| 1. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
- 2008
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Ingår i: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 4:2, s. 151-175
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Forskningsöversikt (refereegranskat)abstract
- Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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| 2. |
- Kjaer, Susanne K., et al.
(författare)
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A Pooled Analysis of Continued Prophylactic Efficacy of Quadrivalent Human Papillomavirus (Types 6/11/16/18) Vaccine against High-grade Cervical and External Genital Lesions
- 2009
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Ingår i: Cancer Prevention Research. - 1940-6207. ; 2:10, s. 868-878
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Tidskriftsartikel (refereegranskat)abstract
- Quadrivalent human papillomavirus (HPV) vaccine has been shown to provide protection from HPV 6/11/16/18-related cervical, vaginal, and vulvar disease through 3 years. We provide an update on the efficacy of the quadrivalent HPV vaccine against high-grade cervical, vaginal, and vulvar lesions based on end-of-study data from three clinical trials. Additionally, we stratify vaccine efficacy by several baseline characteristics, including age, smoking status, and Papanicolaou (Pap) test results. A total of 18,174 females ages 16 to 26 years were randomized and allocated into one of three clinical trials (protocols 007, 013, and 015). Vaccine or placebo was given at baseline, month 2, and month 6. Pap testing was conducted at regular intervals. Cervical and anogenital swabs were collected for HPV DNA testing. Examination for the presence of vulvar and vaginal lesions was also done. Endpoints included high-grade cervical, vulvar, or vaginal lesions (CIN 2/3, VIN 2/3, or VaIN 2/3). Mean follow-up time was 42 months post dose 1. Vaccine efficacy against HPV 6/11/16/18-related high-grade cervical lesions in the per-protocol and intention-to-treat populations was 98.2% [95% confidence interval (95% CI), 93.3-99.8] and 51.5% (95% CI, 40.6-60.6), respectively. Vaccine efficacy against HPV 6/11/16/18-related high-grade vulvar and vaginal lesions in the per-protocol and intention-to-treat populations was 100.0% (95% CI, 82.6-100.0) and 79.0% (95% CI, 56.4-91.0), respectively. Efficacy in the intention-to-treat population tended to be lower in older women, women with more partners, and women with abnormal Pap test results. The efficacy of quadrivalent HPV vaccine against high-grade cervical and external anogenital neoplasia remains high through 42 months post vaccination.
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| 3. |
- Olsson, Sven-Eric, et al.
(författare)
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Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection
- 2009
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Ingår i: Human Vaccines. - 1554-8600. ; 5:10, s. 696-704
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Tidskriftsartikel (refereegranskat)abstract
- Objective: In the quadrivalent (types 6/11/16/18) HPV vaccine (GARDASIL (R)/SILGARD (R)) clinical program, 73% of women aged 16-26 were naive to all vaccine HPV types. In these women, prophylactic administration of the vaccine was highly effective in preventing HPV 6/11/16/18-related cervical disease. Of the remaining women, 15% of had evidence of past infection with one or more vaccine HPV types (seropositive and DNA negative) at the time of enrollment. Here we present an analysis in this group of women to determine the efficacy of the HPV 6/11/16/18 vaccine against new cervical and external anogenital disease related to the same vaccine HPV type which had previously been cleared. Vaccine tolerability in this previously infected population was also assessed. Results: Subjects were followed for an average of 40 months. Seven subjects in the placebo group developed cervical disease, and eight subjects developed external genital disease related to a vaccine HPV type they had previously encountered. No subject receiving HPV 6/11/16/18 vaccine developed disease to a vaccine HPV type to which they were seropositive and DNA negative at enrollment. Methods: 18,174 women were enrolled into three clinical studies. The data presented comprise a subset of these subjects (n = 2,617) who were HPV seropositive and DNA negative at enrollment (for >= 1 vaccine type). In each study, subjects were randomized in a 1:1 ratio to receive HPV 6/11/16/18 vaccine or placebo at day 1, month 2 and month 6 (without knowledge of baseline HPV status). Procedures performed for efficacy data evaluation included detailed genital examination, Pap testing and collection of cervicovaginal and external genital specimens. Analyses of efficacy were carried out in a population stratified by HPV serology and HPV DNA status at enrollment. Conclusions: These results suggest that natural HPV infection-elicited antibodies may not provide complete protection over time, however the immune response to the HPV 6/11/16/18 vaccine appears to prevent reinfection or reactivation of disease with vaccine HPV types. Vaccine-related adverse experiences were higher among subjects receiving vaccine, mostly due to increased injection site adverse experiences.
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| 4. |
- Villa, Luisa L., et al.
(författare)
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Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18
- 2006
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Ingår i: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 24:27-28, s. 5571-5583
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Tidskriftsartikel (refereegranskat)abstract
- Human papillomavirus (HPV) infection causes cervical cancer and genital warts. Young women (1106) were randomized to receive one of three formulations of a quadrivalent HPV (Types 6/11/16/18) L1 virus-like particle (VLP) vaccine or one of two placebo formulations. The goal was to assess vaccine safety and immunogenicity in baseline HPV 6/11/16 or 18-naive and previously infected subjects. All three formulations were highly immunogenic. At Month 2 (postdose 1), among women with vaccine-type antibodies at baseline, vaccine-induced anti-HPV responses were similar to 12- to 26-fold higher than those observed in baseline-naive women, suggesting an anamnestic response. Following an initial, similar sized decline, anti-HPV responses plateaued and remained stable through end-of-study (3.0 years). No vaccine-related serious adverse experiences were reported. (c) 2006 Elsevier Ltd. All rights reserved.
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| 5. |
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| 6. |
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| 7. |
- Klyubin, Igor, et al.
(författare)
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Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization.
- 2008
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 28:16, s. 4231-7
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Tidskriftsartikel (refereegranskat)abstract
- The current development of immunotherapy for Alzheimer's disease is based on the assumption that human-derived amyloid beta protein (Abeta) can be targeted in a similar manner to animal cell-derived or synthetic Abeta. Because the structure of Abeta depends on its source and the presence of cofactors, it is of great interest to determine whether human-derived oligomeric Abeta species impair brain function and, if so, whether or not their disruptive effects can be prevented using antibodies. We report that untreated ex vivo human CSF that contains Abeta dimers rapidly inhibits hippocampal long-term potentiation in vivo and that acute systemic infusion of an anti-Abeta monoclonal antibody can prevent this disruption of synaptic plasticity. Abeta monomer isolated from human CSF did not affect long-term potentiation. These results strongly support a strategy of passive immunization against soluble Abeta oligomers in early Alzheimer's disease.
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| 8. |
- Malmström, Per-Uno, et al.
(författare)
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An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non-muscle-invasive bladder cancer
- 2009
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 56:2, s. 247-56
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with non-muscle-invasive bladder cancer with an intermediate or high risk need adjuvant intravesical therapy after surgery. Based largely on meta-analyses of previously published results, guidelines recommend using either bacillus Calmette-Guérin (BCG) or mitomycin C (MMC) in these patients. Individual patient data (IPD) meta-analyses, however, are the gold standard. OBJECTIVE: To compare the efficacy of BCG and MMC based on an IPD meta-analysis of randomised trials. DESIGN, SETTING, AND PARTICIPANTS: Trials were searched through Medline and review articles. The relevant trial investigators were contacted to provide IPD. MEASUREMENTS: The drugs were compared with respect to time to recurrence, progression, and overall and cancer-specific death. RESULTS AND LIMITATIONS: Nine trials that included 2820 patients were identified, and IPD were obtained from all of them. Patient characteristics were 71% primary, 54% Ta, 43% T1, 25% G1, 58% G2, and 16% G3, and 7% had prior intravesical chemotherapy. Based on a median follow-up of 4.4 yr, 43% recurred. Overall, there was no difference in the time to first recurrence (p=0.09) between BCG and MMC. In the trials with BCG maintenance, a 32% reduction in risk of recurrence on BCG compared to MMC was found (p<0.0001), while there was a 28% risk increase (p=0.006) for BCG in the trials without maintenance. BCG with maintenance was more effective than MMC in both patients previously treated and those not previously treated with chemotherapy. In the subset of 1880 patients for whom data on progression, survival, and cause of death were available, 12% progressed and 24% died, and, of those, 30% of the deaths were due to bladder cancer. No statistically significant differences were found for these long-term end points. CONCLUSIONS: For prophylaxis of recurrence, maintenance BCG is required to demonstrate superiority to MMC. Prior intravesical chemotherapy was not a confounder. There were no statistically significant differences regarding progression, overall survival, and cancer-specific survival between the two treatments.
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| 9. |
- Meister, Annette, et al.
(författare)
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Temperature-dependent self-assembly and mixing behavior of symmetrical single-chain bolaamphiphiles
- 2008
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 24:12, s. 6238-46
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Tidskriftsartikel (refereegranskat)abstract
- The temp.-dependent self-assembly and the mixing behavior of sym. single-chain bolaamphiphiles with different polymethylene chain lengths and different headgroup structures were investigated in water by differential scanning calorimetry (DSC), cryo transmission electron microscopy (cryo-TEM), and small angle neutron scattering (SANS). The even-numbered polymethylene-1,w-bis(phosphocholines) (PC-Cn-PC) are known to form nanofibers composed of stretched mols. with an all-trans alkyl chain conformation (Drescher, S.; Meister, A.; Blume, A.; Karlsson, G.; Almgren, M.; Dobner, B. Chem.-Eur. J.2007, 13, 5300-5307). The odd-numbered analogs were synthesized to study a possible even-odd effect of these bolaamphiphiles during their aggregation in water. In addn. to these bolaamphiphiles with phosphocholine headgroups, a new series of polymethylene-1,w-bis(phosphodimethylethanolamines) (Me2PE-Cn-Me2PE) with smaller headgroup sizes was synthesized. These bolaamphiphiles show an addnl. fiber-fiber transition when the alkyl chain length exceeds 26 carbon atoms. The mixing behavior of both types of bolaamphiphiles indicates that differences in the alkyl chain length up to six carbon atoms are tolerated within the fiber structure. The mixing of two Me2PE-Cn-Me2PE or PC-Cn-PC type bolaamphiphiles with different alkyl chain lengths offers the possibility to adjust the temp., where the crosslinking of the fibers is disrupted and where the fibers break apart. As a consequence, temp. switchable hydrogels are obtained that can be fine-tuned for drug delivery applications. The comparison with dotriacontane-1,32-diyl-bis[2-(methylammonio)-ethylphosphate] (MePE-C32-MePE), a new bolaamphiphile with even smaller phosphomonomethylammonio headgroups, illustrates the importance of the headgroup size for the aggregation behavior. This bolaamphiphile self-assembles exclusively into lamellar structures, and this aggregate type persists in mixts. with the fiber forming Me2PE-C32-Me2PE.
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| 10. |
- Meyer, Linda M, et al.
(författare)
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Absence of glutaredoxin1 increases lens susceptibility to oxidative stress induced by UVR-B
- 2009
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Ingår i: Experimental Eye Research. - : Elsevier BV. - 0014-4835 .- 1096-0007. ; 89:6, s. 833-839
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Tidskriftsartikel (refereegranskat)abstract
- We investigated if the absence of glutaredoxin1, a critical protein thiol repair enzyme, increases lens susceptibility to oxidative stress caused by in vivo exposure to ultraviolet radiation type B (UVR-B). Glrx(-/-) mice and Glrx(+/+) mice were unilaterally exposed in vivo to UVR-B for 15 min. Groups of 12 animals each received 4.3, 8.7, and 14.5 kJ/m(2) respectively. 48 h post UVR-B exposure, the induced cataract was quantified as forward lens light scattering. Cataract morphology was documented with darkfield illumination photography. Glutathione (GSH/GSSG) content was analyzed in Glrx(-/-) and Glrx(+/+) lenses. UVR-B exposure induced anterior sub-capsular cataract (ASC) in Glrx(-/-) and Glrx(+/+) mice. In Glrx(-/-) lenses the opacities extended further towards the lens equator than in wild type animals (Glrx(+/+)). Lens light scattering in Glrx(-/-) mice was increased in all dose groups compared to lenses with normal glutaredoxin1 function. The difference was more pronounced with increasing exposure dose. Lens sensitivity for UVR-B induced damage was significantly higher in Glrx(-/-) lenses compared to Glrx(+/+) lenses. The Glrx gene provides a 44% increase of protection against close to threshold UVR-B induced oxidative stress compared to the absence of the Glrx gene. In conclusion, the absence of glutaredoxin1 increases lens susceptibility to UVR-B induced oxidative stress in the mouse.
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