Association Between Breastfeeding and the Development of Childhood Diabetes Mellitus Type I (DM I): The Effect of Prolonged Exclusive Breastfeeding on Gut Microbiome and the Link with DM I

The role of breastfeeding and dietary habits was studied in 10 children with DM I (case group) and compared with 10 healthy controls. Our results showed that the case group had significantly shorter exclusive breastfeeding duration compared with the control group (p = 0.006). An in silico comparative analysis of gut microbiota data from two recent studies was also performed in order to identify any specific bacterial genera potentially associated with DM I, due to prolonged breastfeeding. The Pasteurellaceae family, found in breast milk, was shown to have a significantly higher population in the intestine in the control group (p = 0.010). Overall, this preliminary study showed that exclusive breastfeeding duration is strongly associated with DM I. An association between breast milk microbiome and gut microbiome was also observed. This should encourage further research, aiming to examine both the effect of breastfeeding on gut microbiome and the possible links with DM I

Progression of mouse skin carcinogenesis is associated with increased ERα levels and is repressed by a dominant negative form of ERα.

Estrogen receptors (ER), namely ERα and ERβ, are hormone-activated transcription factors with an important role in carcinogenesis. In the present study, we aimed at elucidating the implication of ERα in skin cancer, using chemically-induced mouse skin tumours, as well as cell lines representing distinct stages of mouse skin oncogenesis. First, using immunohistochemical staining we showed that ERα is markedly increased in aggressive mouse skin tumours in vivo as compared to the papilloma tumours, whereas ERβ levels are low and become even lower in the aggressive spindle tumours of carcinogen-treated mice. Then, using the multistage mouse skin carcinogenesis model, we showed that ERα gradually increases during promotion and progression stages of mouse skin carcinogenesis, peaking at the most aggressive stage, whereas ERβ levels only slightly change throughout skin carcinogenesis. Stable transfection of the aggressive, spindle CarB cells with a dominant negative form of ERα (dnERα) resulted in reduced ERα levels and reduced binding to estrogen responsive elements (ERE)-containing sequences. We characterized two highly conserved EREs on the mouse ERα promoter through which dnERα decreased endogenous ERα levels. The dnERα-transfected CarB cells presented altered protein levels of cytoskeletal and cell adhesion molecules, slower growth rate and impaired anchorage-independent growth in vitro, whereas they gave smaller tumours with extended latency period of tumour onset in vivo. Our findings suggest an implication of ERα in the aggressiveness of spindle mouse skin cancer cells, possibly through regulation of genes affecting cell shape and adhesion, and they also provide hints for the effective targeting of spindle cancer cells by dnERα

Effect of chemical degradation followed by toothbrushing on the surface roughness of restorative composites

OBJECTIVES: The aim of the present study was to assess the effect of the exposure to food-simulating liquids prior to brushing simulation on the surface roughness of five composite materials (Quixfil, Filtek Supreme, Esthet-X, Filtek Z250, Tetric Ceram). MATERIAL AND METHODS: Twenty cylinders (5 mm diameter and 4 mm height) of each composite were randomly allocated to 4 groups (n=5), according to the food-simulating liquid in which they were immersed for 7 days at 37ºC: artificial saliva, heptane, citric acid, and ethanol. After this period, the top surface of composite cylinders was submitted to 7,500 brushing cycles (200 g load). Measurements of the surface roughness (Ra, µm) were carried out before and after the exposure to the chemicals/brushing simulation. Changes on the morphology of composite surfaces were observed through scanning electron microscopy (SEM). RESULTS: The statistical analysis (ANOVA with cofactor / Tukey's test, α=5%) detected a significant interaction between solutions and composite resins. Esthet-X, Filtek Z250 and Tetric Ceram were not affected by the food-simulating liquids/toothbrushing. Citric acid and ethanol increased the surface roughness of Quixfil and Filtek Supreme, respectively. SEM images corroborate the surface roughness findings, demonstrating the negative effect from chemical solutions and mechanical abrasion. CONCLUSIONS: The surface roughness of composite resin materials are differently affected by the food-simulating solutions, depending on the immersion media

Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins

The Cdc6 replication licensing factor acts as a molecular switch at the E-cadherin locus, leading to E-cadherin transcriptional repression and local activation of replication

Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing

The cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4–CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery—an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs

Study of deregulated activating mechanisms of hCdt1 and hCdc6 during genome replication in cancer cell line systems

The accurate execution of DNA replication requires a strict control of the replication licensing factors hCdt1 and hCdc6. The role of these key replication molecules in carcinogenesis has not been clarified. To examine how early during cancer development deregulation of these factors occurs, we investigated their status in epithelial lesions covering progressive stages of hyperplasia, dysplasia, and full malignancy, mostly from the same patients. Abnormal accumulation of both proteins occurred early from the stage of dysplasia. A frequent cause of unregulated hCdc6 and hCdt1 expression was gene amplification, suggesting that these components can play a role per se in cancer development. Overexpression of hCdt1 and hCdc6 promoted rereplication and generated a DNA damage response, which activated the antitumor barriers of senescence and apoptosis. Generating an inducible hCdt1 cellular system, we observed that continuous stimulus by deregulated hCdt1 led to abrogation of the antitumor barriers and resulted in the selection of clones with more aggressive properties. In addition, stable expression of hCdc6 and hCdt1 inpremalignant papilloma cells led to transformation of the cells that produced tumors upon injection into nude mice depicting the oncogenic potential of their deregulation