1350 S Kings Dr
Charlotte NC 28207
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In vitro and in vivo evaluation of effect of excipients in local delivery of paclitaxel using microporous infusion balloon catheters. - Journal of biomedical materials research. Part B, Applied biomaterials
Drug-infusion balloons are one of the currently used local drug delivery devices for preventing restenosis after endovascular treatments. An antiproliferative drug (paclitaxel, PAT) is infused through the balloon using a cremophor-based formulation to control restenosis. However, the major limitations of this approach are poor in vivo drug uptake and a limit in the amount of PAT delivered because of cremophor toxicity. In this study, we have investigated the use of different excipients for effectively infusing PAT out of the balloon for improved drug uptake in the tissue. The excipients include nanoparticle albumin-bound PAT (nab-PAT, a nanobiomaterial used in cancer therapy), urea (a hydrophilic agent used for faster drug transfer), iodixanol (a contrast agent used for coronary angiography), and cremophor-PAT (the most commonly used PAT formulation). An in vitro drug release, smooth muscle cell (SMC) response, endothelial cell (EC) response, and in vivo drug uptake were investigated for all the different excipients of PAT infused through the balloon. The nab-PAT was as effective as cremophor in infusing out of the balloon and inhibiting SMC growth. Also, nab-PAT showed a significantly greater amount of in vivo PAT uptake than that of cremophor-PAT. Urea and iodixanol were not effective in delivering a clinically relevant dose of PAT due to the poor solubility of PAT in these excipients. Urea eradicated all the SMCs and ECs, suggesting a toxic effect, which impedes its use in balloon-based therapy. Thus, this study demonstrated that nab-PAT is an effective formulation to locally deliver PAT through infusion balloons. Â© 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2015.Â© 2015 Wiley Periodicals, Inc.
Liminality in preregistration mental health nurse education: a review of the literature. - Nurse education in practice
This paper provides an analysis of the anthropological concept of liminality in relation to undergraduate preregistration mental health nurse education, and considers implications both for students and nurse educators working in this field. A review of educational and professional literature was undertaken in order to clarify the concept of liminality within the context of nurse education to aid in understanding how nurse educators could maximise the potential of liminality within the mental health preregistration nursing programme, and to consider the relationship between liminality and the preparation of future mental health nursing practitioners. A survey of the findings and conclusions of the selected studies yielded two key areas in which the concept has an explanatory function: in relation to "threshold concepts" in nurse education and as a way of describing a stage in the development of a role and identity. Discussion of each of these areas points to suggestions for changes in the understanding of education and training for mental health nurses, particularly in the context of the United Kingdom.Copyright Â© 2014 Elsevier Ltd. All rights reserved.
Effects of APC De-targeting and GAr modification on the duration of luciferase expression from plasmid DNA delivered to skeletal muscle. - Current gene therapy
Immune responses to expressed foreign transgenes continue to hamper progress of gene therapy development. Translated foreign proteins with intracellular location are generally less accessible to the immune system, nevertheless they can be presented to the immune system through both MHC Class I and Class II pathways. When the foreign protein luciferase was expressed following intramuscular delivery of plasmid DNA in outbred mice, expression rapidly declined over 4 weeks. Through modifications to the expression plasmid and the luciferase transgene we examined the effect of detargeting expression away from antigen-presenting cells (APCs), targeting expression to skeletal muscle and fusion with glycine-alanine repeats (GAr) that block MHC-Class I presentation on the duration of luciferase expression. De-targeting expression from APCs with miR142-3p target sequences incorporated into the luciferase 3'UTR reduced the humoral immune response to both native and luciferase modified with a short GAr sequence but did not prolong the duration of expression. When a skeletal muscle specific promoter was combined with the miR target sequences the humoral immune response was dampened and luciferase expression persisted at higher levels for longer. Interestingly, fusion of luciferase with a longer GAr sequence promoted the decline in luciferase expression and increased the humoral immune response to luciferase. These studies demonstrate that expression elements and transgene modifications can alter the duration of transgene expression but other factors will need to overcome before foreign transgenes expressed in skeletal muscle are immunologically silent.
Alteration of mammary gland development and gene expression by in utero exposure to arsenic. - Reproductive toxicology (Elmsford, N.Y.)
Early life exposure to estrogens and estrogen like contaminants in the environment is thought to contribute to the early onset of puberty and consequently increases the risk of developing breast cancer in the exposed female. The results of this study show that in utero exposure to the metalloestrogen arsenite altered mammary gland development prior to its effect on puberty onset. In the prepubertal gland, in utero exposure resulted in an increase in the number of mammosphere-forming cells and an increase in branching, epithelial cells, and density. In the postpubertal gland, in utero exposure resulted in the overexpression of estrogen receptor-alpha (ERÎ±) that was due to the increased and altered response of the ERÎ± transcripts derived from exons O and OT to estradiol. These results suggest that, in addition to advancing puberty onset, in utero exposure to arsenite alters the pre- and postpubertal development of the mammary gland and possibly, the risk of developing breast cancer.Copyright Â© 2014 Elsevier Inc. All rights reserved.
How many Coccolithovirus genotypes does it take to terminate an Emiliania huxleyi bloom? - Virology
Giant viruses are known to be significant mortality agents of phytoplankton, often being implicated in the terminations of large Emiliania huxleyi blooms. We have previously shown the high temporal variability of E. huxleyi-infecting coccolithoviruses (EhVs) within a Norwegian fjord mesocosm. In the current study we investigated EhV dynamics within a naturally-occurring E. huxleyi bloom in the Western English Channel. Using denaturing gradient gel electrophoresis and marker gene sequencing, we uncovered a spatially highly dynamic Coccolithovirus population that was associated with a genetically stable E. huxleyi population as revealed by the major capsid protein gene (mcp) and coccolith morphology motif (CMM), respectively. Coccolithoviruses within the bloom were found to be variable with depth and unique virus populations were detected at different stations sampled indicating a complex network of EhV-host infections. This ultimately will have significant implications to the internal structure and longevity of ecologically important E. huxleyi blooms.Copyright Â© 2014 The Authors. Published by Elsevier Inc. All rights reserved.
Epitope-based DNA vaccine for Alzheimer's disease: translational study in macaques. - Alzheimer's & dementia : the journal of the Alzheimer's Association
Clinical trials with passive and active Alzheimer's disease (AD) vaccines suggest that early interventions are needed for improvement of cognitive and/or functional performance in patients, providing impetus for the development of safe and immunologically potent active vaccines targeting amyloid Î² (AÎ²). The AN-1792 trial has indicated that AÎ²-specific T cells may be unsafe for humans; therefore, other vaccines based on small AÎ² epitopes are undergoing preclinical and clinical testing.Humoral and cellular immune responses elicited in response to a novel DNA epitope-based vaccine (AV-1955) delivered to rhesus macaques using the TriGrid electroporation device were evaluated. Functional activities of anti-AÎ² antibodies generated in response to vaccination were assessed in vitro.AV-1955 generates long-term, potent anti-AÎ² antibodies and cellular immune responses specific to foreign T-helper epitopes but not to self-AÎ².This translational study demonstrates that a DNA-based epitope vaccine for AD could be appropriate for human clinical testing.Copyright Â© 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
In vivo electroporation improves therapeutic potency of a DNA vaccine targeting hepadnaviral proteins. - Virology
This preclinical study investigated the therapeutic efficacy of electroporation (EP)-based delivery of plasmid DNA (pDNA) encoding viral proteins (envelope, core) and IFN-Î³ in the duck model of chronic hepatitis B virus (DHBV) infection. Importantly, only DNA EP-therapy resulted in a significant decrease in mean viremia titers and in intrahepatic covalently closed circular DNA (cccDNA) levels in chronic DHBV-carrier animals, compared with standard needle pDNA injection (SI). In addition, DNA EP-therapy stimulated in all virus-carriers a humoral response to DHBV preS protein, recognizing a broader range of major antigenic regions, including neutralizing epitopes, compared with SI. DNA EP-therapy led also to significant higher intrahepatic IFN-Î³ RNA levels in DHBV-carriers compared to other groups, in the absence of adverse effects. We provide the first evidence on DNA EP-therapy benefit in terms of hepadnaviral infection clearance and break of immune tolerance in virus-carriers, supporting its clinical application for chronic hepatitis B.Copyright Â© 2012 Elsevier Inc. All rights reserved.
Regional variation in lytic and lysogenic viral infection in the Southern Ocean and its contribution to biogeochemical cycling. - Applied and environmental microbiology
Lytic and lysogenic viral infection was investigated throughout the Southern Ocean at sites spanning the sub-Antarctic zone, the Antarctic Circumpolar Current, and an Antarctic continental sea. Higher lytic virus activity was recorded in the more productive sub-Antarctic zone than in the iron-limited waters of the Antarctic Circumpolar Current during two transects. Reduced lytic viral activity in the Antarctic Circumpolar Current was combined with a shift toward lysogenic infection, probably resulting from the lower concentration of potential prokaryotic hosts. Superimposed on this variation, lytic viral production was lower in a transect completed in the Drake Passage in autumn (1.8 Ã— 10(8) to 1.5 Ã— 10(9) liter(-1) day(-1)) than over the Greenwich Meridian during summer (5.1 Ã— 10(8) to 2.0 Ã— 10(10) cells liter(-1) day(-1)), indicating that viral activity is linked to the overall seasonal fluctuations in biotic activity. Interestingly, while prokaryotic abundance was lowest in the coastal Weddell Sea, levels of bacterial and lytic viral production (4.3 Ã— 10(8) to 1.7 Ã— 10(10) cells liter(-1) day(-1)) in this area were similar to those of the other zones. This may explain the weak relationship between the distribution of prokaryotes and chlorophyll in the Weddell Sea, as a high turnover of prokaryotic biomass may have been stimulated by the availability of substrates in the form of viral lysate. With estimated carbon and iron releases of 0.02 to 7.5 Î¼g liter(-1) day(-1) and 1.5 to 175.7 pg liter(-1) day(-1), respectively, viral activity in the Southern Ocean is shown to be a major contributor to satisfying the elemental requirements of microbes, notably prokaryotes in the Weddell Sea and phytoplankton in the sub-Antarctic zone.
Delivery of a DNA vaccine for Alzheimer's disease by electroporation versus gene gun generates potent and similar immune responses. - Neuro-degenerative diseases
Induction of a humoral response against amyloid-Î² peptide may be beneficial for Alzheimer's disease (AD) patients and may alleviate the onset and progression of AD. DNA-based vaccination provides a unique alternative method of immunization for treatment and prevention of AD. Currently, the two major delivery methods used for enhancing DNA uptake and immune responses to DNA vaccines in humans are electroporation (EP) and gene gun (GG).The goal of this translational study was to evaluate the efficacy of an AD DNA epitope vaccine (DepVac) delivered intramuscularly by EP or intradermally by GG.Humoral and cellular immune responses to immunization with DepVac were evaluated by ELISA and ELISPOT, respectively. Functional activity of the antibodies was also assessed.EP- and GG-mediated immunizations with DepVac induced similar anti-amyloid-Î² (AÎ²) antibody and T cell responses. Anti-AÎ² antibodies bound to amyloid plaques in AD brain tissue and to toxic forms of AÎ²(42) peptide.Both delivery methods are effective at promoting potent antibodies specific for AÎ².Copyright Â© 2012 S. Karger AG, Basel.
Enhanced magnitude and breadth of neutralizing humoral response to a DNA vaccine targeting the DHBV envelope protein delivered by in vivo electroporation. - Virology
We explored in the duck hepatitis B virus (DHBV) model the impact of electroporation (EP)-mediated DNA vaccine delivery on the neutralizing humoral response to viral preS/S large envelope protein. EP enhanced the kinetics and magnitude of anti-preS response compared to the standard needle DNA injection (SI). Importantly, EP dramatically enhanced the neutralizing potency of the humoral response, since antibodies induced by low DNA dose (10 Î¼g) were able to highly neutralize DHBV and to recognize ten antigenic regions, including four neutralization epitopes. Whereas, SI-induced antibodies by the same low DNA dose were not neutralizing and the epitope pattern was extremely narrow, since it was limited to only one epitope. Thus, EP-based delivery was able to improve the dose efficiency of DNA vaccine and to maintain a highly neutralizing, multi-specific B-cell response, suggesting that it may be an effective approach for chronic hepatitis B therapy at clinically feasible DNA dose.Copyright Â© 2012 Elsevier Inc. All rights reserved.
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1350 S Kings Dr Charlotte, NC 28207
2001 Vail Ave 4Th Floor Mmp
1915 Randolph Rd
2001 Vail Ave Suite 200