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1.
Cancer Gene Ther ; 20(8): 469-77, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23846252

ABSTRACT

Murine dendritic cells (DC) transduced to express the Type-1 transactivator T-bet (i.e. mDC.Tbet) and delivered intratumorally as a therapy are superior to control wild-type DC in slowing the growth of established subcutaneous MCA205 sarcomas in vivo. Optimal antitumor efficacy of mDC.Tbet-based gene therapy was dependent on host natural killer (NK) cells and CD8(+) T cells, and required mDC.Tbet expression of major histocompatibility complex class I molecules, but was independent of the capacity of the injected mDC.Tbet to produce proinflammatory cytokines (interleukin-12 family members or interferon-γ) or to migrate to tumor-draining lymph nodes based on CCR7 ligand chemokine recruitment. Conditional (CD11c-DTR) or genetic (BATF3(-/-)) deficiency in host antigen-crosspresenting DC did not diminish the therapeutic action of intratumorally delivered wild-type mDC.Tbet. Interestingly, we observed that intratumoral delivery of mDC.Tbet (versus control mDC.Null) promoted the acute infiltration of NK cells and naive CD45RB(+) T cells into the tumor microenvironment (TME) in association with elevated expression of NK- and T-cell-recruiting chemokines by mDC.Tbet. When taken together, our data support a paradigm for extranodal (cross)priming of therapeutic Type-1 immunity in the TME after intratumoral delivery of mDC.Tbet-based gene therapy.


Subject(s)
Dendritic Cells/immunology , Genetic Therapy/methods , Immunotherapy, Adoptive/methods , T-Box Domain Proteins/genetics , T-Box Domain Proteins/immunology , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , Animals , Cell Line, Tumor , Female , Mice , Mice, Inbred C57BL , Mice, Transgenic , Sarcoma/genetics , Sarcoma/immunology , Sarcoma/therapy , Transduction, Genetic
2.
Cell Mol Life Sci ; 64(18): 2391-403, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17565444

ABSTRACT

Cancer immunotherapy faces many obstacles that include eliciting immune reactions to self antigens as well as overcoming tumor-derived immunosuppressive networks and evasion tactics. Within the vaccine arsenal for inhibiting cancer proliferation, plasmid DNA represents a novel immunization strategy that is capable of eliciting both humoral and cellular arms of the immune response in addition to being safely administered and easily engineered and manufactured. Unfortunately, while DNA vaccines have performed well in preventing and treating malignancies in animal models, their overall application in human clinical trials has not impacted cancer regression to date. Since the establishment of these early trials, progress has been made in terms of increasing DNA vaccine immunogenicity and subverting the suppressive properties of tumor cells. Therefore, the success of future plasmid DNA use in cancer patients will depend on combinatorial strategies that enhance and direct the DNA vaccine immune response while also targeting tumor evasion mechanisms.


Subject(s)
Cancer Vaccines/immunology , Neoplasms/immunology , Neoplasms/therapy , Vaccines, DNA/immunology , Humans , Immunotherapy
3.
Cell Mol Life Sci ; 64(7-8): 803-14, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17260087

ABSTRACT

SV40 was discovered as a contaminate of poliovirus vaccine lots distributed to millions of individuals in the United States between 1955 and 1963 while contaminated vaccine batches were later circulated worldwide. After SV40 was observed to cause in vitro animal and human cell transformations and in vivo tumor formations in animals, the search for a connection between the virus and human malignancies has continued to the present day. Different molecular methods have been used to detect SV40 gene products in a variety of human cancers, though SV40 causality in these tumor types has yet to be established. These data, however, are not without controversial issues related to inconclusive SV40 serological and epidemiological evidence alongside tools and methodologies that may contribute to false-positive results in human specimens. This review will also explore how vaccination against SV40 protein products may be used to help prevent and treat individuals with SV40-expressing cancers.


Subject(s)
Antigens, Polyomavirus Transforming/immunology , Neoplasms/immunology , Neoplasms/virology , Simian virus 40/immunology , Simian virus 40/isolation & purification , Animals , Cancer Vaccines , Humans , Immunotherapy , Neoplasms/therapy , Polyomavirus Infections/transmission , Polyomavirus Infections/virology , Tumor Virus Infections/transmission , Tumor Virus Infections/virology
4.
Eur J Pharmacol ; 431(2): 189-200, 2001 Nov 16.
Article in English | MEDLINE | ID: mdl-11728425

ABSTRACT

The present studies were designed to assess whether the novel muscarinic M(2) receptor antagonist 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-1-piperazineacetonitrile (SCH 57790) could increase acetylcholine release in the central nervous system (CNS) and enhance cognitive performance in rodents and nonhuman primates. In vivo microdialysis studies show that SCH 57790 (0.1-10 mg/kg, p.o.) produced dose-related increases in acetylcholine release from rat hippocampus, cortex, and striatum. SCH 57790 (0.003-1.0 mg/kg) increased retention times in young rat passive avoidance responding when given either before or after training. Also, SCH 57790 reversed scopolamine-induced deficits in mice in a passive avoidance task. In a working memory operant task in squirrel monkeys, administration of SCH 57790 (0.01-0.03 mg/kg) improved performance under a schedule of fixed-ratio discrimination with titrating delay. The effects observed with SCH 57790 in behavioral studies were qualitatively similar to the effects produced by the clinically used cholinesterase inhibitor donepezil, suggesting that blockade of muscarinic M(2) receptors is a viable approach to enhancing cognitive performance.


Subject(s)
Acetylcholine/metabolism , Cognition/drug effects , Muscarinic Antagonists/pharmacology , Piperazines/pharmacology , Receptors, Muscarinic/drug effects , Animals , Blood Pressure/drug effects , Brain/drug effects , Brain/metabolism , CHO Cells , Cricetinae , Heart Rate/drug effects , Male , Mice , Microdialysis , Molecular Structure , Piperazines/chemistry , Rats , Rats, Sprague-Dawley , Receptor, Muscarinic M2 , Saimiri , Scopolamine/pharmacology , Time Factors
6.
Meat Sci ; 28(4): 321-9, 1990.
Article in English | MEDLINE | ID: mdl-22055663

ABSTRACT

Variation in chemically determined total haem pigment concentration and instrumentally determined colour was examined in 223 samples of M. longissimus dorsi (LD) representative of the majority of slaughter pigs currently produced in the UK. Whether pigs were sired by White (Large White or Landrace) or Meat-line boars did not affect any measured characteristic but source breeding company influenced total haem pigment concentration (P < 0·01). Haem pigment concentration was higher in muscles from gilts, compared with castrates, boars being intermediate. Gilts also had darker muscles, based on EEL Reflectance values (P < 0·05), and lower hue values (P < 0·05). When compared with animals fed ad-libitum, restricted-fed pigs had higher concentrations of muscle haem pigment (P < 0·001) and this resulted in meat that was slightly darker (P < 0·05), despite having lower ultimate pH (pHu) (P < 0·05), and had a lower hue value (P < 0·001). Measurements of reflectance, total soluble protein and pHu indicated that differences in the incidence of potentially pale, soft, exudative or dark, firm, dry muscle were unlikely to be important contributors to variation in the colour of the meat in this study.

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