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  • 1
    Keywords: CANCER ; CELLS ; proliferation ; CELL ; DISEASE ; PROTEIN ; INFECTION ; ANTIGEN ; T-CELL ; T-CELLS ; papillomavirus ; IMMUNE-RESPONSES ; TRIAL ; LESIONS ; NEOPLASIA ; OVARIAN-CANCER ; WOMEN ; CERVICAL-CANCER ; human papillomavirus ; HPV ; IMMUNE-RESPONSE ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; FAILURE ; ANTITUMOR IMMUNITY ; SUBSETS ; FUSION PROTEIN ; PHASE-II ; ONCOLOGY ; REGRESSION ; REGULATORY T-CELLS ; PHASE ; PHOTODYNAMIC THERAPY ; imiquimod ; CD4+T-CELL IMMUNITY ; IMMUNE ; T regulatory cells ; CLINICAL-RESPONSES ; SEXUAL FUNCTION ; therapeutic HPV vaccination ; vulval intraepithelial neoplasia (VIN)
    Abstract: BACKGROUND: Vulval intraepithelial neoplasia (VIN) is a premalignant condition, which is frequently associated with type HPV16 infection, and multifocal disease has high rates of surgical treatment failure. METHODS: We report a phase II clinical trial of the topical immunomodulator, imiquimod, for 8 weeks, followed by 3 doses (weeks 10, 14 and 18) of therapeutic human papillomavirus (HPV) vaccination (TA-CIN, fusion protein HPV16 E6E7L2) in 19 women with VIN grades 2 and 3. Histology and HPV testing of biopsies were performed at weeks 0, 10, 20 and 52. Intralesional infiltration of T-cell subsets and lymphocyte proliferation for HPV systemic immune responses were also assessed. RESULTS: Lesion response (complete regression of VIN on histology) was observed in 32% (6 out of 19) of women at week 10, increasing to 58% (11 out of 19) at week 20 and 63% (12 out of 19) at week 52. At this time, 36% (5 out of 14) of lesions showed HPV16 clearance and 79% (15 out of 19) of women were symptom free. At week 20, after treatment with imiquimod and vaccination, there was significantly increased local infiltration of CD8 and CD4 T cells in lesion responders; in contrast, non-responders (persistent VIN by histology) showed an increased density of T regulatory cells. After vaccination, only lesion responders had significantly increased lympho-proliferation to the HPV vaccine antigens. CONCLUSION: The therapeutic effect of treatment depends on the differential immune response of responders and non-responders with affect locally and systemically. British Journal of Cancer (2010) 102, 1129-1136. doi:10.1038/sj.bjc.6605611 www.bjcancer.com Published online 16 March 2010 (C) 2010 Cancer Research UK
    Type of Publication: Journal article published
    PubMed ID: 20234368
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  • 2
    ISSN: 1432-0789
    Keywords: Nitrogen fractions ; Amino acids ; Amino sugars ; Microbial respiration ; Household waste ; Domestic garbage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract An incubation experiment was performed to determine how the mixing of soil with municipal organic refuse compost affects C mineralization, growth of the microbial biomass, and changes in organic components, especially in the fractions of amino acids and amino sugars. Compost and soil differed in almost every parameter measured, with the organic C content of the compost representing only 10.8% of the dry weight. The fractions of K2SO4-extractable organic C and of non-hydrolyzable C were larger in the compost (1.24 and 62.9% of organic C, respectively) than in the soil (0.56 and 41.6% of organic C). These two fractions increased in proportion to the addition of compost, in contrast to amino sugar and amino acid C which were identified overproportionately in the mixture treatments, especially in the 30% compost treatment. Overproportionate increases in the microbial biomass C content and CO2 evolution rate were also measured in this treatment. The adsorption of compost colloids on the surface of regular soil silicates increased both the availability for microbial enzymes and the detectability for chemical analysis.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Anaesthesia 47 (1992), S. 0 
    ISSN: 1365-2044
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Two cases of emergency prehospital airway control using the laryngeal mask are described. The patients were trapped following road traffic accidents and limited access prevented tracheal intubation. The laryngeal mask airway may be a useful alternative to tracheal intubation in some cases of prehospital trauma care.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1440
    Keywords: Carvedilol ; β1 and β2 Receptors ; α1-Blockade ; Myocardial adrenergic receptors ; Lymphocyte β-adrenergic receptors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Carvedilol, a new β-blocker with vasodilating properties due to α1-blockade, was investigated in preparations of human ventricular myocardium. Carvedilol demonstrated a high affinity and is a slightly β1-selective competitive β-blocking agent, with a K D for β1-receptors of approximately 4–5 nM and a mild selectivity for β1 vs. β2 receptors of 6- to 39-fold, depending on the method employed to assess subtype potency. In addition, carvedilol was also a potent α1-blocking agent, with a β1:α1 blocking relative potency of 1.7-fold. In human lymphocytes containing β2-receptors and in human myocardial membranes containing both β1- and β2-receptors carvedilol exhibited the unique property of guanine nucleotide modulatable binding. Despite this, no intrinsic sympathomimetic activity of carvedilol was detected in preparations of isolated human heart or in myocardial membranes. Vasodilation related to α1-blockade and the lack of intrinsic activity should translate into improved tolerability and good efficacy in the treatment of heart failure.
    Type of Medium: Electronic Resource
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  • 5
    Publication Date: 2018-07-18
    Description: To address how L2-specific antibodies prevent human papillomavirus (HPV) infection of the genital tract, we generated neutralizing monoclonal antibodies (MAbs) WW1, a rat IgG2a that binds L2 residues 17 to 36 (like mouse MAb RG1), and JWW3, a mouse IgG2b derivative of Mab24 specific for L2 residues 58 to 64. By Western blotting, WW1 recognized L2 of 29/34 HPV genotypes tested, compared to only 13/34 for RG1 and 25/34 for JWW3. WW1 IgG and F(ab') 2 bound HPV16 pseudovirions similarly; however, whole IgG provided better protection against HPV vaginal challenge. Passive transfer of WW1 IgG was similarly protective in wild-type and neonatal Fc receptor (FcRn)-deficient mice, suggesting that protection by WW1 IgG is not mediated by FcRn-dependent transcytosis. Rather, local epithelial disruption, required for genital infection and induced by either brushing or nonoxynol-9 treatment, released serum IgG in the genital tract, suggesting Fc-independent exudation. Depletion of neutrophils and macrophages reduced protection of mice upon passive transfer of whole WW1 or JWW3 IgGs. Similarly, IgG-mediated protection by L2 MAbs WW1, JWW3, and RG1 was reduced in Fc receptor knockout compared to wild-type mice. However, levels of in vitro neutralization by WW1 IgG were similar in TRIM21 knockout and wild-type cells, indicating that Fc does not contribute to antibody-dependent intracellular neutralization (ADIN). In conclusion, the Fc domain of L2-specific IgGs is not active for ADIN, but it opsonizes bound extracellular pseudovirions for phagocytes in protecting mice from intravaginal HPV challenge. Systemically administered neutralizing IgG can access the site of infection in an abrasion via exudation without the need for FcRn-mediated transcytosis. IMPORTANCE At least 15 alpha HPV types are causative agents for 5% of all cancers worldwide, and beta types have been implicated in nonmelanoma skin cancer, whereas others produce benign papillomas, such as genital warts, associated with considerable morbidity and health systems costs. Vaccines targeting the minor capsid protein L2 have the potential to provide broad-spectrum immunity against medically relevant HPVs of divergent genera via the induction of broadly cross-neutralizing serum IgG. Here we examine the mechanisms by which L2-specific serum IgG reaches the viral inoculum in the genital tract to effect protection. Abrasion of the vaginal epithelium allows the virus to access and infect basal keratinocytes, and our findings suggest that this also permits the local exudation of neutralizing IgG and vaccine-induced sterilizing immunity. We also demonstrate the importance of Fc-mediated phagocytosis of L2 antibody-virion complexes for humoral immunity, a protective mechanism that is not detected by current in vitro neutralization assays.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 6
    Publication Date: 2018-02-23
    Description: Earlier detection is key to reducing cancer deaths. Here, we describe a blood test that can detect eight common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA. We applied this test, called CancerSEEK, to 1005 patients with nonmetastatic, clinically detected cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. CancerSEEK tests were positive in a median of 70% of the eight cancer types. The sensitivities ranged from 69 to 98% for the detection of five cancer types (ovary, liver, stomach, pancreas, and esophagus) for which there are no screening tests available for average-risk individuals. The specificity of CancerSEEK was greater than 99%: only 7 of 812 healthy controls scored positive. In addition, CancerSEEK localized the cancer to a small number of anatomic sites in a median of 83% of the patients.
    Keywords: Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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