BackgroundNC1 domains from α1, α2, α3 and α6(IV) collagen chains were shown to exert anti-tumor or anti-angiogenic activities, whereas the NC1 domain of the α4(IV) chain did not show such activities so far.Methodology/Principal FindingsWe demonstrate in the present paper that the NC1 α4(IV) domain exerts a potent anti-tumor activity both in vitro and in an experimental human melanoma model in vivo. The overexpression of NC1 α4(IV) in human UACC-903 melanoma cells strongly inhibited their in vitro proliferative (–38%) and invasive (–52%) properties. MT1-MMP activation was largely decreased and its cellular distribution was modified, resulting in a loss of expression at the migration front associated with a loss of migratory phenotype. In an in vivo xenograft model in athymic nude mice, the subcutaneous injection of NC1 α4(IV)-overexpressing melanoma cells induced significantly smaller tumors (–80% tumor volume) than the Mock cells, due to a strong inhibition of tumor growth. Exogenously added recombinant human NC1 α4(IV) reproduced the inhibitory effects of NC1 α4(IV) overexpression in UACC-903 cells but not in dermal fibroblasts. An anti-αvβ3 integrin blocking antibody inhibited cell adhesion on recombinant human NC1 α4(IV) substratum. The involvement of αvβ3 integrin in mediating NC1 α4(IV) effect was confirmed by surface plasmon resonance (SPR) binding assays showing that recombinant human NC1 α4(IV) binds to αvβ3 integrin (KD = 148±9.54 nM).Conclusion/SignificanceCollectively, our results demonstrate that the NC1 α4(IV) domain, named tetrastatin, is a new endogenous anti-tumor matrikine.

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Herpes simplex virus 1 (HSV-1) esophagitis diagnosis is routinely based on the endoscopic findings confirmed by histopathological examination of the esophagitis lesions. Virological diagnosis is not systematically performed and restricted to viral culture or to qualitative PCR assay from esophagitis biopsy specimens. The aim of this study was to assess the interest of quantitative real-time PCR assay in HSV-1 esophagitis diagnosis by comparing the results obtained to those of histological examination associated with immunohistochemical staining, which is considered the "gold standard." From 53 esophagitis biopsy specimens, the PCR assay detected HSV-1 in 18 of 19 histologically proven to have herpetic esophagitis and in 9 of 34 that had esophagitis related to other causes, demonstrating sensitivity, specificity, positive predictive value, and negative predictive value of 94.7%, 73%, 66.7%, and 96%, respectively. Interestingly, HSV-1 was not detected in 16 specimens without the histological aspect of esophagitis. The viral loads normalized per g of total extracted DNA in each biopsy specimen detected positive by HSV PCR were then compared and appeared to be significantly higher in histopathologically positive herpetic esophagitis (median ‫؍‬ 2.9 ؋ 10 6 ؎ 1.1 ؋ 10 8 ) than in histopathologically negative herpetic esophagitis (median ‫؍‬ 3.1 ؋ 10 3 ؎ 6.2 ؋ 10 3 ) (P ‫؍‬ 0.0009). Moreover, a receiver operating characteristics analysis revealed that a viral load threshold greater than 2.5 ؋ 10 4 copies would allow an HSV-1 esophagitis diagnosis with a sensitivity and specificity of 83.3% and 100%, respectively. In conclusion, this work demonstrated that HSV quantitative PCR results for paraffin-embedded esophageal tissue was well correlated to histopathological findings for an HSV-1 esophagitis diagnosis and could be diagnostic through viral load assessment when histopathological results are missing or uncertain. Herpes simplex virus 1 (HSV-1) is the second most common infectious etiological cause of esophagitis after Candida albicans (15,18,22). HSV-1 esophagitis is well documented in immunocompromised patients, whereas this clinical entity is rare in immunocompetent patients (2,4,5,9). HSV-1 esophagitis may represent a primary infection in particular in the immunocompetent host but is commonly due to a reactivation of a latent infection in the immunocompromised host (7).Friable mucosa, numerous ulcers, and whitish exudates commonly involving the distal or the midesophagus are classical endoscopic aspects in HSV-1 esophagitis (10,11,14,19). These findings require confirmation by histological examination completed with immunohistochemical staining of the biopsy specimens from the ulcer edges, which still remains the "gold standard" for HSV-1 esophagitis diagnosis (13,14,19). Virological diagnosis has been reported to optimize the diagnostic sensitivity of HSV-1 esophagitis (2,16,19). However, it is not systematically performed and is restricted to viral culture or to qualitative PCR assay from esophageal biopsy speci...

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