Currently, due to the chemotherapies lack of specificity and efficacy that cause several side effects, new targeted therapies are thus developed. Among these, we study a gene directed enzyme pro-drug therapy which allow the direct CYP2B6 transfer into cancer cells. This enzyme is able to convert cyclophosphamide into cyto-toxic metabolites (phosphoramide mustard) directly in tumor site. Two vectors can be used to target cancer cells, the first one is lenti-virus and the second one is mesenchymal stem cells, which are known to be attracted by microenvironment tumor. We have tested this strategy on three cancer cell types and demonstrated that the first strategy with lentivirus is not efficient to kill all cancer cell types. Indeed, breast cancer cell lines are not sensitive to CPA after transduction with lentivirus. In opposite, all tested cancer cell types are sensitive to CPA in presence of MSC. Therefore, our results show that MSC strategy is more efficient than lentivirus. Moreover, first in vivo studies confirm MSC efficiency as a vector for CYP2B6TM-RED transgene and enable to consider it for a new anti-cancer therapy.

Rong Zhang is currently a Doctoral candidate at the Fourth Military Medical University and is also performing research as a joint PhD in Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine. He has done some work concerning the genotype and treatment of genetic diseases and is now doing research mainly on immunoregulatory properties of mesenchymal stem cells on immune cells. He has published 2 papers in reputed journals.

IL-10 is an important anti-inflammatory cytokine that has been implicated in a variety of autoimmune conditions, including multiple sclerosis (MS). It has been shown that anti-CD226 treatment ameliorates experimental autoimmune encephalomyelitis (EAE), the widely accepted model of MS. However, the mechanism still needs to be elucidated. Here we show that CD226 ligation by anti-CD226 mAb LeoA1 efficiently promoted IL-10 production in human peripheral blood monocytes (PBMC) or in mixed lymphocyte culture (MLC) system. Meanwhile, LeoA1 treatment significantly induced the CD4+IL-10+ T cell differentiation while suppressing the generation of Th1 and Th17 through modulating IL-10R1 dependent STAT signaling pathway. Furthermore, CD226 pAb administration in vivo effectively reduced the onset of EAE in mice by promoting IL-10 production and regulating T cell differentiation. More importantly, the onset and severity of EAE in CD226 knockout mice was reduced and the serum IL-10 expression levels in CD226 knockout mice with EAE were higher than that in control mice. These findings establish that CD226 plays an important role in mediating autoimmune diseases and IL-10 is an important factor that mediates the inhibitory effects of CD226 ligation on EAE. Our findings thus provide hitherto unrecognized mechanism of CD226 targeted therapy of EAE. In conclusion, our data suggest manipulating IL-10 and its relative signaling pathway could be a feasible therapeutic strategy to improve the efficacy of CD226 associated treatment of human autoimmune diseases and disorders.

Sanam Salimi Elizei is a PhD student in the Experimental Medicine program of University of British Columbia, under the supervision of Dr. Aziz Ghahary since September 2011. He has examined the immune-regulatory effects of IDO expressing fibroblasts on pathogenesis of Psoriasis, an immune-mediated cutaneous disease

Psoriasis is a common inflammatory disease of human skin characterized by raised cutaneous plaques with scaling and variable erythema. It is believed that psoriasis is triggered by specific stimuli, such as trauma or bacterial infections, which in turn induce resident dendritic cells (DC), macrophages and Th17 cells to produce cytokines that initiate a cascade of events. Recently it was shown that expression of cytokines by dendritic cells increase in the Psoriasis lesion and this induces the expression of IL-17 by ϒδ+Tcell and Th17. We have previously shown that an immuno-modulatory enzyme, indole-amine 2, 3-dioxygenase (IDO) in dermal fibroblasts generates a tryptophan-deficient environment that selectively inhibits proliferation and induces apoptosis in CD4+ T cells. Because of that we hypothesized that IDO-expressing fibroblasts can serve as source of the local immunosuppression treatment for Psoriasis. Injected IDO-expressing mice showed significantly reduced dermal thickness and erythema and scaling score as compared to untreated group. Analysis of immune cell infiltration in skin showed a significant reduction in the frequency ofneutrophils, CD4+IL-17+ Tcells and ϒδ+ IL-17+ T cell. This finding suggests that IDO-expressing fibroblasts might be a potential immune suppressive treatment for Psoriasis.

Ch. Sushma completed her Bachelors’ degree in Genetics in 2007 as combination subjects, followed by Master’s in Genetics in 2009 and joined PhD in 2011 in Department of Genetics under the supervision of Prof. K Rudrama Devi. She is interested in research and especially to work on woman related cancers. She has collaboration with Indo American Cancer Hospitals for specimen collection and collected about 150 paired tissue specimens for the research work. Two of her manuscripts have been accepted in international journals; “Asian Pacific Journal of Cancer” and “International Journal of Biotechnology”. She has been working on 4 different gene polymorphisms and conducting the correlation study with each impact on breast cancer.

Weak immunity surveillance has been the main reason for progression and rapid development of various cancers reported. Though the association between cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene 49 G/A polymorphism and breast cancer has been widely assessed, a definitive conclusion remains elusive and is still focused by scientific community. The present study aims to evaluate the potential influences of CTLA-4 gene polymorphisms on breast cancer risk in invasive ductal carcinoma of tumor tissue and healthy tissues. Tumor tissue of forty confirmed that breast cancer patients were included as cases. The same forty patients’ adjacent non-tumor tissue samples were considered as controls. The prevalence of AA, GG and AG genotypes was 42.1%, 15.82% and 42.8% in the tumor tissue and non-tumor tissues respectively. Individuals containing tumor and non-tumor tissue samples showed significance in breast cancer, in which homozygous A/A and heterozygote G/A found to be more significant than G/G genotype. The study confirmed that the presence of at least one ‘A’ allele may increase the risk of breast cancer when compared to the presence of ‘G’ allele in same patient.

Li-li Cui has completed her M.D. at the age of 23 years from China Medical University. She is now a Ph.D student in the Institute of Clinical Medicine, University of Eastern Finland. She has published more than 7 papers in reputed journals.

Intra-Arterial (IA) cell infusion is an efficient delivery route to target organs, but related adverse events like micro-embolisms were recently reported. We tested the hypothesis that cell dose, infusion volume and infusion velocity might be related to the complications after IA cell delivery. Forty-two rats were subjected to a sham middle cerebral artery occlusion procedure before being infused with allogeneic bone-marrow mesenchymal stem cells through the external carotid artery at different doses (0-1.0×106), infusion volumes (0.5-1.0 ml), and infusion times (3-6 min). Laser Doppler flowmetry and MRI was performed to reveal possible complications. Open field test was conducted to assess sensorimotor functions.There was a cell dose-related reduction in cerebral blood flow, an increase in embolic events as well as sensorimotor impairment. A low infusion velocity (0.5 ml/6 min) was associated with high rate of complications. Particularly cell dose but also infusion velocity should be considered before planning efficacy studies.

Mitochondrial dysfunction is an early and prominent feature of Alzheimer’s disease (AD). In brains of human AD cases as well as AD-like, Aβ plaques are accumulated in mitochondria and may cause structural and functional abnormalities of mitochondria. In addition, mitochondrial abnormalities are found to arise before Aβ plaque deposition. Mitochondria from AD brains show fractured cristae, reduced respiratory capacity and increased mitochondrial fragmentation. Both the treatment of Aβ and the overexpression of Aβ precursor protein (APP) highly induce synaptic injury in neuronal cells as well as massive mitochondrial fragmentation. Exposure to oligomeric Aβ or excessive NO can lead to S-nitrosylation of Drp1 (SNO-Drp1) at Cys644 which activates Drp1 GTPase activity and results in the accumulation of excessively fragmented mitochondria. Moreover, Drp1 activity and the level of SNO-Drp1 were significantly elevated in the brains of sporadic AD cases. Therefore, the adjustment of imbalance of mitochondrial dynamics may have beneficial effects on mitochondrial structure, function and neuronal survival in AD. However, it remains to be determined whether inhibition of excessive mitochondrial fission is beneficial in mammal models of AD. In this study, we evaluated the effect of Drp1 inhibitor mdivi-1 on mitochondrial dysfunction and AD-like neuropathology in APP/PS1 double transgenic AD mice.

Natalia Martínez Gil is a PhD Student at School of Medicine and Dentistry in Catholic University of Valencia, Spain. She’s working with cellular communication via exosomes in retina. Specifically she is studying the effect of ethanol in the retinal pigment epithelium.

Exosomes are small membrane vesicles from MVB and are released by a wide variety of cell types. Exosomes contain proteins and genetic material. Retinal pigment epithelium (RPE) plays a critical role in the homeostasis of the retina and any alterations therein may trigger a cell change. Previous studies showed that ethanol induces activation of VEGF causing cell proliferation and the formation of new vessels. However, the presence of VEGF receptors in exosomes derived from a cell line of human RPE (ARPE-19) and the effect of ethanol on their content have not yet been explored. Exosomes derived from ARPE-19 cells were isolated by ultracentrifugation and characterized by electron microscopy. Exosomes were quantified by means of flow cytometry and the protein profile and content of VEGFR-1 analyzed by Western blot. qPCR was conducted to assess the RNA content of VEGFR-1 and VEGFR-2. An oxidative insult initiated by ethanol induces the release of increased amounts of exosomes in ARPE-19 cells. These “pathologic” exosomes demonstrate greater concentrations of membrane-bound VEGFR-1 and VEGFR-2, which contribute essentially to the formation of new vessels in retinal disorders.