Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression

Purpose: Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets.Experimental Design: By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma, we evaluated the effect of tumor extracellular vesicle (EV)-educated mesenchymal stem cells (TEMSC) on osteosarcoma progression. Characterization and functional studies were designed to assess the mechanisms underlying MSC education. Independent series of tissue specimens were analyzed to corroborate the preclinical findings, and the composition of patient serum EVs was analyzed after isolation with size-exclusion chromatography.Results: We show that EVs secreted by highly malignant osteosarcoma cells selectively incorporate a membrane-associated form of TGFβ, which induces proinflammatory IL6 production by MSCs. TEMSCs promote tumor growth, accompanied with intratumor STAT3 activation and lung metastasis formation, which was not observed with control MSCs. Importantly, intravenous administration of the anti-IL6 receptor antibody tocilizumab abrogated the tumor-promoting effects of TEMSCs. RNA-seq analysis of human osteosarcoma tissues revealed a distinct TGFβ-induced prometastatic gene signature. Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in TEMSC-treated mice. Finally, we isolated pure populations of EVs from serum and demonstrated that circulating levels of EV-associated TGFβ are increased in osteosarcoma patients.Conclusions: Collectively, our findings suggest that TEMSCs promote osteosarcoma progression and provide the basis for testing IL6- and TGFβ-blocking agents as new therapeutic options for osteosarcoma patients

Occupational futures? Real estate refinancing and restructuring

SIGLEAvailable from British Library Document Supply Centre-DSC:m01/13222 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

A snapshot of exhaled nitric oxide and asthma characteristics: experience from high to low income countries

Nitric oxide is a gas produced in the airways of asthmatic subjects and related to T2 inflammation. It can be measured as fractional nitric oxide (FeNO) in the exhaled air and used as a non-invasive, easy to evaluate, rapid marker. It is now widely used in many settings to determine airway inflammation. The aim of this narrative review is to report relationship between FeNO and the physiopathologic characteristics of asthmatic patients. Factors affecting FeNO levels have also been analysed as well as the impact of corticosteroid, target therapies and rehabilitation programs. Considering the availability of the test, spreading this methodology to low income countries has also been considered as a possibility for evaluating airway inflammation and monitoring adherence to inhaled corticosteroid therapy. PubMed data search has been performed restricted to English language papers. Research was limited to studies in adults unless studies in children were the only ones reported for a particular issue. This revision could be useful to summarize the role of FeNO in relation to asthma characteristics and help in the use of FeNO in different clinical settings particularly in low income countries

SdeK, a Histidine Kinase Required for Myxococcus xanthus Development

The sdeK gene is essential to the Myxococcus xanthus developmental process. We reported previously, based on sequence analysis (A. G. Garza, J. S. Pollack, B. Z. Harris, A. Lee, I. M. Keseler, E. F. Licking, and M. Singer, J. Bacteriol. 180:4628–4637, 1998), that SdeK appears to be a histidine kinase. In the present study, we have conducted both biochemical and genetic analyses to test the hypothesis that SdeK is a histidine kinase. An SdeK fusion protein containing an N-terminal polyhistidine tag (His-SdeK) displays the biochemical characteristics of a histidine kinase. Furthermore, histidine 286 of SdeK, the putative site of phosphorylation, is required for both in vitro and in vivo protein activity. The results of these assays have led us to conclude that SdeK is indeed a histidine kinase. The developmental phenotype of a ΔsdeK1 strain could not be rescued by codevelopment with wild-type cells, indicating that the defect is not due to the mutant's inability to produce an extracellular signal. Furthermore, the ΔsdeK1 mutant was found to produce both A- and C-signal, based on A-factor and codevelopment assays with a csgA mutant, respectively. The expression patterns of several Tn5lacZ transcriptional fusions were examined in the ΔsdeK1-null background, and we found that all C-signal-dependent fusions assayed also required SdeK for full expression. Our results indicate that SdeK is a histidine kinase that is part of a signal transduction pathway which, in concert with the C-signal transduction pathway, controls the activation of developmental-gene expression required to progress past the aggregation stage