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  • 11
    Keywords: CELL, DIFFERENTIATION, FAMILY, FOLLICLE, GENE DOMAIN, Germany, human, Jun, keratin, MEMBERS, NEW-YOR
    Type of Publication: Journal article published
    PubMed ID: 17301834
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  • 12
    Keywords: CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; CLINICAL-TRIAL ; COMBINATION ; evaluation ; Germany ; human ; IN-VIVO ; MODEL ; THERAPY ; NEW-YORK ; EFFICIENCY ; TRANSDUCTION ; primary ; prognosis ; DOMAIN ; culture ; GLYCOPROTEIN ; virus ; TRIAL ; TRIALS ; VECTORS ; VECTOR ; MEMBRANE ; CLINICAL-TRIALS ; chemotherapy ; EFFICIENT ; MELANOMA ; MALIGNANT-MELANOMA ; malignant melanoma ; CUTANEOUS MELANOMA ; ADENOVIRUS ; DACARBAZINE ; DOMAINS ; THERAPIES ; MELANOMA-CELLS ; VIROTHERAPY ; USA ; EFFICIENT TRANSDUCTION ; SHORT-TERM ; xenograft ; clinical trial ; ONCOLYTIC ADENOVIRUSES ; B ADENOVIRUSES ; CELLULAR RECEPTOR ; FUSOGENIC MEMBRANE-GLYCOPROTEINS ; REPLICATING ADENOVIRUS ; SUICIDE GENE-THERAPY ; ADENOVIRUS VECTORS ; IMMUNE-MEDIATED CONTROL ; oncolytic adenovirus
    Abstract: Advanced melanoma is associated with poor prognosis warranting the development of new therapeutics, such as oncolytic adenoviruses for immunovirotherapy. Since this approach critically depends on efficient transduction of targeted tumor cells, we screened a panel of 22 different adenovirus types for their internalization efficiency in melanoma cells. We demonstrated that the virions of Ad35, Ad38, and Ad3 have significantly higher internalization efficiency in melanoma cells than Ad5, so far the only adenovirus type used in clinical trials for melanoma. Therefore, we developed a conditionally replication-competent Ad5-based vector with the Ad35 fiber shaft and knob domains (Ad5/35) and compared its therapeutic efficacy with the homologous vector carrying the native Ad5 fiber. To further enhance virotherapy, we combined the oncolytic adenovirus vectors with intratumoral expression of measles virus fusogenic membrane glycoproteins H and F (MV-H/F) and dacarbazine chemotherapy. In a human melanoma xenograft model, established from a short-term culture of primary melanoma cells, we demonstrated that the Ad5/35-based therapy had a significantly greater anti-neoplastic effect than the homologous Ad5-based therapy. Furthermore, the combination of virotherapy, intratumoral expression of MV-H/F, and chemotherapy was clearly superior to single- or double-agent therapy. In conclusion, Ad35-based vectors are promising for the treatment of melanoma
    Type of Publication: Journal article published
    PubMed ID: 17960177
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  • 13
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; GROWTH ; CELL ; Germany ; human ; MODEL ; GENE ; GENES ; transcription ; LIGAND ; SKIN ; BIOLOGY ; fibroblasts ; TARGET ; IN-SITU ; MONOCLONAL-ANTIBODIES ; EPITHELIAL-CELLS ; INDIVIDUALS ; TARGETS ; RECEPTORS ; DISSECTION ; SERUM ; mRNA ; hair ; USA ; THYROTROPIN RECEPTOR ; HPA axis ; CONNECTIVE-TISSUE ; CORTICOTROPIN-RELEASING HORMONE ; FUNCTIONAL-ROLE ; PIGMENTARY UNIT ; SMOOTH MUSCLE ACTIN ; TSH RECEPTOR
    Abstract: Pituitary thyroid-stimulating hormone (TSH) regulates thyroid hormone synthesis via receptors (TSH-R) expressed on thyroid epithelial cells. As the hair follicle (HF) is uniquely hormone-sensitive and, hypothyroidism with its associated, increased TSH serum levels clinically can lead to hair loss, we asked whether human HFs are a direct target for TSH. Here, we report that normal human scalp skin and microdissected human HFs express TSH-R mRNA. TSH-R- like immunoreactivity is limited to the mesenchymal skin compartments in situ. TSH may alter HF mesenchymal functions, as it upregulates alpha-smooth muscle actin expression in HF fibroblasts. TSH-R stimulation by its natural ligand in organ culture changes the expression of several genes of human scalp HFs (for example keratin K5), upregulates the transcription of classical TSH target genes and enhances cAMP production. Although the functional role of TSH in human HF biology awaits further dissection, these findings document that intracutaneous TSH-Rs are fully functional in situ and that HFs of female individuals are direct targets for nonclassical, extrathyroidal TSH bioregulation. This suggests that organ-cultured scalp HFs provide an instructive and physiologically relevant human model for exploring nonclassical functions of TSH, in and beyond the skin
    Type of Publication: Journal article published
    PubMed ID: 19052559
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  • 14
    Keywords: CELLS ; tumor ; CELL ; human ; COMMON ; DISEASE ; SITES ; PROTEINS ; SAMPLE ; SAMPLES ; TUMORS ; TIME ; PATIENT ; DNA ; SKIN ; papillomavirus ; antibody ; IN-SITU ; LESIONS ; COPY NUMBER ; human papillomavirus ; GENOTYPES ; HPV ; REPLICATION ; glutathione-S-transferase ; PSORIASIS ; EPIDERMODYSPLASIA-VERRUCIFORMIS ; hair ; GENOTYPE ; NONMELANOMA SKIN-CANCER ; USA ; PLUCKED EYEBROW HAIRS ; CLINICAL-ASPECTS ; HAIRS ; HUMAN-PAPILLOMAVIRUS-DNA
    Abstract: Epidermodysplasia verruciformis (EV) is a rare disease, characterized by cutaneous warts and associated with a strong predisposition to beta-genus human papillomavirus (HPV). Earlier studies reported high copy numbers of HPV-DNA in nearly all skin tumors from EV patients, but neither HPV replication status in non-lesional skin nor anti-HPV seroreactivity in these patients have been reported yet. We therefore performed a comprehensive viral load analysis for the more common beta-HPV types on skin samples and plucked eyebrow hairs from four EV patients treated at our dermatology department. The results clearly demonstrate that they carry a multiplicity (up to eighteen types) of beta-HPV genotypes in both skin sites. Worthy of note, a high intrapatient concordance for specific types between hair bulbs and skin biopsies was observed and the same beta-PV profile was maintained over time. Viral load analysis revealed a load range between less than one HPV-DNA copy per 100 cells to more than 400 HPV-DNA copies per cell in both eyebrow hairs and skin proliferative lesions. Evaluation of seroreactivity to beta-HPV types in the four EV patients revealed that antibodies against the 16 beta-HPV were significantly more prevalent and showed higher titers than in the controls
    Type of Publication: Journal article published
    PubMed ID: 18923444
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  • 15
    Keywords: EXPRESSION ; Germany ; PATHWAY ; COMMON ; COHORT ; EPIDEMIOLOGY ; GENE ; GENES ; DIFFERENTIATION ; PATIENT ; FAMILY ; DISORDER ; MOUSE ; IDENTIFICATION ; MUTATION ; MUTATIONS ; PHENOTYPE ; CHROMOSOMAL LOCALIZATION ; molecular epidemiology ; HETEROGENEITY ; DISORDERS ; FAMILIES ; USA ; GENOMIC STRUCTURE ; GENETIC-HETEROGENEITY ; EPIDERMIS-TYPE LIPOXYGENASES ; 12R-LIPOXYGENASE ; 12(R)-LIPOXYGENASE ALOX12B ; ERYTHRODERMA
    Abstract: In recent years several new genes for autosomal recessive congenital ichthyosis (ARCI) have been identified. However, little is known about the molecular epidemiology and pathophysiology of this genetically and clinically heterogeneous group of severe disorders of keratinization. ARCI is characterized by intense scaling of the whole integument often associated with erythema. We and others have shown that mutations in ALOX12B and ALOXE3, coding for the lipoxygenases 12R-LOX and eLOX-3 predominantly synthesized in the epidermis, can underlie this rare condition. Here we have surveyed a large group of 250 patients with ARCI for mutations in these two genes. We have identified 11 different previously unreported mutations in ALOX12B and ALOXE3 in 21 ARCI patients from 19 unrelated families and demonstrated that mutations in the two genes are the second most common cause for ARCI in this cohort of patients. Examination of the molecular data revealed allelic heterogeneity for ALOX12B and two mutational hotspots in ALOXE3. Functional analysis of all missense mutations and a splice site mutation demonstrated that complete loss of function of the enzymes underlies the phenotype. Our findings further establish the pivotal role of the 12-lipoxygenase pathway during epidermal differentiation. Journal of Investigative Dermatology (2009) 129, 1421-1428; doi:10.1038/jid.2008.409; published online 8 January 2009
    Type of Publication: Journal article published
    PubMed ID: 19131948
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  • 16
    Keywords: ACTIVATION, ADHESION, ADHESION MOLECULE, BEHAVIOR, CARCINOEMBRYONIC ANTIGEN FAMILY, CEACAM1, CEACAM-
    Abstract: Keratinocyte migration is essential for the rapid closure of the epidermis in the process of wound healing. Mesenchymal cell-derived hepatocyte growth factor (HGF) is a central regulator of this process. However, the molecular mechanisms and relevant genes that facilitate this cellular response are still poorly defined. We used heterologous cocultures combining primary human keratinocytes and genetically modified murine fibroblasts to identify key factors mediating HGF-induced epidermal cell migration. The absence of c-Jun activity in fibroblasts completely abolished the expression of HGF in these cells and consequently altered the behavior of keratinocytes. Time-resolved expression series of keratinocytes stimulated with HGF disclosed target genes regulating HGF-dependent motility. In addition to well-established HGF-dependent wound healing-associated genes, carcinoembryogenic antigen-related cell adhesion molecule (CEACAM)-1 and the urokinase plasminogen activator (uPA)/uPA-receptor (uPAR) pathway were identified as possible mediators in HGF-induced keratinocyte migration. The functional relevance of CEACAM-1 and uPA/uPAR on epidermal cell motility was demonstrated using the HaCaT cell culture model. In conclusion, the distinct spatiotemporal regulation of genes by HGF is essential for proper epidermal cell migration in cutaneous wound healing
    Type of Publication: Journal article published
    PubMed ID: 19020551
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  • 17
    Abstract: Little is known regarding the incidence trends of squamous cell skin carcinoma (SCC) and rare skin tumors, including Merkel cell carcinoma (MCC) and dermatofibrosarcoma protuberans (DFSP). The purpose of this study was to examine recent incidence trends for these cancers from 1990 to 2005 using the population-based Swedish National Cancer Registry. SCC incidence increased significantly over the study period and increased sharply with age. MCC incidence increased significantly for men for tumors at sun-exposed sites, and increased sharply with age. DFSP incidence was similar for sun-exposed and covered sites and decreased significantly only at exposed sites. A combination of behavioral, biological, and environmental factors likely explains the trends observed for these skin cancers.
    Type of Publication: Journal article published
    PubMed ID: 20090766
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  • 18
    Keywords: CELLS ; EXPRESSION ; Germany ; FOLLICLE ; HUMAN TYPE-I ; INNER-ROOT-SHEATH ; COMPANION LAYER ; EPITHELIAL KERATIN ; GENE FAMILY ; INTERMEDIATE-FILAMENT STRUCTURE ; MOUSE TAIL EPIDERMIS ; SCALP HAIR
    Abstract: We have investigated the expression of 52 of the 54 keratins in beard hair medulla. We found that not only 12 hair keratins but, unexpectedly, also 12 epithelial keratins are potentially expressed in medulla cells. The latter comprise keratins also present in outer- and inner-root sheaths and in the companion layer. Keratins K5, K14, K17, K25, K27, K28, and K75 define a "pre-medulla,'' composed of cells apposed to the upper dermal papilla. Besides K6, K16, K7, K19, and K80, all pre-medullary epithelial keratins continue to be expressed in the medulla proper, along with the 12 hair keratins. Besides this unique feature of cellular keratin co-expression, the keratin pattern itself is highly variable in individual medulla cells. Remarkably, both epithelial and hair keratins behave highly promiscuously with regard to heterodimer- and IF formation, which also includes keratin chain interactions in IF bundles. We also identified cortex cells within the medullary column. These exhibit all the properties of genuine cortex cells, including a particular type of keratin heterogeneity of their compact IF bundles. In both keratin expression profile and keratin number, medulla cells are distinct from all other cells of the hair follicle or from any other epithelium
    Type of Publication: Journal article published
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  • 19
    Keywords: CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; proliferation ; SURVIVAL ; CELL ; CELL-PROLIFERATION ; Germany ; IN-VIVO ; VIVO ; microarray ; RNA ; ADHESION MOLECULES ; MOLECULES ; TISSUE ; SUPPRESSION ; BREAST-CANCER ; TARGET ; CELL-SURVIVAL ; PROGRESSION ; METASTASIS ; MELANOMA ; ADHESION ; MIGRATION ; EPITHELIAL-CELLS ; L1 ; MALIGNANT-MELANOMA ; TARGETS ; CELL-ADHESION MOLECULE ; OVEREXPRESSION ; DIFFERENTIAL EXPRESSION ; AMYLOID PRECURSOR PROTEIN ; chemoresistance ; CELL-GROWTH ; E-cadherin ; development ; tissue microarray ; ALPHA-SECRETASE
    Abstract: ADAM10 (a disintegrin and metalloproteinase 10) is involved in the ectodomain shedding of various substrates, including adhesion molecules such as L1 cell adhesion molecule (L1-CAM) and CD44, which are known to have important roles in the development of malignant melanoma. In our Study, we characterized the expression of ADAM10 in melanoma cells in vitro and in vivo Immunohistochemical analysis oil tissue microarrays indicated that ADAM-10 expression was significantly elevated in melanoma metastasis compared with primary melanomas. In vitro downregulation of ADAM10 with specific small interfering RNA (siRNA) resulted in a suppression of the anchorage-independent cell growth and reduced the migration of melanoma cells. In addition, overexpression of ADAM-10 induced the migration of melanoma cells. In cell lines from melanoma patients with metastasis, ADAM10 was significantly overexpressed, and ADAM10 expression correlated with increased cell proliferation. Furthermore, we present evidence that ADAM-10 is involved in the release of L1-CAM from melanoma cells. It is important that knockdown of cellular L1-CAM reduced the migration of melanoma cells and abrogated the chemoresistance against cisplatin. In contrast, soluble L1-CAM had no effect on melanoma cell migration or cell survival. Taken together, Our data demonstrate that ADAM10 and L1-CAM have important roles during melanoma progression and both molecules represent attractive targets for therapeutical intervention of melanomas
    Type of Publication: Journal article published
    PubMed ID: 19865098
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  • 20
    Keywords: CELLS ; ACTIVATION ; KERATINOCYTES ; SKIN ; CYCLE ; MIGRATION ; E6 ; E-cadherin ; EPIDERMODYSPLASIA-VERRUCIFORMIS ; LIFE ; DNA LOADS
    Abstract: Human papillomaviruses (HPVs), which are contained in the alpha, beta, gamma, mu, and nu genera, differ in their oncogenic potential and their tropism for cutaneous or mucosal epidermis. Langerhans cells (LC), the only epidermal professional antigen-presenting cells, are readily detected in normal mucosal and cutaneous epithelium. The aim of this study is to determine whether LC loss, which has been reported for HPV16, occurs in other HPV genera and establish its significance in viral pathology. We found that, as for HPV16, LCs were reduced in lesions infected with high-risk mucosal (alpha 7 and alpha 9 species) and low-risk cutaneous (gamma and mu) types. Lesions infected with alpha 10 low-risk genital types had reduced LC but contained epidermal LC patches, coincident with dermis-localized regulatory T cells (T-regs). In contrast to other genera, LCs were common in the epidermis, and T-regs occupied the dermis of the potentially high-risk cutaneous beta-HPV type infected lesions. Therefore, LC loss in the infected lesions occurred irrespective of tropism or oncogenic potential of the HPV type. LC depletion in the HPV-infected epidermis may create an environment that is permissive for viral persistence and in HPV lesions in which LCs are found, the presence of typically immunosuppressive T-regs may compensate for their continued presence
    Type of Publication: Journal article published
    PubMed ID: 19759549
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