87 research outputs found

    Changes in the secretory profile of NSCLC-associated fibroblasts after ablative radiotherapy: potential impact on angiogenesis and tumor growth

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    In the context of radiotherapy, collateral effects of ablative ionizing radiation (AIR) on stromal components of tumors remains understudied. In this work, cancer-associated fibroblasts (CAFs) isolated from freshly resected human lung tumors were exposed to AIR (1x18Gy) and analyzed for their release of paracrine factors. Inflammatory mediators and regulators of angiogenesis and tumor growth were analyzed by multiplex protein assays in conditioned medium (CM) from irradiated and non-irradiated CAFs. Additionally, the profile of secreted proteins was examined by proteomics. In functional assays, effects of CAF-CM on proliferative and migratory capacity of lung tumor cells (H-520/H-522) and endothelial cells (HUVECs), and on the tube-forming capacity of endothelial cells was assessed. Our data show that exposure of CAFs to ablative doses of ionizing radiation results in a) down-regulated release of angiogenic factors SDF-1, angiopoietin and thrombospondin-2; b) up-regulated release of growth factor bFGF from most donors, and c) unaffected expression-levels of HGF and inflammatory mediators IL-6, IL-8, IL-1ƒÒ and TNF-£. Conditioned medium from irradiated and control CAFs did not affect differently the proliferative or migratory capacity of tumor cells (H-520/H-522), whereas migratory capacity of endothelial HUVEC cells was partially reduced in the presence of irradiated CAF conditioned medium. Overall we conclude that AIR mediates a transformation on the secretory profile of CAFs that could influence the behavior of other cells in the tumor tissue and hence guide to some extent therapeutic outcomes. The downstream consequences of the changes observed in this study merits further investigations

    Large-scale secretome analyses unveil the superior immunosuppressive phenotype of umbilical cord stromal cells as compared to other adult mesenchymal stromal cells

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    Mesenchymal stromal cells (MSCs), given their regenerative potential, are being investigated as a potential therapeutic tool for cartilage lesions. MSCs express several bioactive molecules which act in a paracrine fashion to modulate the tissue microenvironment. Yet, little is known about the divergence of these signalling molecules in different MSC populations. The present study investigated secretomes of stromal cells harvested from Hoffa’s fat pad (HFPSCs), synovial membrane (SMSCs), umbilical cord (UCSCs) and cartilage (ACs) by quantitative liquid chromatography-mass spectrometry (LC-MS/MS) proteomics. Also, multiplex protein arrays and functional assays were performed to compare the constitutive immunomodulatory capabilities of different MSCs. Proteins involved in extracellular matrix degradation and inflammation, such as matrix metalloproteinases (MMPs), interleukin (IL)-17 and complement factors, were downregulated in UCSCs as compared to adult cell sources. Additionally, secretion of transforming growth factor (TGF)-β1 and prostaglandin E2 (PGE2) was enhanced in UCSC supernatants. UCSCs were superior in inhibiting peripheral blood mononuclear cell (PBMC) proliferation, migration and cytokine secretion as compared to adult stromal cells. SMSCs significantly suppressed the proliferation of PBMCs only if they were primed with pro-inflammatory cytokines. Although all cell types repressed human leukocyte antigen-DR isotype (HLA-DR) surface expression and cytokine release by activated macrophages, only UCSCs significantly blocked IL-6 and IL-12 production. Furthermore, UCSCs supernatants increased aggrecan gene expression in two-dimensional chondrocyte cultures. The data demonstrated that UCSCs displayed superior anti-inflammatory and immunosuppressive properties than stromal cells from adult tissues. This allogeneic cell source could potentially be considered as an adjuvant therapy for articular cartilage repair

    Impacto del proceso de enseñanza endoscópica en la detección de adenomas colónicos

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    ResumenAntecedentesEl impacto que el proceso de entrenamiento endoscópico ejerce sobre la calidad de la colonoscopia en un medio hispanoamericano es escasa.ObjetivoDeterminar el efecto del entrenamiento en la técnica de colonoscopia sobre la detección de adenomas.Materiales y métodosEntre julio del 2012 y julio del 2013, 3 médicos recibieron entrenamiento en colonoscopia por parte de 4 endoscopistas experimentados; Las colonoscopias realizadas por endoscopistas en entrenamiento supervisados fueron comparadas con aquellas realizadas por endoscopistas experimentados.ResultadosSe incluyeron 318 colonoscopias realizadas por alguno de los 3 endoscopistas en entrenamiento bajo supervisión y 367 realizadas por alguno de los endoscopistas entrenados. El análisis univariado mostró una diferencia no significativa en la tasa de detección de adenomas (30.4 vs. 24.7%; p = 0.09). En el análisis multivariado, la tasa de detección de adenomas fue significativamente mayor en las colonoscopias realizadas por alguno de los 3 endoscopistas en entrenamiento (odds ratio = 1.72 [1.19-2.48]).ConclusiónEl involucramiento de endoscopistas en formación tiene un efecto positivo sobre la detección de adenomas.AbstractBackgroundThere has been little reported experience in the Latin American hospital setting in relation to the impact of the endoscopic training process on colonoscopy quality.AimsTo determine the effect that training in the technique of colonoscopy has on adenoma detection in an Argentinian teaching hospital.Material and methodWithin the time frame of July 2012 and July 2013, 3 physicians received training in colonoscopy from 4 experienced endoscopists. The colonoscopies performed by the supervised trainees were compared with those carried out by the experienced endoscopists.ResultsA total of 318 colonoscopies performed by any one of the 3 supervised trainees and 367 carried out by any one of the experienced endoscopists were included. The univariate analysis showed a non-significant difference in the detection rate of adenomas (30.4 vs. 24.7%, P=.09). In the multivariate analysis, the detection rate of adenomas was significantly higher in the colonoscopies performed by one of the 3 trainees (odds ratio = 1.72 [1.19-2.48]).ConclusionsThe supervised involvement of endoscopic trainees has a positive effect on adenoma detection

    A novel class of sulphonamides potently block malaria transmission by targeting a Plasmodium vacuole membrane protein

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    Phenotypic cell-based screens are critical tools for discovering candidate drugs for development, yet identification of the cellular target and mode of action of a candidate drug is often lacking. Using an imaging-based screen, we recently discovered an N-[(4-hydroxychroman-4-yl)methyl]-sulphonamide (N-4HCS) compound, DDD01035881, that blocks male gamete formation in the malaria parasite life cycle and subsequent transmission of the parasite to the mosquito with nanomolar activity. To identify the target(s) of DDD01035881, and of the N-4HCS class of compounds more broadly, we synthesised a photoactivatable derivative, probe 2. Photoaffinity labelling of probe 2 coupled with mass spectrometry identified the 16 kDa Plasmodium falciparum parasitophorous vacuole membrane protein Pfs16 as a potential parasite target. Complementary methods including cellular thermal shift assays confirmed that the parent molecule DDD01035881 stabilised Pfs16 in lysates from activated mature gametocytes. Combined with highresolution, fluorescence and electron microscopy data, which demonstrated that parasites inhibited with N-4HCS compounds phenocopy the targeted deletion of Pfs16 in gametocytes, these data implicate Pfs16 as a likely target of DDD01035881. This finding establishes N-4HCS compounds as being flexible and effective starting candidates from which transmission-blocking antimalarials can be developed in the future

    Reduced hippocampal subfield volumes and memory performance in preterm children with and without germinal matrix intraventricular hemorrhage.

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    Preterm newborns with germinal matrix-intraventricular hemorrhage (GM-IVH) are at a higher risk of evidencing neurodevelopmental alterations. Present study aimed to explore the long-term efects that GM-IVH have on hippocampal subfelds, and their correlates with memory. The sample consisted of 58 participants, including 36 preterm-born (16 with GM-IVH and 20 without neonatal brain injury), and 22 full-term children aged between 6 and 15 years old. All participants underwent a cognitive assessment and magnetic resonance imaging study. GM-IVH children evidenced lower scores in Full Intelligence Quotient and memory measures compared to their low-risk preterm and full-term peers. High-risk preterm children with GM-IVH evidenced signifcantly lower total hippocampal volumes bilaterally and hippocampal subfeld volumes compared to both low-risk preterm and full-term groups. Finally, signifcant positive correlations between memory and hippocampal subfeld volumes were only found in preterm participants together; memory and the right CA-feld correlation remained signifcant after Bonferroni correction was applied (p= .002). In conclusion, memory alterations and both global and regional volumetric reductions in the hippocampus were found to be specifcally related to a preterm sample with GM-IVH. Nevertheless, results also suggest that prematurity per se has a long-lasting impact on the association between the right CA-feld volume and memory during childhood

    Tunable and precise two-bunch generation at FLASHForward

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    Beam-driven plasma-wakefield acceleration based on external injection has the potential to significantly reduce the size of future accelerators. Stability and quality of the acceleration process substantially depends on the incoming bunch parameters. Precise control of the current profile is essential for optimising energy-transfer efficiency and preserving energy spread. At the FLASHForward facility, driver--witness bunch pairs of adjustable bunch length and separation are generated by a set of collimators in a dispersive section, which enables fs-level control of the longitudinal bunch profile. The design of the collimator apparatus and its commissioning is presented.Comment: 7 pages, 5 figures, to be published in the proceedings of the 4th European Advanced Accelerator Concepts Workshop, 15-21 September 2019, La Biodola Bay, Isola d'Elba, Ital

    Types of cover for the culture of Eisenia fetida (Oligochaeta, Lumbricidae). Incidence on distribution and density

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    La cobertura de un vermicultivo constituye una interfase de la que se espera contribuya a un control de malezas, brinde aislamiento térmico, facilite la infiltración del agua y el intercambio gaseoso, restrinja la evaporación, proteja de predadores y reduzca las fugas. Los materiales comúnmente usados para cubrir los vermicultivos suelen ser de naturaleza vegetal, sintética o bien mixta. Con el fin de establecer ventajas e inconvenientes derivados del uso de estas y simultáneamente proporcionar criterios objetivos para adoptar la cobertura más conveniente, se delimitaron parcelas con diferentes coberturas en dos lombricultivos experimentales bajo distintas estrategias de conducción (autosiembra y alimentación sucesiva). Se muestreó y evaluó la distribución y densidad de lombrices/Lecho para distinto tipos - combinaciones de materiales de cobertura (pastos secos, nylon y red semisombra doble del 80%). Se estableció que las cubiertas impermeables afectan negativamente a la capacidad de porte del sustrato, particularmente en profundidad, movilizando los animales subadultos y adultos hacia la superficie, reduciéndose, en algunos casos, la densidad a menos de la mitad de las lombrices que albergan coberturas permeables. Se recomienda la utilización de coberturas naturales en combinación con malla del tipo semisombra, simple, del 50%, o aún menos densas, desaconsejándose la utilización de nylon-polietileno.The cover of the vermiculture is an interface that is expected to contribute to weed control, offer thermal isolation, facilitate water infiltration and gas exchange, restrict evaporation, protect from predators and reduce animals escape. The materials commonly used for vermiculture may be vegetable, synthetic or mixed. With the purpose of assessing the advantages and disadvantages derived from the use of these materials, as well as establishing objective criteria for the adoption of the most convenient cover. Land plots with different covers were prepared in two experimental vermicultures run under different management strategies (self-inoculation and periodic feeding). The distribution and density of earthworms/Bed -2m - sampled and evaluated 2 for different types-combinations of cover materials (dry grass, nylon, 80% knitted shadecloth). It was established that impermeable covers affect the carrying capacity of the substratum, particularly in deep regions. Subadult and adult animals move towards the surface and density was reduced in some cases to less than half of the worms supported using permeable covers. We recommend the use of natural covers combined with simple, shadecloth (less than 80%), whereas the use of impermeable films is discouraged.Facultad de Ciencias Naturales y Muse

    Types of cover for the culture of Eisenia fetida (Oligochaeta, Lumbricidae). Incidence on distribution and density

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    La cobertura de un vermicultivo constituye una interfase de la que se espera contribuya a un control de malezas, brinde aislamiento térmico, facilite la infiltración del agua y el intercambio gaseoso, restrinja la evaporación, proteja de predadores y reduzca las fugas. Los materiales comúnmente usados para cubrir los vermicultivos suelen ser de naturaleza vegetal, sintética o bien mixta. Con el fin de establecer ventajas e inconvenientes derivados del uso de estas y simultáneamente proporcionar criterios objetivos para adoptar la cobertura más conveniente, se delimitaron parcelas con diferentes coberturas en dos lombricultivos experimentales bajo distintas estrategias de conducción (autosiembra y alimentación sucesiva). Se muestreó y evaluó la distribución y densidad de lombrices/Lecho para distinto tipos - combinaciones de materiales de cobertura (pastos secos, nylon y red semisombra doble del 80%). Se estableció que las cubiertas impermeables afectan negativamente a la capacidad de porte del sustrato, particularmente en profundidad, movilizando los animales subadultos y adultos hacia la superficie, reduciéndose, en algunos casos, la densidad a menos de la mitad de las lombrices que albergan coberturas permeables. Se recomienda la utilización de coberturas naturales en combinación con malla del tipo semisombra, simple, del 50%, o aún menos densas, desaconsejándose la utilización de nylon-polietileno.The cover of the vermiculture is an interface that is expected to contribute to weed control, offer thermal isolation, facilitate water infiltration and gas exchange, restrict evaporation, protect from predators and reduce animals escape. The materials commonly used for vermiculture may be vegetable, synthetic or mixed. With the purpose of assessing the advantages and disadvantages derived from the use of these materials, as well as establishing objective criteria for the adoption of the most convenient cover. Land plots with different covers were prepared in two experimental vermicultures run under different management strategies (self-inoculation and periodic feeding). The distribution and density of earthworms/Bed -2m - sampled and evaluated 2 for different types-combinations of cover materials (dry grass, nylon, 80% knitted shadecloth). It was established that impermeable covers affect the carrying capacity of the substratum, particularly in deep regions. Subadult and adult animals move towards the surface and density was reduced in some cases to less than half of the worms supported using permeable covers. We recommend the use of natural covers combined with simple, shadecloth (less than 80%), whereas the use of impermeable films is discouraged.Facultad de Ciencias Naturales y Muse

    A high throughput screen for next-generation leads targeting malaria parasite transmission

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    Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2–1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male–female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population
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