Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers

The Notochord, Notochordal cell and CTGF/CCN-2: ongoing activity from development through maturation

The growth regulating factor CTGF/CCN-2 is an integral factor in growth and development, connective tissue maintenance, wound repair and cell cycle regulation. It has recently been reported that CTGF/CCN-2 is involved in very early development having been detected in early notochord formation in zebrafish using CTGF/CCN-2 promoter-driven green fluorescent protein (GFP) plasmids. In these studies fluorescence was detected early in the developing embryos, a finding of considerable significance in that CTGF/CCN-2 deficient mutant mice die early after birth due to severe cartilage and skeletal dysplasia and respiratory failure. Such findings confirm the importance of CTGF/CCN-2 in development and of the necessary and sufficient role of this molecule in formation of the skeleton, extracellular matrix and chondrogenesis. Of particular relevance to the relationship between the notochordal cell and CTGF/CCN-2 there is a remarkable sub-species of canine, the ‘non-chondrodystrophic’ canine that is protected from developing degenerative disc disease (DDD). These animals are unique in that they preserve the population of notochordal cells within their disc nucleus (NP) and these cells secrete CTGF/CCN-2. We have detected CTGF/CCN-2 within conditioned medium developed from the notochordal cells of these animals (NCCM) and used this conditioned medium to demonstrate robustly increased proteoglycan production. The addition of recombinant human CTGF/CCN-2 to totally serum-free media containing cultures of bovine NP cells replicated the robustly increased aggrecan gene expression found with NCCM alone strongly suggesting the importance of the effect of CTGF/CCN-2 in notochordal cell biology within the disc nucleus of non-chondrodystrophic canines. The chondrodystrophic canine, another sub-species on the other hand are almost totally devoid of notochordal cells and they develop DDD profoundly and early. These two sub-species of canine reflect a naturally occurring animal model that is an excellent example of differential notochordal cell survival and possible associated developmental differences in extracellular maintenance

Archaeoseismology: Methodological issues and procedure

Archaeoseismic research contributes important data on past earthquakes. A limitation of the usefulness of archaeoseismology is due to the lack of continuous discussion about the methodology. The methodological issues are particularly important because archaeoseismological investigations of past earthquakes make use of a large variety of methods. Typical in situ investigations include: (1) reconstruction of the local archaeological stratigraphy aimed at defining the correct position and chronology of a destruction layer, presumably related to an earthquake; (2) analysis of the deformations potentially due to seismic shaking or secondary earthquake effects, detectable on walls; (3) analysis of the depositional characteristics of the collapsed material; (4) investigations of the local geology and geomorphology to define possible natural cause(s) of the destruction; (5) investigations of the local factors affecting the ground motion amplifications; and (6) estimation of the dynamic excitation, which affected the site under investigation. Subsequently, a 'territorial' approach testing evidence of synchronous destruction in a certain region may delineate the extent of the area struck by the earthquake. The most reliable results of an archaeoseismological investigation are obtained by application of modern geoarchaeological practice (archaeological stratigraphy plus geological–geomorphological data), with the addition of a geophysical-engineering quantitative approach and (if available) historical information. This gives a basic dataset necessary to perform quantitative analyses which, in turn, corroborate the archaeoseismic hypothesis. Since archaeoseismological investigations can reveal the possible natural causes of destruction at a site, they contribute to the wider field of environmental archaeology, that seeks to define the history of the relationship between humans and the environment. Finally, through the improvement of the knowledge on the past seismicity, these studies can contribute to the regional estimation of seismic hazard

Parosteal osteosarcoma with myocardial metastasis 13 years after follow-up Osteossarcoma parostal com metástase miocárdica após 13 anos de seguimento

PURPOSE: To report the case of a woman with a diagnosis of grade II (low grade) parosteal osteosarcoma with the occurrence of myocardial metastasis 13 years after resection, and to present a review of the existing literature on the subject. METHODS: Description of the case and review of the literature. CONCLUSION: The review leads to the conclusion that the occurrence of metastasis from parosteal osteosarcoma can occur in up to 38% of the cases, in spite of its relatively low aggressiveness. However, myocardial metastasis of a parosteal osteosarcoma is an event that was not found in the literature.<br>OBJETIVOS: Os autores relatam um caso de uma paciente do sexo feminino, com diagnóstico de osteossarcoma parostal grau II (baixo grau), que evoluiu com a ocorrência de metástase miocárdica 13 anos após a ressecção do tumor e incluem uma revisão da literatura sobre o assunto. MÉTODOS: Descrição do caso e revisão da literatura. CONCLUSÕES: A revisão leva à conclusão que a existência de metástases oriundas do osteossarcoma parosteal pode ocorrer em até 38 % dos casos, a despeito da sua relativa baixa agressividade. No entanto, a metástase miocárdica constitui um evento não relatado na literatura

Contribution of vascular endothelial growth factor receptor-2 sialylation to the process of angiogenesis

Vascular endothelial growth factor receptor-2 (VEGFR2) is the main pro-angiogenic receptor expressed by endothelial cells (ECs). Using surface plasmon resonance, immunoprecipitation, enzymatic digestion, immunofluorescence and cross-linking experiments with specific sugar-binding lectins, we demonstrated that VEGFR2 bears both α,1-fucose and α(2,6)-linked sialic acid (NeuAc). However, only the latter is required for VEGF binding to VEGFR2 and consequent VEGF-dependent VEGFR2 activation and motogenic response in ECs. Notably, downregulation of β-galactoside α(2,6)-sialyltransferase expression by short hairpin RNA transduction inhibits VEGFR2 α(2,6) sialylation that is paralleled by an increase of β-galactoside α(2,3)-sialyltransferase expression. This results in an ex-novo α(2,3)-NeuAc sialylation of the receptor that functionally replaces the lacking α(2,6)-NeuAc, thus allowing VEGF/VEGFR2 interaction. In keeping with the role of VEGFR2 sialylation in angiogenesis, the α(2,6)-NeuAc-binding lectin Sambucus nigra (SNA) prevents VEGF-dependent VEGFR2 autophosphorylation and EC motility, proliferation and motogenesis. In addition, SNA exerts a VEGF-antagonist activity in tridimensional angiogenesis models in vitro and in the chick-embryo chorioallantoic membrane neovascularization assay and mouse matrigel plug assay in vivo. In conclusion, VEGFR2-associated NeuAc plays an important role in modulating VEGF/VEGFR2 interaction, EC pro-angiogenic activation and neovessel formation. VEGFR2 sialylation may represent a target for the treatment of angiogenesis-dependent diseases.Oncogene advance online publication, 7 August 2017; doi:10.1038/onc.2017.243