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  • 1
    Electronic Resource
    Electronic Resource
    Oxford, UK; Malden, USA : Munksgaard International Publishers
    Experimental dermatology 14 (2005), S. 0 
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Properly regulated keratinocyte cell death is fundamentally important to maintain structural integrity and homeostatic function of epidermis. Moreover, from an oncological perspective, therapeutic approaches selectively targeting apoptosis of malignant cell types while sparing normal keratinocytes in surrounding skin is desirable. Apo2Ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) has been observed to preferentially induce cytopathic effects on transformed/malignant cell types compared with their non-neoplastic counterparts. In this report, two different biologically active preparations of Apo2L/TRAIL, a non-tagged version, NT-Apo2L/TRAIL, and a leucine zipper fusion protein, LZ-Apo2L/TRAIL, were examined for their ability to trigger apoptosis in normal human keratinocytes, and in an immortalized cell line (HaCaT cells). Differences between these preparations were observed, including: NT-Apo2L/TRAIL induced less keratinocyte apoptosis compared with LZ-Apo2L/TRAIL; NT-Apo2L/TRAIL also induced less apoptosis of HaCaT cells compared with LZ-Apo2L/TRAIL; LZ-Apo2L/TRAIL but not NT-Apo2L/TRAIL induced cytotoxic effects when keratinocytes became growth arrested due to undergoing spontaneous replicative senescence – a biological state previously observed to be resistant to UV-light-induced apoptosis. Similarities between preparations included: an enhanced ability for both Apo2L/TRAIL preparations to kill a greater relative percentage of HaCaT cells compared with keratinocytes; enhanced cytotoxicity towards keratinocytes that had their NF-B activity inhibited; a dependence of both Apo2L/TRAIL preparations on FADD and caspase activation; triggering of the same caspase cascades including caspase 8 and 3; and an ability to induce apoptosis even when HaCaT cells and keratinocytes were transduced to overexpress either Bcl-2 or Bcl-xL (survival factors that reduce susceptibility to UV-light-induced apoptosis). These results indicate that while both preparations of Apo2L/TRAIL possess biological activity, there are important differences as regards their ability to induce apoptosis in normal and immortalized keratinocytes. Moreover, the death receptor pathway triggered by LZ-Apo2L/TRAIL can overcome the apoptotic resistance normally observed in response to UV-light mediated by Bcl-2/Bcl-xL, as well as by the state of cellular senescence. Unraveling the molecular basis for these differential biological effects may reveal a new strategic role for these death receptor/ligands linked to apoptosis in maintaining the dynamic balance of keratinocyte proliferation, differentiation, and cell death necessary to achieve a homeostatic thickness and function of normal skin. In addition, it may be possible to utilize these Apo2L/TRAIL preparations for the treatment of various sun-induced skin cancers as they can differentially trigger apoptosis of transformed keratinocytes, or keratinocytes with abnormal NF-κB signaling, while sparing adjacent normal keratinocytes.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1600-079X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Day length affects somatic and reproductive physiology of Siberian hamsters via regulation of the duration of nocturnal pineal melatonin secretion. Nightly ‘long’ (e.g. 12 hr) or ‘short’ (e.g. 6 hr) melatonin signals inhibit or stimulate gonadal growth, respectively. When long and short signals are presented in combination, however, neuroendocrine mechanisms exhibit a frequency-dependent response, stimulating gonadal growth only if short signals are presented every second night or more frequently. The present experiments further assessed formal models for the temporal integration of melatonin signals changing abruptly in duration from night to night. Photo-inhibited Siberian hamsters were housed in constant light and infused subcutaneously with various combinations of nightly short or long melatonin signals according to one of the several regimes that varied the frequency of short melatonin signal occurrence, average duration of the nightly melatonin signal, or both. Six weeks of nightly alternating short and long signals yielded different gonadal responses depending on the average melatonin signal duration. Moreover, when average melatonin signal duration was held constant between groups, gonadal stimulation was independent of the frequency of the constituent melatonin signals except when the duration of the short signal was reduced to 3 hr. Thus, neuroendocrine mechanisms do not solely categorize melatonin signals as either long or short but attend also to the duration of each component signal. In the majority (six of seven) of infusion regimes, reproductive responses to chimeric patterns of long and short melatonin signals were compatible with a simple signal-averaging mechanism.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1398-9995
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background: Clarification of the relationship between atopy and bronchial hyperresponsiveness (BHR), both key features of asthma, is critical to our understanding of the disease. We therefore investigated the putative relationship between skin-prick reactivity to aeroallergens and BHR to direct and indirect stimuli.Methods: We performed a retrospective analysis of data from 332 patients presenting with a diagnosis of asthma. Patients were characterized by skin prick tests (SPT), spirometry and bronchial challenge with methacholine and adenosine monophosphate (AMP).Results: For patients who had BHR to methacholine but not AMP, the presence of atopy was associated with a lower PD20 (the provocative dose of methacholine producing a fall in FEV1 of 20%), amounting to a geometric mean (95% confidence interval (CI)) of 2.3-fold (1.4–4.0) difference. Furthermore, the number of skin-prick positive (SPP) responses was related to methacholine reactivity: 0–1 SPP, PD20 = 69.9 µg; 2–4 SPP, PD20 = 47.8 µg; 5–8 SPP, PD20 = 35.6 µg. There was a 2.0- fold (1.1–3.6) difference between the groups with a low (0–1 SPP) and high (5–8 SPP) degree of skin-prick reactivity. A similar pattern was seen when data were analyzed including only perennial allergens. Spirometry was unrelated to the degree of skin-prick reactivity.Discussion: These results suggest that skin-prick reactivity to aeroallergens is associated with BHR to methacholine.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1600-0501
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Few investigations have studied the long-term fate of bone formed following the technique of guided tissue regeneration. The aim of the present study was to evaluate bone fill around implant fixtures with dehiscence defects and to study its response to loading. Ten patients were treated with overdentures supported by 2 fixtures ad modum Brånemark. A third 7 mm x 3.75 mm diameter fixture was placed for the purposes of the study in the most anterior part of the mandible with a dehiscence defect of 4 to 5 mm on the buccal aspect (and 3 to 4 threads exposed) which was covered with a Gore-Tex membrane and buried beneath the mucosa. Fixtures were exposed after 5 months (stage 2), ball abutments connected and loaded through an overdenture for 1 year. Nine fixtures were functioning well after 1 year of loading, 6 of which were retrieved with a trephine for histological examination and compared with 6 unloaded fixtures retrieved in our previously reported study. The bone area filling the thread profiles (BA%) and the bone to metal contact (BMC%) were measured in the 3 most apical and 3 most coronal thread profiles on the buccal and lingual surfaces. Statistically significant higher BMC% (P〈0.01) were observed in loaded fixtures in the apical regions (buccal: loaded 51%. unloaded 25%; lingual: loaded 49%, unloaded 24%). Differences approached significance for the regeneration site (loaded 22%, unloaded 6%) but were no different for the coronal lingual region (loaded 28%, unloaded 20%). There were no differences for BA%. This study confirms that there is an increase in bone to metal contact with time and following fixture loading and that this may also occur with bone regenerated under Gore-Tex membranes.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract:  It has been established that Id proteins can block the basic helix–loop–helix (HLH) transcription factors, thereby impacting the onset of senescence in keratinocytes, as well as influencing tumorigenesis involving squamous cell carcinomas. However, the ability of Id-1 to influence the immunologic response of epithelial cells to cytokines implicated in cutaneous oncology such as gamma interferon (IFN-γ) has not been determined. Using a whole population of human keratinocytes infected with a retrovirus to induce over-expression of Id-1, the influence on early differentiation of rapidly proliferating keratinocytes was assessed, as was the response to IFN-γ. While induction of involucrin, a marker of early differentiation, was not altered in Id-1 overexpressing keratinocytes, the IFN-γ mediated increase in intercellular adhesion molecule-1 (ICAM-1) and HLA-DR was reduced. No change in constitutive or inducible levels of MHC class I antigen, CD95 (Fas antigen) or LFA-3 (CD58) was observed in this system. Immunostaining and Western blot analysis revealed over-expression of Id-1 in basal cell carcinomas (BCCs). These tumors not only strongly and diffusely expressed Id-1, but were also characterized by reduced ICAM-1 and HLA-DR expression. Thus, dysregulated Id-1 may not only contribute to delaying the senescence program in keratinocytes, it may also contribute to the escape of the relatively undifferentiated tumor cells in BCC from immune surveillance.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Copenhagen : Munksgaard International Publishers
    Journal of cutaneous pathology 28 (2001), S. 0 
    ISSN: 1600-0560
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: From an oncological and immunological perspective, the T-cell-mediated induction of psoriatic plaques should be prone to malignant transformation as the phenotype of psoriatic plaques includes: chronic inflammation, epidermal hyperplasia, prolonged survival and elevated telomerase levels in lesional keratinocytes, as well as angiogenesis, exposure to carcinogens and immunosuppressants. However, conversion of a psoriatic plaque to squamous cell carcinoma is exceedingly rare. This paper explores the possible molecular mechanism for the tumor suppressor pathway in psoriatic lesions, with an emphasis on a putative senescence-switch involving p16.
    Type of Medium: Electronic Resource
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