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1.  Intramuscular Delivery of Adenovirus Serotype 5 Vector Expressing Humanized Protective Antigen Induces Rapid Protection against Anthrax That May Bypass Intranasally Originated Preexisting Adenovirus Immunity 
Developing an effective anthrax vaccine that can induce a rapid and sustained immune response is a priority for the prevention of bioterrorism-associated anthrax infection. Here, we developed a recombinant replication-deficient adenovirus serotype 5-based vaccine expressing the humanized protective antigen (Ad5-PAopt). A single intramuscular injection of Ad5-PAopt resulted in rapid and robust humoral and cellular immune responses in Fisher 344 rats. Animals intramuscularly inoculated with a single dose of 108 infectious units of Ad5-PAopt achieved 100% protection from challenge with 10 times the 50% lethal dose (LD50) of anthrax lethal toxin 7 days after vaccination. Although preexisting intranasally induced immunity to Ad5 slightly weakened the humoral and cellular immune responses to Ad5-PAopt via intramuscular inoculation, 100% protection was achieved 15 days after vaccination in Fisher 344 rats. The protective efficacy conferred by intramuscular vaccination in the presence of preexisting intranasally induced immunity was significantly better than that of intranasal delivery of Ad5-PAopt and intramuscular injection with recombinant PA and aluminum adjuvant without preexisting immunity. As natural Ad5 infection often occurs via the mucosal route, the work here largely illuminates that intramuscular inoculation with Ad5-PAopt can overcome the negative effects of immunity induced by prior adenovirus infection and represents an efficient approach for protecting against emerging anthrax.
PMCID: PMC3910935  PMID: 24307239
2.  Single nucleotide polymorphisms in thymic stromal lymphopoietin gene are not associated with allergic rhinitis susceptibility in Chinese subjects 
BMC Medical Genetics  2012;13:79.
Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine, implicated in the development and progression of allergic diseases. Recent studies have demonstrated significantly increased expression and synthesis of TSLPin nasal mucosa of patients with allergic rhinitis (AR), compared with nonallergic control subjects. Also, there is significant correlation between the level of TSLP mRNA and symptom severity in AR patients. In this study, we investigated whether polymorphisms in the TSLP gene were associated with increased risk of AR in the Chinese population.
In a candidate gene association study, we tested 11 single nucleotide polymorphisms (SNPs) in the TSLP gene in 368 AR and 325 control adult Han Chinese subjects from Beijing. The 11 SNPs were selected from the Chinese HapMap genotyping dataset to ensure complete genetic coverage. AR was established by questionnaire and clinical examination, and blood was drawn from all subjects for DNA extraction. The PLINK software package was used to perform statistical testing.
In the single-locus analysis of AR risk, no significant differences in allele and genotype frequencies were found between AR and control subjects. Further logistic regression analyses adjusted for age and gender also failed to reveal significant associations between AR and the selected SNPs. Similarly, analysis stratified by gender, and haplotype or diplotype did not reveal any association with AR risk.
Although TSLP presents itself as a good candidate for contributing to allergy, this study failed to find an association between specific SNPs in the TSLP gene and AR susceptibility in the Han Chinese population.
PMCID: PMC3459694  PMID: 22973903
Allergic rhinitis; Chinese subjects; Genotyping; Thymic stromal lymphopoietin; Single nucleotide polymorphism
3.  Prediction and identification of mouse cytotoxic T lymphocyte epitopes in Ebola virus glycoproteins 
Virology Journal  2012;9:111.
Ebola viruses (EBOVs) cause severe hemorrhagic fever with a high mortality rate. At present, there are no licensed vaccines or efficient therapies to combat EBOV infection. Previous studies have shown that both humoral and cellular immune responses are crucial for controlling Ebola infection. CD8+ T cells play an important role in mediating vaccine-induced protective immunity. The objective of this study was to identify H-2d-specific T cell epitopes in EBOV glycoproteins (GPs).
Computer-assisted algorithms were used to predict H-2d-specific T cell epitopes in two species of EBOV (Sudan and Zaire) GP. The predicted peptides were synthesized and identified in BALB/c mice immunized with replication-deficient adenovirus vectors expressing the EBOV GP. Enzyme-linked immunospot assays and intracellular cytokine staining showed that the peptides RPHTPQFLF (Sudan EBOV), GPCAGDFAF and LYDRLASTV (Zaire EBOV) could stimulate splenoctyes in immunized mice to produce large amounts of interferon-gamma.
Three peptides within the GPs of two EBOV strains were identified as T cell epitopes. The identification of these epitopes should facilitate the evaluation of vaccines based on the Ebola virus glycoprotein in a BALB/c mouse model.
PMCID: PMC3411508  PMID: 22695180
Ebola virus; T cell epitope; Replication-deficient adenovirus; Computer-assisted algorithms
4.  A Conformational Change of C Fragment of Tetanus Neurotoxin Reduces Its Ganglioside-Binding Activity but Does Not Destroy Its Immunogenicity ▿ 
Clinical and Vaccine Immunology : CVI  2011;18(10):1668-1672.
The C fragment of tetanus neurotoxin (TeNT-Hc) with different conformations was observed due to the four cysteine residues within it which could form different intramolecular disulfide bonds. In this study, we prepared and compared three types of monomeric TeNT-Hc with different conformational components: free sulfhydryls (50 kDa), bound sulfhydryls (44 kDa), and a mixture of the two conformational proteins (half 50 kDa and half 44 kDa). TeNT-Hc with bound sulfhydryls reduced its binding activity to ganglioside GT1b and neuronal PC-12 cells compared to what was seen for TeNT-Hc with free sulfhydryls. However, there was no significant difference among their immunogenicities in mice, including induction of antitetanus toxoid IgG titers, antibody types, and protective capacities against tetanus neurotoxin challenge. Our results showed that the conformational changes of TeNT-Hc resulting from disulfide bond formation reduced its ganglioside-binding activity but did not destroy its immunogenicity, and the protein still retained continuous B cell and T cell epitopes; that is, the presence of the ganglioside-binding site within TeNT-Hc may be not essential for the induction of a fully protective antitetanus response. TeNT-Hc with bound sulfhydryls may be developed into an ideal human vaccine with a lower potential for side effects.
PMCID: PMC3187031  PMID: 21813664
5.  Dual Inhibitors of Thymidylate Synthase and Dihydrofolate Reductase as Antitumour Agents: Design, Synthesis and Biological Evaluation of Classical and Nonclassical Pyrrolo[2,3-d]pyrimidine Antifolates1 
Journal of medicinal chemistry  2006;49(3):1055-1065.
We designed and synthesized a classical analog N-[4-[(2-amino-6-ethyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thio]benzoyl]-L-glutamic acid (4) and thirteen nonclassical analogs 5-17 as potential dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors and as antitumour agents. The key intermediate in their synthesis was 2-amino-6-ethyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidine, 22, to which various aryl thiols were conveniently attached at the 5-position via an oxidative addition reaction using iodine. For the classical analog 4, the ester obtained from the reaction was deprotected and coupled with diethyl-L-glutamate followed by saponification. Compound 4 was a potent dual inhibitor of human TS (IC50 = 90 nM) and human DHFR (IC50 = 420 nM). Compound 4 was not a substrate for human FPGS. Metabolite protection studies established TS as its principal target. Most of the nonclassical analogs were only inhibitors of human TS with IC50 values of 0.23-26 μM.
PMCID: PMC2547132  PMID: 16451071
6.  Clinicopathological Significance of VEGF-C, VEGFR-3 and Cyclooxygenase-2 in Early-Stage Cervical Cancer 
To investigate the roles of VEGF-C, VEGFR-3 and cyclooxygenase-2 (COX-2) in tumor progression and lymph node metastasis. The expression of VEGF-C, VEGFR-3 and COX-2 were examined in 93 cases of surgical speciments of cervical diseases by immunohistochemical staining. The correlation between expression of these factors and tumor aggressiveness was evaluated. The expression levels of VEGF-C and COX-2 were much higher in cervical cancer than in cervical intraepithelial neoplasia (CIN) and in chronic cervicitis. VEGF-C expression correlated with lymph node metastases (P<0.01). Multivariate analysis indicated that lymph vessel density (LVD) was associated with the coexpression of VEGF-C and COX-2. Expression of VEGF-C and VEGFR-3 were both in coincidence with lymph node metastasis. VEGF-C and COX-2 may promote the canceration of cervical cancer and that VEGF-C/ VEGFR-3 system had a significant association with the lymphagiogenesis and lymph node metastasis.
PMCID: PMC3614667  PMID: 23675067
vascular endothelial growth factor-C; vascular endothelial growth factor receptor-3; cyclooxygenase-2; lymphagiogenesis; lymph node metastasis; cervical cancer

Results 1-6 (6)