Mosaic subclinical melanoderma: an Achilles heel for UV-related epidermal carcinogenesis?

Cutaneous cancers are not uncommon on the face of elderly patients. Melanin should protect, at least in part, against the ultraviolet (UV)-induced neoplastic damage. However, the density in melanin chromatophores is heterogeneous in the epidermis of Caucasian adults. The computerized UV light-enhanced visualization (ULEV) method is a sensitive tool to assess non-invasively this mosaic pattern of intra-epidermal melanin load. In this study, the combination of ULEV pattern analysis and image analysis were performed involving four groups of phototype III Caucasian subjects. The first group was composed of 55 patients aged from 65 to 75 years who suffered from several malignancies of facial skin. The second control group of 55 patients who never had developed skin cancers were matched with the first group for age, sex and phototype. The third group was composed of 80 patients aged from 49 to 59 years who had developed a single basal cell carcinoma. The fourth group comprised 80 age, sex and phototype-matched healthy control subjects. Irrespective of the groups of subjects, a correlation was found between the pattern grading and the objectively determined relative area of subclinical melanoderma. Patients with multiple skin cancers differed from the other groups by the fact that a significantly higher proportion of them exhibited an extensive type of subclinical melanoderma. This feature was also seen in a minority of patients with a single basal cell carcinoma. The extensive subclinical melanoderma pattern is interpreted as a clue for risk, but not as a cause of UV-induced skin carcinogenesis.     

Gamma-secretase-dependent proteolysis of CD44 promotes neoplastic transformation of rat fibroblastic cells

The metalloprotease-dependent extracellular domain cleavage of the adhesion molecule CD44 is frequently observed in human tumors and is thought to promote metastasis. This cleavage is followed by gamma-secretase-dependent release of CD44 intracellular domain (CD44-ICD), which exhibits nuclear signaling activity. Using a reversible Ret-dependent oncogenic conversion model and a restricted proteomic approach, we identified a positive correlation between the neoplastic transformation of Rat-1 cells and the expression of standard CD44. In these transformed cells, CD44 was found to undergo a sequential metalloprotease and gamma-secretase cleavage, resulting in an increase in expression of CD44-ICD. We showed that this proteolytic fragment possesses a transforming activity. In support of this role, a significant and specific reduction in Ret-induced transformation of Rat-1 cells was observed following drug-mediated inhibition of gamma-secretase. Taken together, these findings suggest that the shedding of CD44 may not only modulate metastasis but also affects earlier events in tumorigenesis through the release of CD44-ICD.     

Skin weathering and ashiness in black Africans

Ashiness describes a common physiological skin condition that may develop in people with dark skin complexion. Environmental influences, particularly cold and dry weather, seem obvious. This condition has seldom been studied so far. In the present study, skin ashiness was assessed in 37 black African women by means of colorimetric assessments and xerosis ratings. Colour changes were measured by the parameters a* and the individual typology angle ITA degrees. Xerosis was assessed by visual inspection, the ultraviolet light-enhanced visualization (ULEV) method, and the cyanoacrylate skin surface stripping (CSSS) method. The assessments were performed on ashy skin of the legs and on the normal looking forehead during the winter season. Ashy skin was lighter but not erythematous. The ITA-revealed colour changes were correlated with xerosis severity as assessed by dry dermoscopy and by the ULEV and CSSS methods. In conclusion, ashiness due to skin weathering does not appear to be related to mild inflammation. It corresponds to a peculiar type of xerosis with reduction in Fresnel reflection by the stratum corneum.     

Transposition of a reconstructed Harbinger element in human cells and functional homology with two transposon-derived cellular genes

Ancient, inactive copies of transposable elements of the PIF/Harbinger superfamily have been described in vertebrates. We reconstructed components of the Harbinger3_DR transposon in zebrafish, including a transposase and a second, transposon-encoded protein that has a Myb-like trihelix domain. The reconstructed Harbinger transposon shows efficient cut-and-paste transposition in human cells and preferentially inserts into a 15-bp consensus target sequence. The Myb-like protein is required for transposition and physically interacts with the N-terminal region of the transposase via its C-terminal domain. The Myb-like protein enables transposition in part by promoting nuclear import of the transposase, by directly binding to subterminal regions of the transposon, and by recruiting the transposase to the transposon ends. We investigated the functions of two transposon-derived human proteins: HARBI1, a domesticated transposase-derived protein, and NAIF1, which contains a trihelix motif similar to that described in the Myb-like protein. Physical interaction, subcellular localization, and DNA-binding activities of HARBI1 and NAIF1 suggest strong functional homologies between the Harbinger3_DR system and their related, host-encoded counterparts. The Harbinger transposon will serve as a useful experimental system for transposon biology and for investigating the enzymatic functions of domesticated, transposon-derived cellular genes.     

Design, synthesis, and biological evaluation of (hydroxyphenyl)naphthalene and -quinoline derivatives: potent and selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) for the treatment of estrogen-dependent diseases

Human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the reduction of the weak estrogen estrone (E1) to the highly potent estradiol (E2). This reaction takes place in the target cell where the estrogenic effect is exerted via the estrogen receptor (ER). Estrogens, especially E2, are known to stimulate the proliferation of hormone-dependent diseases. 17beta-HSD1 is overexpressed in many breast tumors. Thus, it is an attractive target for the treatment of these diseases. Ligand- and structure-based drug design led to the discovery of novel, selective, and potent inhibitors of 17beta-HSD1. Phenyl-substituted bicyclic moieties were synthesized as mimics of the steroidal substrate. Computational methods were used to obtain insight into their interactions with the protein. Compound 5 turned out to be a highly potent inhibitor of 17beta-HSD1 showing good selectivity (17beta-HSD2, ERalpha and beta), medium cell permeation, reasonable metabolic stability (rat hepatic microsomes), and little inhibition of hepatic CYP enzymes.     

Acoustic radiation force impulse imaging for assessing liver fibrosis in alcoholic liver disease

AIM: To evaluate the performance of elastography by ultrasound with acoustic radiation force impulse(ARFI) in determining fibrosis stage in patients with alcoholic liver disease(ALD) undergoing alcoholic detoxification in relation to biopsy.METHODS: Eighty-three patients with ALD undergoing detoxification were prospectively enrolled. Each patient underwent ARFI imaging and a liver biopsy onthe same day. Fibrosis was staged according to the METAVIR scoring system. The median of 10 valid ARFI measurements was calculated for each patient.RESULTS: Sixty-nine males and thirteen females(one patient excluded due to insufficient biopsy size) were assessed with a mean alcohol consumption of 132.4 ± 128.8 standard drinks per week and mean cumulative year duration of 17.6 ± 9.5 years. Sensitivity and specificity were respectively 82.4%(0.70-0.95) and 83.3%(0.73-0.94)(AUROC = 0.87) for F ≥ 2 with a cut-off value of 1.63m/s; 82.4%(0.64-1.00) and 78.5%(0.69-0.89)(AUROC = 0.86) for F ≥ 3 with a cut-off value of 1.84m/s; and 92.3%(0.78-1.00] and 81.6%(0.72-0.90)(AUROC = 0.89) for F = 4 with a cut-off value of 1.94 m/s.CONCLUSION: ARFI is an accurate, non-invasive and easy method for assessing liver fibrosis in patients with ALD undergoing alcoholic detoxification.     

Antibodies against the node of Ranvier: a real-life evaluation of incidence,clinical features and response to treatment based on a prospective analysis of 1500 sera

Journal of Neurology - IgG4 antibodies against neurofascin (Nfasc155 and Nfasc140/186), contactin (CNTN1) and contactin-associated protein (Caspr1) are described in specific subtypes of chronic...     

A Decentralized Study Setup Enables to Quantify the Effect of Polymerization and Linkage of α-Glucans on Post-Prandial Glucose Response

The complexity of the carbohydrate structure is associated with post-prandial glucose response and diverse health benefits. The aim of this study was to determine whether, thanks to the usage of minimally invasive glucose monitors, it was possible to evaluate, in a decentralized study setup, the post-prandial glycemic response (PPGR) of α-glucans differing systematically in their degree of polymerization (DP 3 vs. DP 60) and in their linkage structure (dextrin vs. dextran). Ten healthy subjects completed a double-blind, randomized, decentralized crossover trial, testing at home, in real life conditions, four self-prepared test beverages consisting of 25 g α-glucan dissolved in 300 mL water. The incremental area under the curve of the 120 min PPGR (2h-iAUC) was the highest for Dextrin DP 3 (163 ± 27 mmol/L*min), followed by Dextrin DP 60 (−25%, p = 0.208), Dextran DP 60 (−59%, p = 0.002), and non-fully caloric Resistant Dextrin (−68%, p = 0.002). These results show that a fully decentralized crossover study can be successfully used to assess the influence of both polymerization and structure of α-glucans on PPGR.