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- Chamcheu, Jean Christopher, et al.
(författare)
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Chemical Chaperones Protect Epidermolysis Bullosa Simplex Keratinocytes from Heat Stress-Induced Keratin Aggregation : Involvement of Heat Shock Proteins and MAP Kinases
- 2011
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 131:8, s. 1684-1691
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Tidskriftsartikel (refereegranskat)abstract
- Epidermolysis bullosa simplex (EBS) is a blistering skin disease caused by mutations in keratin genes (KRT5 or KRT14), with no existing therapies. Aggregates of misfolded mutant keratins are seen in cultured keratinocytes from severe EBS patients. In other protein-folding disorders, involvement of molecular chaperones and the ubiquitin-proteasome system may modify disease severity. In this study, the effects of heat stress on keratin aggregation in immortalized cells from two patients with EBS (KRT5) and a healthy control were examined with and without addition of various test compounds. Heat-induced (43 °C, 30 minutes) aggregates were observed in all cell lines, the amount of which correlated with the donor phenotype. In EBS cells pre-exposed to proteasome inhibitor, MG132, and p38-mitogen-activated protein kinase (MAPK) inhibitor, SB203580, the proportion of aggregate-positive cells increased, suggesting a role of proteasomes and phosphorylation in removing mutated keratin. In contrast, aggregates were reduced by pretreatment with two chemical chaperones, trimethylamine N-oxide (TMAO) and 4-phenylbutyrate (4-PBA). TMAO also modulated stress-induced p38/c-jun N-terminal kinase (JNK) activation and expression of heat shock protein (HSPA1A), the latter of which colocalized with phosphorylated keratin 5 in EBS cells. Taken together, our findings suggest therapeutic targets for EBS and other keratinopathies.
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- Chen, Tianhui, et al.
(författare)
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Effect of a Detailed Family History of Melanoma on Risk for Other Tumors: A Cohort Study Based on the Nationwide Swedish Family-Cancer Database
- 2014
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 1523-1747 .- 0022-202X. ; 134:4, s. 930-936
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Tidskriftsartikel (refereegranskat)abstract
- Using the Swedish Family-Cancer Database, we assessed the effect of a detailed family history of melanoma on risk for other tumors (other than melanoma). Among 248,011 individuals with a family history of melanoma, 43,931 other tumors were diagnosed from 1958 to 2010. Standardized incidence ratios (SIRs) were calculated for other tumors in patients who had a family history of melanoma, as compared with those without. A detailed family history of melanoma was investigated according to an increasing number of melanomas in either 1 or >= 2 first-degree relatives (FDRs). Associations were considered significant when there were at least two independently significant SIRs or a statistically significant trend of increasing SIRs with increasing number of melanomas in relatives. The applied criteria for significant associations were convincingly met by pancreatic, breast, prostate, and squamous cell skin tumors and ependymoma, although there was significant but not overwhelming evidence for thyroid, parathyroid, lung, and unknown primary tumors, meningioma, mycosis fungoides, and myeloid leukemia. To our knowledge, no studies have previously considered a detailed family history of melanoma and the use of internal validation to assess familial associations of melanoma with other tumors. We established associations for 12 other tumors, and the associations for myeloid leukemia, parathyroid, and unknown primary tumors are, to our knowledge, previously unreported.
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- Cui, Chang-Yi, et al.
(författare)
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Frizzled6 Deficiency Disrupts the Differentiation Process of Nail Development
- 2013
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 133:8, s. 1990-1997
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Tidskriftsartikel (refereegranskat)abstract
- Nails protect the soft tissue of the tips of digits. The molecular mechanism of nail (and claw) development is largely unknown, but we have recently identified a Wnt receptor gene, Frizzled6 (Fzd6), that is mutated in a human autosomal-recessive nail dysplasia. To investigate the action of Fzd6 in claw development at the molecular level, we compared gene expression profiles of digit tips of wild-type and Fzd6(-/-) mice, and showed that Fzd6 regulates the transcription of a striking number of epidermal differentiation related genes. Sixty-three genes encoding keratins (Krts), keratin-associated proteins, and transglutaminases (Tgms) and their substrates were significantly downregulated in the knockout mice. Among them, four hard Krts, Krt86, Krt81, Krt34, and Krt31; two epithelial Krts, Krt6a and Krt6b; and Tgm 1 were already known to be involved in nail abnormalities when dysregulated. Immunohistochemical studies revealed decreased expression of Krt86, Krt6b, and involucrin in the epidermal portion of the claw field in the knockout embryos. We further showed that Dkk4, a Wnt antagonist, was significantly downregulated in Fzd6(-/-) mice along with Wnt, Bmp, and Hh family genes; and Dkk4 transgenic mice showed a subtly but appreciably modified claw phenotype. Thus, Fzd6-mediated Wnt signaling likely regulates the overall differentiation process of nail/claw formation.
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- Hussain, Shehnaz K., et al.
(författare)
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Incidence Trends of Squamous Cell and Rare Skin Cancers in the Swedish National Cancer Registry Point to Calendar Year and Age-Dependent Increases
- 2010
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 1523-1747 .- 0022-202X. ; 130:5, s. 1323-1328
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Tidskriftsartikel (refereegranskat)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.
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- Kuhn, Annegret, et al.
(författare)
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Photoprovocation in Cutaneous Lupus Erythematosus : A Multicenter Study Evaluating a Standardized Protocol
- 2011
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 131:8, s. 1622-1630
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Tidskriftsartikel (refereegranskat)abstract
- Photosensitivity is an important and distinguishing sign in various subtypes of cutaneous lupus erythematosus (CLE); however, it remains poorly defined. The purpose of this study was to evaluate whether standardized photoprovocation is a reproducible method to assess photosensitivity in subjects with CLE. A total of 47 subjects with CLE (subacute cutaneous lupus erythematosus (SCLE), n = 14; discoid lupus erythematosus (DLE), n = 20; lupus erythematosus tumidus (LET), n = 13) and 13 healthy volunteers underwent photoprovocation at seven European sites. Of these, 22 (47%) subjects (57% SCLE, 35% DLE, and 54% LET) and none of the healthy volunteers developed photoprovoked lesions according to clinical analysis. Of these 22 subjects, 19 (86%) developed lesions that were histopathologically confirmed as specific for lupus erythematosus (LE). In CLE subjects who developed UV-induced lesions, 86% had Fitzpatrick's phototypes I or II, and the mean minimal erythema dose (MED) was significantly lower compared with subjects without UV-induced lesions (P = 0.004). No significant differences in photoprovocation results were observed between study sites. Safety parameters showed no clinically meaningful differences between CLE subjects and healthy volunteers after photoprovocation. In conclusion, a standardized, safe, and reproducible protocol for photoprovocation using UVA and UVB radiation induced skin lesions in approximately half of all CLE subjects and showed comparable results across multiple sites. This method may therefore be used for future diagnostic testing and clinical trials.
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- Li, Hao, 1984-, et al.
(författare)
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The expression of epidermal lipoxygenases and transglutaminase-1 is perturbed by NIPAL4 mutations : indications of a common metabolic pathway essential for skin barrier homeostasis
- 2012
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 132:10, s. 2368-2375
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin barrier diseases due inter alia to mutations in transglutaminase-1 (TGM1), in lipoxygenases (LOXs) of the hepoxilin pathway, and in ichthyin, a putative Mg2+ transporter encoded by the NIPAL4 gene. In search of a common pathogenic pathway for ARCI, we investigated the epidermal expression of TGM1, 12R-LOX, eLOX-3, and ichthyin in skin biopsies from four healthy controls and nine patients with ARCI. In healthy skin, TGM1, ichthyin, and the LOX enzymes were predominantly expressed in the upper epidermis where colocalization signals could also be demonstrated by in situ proximity ligation assay. In patients with ALOX12B mutations and abnormal 12R-LOX expression, the colocalization signal for eLOX-3 and TGM1 was increased 4-fold. In contrast, patients with NIPAL4 mutations and abnormal ichthyin expression showed increased 12R-LOX and eLOX-3 staining and a colocalization signal of these LOXs that was three times the normal intensity. Treatment of these patients with a retinoid-mimetic drug, liarozole, normalized the expression of 12R-LOX and attenuated the colocalization signal. Altogether, our data indicate that ichthyin and TGM1 are functionally closely related in the lipid processing and that this metabolic pathway can be modified by retinoids.
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| 25. |
- Li, Jian, et al.
(författare)
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Array Comparative Genomic Hybridization of Keratoacanthomas and Squamous Cell Carcinomas: Different Patterns of Genetic Aberrations Suggest Two Distinct Entities
- 2012
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 1523-1747 .- 0022-202X. ; 132:8, s. 2060-2066
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Tidskriftsartikel (refereegranskat)abstract
- Keratoacanthoma (KA) is a benign keratinocytic neoplasm that spontaneously regresses after 3-6 months and shares features with squamous cell carcinomas (SCCs). Furthermore, there are reports of KAs that have metastasized, invoking the question of whether KA is a variant of SCC (Hodak et al., 1993). To date, no reported criteria are sensitive enough to discriminate reliably between KA and SCC, and consequently there is a clinical need for discriminating markers. Our previous study analyzed 132 KAs and 29 SCCs and revealed significantly different regions of genomic aberrations using chromosomal comparative genomic hybridization (CGH). In the present study, we applied array CGH to investigate 98 KAs and 22 SCCs from the above samples. The result shows that all KAs and SCCs have some degree of genetic aberrations. The distribution of numbers of aberrant clones per sample differed significantly between KAs and SCCs (P<0.02), which also demonstrated recurrent aberrations that differed significantly (P<0.001), as illustrated by unsupervised cluster analysis. Classifiers for clinicopathological parameters of KAs were established based on t-test statistics and permutation tests. Tumor size, fibrosis, and inflammation, which are related to the developmental stages of KAs, showed significant (t-test, permutation test) associations with aberrations of selected genomic regions. This suggests chromosomal instability during the whole life cycle of KAs.
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