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  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; GROWTH ; CELL ; MODEL ; MODELS ; GENE ; transcription ; METABOLISM ; DIFFERENTIATION ; MICE ; ACTIVATION ; DNA ; MECHANISM ; MARKER ; primary ; INDUCTION ; KERATINOCYTES ; mechanisms ; SKIN ; MATURATION ; MOUSE ; NUMBER ; DNA-BINDING ; SIGNALING PATHWAY ; epidermis ; ARCHITECTURE ; desmosomes ; USA ; LOSSES ; HOMEOSTASIS ; BARRIER ; CASPASE-14 ; EPIDERMAL-KERATINOCYTES ; FETAL MOUSE
    Abstract: To investigate the contribution of the glucocorticoid receptor (GR) in skin development and the mechanisms underlying this function, we have analyzed two mouse models in which GR has been functionally inactivated: the knockout GR(-/-) mice and the dimerization mutant GR(dim/dim) that mediates defective DNA binding-dependent transcription. Because GR null mice die perinatally, we evaluated skin architecture of late embryos by histological, immunohistochemical, and electron microscopy studies. Loss of function of GR resulted in incomplete epidermal stratification with dramatically abnormal differentiation of GR(-/-), but not GR(+/-) embryos, as demonstrated by the lack of loricrin, filaggrin, and involucrin markers. Skin sections of GR(-/-) embryos revealed edematous basal and lower spinous cells, and electron micrographs showed increased intercellular spaces between keratinocytes and reduced number of desmosomes. The absent terminal differentiation in GR(-/-) embryos correlated with an impaired activation of caspase-14, which is required for the processing of profilaggrin into filaggrin at late embryo stages. Accordingly, the skin barrier competence was severely compromised in GR(-/-) embryos. Cultured mouse primary keratinocytes from GR(-/-) mice formed colonies with cells of heterogeneous size and morphology that showed increased growth and apoptosis, indicating that GR regulates these processes in a cell-autonomous manner. The activity of ERK1/2 was constitutively augmented in GR(-/-) skin and mouse primary keratinocytes relative to wild type, which suggests that GR modulates skin homeostasis, at least partially, by antagonizing ERK function. Moreover, the epidermis of GR(+/dim) and GR(dim/dim) embryos appeared normal, thus suggesting that DNA-binding-independent actions of GR are sufficient to mediate epidermal and hair follicle development during embryogenesis
    Type of Publication: Journal article published
    PubMed ID: 18039792
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  • 2
    Keywords: RECEPTOR ; CANCER ; IN-VITRO ; DIFFERENTIATION ; FAMILY ; CARCINOGENESIS ; HUMAN-PAPILLOMAVIRUS ; HEAD ; inflammation ; DEPENDENT PATHWAY
    Abstract: S100/calgranulins (S100A8, S100A9 and S100A12) are key players of innate immune function and elevated levels are a characteristic feature of acute and chronic inflammation, and inflammation-associated carcinogenesis. However, reduced S100A8 and S100A9 expression has been detected for squamous cell carcinoma, including the head and neck region (HNSCC), which originate from mucosal epithelia with abundant expression of both proteins under physiological conditions. In contrast to S100A8 and S100A9, only sparse information is available for S100A12 and a comparative study of all three S100/calgranulins in HNSCC is still missing. We analyzed S100/calgranulin protein levels in a retrospective patient cohort (n=131) of oropharyngeal squamous cell carcinoma (OPSCC) by immunohistochemical staining of tissue microarrays. Common characteristics of all three S100/calgranulins were: (i) abundant expression in supra-basal keratinocytes of normal mucosa with predominant nuclear staining, (ii) low expression in 30.4-51.9% of primary OPSCCs and (iii) variable accumulation of S100/calgranulin-positive immune cells in the tumor stroma. These features were associated with histopathological characteristics, such as tumor grade, lymph node metastasis and tumor stage. Furthermore, univariate and multivariate analysis revealed worse overall survival of OPSCC patients with simultaneous reduction of S100A8 and S100A12 expression, while expression of S100A9 or presence of the S100A8/S100A9 heterodimer had no impact, suggesting distinct regulation and function of individual S100/calgranulins in the pathogenesis of HNSCCs. What's new? Inflammation can alter the expression of specific proteins, and in the context of head and neck squamous cell carcinoma (HNSCC), which involves a high degree of inflammation, those changes may be of diagnostic or prognostic significance. Here, reduced expression of calcium-binding S100/calgranulin proteins was found to be a common feature of oropharyngeal SCC. Moreover, simultaneous low protein expression of S100A8 and S100A12 in tumor cells was an independent risk factor for unfavorable overall survival. The regulation and function of S100/calgranulins likely is context-dependent, with differences between mucosal and squamous epithelia.
    Type of Publication: Journal article published
    PubMed ID: 25302747
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  • 3
    Keywords: CELLS ; carcinoma ; PATHWAY ; ACTIVATION ; BREAST-CANCER ; p53 ; DNA-DAMAGE ; AKT ; TUMOR SUPPRESSION ; SECRETORY PHENOTYPE
    Abstract: Myb-binding protein 1A (MYBBP1A) is a nucleolar protein implicated in stress response and carcinogenesis; however, its functional contribution to senescence remains elusive. In this study we show decreased MYBBP1A protein levels in tumor cells after treatment with etoposide, a potent inducer of DNA damage. Although silencing of MYBBP1A expression was not sufficient to induce senescence, it significantly increased the relative abundance of senescent cells after DNA damage. We found an inverse regulation of MYBBP1A and AKT phosphorylation (pAKT(Ser473)), which was characteristic for the pre-senescent state after etoposide administration in vitro. Tissue microarrays with tumor specimens from primary oropharyngeal squamous cell carcinoma (OPSCC) patients (n = 61) by immunohistochemistry revealed a significant correlation between MYBBP1A(low)pAKT(Ser473)(high) staining pattern and shorter progression-free (p = 0.007) or overall survival (p 〈 0.001). Multivariate analysis showed that MYBBP1A(low)pAKT(Ser473)(high) staining pattern is an independent prognosticator for OPSCC. Taken together, our study points to a critical role of MYBBP1A in the regulation of senescence under genotoxic stress and that a MYBBP1A(low)AKT(Ser473)(high) staining pattern serves not only as a marker for the pre-senescent stage but also as an indicator of OPSCC patients at high risk for treatment failure.
    Type of Publication: Journal article published
    PubMed ID: 25543088
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  • 4
    Keywords: GROWTH ; LUNG-CANCER ; PROGNOSTIC-SIGNIFICANCE ; POOR-PROGNOSIS ; PROMOTES ; EPITHELIAL-MESENCHYMAL TRANSITION ; CANCER STEM-CELLS ; TRANSCRIPTION FACTOR SOX2 ; 3Q26-29 AMPLICON ; RESPONSE PROGRAM
    Abstract: Recurrent gain on chromosome 3q26 encompassing the gene locus for the transcription factor SOX2 is a frequent event in human squamous cell carcinoma, including head and neck squamous cell carcinoma (HNSCC). Numerous studies demonstrated that SOX2 expression and function is related to distinct aspects of tumor cell pathophysiology. However, the underlying molecular mechanisms are not well understood, and the correlation between SOX2 expression and clinical outcome revealed conflicting data. Transcriptional profiling after silencing of SOX2 expression in a HNSCC cell line identified a set of up-regulated genes related to cell motility (e.g. VIM, FN1, CDH2). The inverse regulation of SOX2 and aforementioned genes was validated in 18 independent HNSCC cell lines from different anatomical sites. The inhibition of cell migration and invasion by SOX2 was confirmed by constant or conditional gene silencing and accelerated motility of HNSCC cells after SOX2 silencing was partially reverted by down-regulation of vimentin. In a retrospective study, SOX2 expression was determined by immunohistochemical staining on tissue microarrays containing primary tumor specimens of two independent HNSCC patient cohorts. Low SOX2 expression was found in 19.3% and 44.9% of primary tumor specimens, respectively. Univariate analysis demonstrated a statistically significant correlation between low SOX2 protein levels and reduced progression-free survival (Cohort I 51 vs. 16 months; Cohort II 33 vs. 12 months) and overall survival (Cohort I 150 vs. 37 months; Cohort II 33 vs. 16 months). Multivariate Cox proportional hazard model analysis confirmed that low SOX2 expression serves as an independent prognostic marker for HNSCC patients. We conclude that SOX2 inhibits tumor cell motility in HNSCC cells and that low SOX2 expression serves as a prognosticator to identify HNSCC patients at high risk for treatment failure.
    Type of Publication: Journal article published
    PubMed ID: 26040981
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  • 5
    Publication Date: 2018-02-15
    Description: Objective To determine the met need for emergency obstetric care (EmOC) services in three Payams of Torit County, South Sudan in 2015 and to determine the frequency of each major obstetric complication. Design This was a retrospective cross-sectional study. Setting Four primary healthcare centres (PHCCs) and one state hospital in three payams (administrative areas that form a county) in Torit County, South Sudan. Participants All admissions in the obstetrics and gynaecology wards (a total of 2466 patient admission files) in 2015 in all the facilities designated to conduct deliveries in the study area were reviewed to identify obstetric complications. Primary and secondary outcome measures The primary outcome was met need for EmOC, which was defined as the proportion of all women with direct major obstetric complications in 2015 treated in health facilities providing EmOC services. The frequency of each complication and the interventions for treatment were the secondary outcomes. Results Two hundred and fifty four major obstetric complications were admitted in 2015 out of 390 expected from 2602 pregnancies, representing 65.13% met need. The met need was highest (88%) for Nyong Payam, an urban area, compared with the other two rural payams, and 98.8% of the complications were treated from the hospital, while no complications were treated from three PHCCs. The most common obstetric complications were abortions (45.7%), prolonged obstructed labour (23.2%) and haemorrhage (16.5%). Evacuation of the uterus for retained products (42.5%), caesarean sections (32.7%) and administration of oxytocin for treatment of postpartum haemorrhage (13.3%) were the most common interventions. Conclusion The met need for EmOC in Torit County is low, with 35% of women with major obstetric complications not accessing care, and there is disparity with Nyong Payam having a higher met need. We suggest more support supervision to the PHCCs to increase access for the rural population.
    Keywords: Open access
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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