Detachment of epithelial cells from matrix or attachment to an inappropriate matrix engages an apoptotic response known as anoikis, which prevents metastasis. Cellular sensitivity to anoikis is compromised during the oncogenic epithelial-to-mesenchymal transition (EMT), through unknown mechanisms. We report here a pathway through which EMT confers anoikis resistance. NRAGE (neurotrophin receptor-interacting melanoma antigen) interacted with a component of the E-cadherin complex, ankyrin-G, maintaining NRAGE in the cytoplasm. Oncogenic EMT downregulated ankyrin-G, enhancing the nuclear localization of NRAGE. The oncogenic transcriptional repressor protein TBX2 interacted with NRAGE, repressing the tumor suppressor gene p14ARF. P14ARF sensitized cells to anoikis; conversely, the TBX2/NRAGE complex protected cells against anoikis by downregulating this gene. This represents a novel pathway for the regulation of anoikis by EMT and E-cadherin.Metastatic tumor cells survive detachment from their extracellular matrix of origin and/or attachment to inappropriate matrices for extended periods of time, conditions that engage an apoptotic response known as anoikis in normal cells. Tumor cell resistance to anoikis is driven by (epi)genetic alterations or aberrant signaling responses that occur uniquely in the tumor microenvironment, leading to constitutive activation of integrin/growth factor signaling and inactivation of the core apoptotic machinery (23, 27, 28, 30-32, 76, 87).The oncogenic epithelial-to-mesenchymal transition (EMT) is thought to play an important role in tumor progression (46,88,91). The focus of the present study was to understand the molecular basis of the tight correlation between anoikis resistance and the oncogenic EMT (31,51,54,68,89). A common hallmark of EMT is the breakdown of E-cadherin expression or function (103), which suffices to circumvent anoikis in some contexts. For example, the targeted knockout of the E-cadherin gene in a mouse mammary tumor model or the stable knockdown of E-cadherin in a mammary epithelial cell line confers anoikis resistance (19,68). This implies that EMTpromoting transcription factors such as ZEB1/2, Snail1/2 and Twist can abrogate anoikis both by directly regulating apoptosis control genes and by suppressing E-cadherin expression, the latter triggering signaling events-to be addressed here-that control other apoptosis regulatory genes (46,53,75,85,89,92).Ankyrin-G plays a critical role in linking the actin cytoskeleton to the cell membrane and in the biogenesis of the lateral membrane domain of epithelial cells. The N-terminal ankyrin repeat domain interacts with E-cadherin, linking the latter to the cytoskeleton via interaction with spectrin complexes. Accordingly, ankyrin-G localizes primarily to adherens junctions (50,65,73). In addition, ankyrin-G contains two domains, a death domain and a ZU-5 domain, whose homologues in other proteins regulate apoptosis (99, 101). The downregulation of the ankyrin-G gene (ank3) correlates with poor prognosis in diverse human...

The cell-mediated immune profile induced by a recombinant DNA vaccine was assessed in the simian/HIV (SHIV) and macaque model. The vaccine strategy included coimmunization of a DNA-based vaccine alone or in combination with an optimized plasmid encoding macaque IL-15 (pmacIL-15). We observed strong induction of vaccine-specific IFN-␥-producing CD8 ؉ and CD4 ؉ effector T cells in the vaccination groups. Animals were subsequently challenged with 89.6p. The vaccine groups were protected from ongoing infection, and the IL-15 covaccinated group showed a more rapidly controlled infection than the group treated with DNA vaccine alone. Lymphocytes isolated from the group covaccinated with pmacIL-15 had higher cellular proliferative responses than lymphocytes isolated from the macaques that received SHIV DNA alone. Vaccine antigen activation of lymphocytes was also studied for a series of immunological molecules. Although mRNA for IFN-␥ was up-regulated after antigen stimulation, the inflammatory molecules IL-8 and MMP-9 were down-regulated. These observed immune profiles are potentially reflective of the ability of the different groups to control SHIV replication. This study demonstrates that an optimized IL-15 immune adjuvant delivered with a DNA vaccine can impact the cellular immune profile in nonhuman primates and lead to enhanced suppression of viral replication.HIV vaccine ͉ immune response ͉ cytokine adjuvant ͉ T cell immunity

An important goal for human immunodeficiency virus (HIV) vaccines is to develop immunogens that induce broader and more potent cellular immune responses. In this study of DNA vaccine potency, we constructed a novel subtype B env gene (EY2E1-B) with the goal of increasing vaccine antigen immune potency. The vaccine cassette was designed based on subtype B-specific consensus sequence with several modifications, including codon optimization, RNA optimization, the addition of a Kozak sequence, and a substituted immunoglobulin E leader sequence. The V1 and V2 loops were shortened and the cytoplasmic tail was truncated to prevent envelope recycling. Three different strains of mice (BALB/c, C57BL/6, and HLA-A2 transgenic mice) were immunized three times with pEY2E1-B or the primary DNA immunogen pEK2P-B alone. The analysis of specific antibody responses suggested that EY2E1-B could induce a moderate subtype B-specific antibody response. Moreover, this construct was up to four times more potent at driving cellular immune responses. Epitope mapping results indicated that there is an increase in the breadth and magnitude of cross-reactive cellular responses induced by the EY2E1-B immunogen. These properties suggest that such a synthetic immunogen deserves further examination for its potential to serve as a component antigen in an HIV vaccine cocktail.

Available online xxxKeywords: Radionuclide Uranium Radiological risk Toxicity Laser a b s t r a c tIn the present investigations, Laser Fluorimetry technique has been used for the microanalysis of uranium content in drinking water samples collected from different sources like the hand pumps, tube wells of various depths from wide range of locations in the four districts of SW-Punjab, India. The purpose of this study was to investigate the uranium concentration levels of ground water being used for drinking purposes and to determine its health effects, if any, to the local population of this region. Corresponding radiological and chemical risks have also been calculated for the uranium concentrations in ground water samples. Some other heavy elements have also been analysed using the Atomic Absorption Spectrometry. In this region, uranium concentration in 498 drinking water samples has been found to vary between 0.5e579 mgl À1 with an average of 73.5 mgl À1 . Data analysis revealed that 338 of 498 samples had uranium concentration higher than recommended safe limit of 30 mgl À1 (WHO, 2011) while 216 samples exceeded the threshold of 60 mgl À1 recommended by AERB, DAE, India, 2004.

Idiotypic antigens are clearly defined tumor-associated protein antigens, which can induce protective immunity against lymphoma. Because each patient requires an individual vaccine, idiotypic antigens also provide ideal candidates for exploring the feasibility of replacing protein antigens by DNA vaccines. Component idiotypic variable region genes can be identified in patients' tumor biopsies and rapidly assembled as scFv sequences. These can be used to produce recombinant scFv protein in bacteria, or as direct naked DNA vaccines. A preliminary small trial of DNA vaccines for chemotherapy-resistant patients with lymphoma has begun. Intramuscular idiotypic DNA vaccination in a mouse model induces low levels of anti-idiotypic antibody in serum. Levels can be increased dramatically by coinjection of DNA plasmids encoding either IL-2 or GM-CSF, and specific proliferative anti-idiotypic T cells are induced. However protective immunity remains to be demonstrated, and a possible reason for this may lie in the continued secretion of idiotypic scFv antigen which blocks antibody activity by formation of immune complexes. Methods for regulating secretion of antigen are required before this category of tumor antigen can be fully exploited as a vaccine. The power of DNA technology should allow analysis and manipulation of pathways of antigen presentation to induce maximal therapeutic attack on neoplastic B cells. In addition, lymphoma presents a model for application of DNA technology to the wide range of human tumors known to harbor potential tumor antigens.

DNA vaccination is an invaluable approach for immune therapy in that it lacks vector interference and thus permits repeated vaccination boosts. However, by themselves, DNA-based vaccines are typically poor inducers of Ag-specific immunity in humans and non-human primates. Cytokines, such as IL-12 and IL-15, have been shown to be potent adjuvants for the induction and maintenance of cellular immune responses, in particular during HIV infection. In this study, we examined the ability of therapeutic vaccination with SIV-DNA+IL-12 or IL-15 as molecular adjuvants to improve DNA vaccine potency and to enhance memory immune responses in SIV-infected macaques. Our results demonstrate that incorporating IL-12 into the vaccine induces SIV-specific CD8 effector memory T cell (TEM) functional responses and enhances the capacity of IFN-γ-producing CD8 TEM cells to produce TNF. Lower levels of PD-1 were expressed on T cells acquiring dual function upon vaccination as compared with mono-functional CD8 TEM cells. Finally, a boost with SIV-DNA+IL-15 triggered most T cell memory subsets in macaques primed with either DNA-SIV or placebo but only CD8 TEM in macaques primed with SIV-DNA+IL-12. These results indicate that plasmid IL-12 and IL-15 cytokines represent a significant addition to enhance the ability of therapeutic DNA vaccines to induce better immunity.

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Although EI has become a popular tool in organizations there is still a need for increased empirical research on the construct (Salovey, Woolery, & Mayer, 2002). This study contributes to the literature by providing more information about Emotional intelligence which may alleviate Work Engagement Behavior. It does this by building on the small existing pool of knowledge in order to extend the research on EI. The expected outcome of this study was an increased understanding of how EI impacts on Work Engagement Behavior. Emotional intelligence was measured using the 33-item Schutte Self-Report Inventory (SSRI) developed by Schutte and colleagues (Schutte et al, 1998). Engagement was measured using the shortened version of the Utrecht Work Engagement Scale (UWES) . The scale consists of 9 items and was designed to measure the three components of engagement: vigor, absorption, and dedication. The samples of 119 employees who are from information technology services and Information technology enabled services of Chennai city in India, chosen for the study. Self Administered questionnaire distributed and information collected. Research design descriptive type with non probability purposive sampling technique was used for the study. The data were analyzed using SPSS (statistical package for social science) version 14.The statistical tools like Cronbach's Alpha Reliability Test, Correlation, Chi -Square Test, One -Way ANOVA, Post -Hoc Test, Factor Analysis and Regression Analysis were employed for the research study. From these Research Findings, managerial as well as theoretical implications have been discussed in this study.