Asthma is a chronic inflammatory disease characterized by airway inflammation and remodeling, which can lead to progressive decline of lung function. Although mesenchymal stromal cells (MSCs) have ...shown beneficial immunomodulatory properties in preclinical models of allergic asthma, effects on airway remodeling have been limited. Mounting evidence suggests that prior exposure of MSCs to specific inflammatory stimuli or environments can enhance their immunomodulatory properties. Therefore, we investigated whether stimulating MSCs with bronchoalveolar lavage fluid (BALF) or serum from asthmatic mice could potentiate their therapeutic properties in experimental asthma. In a house dust mite (HDM) extract asthma model in mice, unstimulated, asthmatic BALF‐stimulated, or asthmatic serum‐stimulated MSCs were administered intratracheally 24 hours after the final HDM challenge. Lung mechanics and histology; BALF protein, cellularity, and biomarker levels; and lymph‐node and bone marrow cellularity were assessed. Compared with unstimulated or BALF‐stimulated MSCs, serum‐stimulated MSCs further reduced BALF levels of interleukin (IL)‐4, IL‐13, and eotaxin, total and differential cellularity in BALF, bone marrow and lymph nodes, and collagen fiber content, while increasing BALF IL‐10 levels and improving lung function. Serum stimulation led to higher MSC apoptosis, expression of various mediators (transforming growth factor‐β, interferon‐γ, IL‐10, tumor necrosis factor‐α‐stimulated gene 6 protein, indoleamine 2,3‐dioxygenase‐1, and IL‐1 receptor antagonist), and polarization of macrophages to M2 phenotype. In conclusion, asthmatic serum may be a novel strategy to potentiate therapeutic effects of MSCs in experimental asthma, leading to further reductions in both inflammation and remodeling than can be achieved with unstimulated MSCs. Stem Cells Translational Medicine 2019;8:301&312
Compared to unstimulated or bronchoalveolar lavage fluid (BALF)‐stimulated MSCs, serum‐stimulated MSCs reduced levels of interleukin (IL)‐4, IL‐13, and eotaxin, and collagen fiber content, while increasing IL‐10. Serum stimulation yielded higher MSC apoptosis, expressions of: transforming growth factor (TGF)‐β, IFN (interferon)‐γ, IL‐10, TSG6 (tumor necrosis factor‐α‐stimulated gene 6), IDO (indoleamine 2,3‐dioxygenase)‐1, and IL‐1RN, and polarization of macrophages to the M2 phenotype.
Human hotspot TERT promoter (TERTp) mutations have been reported in a wide range of tumours. Several studies have shown that TERTp mutations are associated with clinicopathological features; in some ...instances, TERTp mutations were considered as biomarkers of poor prognosis. The rs2853669 SNP, located in the TERT promoter region, was reported to modulate the increased TERT expression levels induced by the recurrent somatic mutations. In this study we aimed to determine the frequency and prognostic value of TERTp mutations and TERT rs2853669 SNP in 504 gliomas from Portuguese and Brazilian patients. TERTp mutations were detected in 47.8% of gliomas (216/452). Glioblastomas (GBM) exhibited the highest frequency of TERTp mutations (66.9%); in this glioma subtype, we found a significant association between TERTp mutations and poor prognosis, regardless of the population. Moreover, in a multivariate analysis, TERTp mutations were the only independent prognostic factor. Our data also showed that the poor prognosis conferred by TERTp mutations was restricted to GBM patients carrying the rs2853669 A allele and not in those carrying the G allele. In conclusion, the presence of TERTp mutations was associated with worse prognosis in GBM patients, although such association depended on the status of the rs2853669 SNP. The status of the rs2853669 SNP should be taken in consideration when assessing the prognostic value of TERTp mutations in GBM patients. TERTp mutations and the rs2853669 SNP can be used in the future as biomarkers of glioma prognosis.
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Cancer cells avoid senescence in part by reactivating telomerase (TERT), a ribonucleoprotein that replenishes shortening telomeres. Here, the authors discover a positive association between TERT promoter mutations and unfavorable prognosis in glioblastoma patients from Portuguese and Brazilian origin. This association was only observed in patients with a specific allelic background (AA) in a TERT polymorphism (rs2853669) recently linked to enhanced TERT mRNA levels. The authors recommend considering the allelic status of rs2853669 when assessing the prognostic value of TERT promoter mutations in glioblastoma patients.
Although several studies have demonstrated that mesenchymal stromal cells (MSCs) exhibit beneficial immunomodulatory properties in preclinical models of allergic asthma, effects on airway remodeling ...have been controversial. Recent evidence has shown that MSCs modify their in vivo immunomodulatory actions depending on the specific inflammatory environment encountered. Accordingly, we assessed whether the therapeutic properties of human mesenchymal stromal cells (hMSCs) could be potentiated by conditioning these cells with serum (hMSC-serum) obtained from patients with asthma and then transplanted in an experimental model of house dust mite (HDM)-induced allergic asthma.
hMSC and hMSC-serum were administered intratracheally 24 h after the final HDM challenge. hMSC viability and inflammatory mediator production, lung mechanics and histology, bronchoalveolar lavage fluid (BALF) cellularity and biomarker levels, mitochondrial structure and function as well as macrophage polarization and phagocytic capacity were assessed.
Serum preconditioning led to: (i) increased hMSC apoptosis and expression of transforming growth factor-β, interleukin (IL)-10, tumor necrosis factor-α–stimulated gene 6 protein and indoleamine 2,3-dioxygenase-1; (ii) fission and reduction of the intrinsic respiratory capacity of mitochondria; and (iii) polarization of macrophages to M2 phenotype, which may be associated with a greater percentage of hMSCs phagocytosed by macrophages. Compared with mice receiving hMSCs, administration of hMSC-serum led to further reduction of collagen fiber content, eotaxin levels, total and differential cellularity and increased IL-10 levels in BALF, improving lung mechanics. hMSC-serum promoted greater M2 macrophage polarization as well as macrophage phagocytosis, mainly of apoptotic hMSCs.
Serum from patients with asthma led to a greater percentage of hMSCs phagocytosed by macrophages and triggered immunomodulatory responses, resulting in further reductions in both inflammation and remodeling compared with non-preconditioned hMSCs.
•Gliosarcoma is a rare primary central nervous system tumor.•So far, there is only one description of a primary gliosarcoma of the optic nerve.•As far as we know, we describe the second reported case ...of a primary gliosarcoma of the optic nerve.
Gliosarcoma is a rare primary central nervous system tumor with a biphasic tissue pattern, displaying glial and mesenchymal differentiation. So far, there is only one description of an optic nerve gliosarcoma. We describe the case of a 66 years old patient who developed left eye pain that evolved to visual deficit and papilledema. The cerebral MRI showed a contrast enhancement of the left optic nerve in T1 weighted images. We performed an open biopsy that revealed a gliosarcoma.
The detailed palynostratigraphic study of four boreholes in the Muarádzi sub-basin, Moatize-Minjova Coal Basin (MMCB) southeast of Moatize, allowed the assignment of relative ages to the ...stratigraphic units. Three assemblages were studied in detail and are assigned to the Lopingian. Assemblage L1 is characterized by the rich occurrence of Guttulapollenites and Weylandites. Assemblage L2 is defined on the first occurrence (FO) of abundant Thymospora pseudothiessenii together with Indotriradites niger, Kraeuselisporites spp., Polypodiisporites mutabilis and Polypodiidites sp. Assemblage L3 is characterized by the first occurrence of Osmundacidites senectus together with the taxa described from the previous assemblages. Palynological correlation with other Karoo basins is discussed and three distinct palynostratigraphic events emerge based on the FO and abundance of key taxa (as for instance, FO of G. hannonicus, T. pseudothiensenii and O. senectus). A close palynological correlation between Mozambique (Moatize-Minjova Basin), Tanzania (Selous Basin), Zambia (mid-Zambezi Basin) and Madagascar palynoevents is established. This major region can be assigned to the northern Karoo-aged basins of south-central Africa and the palynoevents can be correlated with Lopingian assemblages of Pakistan, India and some basins of East Antarctica. The southern Karoo-aged basins of south-central Africa, including South Africa and Zimbabwe, show different Lopingian palynoevents and a direct correlation is demanding. These palynological data may open new perspectives for coal exploration in the MMCB as the coal deposits show a wider stratigraphic distribution, reaching until the latest Lopingian.
•Detailed palynostratigraphy of late Permian in Karoo succession of Mozambique•Palynological events through the Karoo central Gondwana paleobiogeographic basins•New data opens new perspectives for coal exploration.
The aim of this work is to provide a first approach to the evolution of Iberia's vegetation during the Cenozoic (with the exclusion of the Quaternary). The Palaeogene was floristically defined by ...Palaeotropical elements forming tropical/subtropical rainforests, mangrove swamps, edaphically-mediated laurophyllous forests and leguminous-sclerophyllous communities. During the Miocene, Iberian landscapes were drastically modified due to geographic and climatic changes (mainly cooling and aridification) changes. Open, steppe-like environments developed towards the interior of the peninsula and Arctotertiary elements invaded mountainous and riparian ecosystems, coexisting with or becoming part of evergreen, broadleaved forests of Palaeotropical species. From the Late Miocene onwards these forests suffered changes due to the extinction of taxa, the impact of environmental change on the survivors, and the perturbations caused by the arrival of further Arctotertiary elements. However, several Palaeotropical taxa overcame the environmental and climatic changes of the Miocene and Pliocene to form a part of the modern flora of the Iberian Peninsula.
To evaluate different intratracheal flow rates on extracellular matrix content and lung mechanics in an established lung decellularization protocol.
Healthy mice were used: 15 for decellularization ...and five to serve as controls. Fluids were instilled at 5, 10 and 20 ml/min flow rates through tracheal cannula and right ventricular cavity (0.5 ml/min) in all groups.
The 20 ml/min rate better preserved collagen content in decellularized lungs. Elastic fiber content decreased at 5 and 10 ml/min, but not at 20 ml/min, compared with controls. Chondroitin, heparan and dermatan content was reduced after decellularization.
An intratracheal flow rate of 20 ml/min was associated with lower resistance and greater preservation of collagen to that observed in
control lungs.
Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in the understanding of its pathophysiology, asthma remains a major public health problem ...and, at present, there are no effective interventions capable of reversing airway remodeling. Mesenchymal stromal cell (MSC)-based therapy mitigates lung inflammation in experimental allergic asthma; however, its ability to reduce airway remodeling is limited. We aimed to investigate whether pre-treatment with eicosapentaenoic acid (EPA) potentiates the therapeutic properties of MSCs in experimental allergic asthma. Seventy-two C57BL/6 mice were used. House dust mite (HDM) extract was intranasally administered to induce severe allergic asthma in mice. Unstimulated or EPA-stimulated MSCs were administered intratracheally 24 h after final HDM challenge. Lung mechanics, histology, protein levels of biomarkers, and cellularity in bronchoalveolar lavage fluid (BALF), thymus, lymph nodes, and bone marrow were analyzed. Furthermore, the effects of EPA on lipid body formation and secretion of resolvin-D
(RvD
), prostaglandin E
(PGE
), interleukin (IL)-10, and transforming growth factor (TGF)-β1 by MSCs were evaluated
. EPA-stimulated MSCs, compared to unstimulated MSCs, yielded greater therapeutic effects by further reducing bronchoconstriction, alveolar collapse, total cell counts (in BALF, bone marrow, and lymph nodes), and collagen fiber content in airways, while increasing IL-10 levels in BALF and M2 macrophage counts in lungs. In conclusion, EPA potentiated MSC-based therapy in experimental allergic asthma, leading to increased secretion of pro-resolution and anti-inflammatory mediators (RvD
, PGE
, IL-10, and TGF-β), modulation of macrophages toward an anti-inflammatory phenotype, and reduction in the remodeling process. Taken together, these modifications may explain the greater improvement in lung mechanics obtained. This may be a promising novel strategy to potentiate MSCs effects.
To better understand the role of acute normovolemic hemodilution (ANH) in a surgical setting with high risk of bleeding, we analyzed all randomized controlled trials (RCTs) in the setting of cardiac ...surgery that compared ANH with standard intraoperative care. The aim was to assess the incidence of ANH-related number of allogeneic red blood cell units (RBCu) transfused. Secondary outcomes included the rate of allogeneic blood transfusion and estimated total blood loss.
Twenty-nine RCTs for a total of 2439 patients (1252 patients in the ANH group and 1187 in the control group) were included in our meta-analysis using PubMed/MEDLINE, Cochrane Controlled Trials Register, and EMBASE.
Patients in the ANH group received fewer allogeneic RBCu transfusions (mean difference = -0.79; 95% confidence interval CI, -1.25 to -0.34; P = .001; I = 95.1%). Patients in the ANH group were overall transfused less with allogeneic blood when compared with controls (356/845 42.1% in the ANH group versus 491/876 56.1% in controls; risk ratio = 0.74; 95% CI, 0.62 to 0.87; P < .0001; I = 72.5%), and they experienced less postoperative blood loss (388 mL in ANH versus 450 mL in control; mean difference = -0.64; 95% CI, -0.97 to -0.31; P < .0001; I = 91.8%).
ANH reduces the number of allogeneic RBCu transfused in the cardiac surgery setting together with a reduction in the rate of patients transfused with allogeneic blood and with a reduction of bleeding.
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