers younger than 30 and older than 60 were analyzed in order to identify chronological and photoaging processes. Analyses were performed on skin section, and Raman spectra were acquired separately on the different dermal layers. RESULTS: We observed differences in dermal matrix structure and hydration state with skin aging. Chronological aging alters in particular the collagen of the papillary dermis, while photoaging causes a decrease in collagen stability by altering proline and hydroxyproline residues in the reticular dermis. Moreover, chronological aging alters glycosaminoglycan content in both dermal compartments. CONCLUSION: Alterations of the papillary and reticular dermal matrix structures during photo- and chronological aging were clearly depicted by Raman spectroscopy.
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Envejecimiento/fisiología , Dermis/citología , Glicosaminoglicanos/análisis , Envejecimiento de la Piel/patología , Adulto , Biopsia , Nalgas , Dermis/química , Femenino , Antebrazo , Humanos , Persona de Mediana Edad , Envejecimiento de la Piel/fisiología , Espectrometría Raman , Adulto JovenRESUMEN
The number of allopathic emergency medicine (EM) programs has been progressively increasing over the years. In 2018, allopathic EM postgraduate year-1 spots, compared with 2012, increased by around 60% to reach 2278 positions. EM is considered a competitive specialty and therefore, in this article we help guide students interested in EM through the allopathic match requirements, application process, interviews, and ranking EM programs. Additionally, we tackle the combined emergency medicine residency programs, namely the combined EM-Family Medicine (FM), EM-Anesthesiology, EM-Internal Medicine (IM), EM-IM-Critical Care Medicine, and EM-Pediatrics residency programs. Finally, we explain the increased likelihood of matching with the single graduate medical education accreditation system expected to happen in the year 2020.
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Medicina Osteopática/educación , Criterios de Admisión Escolar/estadística & datos numéricos , Educación de Postgrado en Medicina/tendencias , Humanos , Internado y Residencia/métodos , Internado y Residencia/tendencias , Estados UnidosRESUMEN
The H+,K+-ATPase was identified as the primary proton secretory pathway in the gastric parietal cell and is the pharmacological target of agents suppressing acid secretion. Recently, we identified a second acid secretory protein expressed in the parietal cell, the vacuolar H+-ATPase (V-type ATPase). The aim of the present study was to further characterize H+-ATPase activation by modulations in extracellular calcium via the calcium sensing receptor (CaSR). Isolated gastric glands were loaded with the pH indicator dye BCECF-AM [2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein acetoxymethyl ester] to measure intracellular pH. Experiments were conducted in the absence of sodium and potassium to monitor H+-ATPase-specific transport activity. CaSR was activated with the calcimimetic R568 (400 nM) and/or by modulations in extracellular Ca2+. Elevation in calcium concentrations increased proton extrusion from the gastric parietal cell. Allosteric modification of the CaSR via R568 and calcium increased vacuolar H+-ATPase activity significantly (ΔpH/minlowCa2+(0.1mM) = 0.001 ± 0.001, ΔpH/minnormalCa2+(1.0mM) = 0.033 ± 0.004, ΔpH/minhighCa2+(5.0mM) = 0.051 ± 0.005). Carbachol significantly suppressed calcium-induced gastric acid secretion via the H+-ATPase under sodium- and potassium-free conditions. We conclude that the V-type H+-ATPase is tightly linked to CaSR activation. We observed that proton pump inhibitor (PPI) exposure does not modulate H+-ATPase activity. This elevated blood calcium activation of the H+-ATPase could provide an explanation for recurrent reflux symptoms while taking a PPI therapy. NEW & NOTEWORTHY This study emphasizes the role of the H+-ATPase in acid secretion. We further demonstrate the modification of this proton excretion pathway by extracellular calcium and the activation of the calcium sensing receptor CaSR. The novelty of this paper is based on the modulation of the H+-ATPase via both extracellular Ca (activation) and the classical secretagogues histamine and carbachol (inactivation). Both activation and inactivation of this proton pump are independent of PPI modulation.
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Calcio , Activación Enzimática , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Células Parietales Gástricas , Inhibidores de la Bomba de Protones/farmacología , Bombas de Protones , Receptores Sensibles al Calcio/metabolismo , Animales , Calcio/sangre , Calcio/metabolismo , Carbacol/farmacología , Agonistas Colinérgicos/farmacología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Ácido Gástrico/metabolismo , Histamina/metabolismo , Transporte Iónico/efectos de los fármacos , Transporte Iónico/fisiología , Células Parietales Gástricas/efectos de los fármacos , Células Parietales Gástricas/fisiología , Bombas de Protones/efectos de los fármacos , Bombas de Protones/metabolismo , Ratas , Ratas Sprague-Dawley , Vías Secretoras/efectos de los fármacos , Vías Secretoras/fisiologíaRESUMEN
BACKGROUND: The pathogenesis of acne vulgaris involves several phases including androgen-dependent hyper-seborrhea, colonization by Propionibacterium acnes, and inflammation. Recent investigations have shown that in fact P. acnes provokes the activation of the inflammasome present in macrophages and dendritic cells. This signaling pathway leads to excessive production of interleukin IL-1ß, a proinflammatory cytokine. Nevertheless, these well-studied phenomena in acne fail to elucidate the mechanisms responsible for the appearance of different lesions. METHODS: We investigate response pathways for specific acne lesions such as microcysts and papules using shot-gun proteomic followed by systemic biology and transcriptomic approaches. RESULTS: Results show that most of the proteins identified as differentially expressed between the normal and acne tissue biopsies associated with the immune system response were identified as highly or exclusively expressed in the papule biopsies. They were also expressed in microcysts, but in lower amounts compared to those in papules. These results are supported by the identification of CAMP factor protein produced by P. acnes in microcysts, indicating its enhanced proliferation in this type of lesion CONCLUSIONS: As CAMP factor protein was not detected in papule biopsies, we can see a clear delineation in the stages of progression of acne pathogenesis, which begins with a hyphenated inflammatory response in the papule stage, followed by imbalance of lipid production, which in turn triggers the enhanced proliferation of P. acnes. GENERAL SIGNIFICANCE: We demonstrate that expression inflammation varies across the two types of lesions, suggesting different pathways enhanced as a function of the progression of P. acnes.
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Acné Vulgar/genética , Acné Vulgar/patología , Proteoma/genética , Transcriptoma/genética , Acné Vulgar/metabolismo , Adolescente , Adulto , Secuencia de Aminoácidos , Péptidos Catiónicos Antimicrobianos , Biopsia/métodos , Catelicidinas/metabolismo , Citocinas/metabolismo , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/microbiología , Inflamación/patología , Masculino , Propionibacterium acnes/patogenicidad , Proteoma/metabolismo , Proteómica/métodos , Transducción de Señal/fisiología , Adulto JovenRESUMEN
OBJECTIVES: The purpose of this study was to examine the associations between perceived ethnic discrimination and (physical and mental) health indicators among North African women and men living in France. METHODS: This study included 82 North Africans, aged 18-64 years. Perceived discrimination was measured at both group level (PGD) and personal level (PPD). The physical health indicator was blood pressure. The mental health indicator was self-reported psychological distress. RESULTS: Multiple regression analyses showed that higher levels of PGD predicted higher blood pressure. PPD was not related to blood pressure. PPD was positively related to psychological distress among women, but not among men. CONCLUSION: PPD and PGD are associated with physical and mental health indicators in different ways among North African women and men in France.
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Presión Sanguínea , Racismo/psicología , Estrés Psicológico/epidemiología , Adulto , África del Norte/etnología , Femenino , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estrés Psicológico/psicología , Adulto JovenRESUMEN
Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesteraseâ 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free inâ vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. Inâ vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18 F-isotopologue validated our liver-targeting approach.
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Hígado/efectos de los fármacos , Inhibidores de PCSK9 , Proproteína Convertasa 9/biosíntesis , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Dosis-Respuesta a Droga , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hígado/enzimología , Hígado/metabolismo , Estructura Molecular , Proproteína Convertasa 9/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
We report a modular three-component dynamic kinetic resolution (DKR) that affords enantiomerically enriched hemiaminal esters derived from azoles and aldehydes. The novel and scalable reaction can be used to synthesize valuable substituted azoles in a regioselective manner by capping (e.g., acylation) of the equilibrating azole-aldehyde adduct. With the use of a prolinol-derived DMAP catalyst as the chiral Lewis base, the products can be obtained in high chemical yield and with high enantiomeric excess. The DKR was performed on a multikilogram scale to produce a tetrazole prodrug fragment for a leading clinical candidate that posed formidable synthesis challenges.
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Azoles/síntesis química , Ésteres/síntesis química , Bases de Lewis/química , Aldehídos/química , Alcanosulfonatos/síntesis química , Alcanosulfonatos/química , Azoles/química , Catálisis , Ésteres/química , Cinética , Estereoisomerismo , TetrazolesRESUMEN
BACKGROUND: Chemokines and their receptors play a decisive role in tumor progression and metastasis. We recently found a new signaling mechanism in malignant glioma cells mediated by transmembrane chemokines that we termed "inverse signaling". According to this hypothesis, soluble (s)-CXCL16 binds to the surface-expressed transmembrane (tm) -CXCL16, and induces signaling and different biological effects in the stimulated cells, so that the transmembrane ligand itself acts as a receptor for its soluble counterpart. Now, we hypothesized that "inverse signaling" via tm-CXCL16 might also take place in meningiomas, a completely different, benign tumor entity. METHODS: We used quantitative reverse-transcription polymerase chain reaction, immunocytochemistry and western blot to detect CXCL16 and CXCR6 in human meningioma cells isolated from 28 human meningiomas. Subsequently, we stimulated cultured human tm-CXCL16-positive, CXCR6-negative meningioma cells with recombinant s-CXCL16 and analyzed binding, signaling and biological effects using RNAi silencing to verify specificity. RESULTS: In fact, cultured human meningioma cells considerably express CXCL16, but substantially lack CXCR6, the only known CXCL16 receptor. These receptor-negative cells could bind s-CXCL16, and responded to s-CXCL16 application with activation of the intracellular kinases ERK1/2 und Akt. As a consequence, we observed increased proliferation and rescue of apoptosis of cultured meningioma cells. Since binding and signaling were abolished by siRNA silencing, we concluded that tm-CXCL16 specifically acts as a receptor for s-CXCL16 also in human meningioma cells. CONCLUSION: These findings underline our recent report on the mechanism of inverse signaling as a broad biological process also observable in more benign tumor cells and contributing to tumor progression.
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Apoptosis , Proliferación Celular , Quimiocinas CXC/metabolismo , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Receptores Depuradores/metabolismo , Transducción de Señal , Células Cultivadas , Quimiocina CXCL16 , Quimiocinas CXC/genética , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Depuradores/genéticaRESUMEN
BACKGROUND/OBJECTIVES: The use of emollients is widely recommended for the management of atopic dermatitis (AD), especially between flares. An imbalance of skin microflora is suspected of playing a key role in exacerbations of AD. Our aim was to evaluate the effect of a new emollient balm on clinical parameters (SCORing Atopic Dermatitis [SCORAD], xerosis, pruritus), skin barrier function (transepidermal water loss and loricrin, filaggrin, corneodesmosin, and involucrin expression], skin microflora biodiversity, and Staphylococcus aureus and Staphylococcus epidermidis balance in children with mild AD. METHODS: Fifty-four children (1-4 yrs old) were enrolled in this randomized, controlled study. Subjects applied a hygiene product and the emollient balm (emollient group, n = 28) or the hygiene product only (control group, n = 26) twice a day for 28 days. RESULTS: We found improvement in favor of the emollient group in SCORAD (p < 0.001), pruritus (p = 0.06), and xerosis (p = 0.06) after 28 days of application. Moreover, transepidermal water loss decreased in the emollient group by 34% (p = 0.06) and involucrin expression by 37% (p = 0.001) at day 28 from baseline in association with improvement in barrier function, whereas other barrier-specific proteins did not vary. S. aureus increased significantly in the control group only (6.5 times, p = 0.01), whereas S. epidermidis remained stable in both groups. The Shannon index (H' = 2.3) did not vary with treatment in either group. CONCLUSION: Twice-daily application of a new emollient balm in children with mild AD protected the skin from S. aureus proliferation and preserved microflora biodiversity.
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Dermatitis Atópica/tratamiento farmacológico , Emolientes/administración & dosificación , Piel/microbiología , Preescolar , Proteínas Filagrina , Humanos , Lactante , Piel/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Staphylococcus epidermidis/efectos de los fármacosRESUMEN
CONTEXT: Skin microbiota takes part in the control of cutaneous inflammation. In skin diseases such as atopic dermatitis (AD) cutaneous dysbiosis and the emergence of Staphylococcus aureus contribute to the pathophysiology of the disease. New therapeutic approaches consist in topical application of natural products able to counteract S. aureus effects through activation of resident immune cells producing anti-inflammatory cytokines such as IL-10. OBJECTIVE: This study investigates the potential immunosuppressive properties of Aquaphilus dolomiae (Neisseriaceae), a flagellated bacterium contained in Avène Thermal Spring Water used in hydrotherapy treatments of AD patients. MATERIALS AND METHODS: An aqueous protein extract of Aquaphilus dolomiae (ADE, 60 µg/mL) was added to human monocyte-derived dendritic cells (moDC) for 24 h. Expression of HLA-DR, CD86 and CD83 was evaluated by flow cytometry and released cytokines (IL-10, IL-12) by cytometry bead array assay. The proliferation of allogeneic CFSE-labelled CD4+ T cells stimulated with ADE-conditioned moDC and S. aureus secretome was analysed by flow cytometry. RESULTS: MoDC exposed to ADE expressed lower levels of HLA-DR and CD86 than untreated cells, no CD83 and secreted barely detectable IL-12 but high amounts of IL-10 (N = 12, p < 0.0002). The proliferative effect of S. aureus secretome on CD4+ T cells was reduced (p < 0.001) in the presence of ADE-moDC. CONCLUSION: ADE counteracted the mitogenic effect of a S. aureus secretome on CD4+T cells. Owing to the role of S. aureus colonization in driving inflammation in AD the immunosuppressive property of the ADE might be useful to reduce disease severity.