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- Abu-Elyazeed, R R, et al.
(författare)
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Safety and immunogenicity of a glycoprotein D genital herpes vaccine in healthy girls 10-17 years of age : results from a randomised, controlled, double-blind trial
- 2013
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 31:51, s. 6136-6143
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The investigational AS04-adjuvanted herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit prophylactic vaccine ('HSV vaccine'; GlaxoSmithKline Vaccines) has been shown to be well tolerated in adults, but limited data exist for pre-teen and adolescent girls, a likely target population. The primary objective of this study was to compare the occurrence of serious adverse events (SAEs) over 12 months between HSV vaccine recipients and saline recipients (placebo control group) in pre-teen and adolescent girls. The immunogenicity of the HSV vaccine was also assessed.METHODS: Healthy girls aged 10-17 years, stratified by age (10-15 years; 16-17 years), were randomised 2:1:1 to receive the HSV vaccine, a hepatitis A vaccine (Havrix™; HAV control) or placebo (saline) according to a 0-, 1-, 6-month schedule. Participants and study personnel not involved in the preparation or administration of vaccines were blinded to treatment. Safety and immunogenicity analyses were performed overall and by age (10-15 years; 16-17 years) and HSV serostatus.RESULTS: No statistically significant difference in the percentage of subjects with SAEs was observed between the HSV and saline group, or between the HSV and pooled control (HAV and saline) groups. The HSV vaccine was well tolerated, although a higher incidence of solicited local symptoms was observed in the HSV group than in the control group. Neither age nor HSV serostatus at the time of study entry had an impact on the safety profile of this vaccine. The HSV vaccine was immunogenic regardless of pre-vaccination HSV serostatus. Higher anti-gD geometric mean concentrations were observed in HSV-1 seropositive participants than in HSV-1 seronegative participants.CONCLUSION: The HSV vaccine had an acceptable safety profile, and was well tolerated and immunogenic when administered to girls aged 10-17 years regardless of age or HSV pre-vaccination serostatus.
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- Lai, De-Hua, et al.
(författare)
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Solanesyl Diphosphate Synthase, an Enzyme of the Ubiquinone Synthetic Pathway, Is Required throughout the Life Cycle of Trypanosoma brucei
- 2014
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Ingår i: Eukaryotic Cell. - 1535-9778 .- 1535-9786. ; 13:2, s. 320-328
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Tidskriftsartikel (refereegranskat)abstract
- Ubiquinone 9 (UQ9), the expected product of the long-chain solanesyl diphosphate synthase of Trypanosoma brucei (TbSPPS), has a central role in reoxidation of reducing equivalents in the mitochondrion of T. brucei. The ablation of TbSPPS gene expression by RNA interference increased the generation of reactive oxygen species and reduced cell growth and oxygen consumption. The addition of glycerol to the culture medium exacerbated the phenotype by blocking its endogenous generation and excretion. The participation of TbSPPS in UQ synthesis was further confirmed by growth rescue using UQ with 10 isoprenyl subunits (UQ10). Furthermore, the survival of infected mice was prolonged upon the downregulation of TbSPPS and/or the addition of glycerol to drinking water. TbSPPS is inhibited by 1-[(n-oct-1-ylamino)ethyl] 1,1-bisphosphonic acid, and treatment with this compound was lethal for the cells. The findings that both UQ9 and ATP pools were severely depleted by the drug and that exogenous UQ10 was able to fully rescue growth of the inhibited parasites strongly suggest that TbSPPS and UQ synthesis are the main targets of the drug. These two strategies highlight the importance of TbSPPS for T. brucei, justifying further efforts to validate it as a new drug target.
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- Kawakatsu, Taiji, et al.
(författare)
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Epigenomic Diversity in a Global Collection of Arabidopsis thaliana Accessions
- 2016
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Ingår i: Cell. - : Elsevier. - 0092-8674 .- 1097-4172. ; 166:2, s. 492-505
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Tidskriftsartikel (refereegranskat)abstract
- The epigenome orchestrates genome accessibility, functionality, and three-dimensional structure. Because epigenetic variation can impact transcription and thus phenotypes, it may contribute to adaptation. Here, we report 1,107 high-quality single-base resolution methylomes and 1,203 transcriptomes from the 1001 Genomes collection of Arabidopsis thaliana. Although the genetic basis of methylation variation is highly complex, geographic origin is a major predictor of genome-wide DNA methylation levels and of altered gene expression caused by epialleles. Comparison to cistrome and epicistrome datasets identifies associations between transcription factor binding sites, methylation, nucleotide variation, and co-expression modules. Physical maps for nine of the most diverse genomes reveal how transposons and other structural variants shape the epigenome, with dramatic effects on immunity genes. The 1001 Epigenomes Project provides a comprehensive resource for understanding how variation in DNA methylation contributes to molecular and non-molecular phenotypes in natural populations of the most studied model plant.
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- Lehtinen, M, et al.
(författare)
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Ten-year follow-up of human papillomavirus vaccine efficacy against the most stringent cervical neoplasia end-point-registry-based follow-up of three cohorts from randomized trials
- 2017
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 7:8, s. e015867-
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Tidskriftsartikel (refereegranskat)abstract
- Due to long lag time between infection/cancer diagnoses human papillomavirus (HPV) vaccination programs will deliver vaccine efficacy (VE) estimates against cancer end-points late. Cancer registry follow-up of population-based, randomised trial cohorts of vaccinated and unvaccinated women was undertaken for the estimation of VE against cervical intraepithelial neoplasia grade three and invasive cancer (CIN3+).MethodsWe report interim results with 98 561 person years of Finnish Cancer Registry -based follow-up of individually and/or cluster randomised cohorts of HPV-16/18 vaccinated and unvaccinated adolescent women enrolled in June 2003/2005, and between May 2004 and April 2005, respectively. The cohorts comprised 15 627 18- to 19-year-old unvaccinated women (NCT01393470), and 2 401 and 64 16- to 17-year-old HPV-16/18 vaccinated women participating the PATRICIA (NCT00122681) and HPV-012 (NCT00169494) trials, respectively. The age-aligned passive follow-up started 6 months after the clinical trials’ end.ResultsDuring the follow-up of 4.5 to 10 years post enrolment we identified 75 cases of cervical intraepithelial neoplasia grade 3 (CIN3) and 4 cases of invasive cervical cancer (ICC) in the unvaccinated cohort, and 4 CIN3 cases in the HPV-16/18 vaccinated women. Diagnostic blocks were available for HPV typing from 87% of the cases. CIN3+ lesions were detectable in 54 cases. HPV16 was found in 26 of 50 unvaccinated CIN3+ cases, and in 3 CIN3+ cases in the HPV-16/18 vaccinated women. The latter were all baseline positive for cervical HPV16 DNA. Baseline data was not available for the unvaccinated women. Intention-to-treat VE against any CIN3+ was 66% (95% CI 8, 88).ConclusionsTen years post vaccination the AS04-adjuvanted HPV-16/18 vaccine shows continued efficacy against CIN3+ irrespectively of HPV type. Vaccine efficacy was not observed in baseline HPV16 DNA positive subjects.Trial registration numberNCT01393470.
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- Paulino, M., et al.
(författare)
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Studies of trypanocidal (inhibitory) power of naphthoquinones: : evaluation of quantum chemical molecular descriptors for structure-activity relationships
- 2008
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234. ; 43:10, s. 2238-2246
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Tidskriftsartikel (refereegranskat)abstract
- Electronic, lipophilic and steric descriptors included in QSAR-2D and -3D are analyzed for a set of ortho- and para-naphthoquinones that have proved to be powerful oxidative agents with potent trypanocidal activities specially against Leptomonas seymouri and Trypanosoma cruzi. Electronic properties are calculated by means of semiempirical (PM3), ab initio (HF/3-21G) and density functional theory (B3LYP/6-31 + G*) methodologies. Three different electronic states, neutral quinones, hydroquinones and semiquinones, are studied to investigate if any one of them are statistically related with the biological activities. The best correlations were obtained at the B3LYP level of theory because it includes electronic correlation. The QSAR-2D indicates that the best trypanocidal growth inhibitors are molecules in the semiquinone electronic state, with the following properties: (a) high negative value of EHOMO, (b) high negative charge in the oxygen atoms of the carbonyl groups, (c) high positive charge in the carbon atom of one of carbonyl moieties and (d) high electronegativity (χ). In a complementary way, the QSAR-3D indicates that the electrostatic field correlates with trypanocidal activity and the presence of bulk moieties would increase activity. The idea of comparing the three electronic states may prove to be of most importance in the general strategy to the design of new trypanocidal drugs. In fact, the experimental results showed that semiquinone is the one really statistically relevant indicating a clear connection between biochemical and theoretical aspects. Finally, we demonstrated that to be a good anti-trypanosomatid compound, the molecule must be a good electron acceptor to reach easily the essential semiquinone state. We expect that the present results motivate new experimental as well as theoretical investigations that confirm our findings.
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