FOXP3+ T cells in uterine sarcomas are associated with favorable prognosis, low extracellular matrix expression and reduced YAP activation.

Uterine sarcomas are rare but deadly malignancies without effective treatment. Immunotherapy is a promising new approach to treat these tumors but has shown heterogeneous effects in sarcoma patients. With the goal of identifying key factors for improved patient treatment, we characterized the tumor immune landscape in 58 uterine sarcoma cases with full clinicopathological annotation. Immune cell characterization revealed the overall prevalence of FOXP3+ cells and pro-tumor M2-like macrophages. Hierarchical clustering of patients showed four tumor type-independent immune signatures, where infiltration of FOXP3+ cells and M1-like macrophages associated with favorable prognosis. High CD8+/FOXP3+ ratio in UUS and ESS correlated with poor survival, upregulation of immunosuppressive markers, extracellular matrix (ECM)-related genes and proteins, and YAP activation. This study shows that uterine sarcomas present distinct immune signatures with prognostic value, independent of tumor type, and suggests that targeting the ECM could be beneficial for future treatments

Clinical and preclinical therapeutic outcome metrics for USH2A-related disease

USH2A variants are the most common cause of Usher syndrome type 2, characterized by congenital sensorineural hearing loss and retinitis pigmentosa (RP), and also contribute to autosomal recessive non-syndromic RP. Several treatment strategies are under development; however, sensitive clinical trial endpoint metrics to determine therapeutic efficacy have not been identified. In the present study, we have performed longitudinal retrospective examination of the retinal and auditory symptoms in (i) 56 biallelic molecularly confirmed USH2A patients and (ii) ush2a mutant zebrafish to identify metrics for the evaluation of future clinical trials and rapid preclinical screening studies. The patient cohort showed a statistically significant correlation between age and both rate of constriction for the ellipsoid zone length and hyperautofluorescent outer retinal ring area. Visual acuity and pure tone audiograms are not suitable outcome measures. Retinal examination of the novel ush2au507 zebrafish mutant revealed a slowly progressive degeneration of predominantly rods, accompanied by rhodopsin and blue cone opsin mislocalization from 6 to 12 months of age with lysosome-like structures observed in the photoreceptors. This was further evaluated in the ush2armc zebrafish model, which revealed similar changes in photopigment mislocalization with elevated autophagy levels at 6 days post fertilization, indicating a more severe genotype-phenotype correlation and providing evidence of new insights into the pathophysiology underlying USH2A-retinal disease

Cyclin-dependent kinase 5 mediates pleiotrophin-induced endothelial cell migration

Pleiotrophin (PTN) stimulates endothelial cell migration through binding to receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) and ανβ3 integrin. Screening for proteins that interact with RPTPβ/ζ and potentially regulate PTN signaling, through mass spectrometry analysis, identified cyclin-dependent kinase 5 (CDK5) activator p35 among the proteins displaying high sequence coverage. Interaction of p35 with the serine/threonine kinase CDK5 leads to CDK5 activation, known to be implicated in cell migration. Protein immunoprecipitation and proximity ligation assays verified p35-RPTPβ/ζ interaction and revealed the molecular association of CDK5 and RPTPβ/ζ. In endothelial cells, PTN activates CDK5 in an RPTPβ/ζ- and phosphoinositide 3-kinase (PI3K)-dependent manner. On the other hand, c-Src, ανβ3 and ERK1/2 do not mediate the PTN-induced CDK5 activation. Pharmacological and genetic inhibition of CDK5 abolished PTN-induced endothelial cell migration, suggesting that CDK5 mediates PTN stimulatory effect. A new pyrrolo[2,3-α]carbazole derivative previously identified as a CDK1 inhibitor, was found to suppress CDK5 activity and eliminate PTN stimulatory effect on cell migration, warranting its further evaluation as a new CDK5 inhibitor. Collectively, our data reveal that CDK5 is activated by PTN, in an RPTPβ/ζ-dependent manner, regulates PTN-induced cell migration and is an attractive target for the inhibition of PTN pro-angiogenic properties

Detrimental effects of tropisetron on permanent ischemic stroke in the rat

<p>Abstract</p> <p>Background</p> <p>Recent <it>in vitro </it>evidence indicates that blockade of 5-hydroxytryptamine (5-HT) receptor 3 (5-HT₃) is able to confer protection in different models of neuronal injury. The purpose of the present study was to investigate the effect of tropisetron, a 5-HT₃receptor antagonist, on infarct size and neurological score in a model of ischemic stroke induced by permanent middle cerebral artery occlusion (pMCAO) in the rat.</p> <p>Methods</p> <p>Two different doses of tropisetron (5 and 10 mg/kg) or vehicle were administered intraperitoneally 30 min before pMCAO. Neurological deficit scores, mortality rate and infarct volume were determined 24 h after permanent focal cerebral ischemia.</p> <p>Results</p> <p>Tropisetron failed to reduce cerebral infarction. Animals receiving tropisetron showed a significant increase (p < 0.05) in neurological deficits and mortality rate.</p> <p>Conclusion</p> <p>Data from this study indicate that blockade of 5-HT₃receptors with tropisetron worsens ischemic brain injury induced by pMCAO. These findings could have important clinical implications. Patients taking tropisetron, and possibly other 5-HT₃antagonists, could potentially have a worse outcome following a brain infarct.</p

Potential growth and biomass productivity of Miscanthus x giganteus as affected by plant density and N-fertilization in central Greece

The potential growth and biomass productivity of Miscanthus x giganteus was investigated under constraint-free conditions during two years with appreciable different climatic conditions in central Greece, and under three different plant densities (0.66, 1, 2 pl m(-2)) and two different nitrogen dressings (N-0 = 50, N-1 = 100 kg N ha(-1)). The field experimental design was a 3 x 2 factorial split plot in four blocks. Plant height, tiller number, leaf area index and dry weight per plant component were measured in subsequent harvests throughout the growing periods of 2001 and 2002. It was found that fertilisation within the studied rates did not affect growth and biomass productivity of the crop, and no interaction between fertilization and plant density was observed in any of the samplings. Contrary to fertilization, a significant effect of plant density was found, with the denser populated plants (10,000-20,000pl ha(-1)) performing growth rates of 250-350kg ha(-1) d(-1) for large parts of the growing period, reaching maximum dry biomass yields in excess of 38t ha(-1) in the more favorable year, 2002, and 28 tha(-1) in the warmer and drier year 2001. Such high yield potentials were explained by the particularly great assimilation rates of this crop that were also measured under light saturation and optimum temperature and water regimes. With such biomass yields (11.2-15.2 t ha(-1) oil equivalent), obtainable particularly under modest fertilisation needs, Miscanthus sinensis should be considered as a very promising crop for biomass production in Greece in the near future. (c) 2006 Elsevier Ltd. All rights reserved

Distribution of heavy metals of agricultural soils of central Greece using the modified BCR sequential extraction method

The state of heavy metal (Cd, Cu, Ni, Zn, Pb, and Cr) pollution was studied, in 440 texturally different soil profiles in Thessaly, an intensely cultivated region in Central Greece. The study was carried out in 2004 and 2005 on 220 soil samples for each year. Soil samples were classified in three soil orders: Endisols, Alfisols, and Vertisols according to the Soil Taxonomy System. The pseudo-total concentrations of heavy metals were determined by the aqua regia procedure. Heavy metals were also determined after division into four fractions by sequential extraction with (a) acetic acid (exchangeable and specifically adsorbed metals), (b) a reducing agent (bound to Fe/ Mn hydroxides), (c) an oxidizing agent (bound to soil organic matter), and (d) aqua regia (bound to mineral structures, residual). The concentrations of all the metals studied were higher in the topsoil (0-30 cm) and lower in the second soil layer (30-60 cm). Concentrations of 70-82% of Cd, 39-64% of Cu, 41-69% of Ni, 29-51% of Zn, 75-89% of Pb, and 52-87% of Cr were found in the first two fractions. Cd appeared to be the most mobile of the metals studied, while Cu and Zn were found in forms associated with soil organic matter. The chemical partitioning patterns of Pb and Cr indicated that these metals are largely associated with the Fe-Mn hydroxides, while Cr was also found in the residual fractions. Significant correlations between heavy metals fractions and soil physicochemical parameters were obtained and discussed

Sorption of Cadmium and Arsenic by Goethite and Clinoptilolite

Cadmium (Cd) and arsenic (As) adsorption and desorption by goethite and clinoptilolite were the subjects of this article. Experimental variables were the concentrations of Cd, As, background electrolyte, and the solution pH. Cadmium adsorption by goethite and clinoptilolite increases with the increase of pH and with the decrease of electrolyte concentration. Maximum Cd desorption by goethite was found at pH6.0 and by clinoptilolite at pH8.0 and 0.1M potassium chloride (KCl). Maximum As desorption by goethite was found at pH8.0 and by clinoptilolite at pH10.0 and 0.01M KCl. The experimental results of Cd adsorption were successfully fitted to Langmuir, Freundlich, and Temkin isotherms, and the experimental results of As adsorption were comparable successfully fitted to Freundlich and Temkin isotherms

Affinity Proteomic Profiling of Plasma, Cerebrospinal Fluid, and Brain Tissue within Multiple Sclerosis

Cet article est basé sur une correspondance inédite (1844-1846) entre une femme suisse de la haute société et son médecin, Antoine Despine. La patiente fut soignée à Aix-les-Bains, en Savoie, par les eaux, l’électrothérapie et le magnétisme animal. Cette correspondance est située dans le contexte historique des controverses de l’époque sur le magnétisme animal et, plus précisément, des théories, des pratiques et du style thérapeutique de Despine. L’article s’attache au personnage féminin et il montre comment la relation patient-thérapeute est en interrelation avec un groupe plus large d’adeptes du magnétisme.This article is based on an unpublished correspondence (1844-1846) between an upper-class Swiss woman and her physician, Antoine Despine. The patient was treated in Aix-les-Bains in Savoy by spa water, electrotherapy and mesmerism. This correspondence is situated within an historical context including controversies of that time on animal magnetism and, more precisely, Despine’s theories, practices and therapeutic style. The article focuses on the female character and analyses how the patient-therapist relationship interplays with a larger group of followers of animal magnetism