Increased circulating PEDF and low sICAM-1 are associated with sickle cell retinopathy.

Sickle cell retinopathy (SCR) develops in up to 30% of sickle cell disease patients (SCD) during the second decade of life. Treatment for this affection remains palliative, so studies on its pathophysiology may contribute to the future development of novel therapies. SCR is more frequently observed in hemoglobin SC disease and derives from vaso-occlusion in the microvasculature of the retina leading to neovascularization and, eventually, to blindness. Circulating inflammatory cytokines, angiogenic factors, and their interaction may contribute to the pathophysiology of this complication. Angiopoietin (Ang)-1, Ang-2, soluble vascular cell adhesion molecule-1, intercellular adhesion molecule (ICAM)-1, E-selectin, P-selectin, IL1-ß, TNF-α, pigment epithelium derived factor (PEDF) and vascular endothelial growth factor plasmatic levels were determined in 37 SCD patients with retinopathy, 34 without retinopathy, and healthy controls. We observed that sICAM-1 is significantly decreased, whereas PEDF is elevated in HbSC patients with retinopathy (P=0.012 and P=0.031, respectively). Ang-1, Ang-2 and IL1-ß levels were elevated in SCD patients (P=0.001, P<0.001 and P=0.001, respectively), compared to controls, and HbSS patients presented higher levels of Ang-2 compared to HbSC (P<0.001). Our study supports the possible influence of sICAM-1 and PEDF on the pathophysiology of retinal neovascularization in SCD patients.

Formulation and evaluation on human skin of a water-in-oil emulsion containing Muscat hamburg black grape seed extract.

BACKGROUND: Vitis vinifera 'muscat hamburg' (Vitaceae) is a blue-black grape variety commonly found in Pakistan. It has been consumed and used in traditional medicine for centuries. Compared to other grapes, M. hamburg records one of the greatest amount of polyphenols and displays potent antioxidant activities, which make it a great candidate for its exploitation in the development of stable cream emulsions destined to improve the skin appearance. OBJECTIVE: Evaluate the effects of stable water-in-oil (W/O) emulsion containing 2% M. hamburg grape seed extract ('formulation') on human cheek skin in comparison with the placebo ('base'). METHODS: An occlusive patch test, containing either the formulation or the base, was topically tested for 8 weeks during a winter period in young adult and healthy Pakistani male volunteers. The subjects were instructed to use twice a day the base and the formulation on their right and left cheek skin, respectively. Non-invasive measurements on these skin areas were carried out every week to assess any effects produced on melanin, elasticity and sebum. Skin compatibility assay (Burchard test) was used to report any potential skin reactivity. ANOVA, paired sample t-test and LSD test were applied to determine the statistical data significance. RESULTS: Significant differences (P ≤ 0.05) were found between the placebo and the formulation in terms of their respective skin effects elicited on melanin, elasticity and sebum content. Nevertheless, placebo and formulation exerted similar effects on skin erythema and moisture contents. Importantly, no skin hypersensitivity cases were reported during the whole course of the study. CONCLUSION: The developed grape-based cream could be efficiently and safely applied to improve a number of skin conditions (e.g. hyper-pigmentation, premature ageing, acne).

Development of mitotane lipid nanocarriers and enantiomers: two-in-one solution to efficiently treat adreno-cortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with a poor prognosis. Treatment options for advanced ACC are limited. Indeed, radical tumor resection can lead to local or metastatic recurrence, and mitotane (Lysodren(®)), the only recognized adrenolytic drug, offers modest response rates, notably due to some of its physico-chemical and pharmacological properties (i.e. hydrophobicity, low bioavailability). Meantime, high cumulative doses of Lysodren(®) usually cause systemic toxicities. To reduce adverse health effects, the search of safe and efficient mitotane nano-formulations as well as the full characterization and testing of its enantiomers can represent valuable therapeutic options. Interestingly, recent investigations showed that solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) could considerably improve the efficacy of mitotane (i.e. enhanced solubility and bioavailability, progressive release of the loaded drug into blood and targeted tissues) as well as its safety (i.e. lower toxicity, higher biocompatibility). These two nano-carriers for mitotane delivery and targeting are of particular interest over other polymeric particles (i.e. low-cost, efficient and simple scaling to an industrial production level following green methods). Besides, emerging studies suggested that the S-(-)- mitotane is more potent than the R-(+)-mitotane for ACC treatment. Therefore, the production of pure and active S-(-)-mitotane might offer synergic or additive benefits for ACC patients when combined to solid lipid-based nanocarriers. In this review, we first provide an updated overview of the ACC disease before emphasizing on the promising mitotane drug nano-systems, as well as on the separation, purification and production of single mitotane enantiomer using state-of-art chromatographic-based methods.

Stem cells, melanoma and cancer stem cells: the good, the bad and the evil?

Most cancers contain morphologically heterogeneous populations of cells. While this observation may partly be explained by the coexistence of multiple genetic sub-clones arising through independent somatic mutations and/or as a result of differentiation processes in the tumor microenvironment, it also implies that the tumor may be formed from undifferentiated ''stem cell-like'' cells called ''cancer stem cells'' or ''cancer-initiating cells''. These cells are thought to constitute one or several rare subpopulations in a given tumor and would be strongly responsible for initiation of tumor development and growth as well as for metastasis and recurrence after cytoreductive therapy. However, while the concept of cancer stem cells has been first established for human myeloid leukemia in the 1960s, it has only much later been extended to other solid tumors such as breast or brain cancers and most recently to melanoma. Thus, it is presently unclear which role a sufficiently characterized population of melanoma stem cells plays in cancer promotion and progression. Here, we review the emerging melanoma stem cell model and discuss the biological and therapeutic implications of the model.

Identification of KIN (KIN17), a human gene encoding a nuclear DNA-binding protein, as a novel component of the TP53-independent response to ionizing radiation.

Ionizing radiation elicits a genetic response in human cells that allows cell survival. The human KIN (also known as KIN17) gene encodes a 45-kDa nuclear DNA-binding protein that participates in the response to UVC radiation and is immunologically related to the bacterial RecA protein. We report for the first time that ionizing radiation and bleomycin, a radiomimetic drug, which produce single- and double-strand breaks, increased expression of KIN in human cells established from tumors, including MeWo melanoma, MCF7 breast adenocarcinoma, and ATM+ GM3657 lymphoblast cells. KIN expression increased rapidly in a dose-dependent manner after irradiation. Under the same conditions, several genes controlled by TP53 were induced with kinetics similar to that of KIN. Using the CDKN1A gene as a marker of TP53 responsiveness, we analyzed the up-regulation of KIN and showed that is independent of the status of TP53 and ATM. In contrast, the presence of a dominant mutant for activating transcription factor 2 (ATF2) completely abolished the up-regulation of KIN. Our results suggest a role for ATF2 in the TP53-independent increase in KIN expression after gamma irradiation.