The effect of lipoprotein-associated phospholipase A2 deficiency on pulmonary allergic responses in Aspergillus fumigatus sensitized mice.

BackgroundLipoprotein-associated phospholipase A2 (Lp-PLA2)/platelet-activating factor acetylhydrolase (PAF-AH) has been implicated in the pathogenesis of cardiovascular disease. A therapeutic targeting of this enzyme was challenged by the concern that increased circulating platelet activating factor (PAF) may predispose to or increase the severity of the allergic airway response. The aim of this study was to investigate whether Lp-PLA2 gene deficiency increases the risk of PAF and IgE-mediated inflammatory responses in vitro and in vivo using mouse models.MethodsLp-PLA2-/- mice were generated and back crossed to the C57BL/6 background. PAF-AH activity was measured using a hydrolysis assay in serum and bronchoalveolar lavage (BAL) samples obtained from mice. Aspergillus fumigatus (Af)-specific serum was prepared for passive allergic sensitization of mice in vivo and mast cells in vitro. β- hexosaminidase release was studied in bone marrow derived mast cells sensitized with Af-specific serum or DNP-IgE and challenged with Af or DNP, respectively. Mice were treated with lipopolysaccharide (LPS) and PAF intratracheally and studied 24 hours later. Mice were sensitized either passively or actively against Af and were studied 48 hours after a single intranasal Af challenge. Airway responsiveness to methacholine, inflammatory cell influx in the lung tissue and BAL, immunoglobulin (ELISA) and cytokine (Luminex) profiles were compared between the wild type (WT) and Lp-PLA2-/- mice.ResultsPAF-AH activity was reduced but not completely abolished in Lp-PLA2-/- serum or by in vitro treatment of serum samples with a high saturating concentration of the selective Lp-PLA2 inhibitor, SB-435495. PAF inhalation significantly enhanced airway inflammation of LPS treated WT and Lp-PLA2-/- mice to a similar extent. Sensitized WT and Lp-PLA2-/- bone-marrow derived mast cells released β-hexosaminidase following stimulation by allergen or IgE crosslinking to equivalent levels. Wild type and Lp-PLA2-/- mice responded to passive or active allergic sensitization by significant IgE production, airway inflammation and hyperresponsiveness after Af challenge. BAL cell influx was not different between these strains while IL-4, IL-5, IL-6 and eotaxin release was attenuated in Lp-PLA2-/- mice. There were no differences in the amount of total IgE levels in the Af sensitized WT and Lp-PLA2-/- mice.ConclusionsWe conclude that Lp-PLA2 deficiency in C57BL/6 mice did not result in a heightened airway inflammation or hyperresponsiveness after PAF/LPS treatment or passive or active allergic sensitization and challenge

Multiple primary melanomas: Is there a correlation between dermoscopic features and germline mutations?

No abstract availabl

An Ulcerated Reddish Nodule of the Chest: When You See, Think …

A 97-year-old man with a previous personal history of multiple nonmelanoma skin cancers presented with a fast-growing, ulcerated reddish nodule on his chest. The nodule was surgically removed, and hematoxylin and eosin stains of the specimen showed an asymmetrical, nonpigmented lesion with architectural and structural impairment, round cells with clear, whitish, foamy cytoplasm, multiple dermal mitoses and nuclear pleomorphism. Our first hypothesis was sebaceous carcinoma, a rare malignant neoplasm derived from epithelial cells showing sebaceous differentiation. A further histopathologic examination showed the presence of pigment in a few areas of the neoplasm. On immunohistochemical study, neoplastic cells were negative for wide-spectrum cytokeratin and diffusely positive for S-100, MART-1, and HMB-45 proteins. Our final diagnosis was nodular malignant melanoma (MM) with balloon epithelioid cells, a “bizarre” presentation of MM in vertical growth phase, mimicking metastatic and primary neoplasms of different lineage derivations

Evaluation of DNA Methylation Profiles of LINE-1, Alu and Ribosomal DNA Repeats in Human Cell Lines Exposed to Radiofrequency Radiation

A large body of evidence indicates that environmental agents can induce alterations in DNA methylation (DNAm) profiles. Radiofrequency electromagnetic fields (RF-EMFs) are radiations emitted by everyday devices, which have been classified as "possibly carcinogenic"; however, their biological effects are unclear. As aberrant DNAm of genomic repetitive elements (REs) may promote genomic instability, here, we sought to determine whether exposure to RF-EMFs could affect DNAm of different classes of REs, such as long interspersed nuclear elements-1 (LINE-1), Alu short interspersed nuclear elements and ribosomal repeats. To this purpose, we analysed DNAm profiles of cervical cancer and neuroblastoma cell lines (HeLa, BE(2)C and SH-SY5Y) exposed to 900 MHz GSM-modulated RF-EMF through an Illumina-based targeted deep bisulfite sequencing approach. Our findings showed that radiofrequency exposure did not affect the DNAm of Alu elements in any of the cell lines analysed. Conversely, it influenced DNAm of LINE-1 and ribosomal repeats in terms of both average profiles and organisation of methylated and unmethylated CpG sites, in different ways in each of the three cell lines studied

Neoplastic Leg Ulcers

Skin biopsy is an important procedure for a correct diagnosis of varying skin conditions, from inflammatory to neoplastic diseases. Nevertheless, some authors still consider this procedure a high risk in patients affected by leg ulcers (LUs) and prefer reserving it for selected cases

Quadrato Motor Training (QMT) is associated with DNA methylation changes at DNA repeats: A pilot study

The control of non-coding repeated DNA by DNA methylation plays an important role in genomic stability, contributing to health and healthy aging. Mind-body practices can elicit psychophysical wellbeing via epigenetic mechanisms, including DNA methylation. However, in this context the effects of movement meditations have rarely been examined. Consequently, the current study investigates the effects of a specifically structured movement meditation, called the Quadrato Motor Training (QMT) on psychophysical wellbeing and on the methylation level of repeated sequences. An 8-week daily QMT program was administered to healthy women aged 40-60 years and compared with a passive control group matched for gender and age. Psychological well-being was assessed within both groups by using self-reporting scales, including the Meaning in Life Questionnaire [MLQ] and Psychological Wellbeing Scale [PWB]). DNA methylation profiles of repeated sequences (ribosomal DNA, LINE-1 and Alu) were determined in saliva samples by deep-sequencing. In contrast to controls, the QMT group exhibited increased Search for Meaning, decreased Presence of Meaning and increased Positive Relations, suggesting that QMT may lessen the automatic patterns of thinking. In the QMT group, we also found site-specific significant methylation variations in ribosomal DNA and LINE-1 repeats, consistent with increased genome stability. Finally, the correlations found between changes in methylation and psychometric indices (MLQ and PWB) suggest that the observed epigenetic and psychological changes are interrelated. Collectively, the current results indicate that QMT may improve psychophysical health trajectories by influencing the DNA methylation of specific repetitive sequences

Age-related DNA methylation changes are sex-specific: a comprehensive assessment

The existence of a sex gap in human health and longevity has been widely documented. Autosomal DNA methylation differences between males and females have been reported, but so far few studies have investigated if DNA methylation is differently affected by aging in males and females. We performed a meta-analysis of 4 large whole blood datasets, comparing 4 aspects of epigenetic age-dependent remodeling between the two sexes: differential methylation, variability, epimutations and entropy. We reported that a large fraction (43%) of sex-associated probes undergoes age-associated DNA methylation changes, and that a limited number of probes show age-by-sex interaction. We experimentally validated 2 regions mapping in FIGN and PRR4 genes and showed sex-specific deviations of their methylation patterns in models of decelerated (centenarians) and accelerated (Down syndrome) aging. While we did not find sex differences in the age-associated increase in epimutations and entropy, we showed that the number of probes having an age-related increase in methylation variability is 15 times higher in males compared to females. Our results can offer new epigenetic tools to study the interaction between aging and sex and can pave the way to the identification of molecular triggers of sex differences in longevity and age-related diseases prevalence

Could Inflammatory Indices and Metabolic Syndrome Predict the Risk of Cancer Development? Analysis from the Bagnacavallo Population Study

Background: Despite the robust data available on inflammatory indices (neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)) and clinical outcome in oncological patients, their utility as a predictor of cancer incidence in the general population has not been reported in literature. Methods: The Bagnacavallo study was performed between October 2005 and March 2009. All citizens of Bagnacavallo (Ravenna, Emilia-Romagna, Italy) aged 30-60 years as of January 2005 were eligible and were invited by written letter to participate to the study. All participants underwent a detailed clinical history and physical examination following the model of the Dionysos Study. All blood values included in the analysis were obtained the day of physical examination. Cancer incidence data were obtained from the population-based Romagna Cancer Registry, which operates according to standard methods. The aim of this analysis was to examine the association between metabolic syndrome and baseline SII, NLR, and PLR levels, and the diagnosis of an invasive cancer in the Bagnacavallo study cohort. Results: At univariate analysis, metabolic syndrome was not associated with an increase of cancer incidence (HR 1.30; p = 0.155). High glucose (HR 1.49; p = 0.0.16), NLR HR 1.54, p = 0.002), PLR (HR 1.58, p = 0.001), and SII (HR 1.47, p = 0.006) were associated with an increase of cancer incidence. After adjusting for clinical covariates (smoking, physical activity, education, age, and gender) SII, PLR, and NLR remained independent prognostic factors for the prediction of cancer incidence. Conclusions: Inflammatory indices are promising, easy to perform, and inexpensive tools for identifying patients with higher risk of cancer in cancer-free population