Management of triggering factor effects in sensitive skin syndrome with a dermo-cosmetic product.

OBJECTIVE: Environmental factors are important in the generation or aggravation of sensitive skin syndrome (SSS). Creams can be useful for patients with SSS, particularly when triggering factors cannot be avoided. Several clinical studies have investigated the safety and efficacy of specific creams in patients with SSS, but the majority were assessed with a single type of triggering factor and were non-comparative. Therefore, this study's aim was to investigate, the benefit of a specific dermo-cosmetic product in response to physical and chemical factors in subjects with SSS. METHODS: Three clinical studies were performed on subjects presenting SSS. The physical impact was assessed in a stripping test, and in a randomized intra-individual study with a newly developed heat-cold stress model. To assess chemical factors, a capsaicin test on the nasolabial fold was performed. RESULTS: The product significantly reduced the increase in skin microcirculation caused by stripping after 30 min versus. The untreated condition (45.8% vs. 62.0%; p < 0.01). Immediately and at D28, the product induced a significant increase in skin hydration even after a heat-cold stress, while the overall score of unpleasant symptoms significantly decreased compared with the control (8.1 vs. 10.7 and 3.7 vs. 8.0, respectively; p < 0.01). Regarding chemical factors, a significant difference in the sensation intensity (p < 0.001) was observed after capsaicin stress, also in terms of the sensation duration due to the product application versus the control (192 s vs. 403 s; p < 0.001). CONCLUSION: These studies show that topical application of a dermo-cosmetic product can prevent unpleasant symptoms and improve the skin state in SSS exposed to physical and chemical triggering factors.

Improvement of Quality of Life in Dialysis and Diabetic Patients by Skin Dryness and Pruritus Management with an Ecobiological Dermo-Cosmetic Product.

Purpose: Xerosis and pruritus are common chronic dermatological disorders among dialysis and diabetic patients that are frequently underdiagnosed or neglected, which can impact the quality of life of these patients. This study aimed to evaluate the efficacy and safety of a specific dermo-cosmetic product in the treatment of dry skin and pruritus associated with dialysis and diabetes. Patients and Methods: Twenty-nine dialysis patients (mean age 62 years) and 40 diabetic patients (mean age 57 years, 88% type 2) were included in two different single-center open-label uncontrolled clinical trials. All patients presented skin dryness according to the Scaling Roughness Redness and Cracks (SRRC) scale, and pruritus and/or insomnia. They applied the dermo-cosmetic product Medi-Secure Atoderm Xereane (NAOS, Laboratoire Bioderma) once or twice a day. The clinical efficacy (SRRC, pruritus, and insomnia), the skin-related quality of life (Dermatological Life Quality Index, DLQI), and the subjective efficacy were assessed at the inclusion visit and after 28 days of product application, as well as the safety. Results: After 28 days of application, the product significantly reduced the SRRC global score of 83% (0.9±0.8 vs 5.1±1.2) and 66% (1.4±1.2 vs 4.2±0.5), pruritus intensity of 76% (1.1±1.3 vs 4.6±2.1) and 78% (0.9±1.7 vs 4.2±2.6), and insomnia intensity of 61% (0.9±1.3 vs 2.4±2.3) and 82% (0.9±1.7 vs 4.8±2.7) in dialysis and diabetic patients, respectively. Furthermore, the product's application led to an improvement of the skin-related quality of life of 50% (5.4 vs 2.7; p<0.0001) in dialysis patients and 71% (6.6 vs 1.9; p<0.0001) in diabetic patients at D28. In addition, the product was greatly appreciated by all patients for its soothing, comforting, repairing, nourishing, and hydrating effects and was very well tolerated by the entire panels. Conclusion: This specific dermo-cosmetic product significantly reduces skin dryness, pruritus, and insomnia in dialysis and diabetic patients, thereby greatly improves their skin-related quality of life. By managing and avoiding bothersome symptoms associated with their disease or treatment, this ecobiological dermo-cosmetic can prevent serious complications that constitute a substantial burden on their daily life.

Burden of Sensitive Skin (BoSS) Questionnaire and Current Perception Threshold: Use as Diagnostic Tools for Sensitive Skin Syndrome.

The assessment of sensitive skin syndrome, characterized by subjective unpleasant sensations, remains a challenge, since there is no international consensus on the best diagnostic tools. This study evaluated the combination of the Burden of Sensitive Skin (BoSS) questionnaire and the current perception threshold as diagnostic tools for sensitive skin syndrome, and the relationship between BoSS and the subjects' smoking status, phototype and skin type. A total of 100 women completed the BoSS questionnaire, and current perception threshold was measured on the face. The BoSS score was significantly higher in the self-reported sensitive skin group compared with the non-sensitive skin group (25.61 vs 14.05; p < 0.001), and in non-smokers vs smokers (23.00 vs 18.37; p < 0.05). In addition, the current perception threshold values were similar between the sensitive and non-sensitive groups. These results suggest that BoSS is a better diagnostic tool for sensitive skin syndrome than the current perception threshold, and that smokers less frequently have sensitive skin than do non-smokers.

A Biomimetic Lipid Membrane Device Reveals the Interaction of Cancer Biomarkers with Human Serum Lipidic Moieties.

A major problem for the detection of cancer biomarkers in plasma or serum is that common clinical practice does not require the patient to be in a fasting state. Considering that lipoproteins are the main population affected by food intake, the authors hypothesized that biomarkers could be embedded in lipid particles and thereby opens a new avenue for detection. Using the recently published biomarker, soluble VE-cadherin (sVE), the authors tested our hypothesis using techniques of biophysics, biochemistry and the tools of nanobiotechnology on serum samples from kidney cancer patients (n = 106). Optical density as well as contact angle measurements of serum revealed heterogeneity in the particle content of the serum samples. Isolation of the lipidic moieties by ultracentrifugation showed that sVE was detected in this compartment. Further, isolation of lipoprotein subclasses by precipitation with sodium phosphotungstate and MgCl2 , showed that HDL carried the majority of sVE. Immunoprecipitation of sVE confirmed that it was associated with Apolipoprotein A1, a major compound of HDL. Using a biomimetic lipid bilayer membrane coupled with impedance spectroscopy the authors quantified, in real-time, that the sVE adsorbed to the lipid bilayer membrane without altering its structure. Taken together, these results show for the first time a direct interaction of a cancer biomarker with lipids. The authors anticipate these results to prompt fasting for future blood tests for large-scale studies in the biomarkers research field.

The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma.

BACKGROUND: Vascular endothelial (VE)-cadherin is an endothelial cell-specific protein responsible for endothelium integrity. Its adhesive properties are regulated by post-translational processing, such as tyrosine phosphorylation at site Y685 in its cytoplasmic domain, and cleavage of its extracellular domain (sVE). In hormone-refractory metastatic breast cancer, we recently demonstrated that sVE levels correlate to poor survival. In the present study, we determine whether kidney cancer therapies had an effect on VE-cadherin structural modifications and their clinical interest to monitor patient outcome. METHODS: The effects of kidney cancer biotherapies were tested on an endothelial monolayer model mimicking the endothelium lining blood vessels and on a homotypic and heterotypic 3D cell model mimicking tumour growth. sVE was quantified by ELISA in renal cell carcinoma patients initiating sunitinib (48 patients) or bevacizumab (83 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials). RESULTS: Human VE-cadherin is a direct target for sunitinib which inhibits its VEGF-induced phosphorylation and cleavage on endothelial monolayer and endothelial cell migration in the 3D model. The tumour cell environment modulates VE-cadherin functions through MMPs and VEGF. We demonstrate the presence of soluble VE-cadherin in the sera of mRCC patients (n = 131) which level at baseline, is higher than in a healthy donor group (n = 96). Analysis of sVE level after 4 weeks of treatment showed that a decrease in sVE level discriminates the responders vs. non-responders to sunitinib, but not bevacizumab. CONCLUSIONS: These data highlight the interest for the sVE bioassay in future follow-up of cancer patients treated with targeted therapies such as tyrosine-kinase inhibitors.

Soluble VE-cadherin in metastatic breast cancer: an independent prognostic factor for both progression-free survival and overall survival.

BACKGROUND: Patients with metastatic breast cancer (MBC) represent a heterogeneous group, with large differences in outcomes from individual patients. VE-cadherin, an endothelial-specific cadherin, was shown to promote tumour proliferation and angiogenesis. Soluble VE-cadherin has been recently associated to breast cancer progression. This study was designed to investigate the prognosis significance of soluble VE-cadherin in hormone-refractory MBC. METHODS: Between 2004 and 2007, 150 patients with a fully documented history of hormone-refractory MBC were included in the prospective SEMTOF study. Serum concentrations of VE-cadherin were measured at inclusion for 141 patients and 6 weeks after the beginning of chemotherapy, using a sandwich enzyme immunoassay. RESULTS: The presence of high levels of serum VE-cadherin was significantly correlated to a shorter progression-free (PFS) and overall survival (OS). In a multivariate analysis along with clinical and biologic prognostic parameters, high serum VE-cadherin level was an independent adverse prognostic variable for PFS (median PFS 9.7 (IC95: 8; 11.9) vs 5.8 (IC95: 4.1; 8) months P=0.0008) and OS (median OS 34 (IC95: 26.6; 47.1) vs 14.8 (IC95: 9.3; 21.4) months P=0.0007). Moreover, VE-cadherin decrease during chemotherapy was also associated with good prognosis. CONCLUSIONS: Serum VE-cadherin levels correlate to poorer survival in patients with hormone-refractory MBC. As sVE-cadherin reflects tumour angiogenesis, this could have therapeutic implications for antiangiogenic treatment.

Soluble vascular endothelial (VE) cadherin and autoantibodies to VE-cadherin in rheumatoid arthritis patients treated with etanercept or adalimumab.

OBJECTIVES: The aim of this study was to investigate the clinical value of sVE and anti-vascular endothelial-cadherin antibodies (AAVE) in RA treated with etanercept or adalimumab combined with methotrexate. METHODS: This was an 18-month prospective multicenter study in which patients had active RA, requiring TNF antagonist. sVE rates and AAVE titers were measured respectively by dot blot and ELISA. The relationship of these biomarkers with parameters reflecting articular or systemic disease activity, progression of structural damage, and response or remission to treatment was analyzed. RESULTS: Forty-eight patients received TNF blocking agents. Variation of sVE rates were significantly correlated with that of C-reactive protein (CRP) levels at weeks 6, 12, 26 and 52. A significant decrease in sVE levels was observed in the group of patients exhibiting a decrease in CRP levels as compared to the patient group with unmodified CRP. AAVE at baseline were correlated with rheumatoid factor. Kinetics analysis of sVE levels and AAVE titers showed that their level were not associated with disease activity score and to methotrexate/adalimumab or etanercept response. CONCLUSIONS: sVE is a biomarker associated with systemic RA activity under anti-TNF. AAVE are related to autoantibodies usually associated to RA.

Mycobacterium tuberculosis exploits the formation of new blood vessels for its dissemination.

The mechanisms by which the airborne pathogen Mycobacterium tuberculosis spreads within the lung and leaves its primary niche to colonize other organs, thus inducing extrapulmonary forms of tuberculosis (TB) in humans, remains poorly understood. Herein, we used a transcriptomic approach to investigate the host cell gene expression profile in M. tuberculosis-infected human macrophages (ΜΦ). We identified 33 genes, encoding proteins involved in angiogenesis, for which the expression was significantly modified during infection, and we show that the potent angiogenic factor VEGF is secreted by M. tuberculosis-infected ΜΦ, in an RD1-dependent manner. In vivo these factors promote the formation of blood vessels in murine models of the disease. Inhibiting angiogenesis, via VEGF inactivation, abolished mycobacterial spread from the infection site. In accordance with our in vitro and in vivo results, we show that the level of VEGF in TB patients is elevated and that endothelial progenitor cells are mobilized from the bone marrow. These results strongly strengthen the most recent data suggesting that mycobacteria take advantage of the formation of new blood vessels to disseminate.

Soluble vascular endothelial-cadherin and auto-antibodies to human vascular endothelial-cadherin in human diseases: Two new biomarkers of endothelial dysfunction.

Vascular endothelial-cadherin is the most important transmembrane component of endothelial adherens junctions, exclusively expressed by endothelial cells in all types of vessels. Targeting either the extracellular domain or the cytoplasmic tail deleteriously affects the junctional strength and leads to vascular permeability. Recently, cytokine-induced phosphorylation of the vascular endothelial-cadherin cytoplasmic domain was reported to trigger cleavage of its extracellular domain, producing the soluble form of the protein - soluble vascular endothelial-cadherin. Hence, the presence of soluble vascular endothelial-cadherin or auto-antibodies to human vascular endothelial-cadherin in human serum could signalize the presence of vascular abnormalities. This systematic review covers many human studies reporting increased levels of soluble vascular endothelial-cadherin, as well as auto-antibodies to human vascular endothelial-cadherin, which could be promising biomarkers of endothelial dysfunction in a large panel of diseases.

Dynamic phosphorylation of VE-cadherin Y685 throughout mouse estrous cycle in ovary and uterus.

We previously reported that vascular endothelial growth factor induced vascular endothelial (VE)-cadherin tyrosine phosphorylation at Y685 in a Src-dependent manner in vitro. Here, we studied the occurrence of Y685 phosphorylation in vivo in the female reproductive tract because it is a unique model of physiological vascular remodeling dependent on vascular endothelial growth factor. We first developed and characterized an anti-phospho-specific antibody against the site Y685 of VE-cadherin to monitor VE-cadherin phosphorylation along the four phases of mouse estrous cycle, termed proestrus, estrus, metestrus, and diestrus. A dynamic profile of tyrosine phosphorylated proteins was observed in both uterus and ovary throughout mouse estrous cycle, including kinase Src, which was found highly active at the estrus phase. The extent of tyrosine phosphorylated VE-cadherin was low at proestrus but strongly increased at estrus and returned to baseline at metestrus and diestrus, suggesting a potent hormonal regulation of this specific process. Indeed, C57Bl/6 female mice treatment with pregnant mare serum gonadotropin and human chorionic gonadotropin confirmed a significant increase in phosphoY685-VE-cadherin compared with that in untreated mice. These results demonstrate that VE-cadherin tyrosine phosphorylation at Y685 is a physiological and hormonally regulated process in female reproductive organs. In addition, this process was concomitant with the early steps of vascular remodeling taking place at estrus stage, suggesting that phosphoY685-VE-cadherin is a biomarker of endothelial cell activation in vivo.

VE-cadherin Y685F knock-in mouse is sensitive to vascular permeability in recurrent angiogenic organs.

Covalent modifications such as tyrosine phosphorylation are associated with the breakdown of endothelial cell junctions and increased vascular permeability. We previously showed that vascular endothelial (VE)-cadherin was tyrosine phosphorylated in vivo in the mouse reproductive tract and that Y685 was a target site for Src in response to vascular endothelial growth factor in vitro. In the present study, we aimed to understand the implication of VE-cadherin phosphorylation at site Y685 in cyclic angiogenic organs. To achieve this aim, we generated a knock-in mouse carrying a tyrosine-to-phenylalanine point mutation of VE-cadherin Y685 (VE-Y685F). Although homozygous VE-Y685F mice were viable and fertile, the nulliparous knock-in female mice exhibited enlarged uteri with edema. This phenotype was observed in 30% of females between 4 to 14 mo old. Histological examination of longitudinal sections of the VE-Y685F uterus showed an extensive disorganization of myometrium and endometrium with highly edematous uterine glands, numerous areas with sparse cells, and increased accumulation of collagen fibers around blood vessels, indicating a fibrotic state. Analysis of cross section of ovaries showed the appearance of spontaneous cysts, which suggested increased vascular hyperpermeability. Electron microscopy analysis of capillaries in the ovary showed a slight but significant increase in the gap size between two adjacent endothelial cell membranes in the junctions of VE-Y685F mice (wild-type, 11.5 ± 0.3, n = 78; and VE-Y685F, 12.48 ± 0.3, n = 65; P = 0.045), as well as collagen fiber accumulation around capillaries. Miles assay revealed that either basal or vascular endothelial growth factor-stimulated permeability in the skin was increased in VE-Y685F mice. Since edema and fibrotic appearance have been identified as hallmarks of initial increased vascular permeability, we conclude that the site Y685 in VE-cadherin is involved in the physiological regulation of capillary permeability. Furthermore, this knock-in mouse model is of potential interest for further studies of diseases that are associated with abnormal vascular permeability.

Evidence for post-translational processing of vascular endothelial (VE)-cadherin in brain tumors: towards a candidate biomarker.

Vessel abnormalities are among the most important features in malignant glioma. Vascular endothelial (VE)-cadherin is of major importance for vascular integrity. Upon cytokine challenge, VE-cadherin structural modifications have been described including tyrosine phosphorylation and cleavage. The goal of this study was to examine whether these events occurred in human glioma vessels. We demonstrated that VE-cadherin is highly expressed in human glioma tissue and tyrosine phosphorylated at site Y(685), a site previously found phosphorylated upon VEGF challenge, via Src activation. In vitro experiments showed that VEGF-induced VE-cadherin phosphorylation, preceded the cleavage of its extracellular adhesive domain (sVE, 90 kDa). Interestingly, metalloproteases (MMPs) secreted by glioma cell lines were responsible for sVE release. Because VEGF and MMPs are important components of tumor microenvironment, we hypothesized that VE-cadherin proteolysis might occur in human brain tumors. Analysis of glioma patient sera prior treatment confirmed the presence of sVE in bloodstream. Furthermore, sVE levels studied in a cohort of 53 glioma patients were significantly predictive of the overall survival at three years (HR 0.13 [0.04; 0.40] p ≤ 0.001), irrespective to histopathological grade of tumors. Altogether, these results suggest that VE-cadherin structural modifications should be examined as candidate biomarkers of tumor vessel abnormalities, with promising applications in oncology.

UGT1A1, UGT1A6 and UGT1A7 genetic analysis: repercussion for irinotecan pharmacogenetics in the São Miguel Island Population (Azores, Portugal).

BACKGROUND: Glucuronidation reactions, catalyzed by uridine-diphosphate glucuronosyltransferase (UGT) enzymes, constitute a detoxification process that adds glucuronic acid to endogenous and exogenous compounds, aiding their excretion. UGT1A proteins have been implicated as risk factors for both the development of cancer and adverse drug effects. METHODS: Here, we assess the genome of 469 individuals from São Miguel Island (Azores, Portugal) in order to determine the frequencies of polymorphisms and haplotypes in UGT1A1, UGT1A6, and UGT1A7, the co-occurrence of reduced enzyme activity UGT1A variants related to irinotecan toxicity, and to calculate the extent of linkage disequilibrium (LD) in the genomic region encompassing these genes. RESULTS: Allelic analysis disclosed the presence of rare alleles - UGT1A1*36 and UGT1A1*37--only found in individuals of African descent, and UGT1A7*4. These alleles confirm our previous results on the São Miguel Island genetic background. We identified five different genotypes in UGT1A1 and UGT1A6 and nine in UGT1A7. Haplotype analysis showed that three haplotypes constituted approximately 80% of the allelic variants. Interestingly, haplotype 3 (UGT1A1*28-UGT1A6*2-UGT1A7*3), with a frequency of 0.235, gathers the three alleles encoding the low-function UGT isoforms. Additionally, LD indicates a strong interaction between functional polymorphisms related to the alteration of the UGT enzyme activity. CONCLUSIONS: In summary, the results demonstrate a high variability of alleles and haplotypes, which have important roles in modifying expression and activity of UGTs. The data presented here could improve the understanding of the predisposition to cancers and susceptibility to the adverse effects of irinotecan in the São Miguel Island population.