Role of particle coating in controlling skin damage photoinduced by titania nanoparticles

TiO₂ nanoparticles hazard is associated to their photocatalytic activity causing release of DNA damaging ROS (Reactive Oxygen Species), lipid peroxidation and skin damage. Various coatings have been proposed to minimize photocatalysis, while keeping the potential to block UV radiations. Uncoated and variously coated commercial nano-titania have been classified on the basis of UVB-induced lipoperoxidation of linoleic acid. A selection of the most and the least protective specimens was then examined by ESR (Electron Spin Resonance) to evidence the presence of surface paramagnetic centres and the release of ROS in aqueous suspensions (spin trapping). Paramagnetic centres and ROS were correlated with the extent of lipid peroxidation. When tested on porcine skin (mimicking the human one), titania acted as on linoleic acid. The combined use of lipid peroxidation of simple fatty acids with ESR analysis is here proposed as a possible screening tool for the evaluation of the potential toxicity of nano-titania in sunscreen preparations.     

Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer

Emerging evidence suggests that metformin, a widely used anti-diabetic drug, may be useful in the prevention and treatment of different cancers. In the present study, we demonstrate that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231). The inhibition is selective for these isoforms, as documented by experiments with purified HK I and II as well as with cell lysates. Measurements of ¹⁸F-fluoro-deoxyglycose uptake document that it is dose- and time-dependent and powerful enough to virtually abolish glucose consumption despite unchanged availability of membrane glucose transporters. The profound energetic imbalance activates phosphorylation and is subsequently followed by cell death. More importantly, the “in vivo” relevance of this effect is confirmed by studies of orthotopic xenografts of MDA-MB-231 cells in athymic (nu/nu) mice. Administration of high drug doses after tumor development caused an evident tumor necrosis in a time as short as 48 h. On the other hand, 1 mo metformin treatment markedly reduced cancer glucose consumption and growth. Taken together, our results strongly suggest that HK inhibition contributes to metformin therapeutic and preventive potential in breast cancer.     

Mesenchymal-to-Endothelial Transition in Kaposi Sarcoma: A Histogenetic Hypothesis Based on a Case Series and Literature Review

Objectives

Although several studies have been conducted regarding Kaposi sarcoma (KS), its histogenesis still remains to be elucidated. The aim of our study was to analyze the immunophenotype of Kaposi sarcoma and to present a hypothesis about the histogenesis of this tumor, based on a case series and a review of relevant literature.

Methods

In 15 cases of KSs diagnosed during 2000–2011, the clinicopathological features were correlated with the immunoexpression of c-Kit, SMA, CD34, CD31, vascular endothelial growth factor (VEGF), COX-2, c-KIT, smooth muscle antigen (SMA), and stem cell surface marker CD105.

Results

Both CD105 and c-KIT rate of the spindle-shaped tumor cell positivity increased in parallel to the pathological stage. All cases displayed CD105 and weak c-KIT positivity in the endothelial cells. SMA, VEGF, and COX-2 were focally expressed in all cases. CD34 marked both endothelium and spindle-shaped tumor cells. No c-KIT expression was noticed in KS of the internal organs.

Conclusions

KS seems to be a variant of myofibroblastic tumors that originates from the viral modified pluripotent mesenchymal cells of the connective tissue transformed in spindle-shaped KS cells, followed by a mesenchymal-endothelial transition and a myofibroblastic-like differentiation. This paper mailnly showed that KS cannot be considered a pure vascular tumor.     

Climate Change and Human Disturbance Can Lead to Local Extinction of Alpine Rock Ptarmigan: New Insight from the Western Italian Alps

Alpine grouses are particularly vulnerable to climate change due to their adaptation to extreme conditions and to their relict distributions in the Alps where global warming has been particularly marked in the last half century. Grouses are also currently threatened by habitat modification and human disturbance, and an assessment of the impact of multiple stressors is needed to predict the fate of Alpine populations of these birds in the next decades. We estimated the effect of climate change and human disturbance on a rock ptarmigan population living in the western Italian Alps by combining an empirical population modelling approach and stochastic simulations of the population dynamics under the a1B climate scenario and two different disturbance scenarios, represented by the development of a ski resort, through 2050.The early appearance of snow-free ground in the previous spring had a favorable effect on the rock ptarmigan population, probably through a higher reproductive success. On the contrary, delayed snowfall in autumn had a negative effect possibly due to a mismatch in time to molt to white winter plumage which increases predation risk. The regional climate model PROTHEUS does not foresee any significant change in snowmelt date in the study area, while the start date of continuous snow cover is expected to be significantly delayed. The net effect in the stochastic projections is a more or less pronounced (depending on the model used) decline in the studied population. The addition of extra-mortality due to collision with ski-lift wires led the population to fatal consequences in most projections. Should these results be confirmed by larger studies the conservation of Alpine populations would deserve more attention. To counterbalance the effects of climate change, the reduction of all causes of death should be pursued, through a strict preservation of the habitats in the present area of occurrence.     

The C. elegans DSB-2 Protein Reveals a Regulatory Network that Controls Competence for Meiotic DSB Formation and Promotes Crossover Assurance

For most organisms, chromosome segregation during meiosis relies on deliberate induction of DNA double-strand breaks (DSBs) and repair of a subset of these DSBs as inter-homolog crossovers (COs). However, timing and levels of DSB formation must be tightly controlled to avoid jeopardizing genome integrity. Here we identify the DSB-2 protein, which is required for efficient DSB formation during C. elegans meiosis but is dispensable for later steps of meiotic recombination. DSB-2 localizes to chromatin during the time of DSB formation, and its disappearance coincides with a decline in RAD-51 foci marking early recombination intermediates and precedes appearance of COSA-1 foci marking CO-designated sites. These and other data suggest that DSB-2 and its paralog DSB-1 promote competence for DSB formation. Further, immunofluorescence analyses of wild-type gonads and various meiotic mutants reveal that association of DSB-2 with chromatin is coordinated with multiple distinct aspects of the meiotic program, including the phosphorylation state of nuclear envelope protein SUN-1 and dependence on RAD-50 to load the RAD-51 recombinase at DSB sites. Moreover, association of DSB-2 with chromatin is prolonged in mutants impaired for either DSB formation or formation of downstream CO intermediates. These and other data suggest that association of DSB-2 with chromatin is an indicator of competence for DSB formation, and that cells respond to a deficit of CO-competent recombination intermediates by prolonging the DSB-competent state. In the context of this model, we propose that formation of sufficient CO-competent intermediates engages a negative feedback response that leads to cessation of DSB formation as part of a major coordinated transition in meiotic prophase progression. The proposed negative feedback regulation of DSB formation simultaneously (1) ensures that sufficient DSBs are made to guarantee CO formation and (2) prevents excessive DSB levels that could have deleterious effects.     

Fibroblast Growth Factor Receptor-2 Expression in Thyroid Tumor Progression: Potential Diagnostic Application

Fibroblast growth factor receptor-2 (FGFR-2) plays an important role in tumorigenesis. In thyroid cancer it has been observed a FGFR-2 down-modulation, but the role of this receptor has not been yet clarified. Therefore, we decided to examine the expression of both FGFR-2 isoform, FGFR-2-IIIb and FGFR-2-IIIc, in different histological thyroid variants such as hyperplasia, follicular adenoma and papillary carcinoma. Immunohistochemistry and quantitative Real-Time PCR analyses were performed on samples of hyperplasia, follicular adenoma and papillary carcinoma, compared with normal thyroid tissue. Thyroid hyperplasia did not show statistically significant reduction in FGFR-2 protein and mRNA levels. Interestingly, in both follicular adenoma and papillary carcinoma samples we observed a strongly reduced expression of both FGFR-2 isoforms. We speculate that FGFR-2 down-modulation might be an early event in thyroid carcinogenesis. Furthermore, we suggest the potential use of FGFR-2 as an early marker for thyroid cancer diagnosis.     

Decreased Insulin Clearance in Individuals with Elevated 1-h Post-Load Plasma Glucose Levels

Reduced insulin clearance has been shown to predict the development of type 2 diabetes. Recently, it has been suggested that plasma glucose concentrations ≥8.6 mmol/l (155 mg/dl) at 1 h during an oral glucose tolerance test (OGTT) can identify individuals at high risk for type 2 diabetes among those who have normal glucose tolerance (NGT 1 h-high). The aim of this study was to examine whether NGT 1 h-high have a decrease in insulin clearance, as compared with NGT individuals with 1-h post-load glucose <8.6 mmol/l (l (155 mg/dl, NGT 1 h-low). To this end, 438 non-diabetic White individuals were subjected to OGTT and euglycemic-hyperinsulinemic clamp to evaluate insulin clearance and insulin sensitivity. As compared with NGT 1 h-low individuals, NGT 1 h-high had significantly higher 1-h and 2-h post-load plasma glucose and 2-h insulin levels as well as higher fasting glucose and insulin levels. NGT 1 h-high exhibited also a significant decrease in both insulin sensitivity (P<0.0001) and insulin clearance (P = 0.006) after adjusting for age, gender, adiposity measures, and insulin sensitivity. The differences in insulin clearance remained significant after adjustment for fasting glucose (P = 0.02) in addition to gender, age, and BMI. In univariate analyses adjusted for gender and age, insulin clearance was inversely correlated with body weight, body mass index, waist, fat mass, 1-h and 2-h post-load glucose levels, fasting, 1-h and 2-h post-load insulin levels, and insulin-stimulated glucose disposal. In conclusion, our data show that NGT 1 h-high have a reduction in insulin clearance as compared with NGT 1 h-low individuals; this suggests that impaired insulin clearance may contribute to sustained fasting and post-meal hyperinsulinemia.