The state of the art: immune-mediated mechanisms of monoclonal antibodies in cancer therapy

A number of antibody products have now become accepted as effective anti-cancer therapies. Despite being mainly designed to act by inhibiting functional tumour antigens, there is increasing evidence that Fc-mediated engagement of the immune system is an important contributor to the efficacy of several of these therapies. The optimisation of this engagement offers the potential not only to augment efficacy against existing targets, but also to exploit non-functional tumour antigens. Antibodies that achieve efficacy wholly or predominantly through Fc-mediated mechanisms, represent rich opportunities for future therapeutics in oncology. This mini review summarises some of the key challenges, which need to be addressed to select the most effective molecules. These include the identification of optimal antibody characteristics and improvement of the drug discovery process, in particular, the relevance and predictive power of existing in vitro and in vivo screening methods. Advances in our understanding of tumour immunobiology and successful application of technologies designed to enhance immune system engagement will further aid this process

Molecular Characterization of Spontaneous Mesenchymal Stem Cell Transformation

Background. We previously reported the in vitro spontaneous transformation of human mesenchymal stem cells (MSC) generating a population with tumorigenic potential, that we termed transformed mesenchymal cells (TMC). Methodology/Principal Findings. Here we have characterized the molecular changes associated with TMC generation. Using microarrays techniques we identified a set of altered pathways and a greater number of downregulated than upregulated genes during MSC transformation, in part due to the expression of many untranslated RNAs in MSC. Microarray results were validated by qRT-PCR and protein detection. Conclusions/Significance. In our model, the transformation process takes place through two sequential steps; first MSC bypass senescence by upregulating c-myc and repressing p16 levels. The cells then bypass cell crisis with acquisition of telomerase activity, Ink4a/Arf locus deletion and Rb hyperphosphorylation. Other transformation-associated changes include modulation of mitochondrial metabolism, DNA damage-repair proteins and cell cycle regulators. In this work we have characterized the molecular mechanisms implicated in TMC generation and we propose a two-stage model by which a human MSC becomes a tumor cell

Traumatic bilateral intraorbital (subperiosteal) hematoma associated with epidural hematoma: case report Hematoma intraorbitário bilateral traumático associado a hematoma epidural: relato de caso

Extradural hematoma (EDH) is a frequent lesion, with an incidence varying from 0.2 to 6% in patients admitted to hospital due to traumatic head injury. The higher incidence is found in patients with more severe injuries. The association of EDH with subperiosteal intraorbital hematomas is rarely reported, and we were not able to find in the literature any report of traumatic bilateral intraorbital hematomas and EDH. We report this case of a 32 year-old man with bilateral intraorbital (subperiosteal) hematoma associated with unilateral EDH. The lesions were treated surgically, but unfortunately with an unfavorable outcome.<br>Hematomas epidurais (HE) são lesões frequentes, com incidência entre 0,2 a 6% em pacientes internados após traumatismo cranioencefálico, sendo a maior incidência associada a pacientes portadores de traumas mais graves. A associação entre o HE e o hematoma intraorbitário é rara, sendo que não conseguimos encontrar na literatura nenhum relato de HE e hematoma intraorbitário bilateral. Relatamos o caso de um paciente de 32 anos com HE associado a hematoma intraorbitário bilateral, tratados cirurgicamente

Tick saliva inhibits differentiation, maturation and function of murine bone-marrow-derived dendritic cells

Haematophagous arthropod vectors such as mosquitoes, tsetse flies, sandflies and ticks have evolved salivary immunomodulatory factors that prevent the vertebrate host from rejecting them meanwhile enhancing pathogen transmission. As dendritic cells (DC) play a major role in host immune responses, we studied the effects of Rhipicephalus sanguineus tick saliva on DC differentiation and maturation. Flow cytometry analysis revealed that the addition of saliva to bone marrow cells inhibits the differentiation of DC and decreased the population of differentiated immature DC, increasing the levels of major histocompatibility complex (MHC) class II while not altering the expression of costimulatory (CD40, CD80 and CD86) and adhesion (CD54) molecules. Furthermore, maturation of DC stimulated by lipopolysaccharide (LPS) in the presence of saliva resulted in a lower expression of costimulatory molecules, but did not alter the up-regulation of MHC class II and CD54. The lipopolysaccharide (LPS)-matured DC cultured with saliva also presented reduced production of interleukin-12, whereas interleukin-10 production was unaltered. Assessment of the function of DC cultured with tick saliva revealed them to be poor stimulators of cytokine production by antigen-specific T cells. Our data indicate a novel modulatory role for the saliva of arthropod vectors at an initial step of the immune response through the inhibition of differentiation and maturation of DC into functional antigen-presenting cells