Epigenome chaos: Stochastic and deterministic dna methylation events drive cancer evolution

Cancer evolution is associated with genomic instability and epigenetic alterations, which contribute to the inter and intra tumor heterogeneity, making genetic markers not accurate to monitor tumor evolution. Epigenetic changes, aberrant DNA methylation and modifications of chromatin proteins, determine the “epigenome chaos”, which means that the changes of epigenetic traits are randomly generated, but strongly selected by deterministic events. Disordered changes of DNA methylation profiles are the hallmarks of all cancer types, but it is not clear if aberrant methylation is the cause or the consequence of cancer evolution. Critical points to address are the profound epigenetic intra-and inter-tumor heterogeneity and the nature of the heterogeneity of the methylation patterns in each single cell in the tumor population. To analyze the methylation heterogeneity of tumors, new technological and informatic tools have been developed. This review discusses the state of the art of DNA methylation analysis and new approaches to reduce or solve the complexity of methylated alleles in DNA or cell populations

The effect of vestibular stimulation on motor functions of children with cerebral palsy

Background: Cerebral palsy (CP) has been defined as a nonprogressive disease of movement and posture development. Physical therapy techniques use different forms of sensory stimulation to improve neuromotor development. Aim: The aim of this study was to assess the efficacy of a vestibular stimulation training in improving motor functions in cerebral palsy. Population: Fourteen children with CP were randomly separated into two different groups in a cross-over trial. Methods: Over a period of 10 weeks, each group performed 10 sessions of 50 min of neurodevelopmental treatment (NDT) and 10 sessions of vestibular training (VR). Children were evaluated with the Gross Motor Function Measurement-88 scale, the Goal Attainment Scale and the root mean square of head accelerations. Results: A significant improvement in the GAS-score (p =.003) was noted after NDT+VR. Conclusions: Vestibular stimulation integrated with NDT proved to be an effective complementary strategy for facilitating motor functioning

Goal-Oriented Scheduling in Sensor Networks With Application Timing Awareness

— Taking inspiration from linguistics, the communications theoretical community has recently shown a significant recent interest in pragmatic, or goal-oriented, communication. In this paper, we tackle the problem of pragmatic communication with multiple clients with different, and potentially conflicting, objectives. We capture the goal-oriented aspect through the metric of Value of Information (VoI), which considers the estimation of the remote process as well as the timing constraints. However, the most common definition of VoI is simply the Mean Square Error (MSE) of the whole system state, regardless of the relevance for a specific client. Our work aims to overcome this limitation by including different summary statistics, i.e., value functions of the state, for separate clients, and a diversified query process on the client side, expressed through the fact that different applications may request different functions of the process state at different times. A query-aware Deep Reinforcement Learning (DRL) solution based on statically defined VoI can outperform naive approaches by 15-20%

PATZ Attenuates the RNF4-mediated Enhancement of Androgen Receptor-dependent Transcription *

PATZ is a transcriptional repressor affecting the basal activity of different promoters, whereas RNF4 is a transcriptional activator. The association of PATZ with RNF4 switches the activation to repression of selected basal promoters. Because RNF4 interacts also with the androgen receptor (AR) functioning as a coactivator and, in turn, RNF4 associates with PATZ, we investigated whether PATZ functions as an AR coregulator. We demonstrate that PATZ does not influence directly the AR response but acts as an AR corepressor in the presence of RNF4. Such repression is not dependent on histone deacetylases. A mutant RNF4 that does not bind PATZ but enhances AR-dependent transcription is not influenced by PATZ, demonstrating that the repression by PATZ occurs only upon binding to RNF4. We also demonstrate that RNF4, AR, and PATZ belong to the same complex in vivo also in the presence of androgen, suggesting that repression is not mediated by the displacement of RNF4 from AR. Finally, we show that the repression of endogenous PATZ expression by antisense expression plasmids in LNCaP cells results in a stronger androgen response. Our findings demonstrate that PATZ is a novel AR coregulator that acts by modulating the effect of a coactivator. This could represent a novel and more general mechanism to finely tune the androgen response

Isolation of a SIR-like gene, SIR-T8, that is overexpressed in thyroid carcinoma cell lines and tissues

We used subtractive library screening to identify the changes that occur in gene expression during thyroid cell neoplastic transformation. Complementary DNA from normal thyroid cells (HTC 2) was subtracted from a complementary DNA library constructed from a human thyroid papillary carcinoma cell line. The library was screened for genes upregulated in human thyroid papillary carcinoma cell line cells, and several cDNA clones were isolated. One of these clones has a sirtuin core and high homology with the human silent information regulator protein family. This clone, designated ‘SIR-T8’, was overexpressed in human thyroid carcinoma cell lines and tissues, but not in adenomas. The human SIR-T8 protein has a molecular weight of 39 kDa and is primarily located in the cytoplasm under the nuclear membrane. The SIR-T8 gene is located on chromosome 17q25-1

Targeted DNA methylation by homology-directed repair in mammalian cells. Transcription reshapes methylation on the repaired gene.

We report that homology-directed repair of a DNA double-strand break within a single copy Green Fluorescent Protein (GFP) gene in HeLa cells alters the methylation pattern at the site of recombination. DNA methyl transferase (DNMT)1, DNMT3a and two proteins that regulate methylation, Np95 and GADD45A, are recruited to the site of repair and are responsible for selective methylation of the promoter-distal segment of the repaired DNA. The initial methylation pattern of the locus is modified in a transcription-dependent fashion during the 15\u201320 days following repair, at which time no further changes in the methylation pattern occur. The variation in DNA modification generates stable clones with wide ranges of GFP expression. Collectively, our data indicate that somatic DNA methylation follows homologous repair and is subjected to remodeling by local transcription in a discrete time window during and after the damage. We propose that DNA methylation of repaired genes represents a DNA damage code and is source of variation of gene expression

Measurement of the structural behaviour of a 3D airless wheel prototype by means of optical non-contact techniques

Additive Manufacturing (AM) is becoming a widely employed technique also in mass production. In this field, compliances with geometry and mechanical performance standards represent a crucial constrain. Since 3D printed products exhibit a mechanical behaviour that is difficult to predict and investigate due to the complex shape and the inaccuracy in reproducing nominal sizes, optical non-contact techniques are an appropriate candidate to solve these issues. In this paper, 2D digital image correlation and thermoelastic stress analysis are combined to map the stress and the strain performance of an airless wheel prototype. The innovative airless wheel samples are 3D-printed by fused deposition modelling and stereolithography in poly-lactic acid and photopolymer resin, respectively. The static mechanical behaviour for different wheel-ground contact configurations is analysed using the aforementioned non-contact techniques. Moreover, the wheel-ground contact pressure is mapped, and a parametric finite element model is developed. The results presented in the paper demonstrate that several factors have great influence on 3D printed airless wheels: a) the type of material used for manufacturing the specimen, b) the correct transfer of the force line (i.e., the loading system), c) the geometric complexity of the lattice structure of the airless wheel. The work confirms the effectiveness of the proposed non-contact measurement procedures for characterizing complex shaped prototypes manufactured using AM

Specific signatures of the gut microbiota and increased levels of butyrate in children treated with fermented cow's milk containing heat-killed Lactobacillus paracasei CBA L74

We recently demonstrated that cow's milk fermented with the probiotic L.paracasei CBA L74 (FM-CBAL74) reduces the incidence of respiratory and gastrointestinal tract infections in young children attending school. This effect apparently derives from a complex regulation of non-immune and immune protective mechanisms. We investigated wheter FM-CBAL74 could regulate gut microbiota composition and butyrate production.We randomly selected 20 healthy children (12-48 months) from the previous randomized controlled trial, before (t0) and after 3 months (t3) of dietary treatment with FM-CBAL74 (FM), or placebo (PL). Fecal microbiota was profiled using 16S rRNA gene amplicon sequencing and fecal butyrate concentration was also measured. Microbial alpha and beta-diversity were not significantly different between groups prior to treatment. FM-CBAL74 but not PL treatment increased the relative abundance of Lactobacillus. Individual Blautia, Roseburia and Faecalibacterium oligotypes were associated to FM-CBAL74 treatment and demonstrated correlative associations with immune biomarkers. Accordingly, PICRUSt analysis predicted an increase in the proportion of genes involved in butyrate production pathways, consistent with an increase in fecal butyrate observed only in the FM group. Dietary supplementation with FM-CBAL74 induces specific signatures in gut microbiota composition and stimulates butyrate production. These effects are associated with changes in innate and acquired immunity.Importance: The use of a fermented milk product containing the heat-killed probiotic strain L.paracasei CBAL74 induces changes in the gut microbiota, promoting the development of butyrate-producers. These changes in the gut microbiota composition correlate with increased levels of innate and acquired immunity biomarkers

Use of statins in lower extremity artery disease: a review

BACKGROUND: Lower extremity artery disease (LE-PAD) is one of the most common manifestations of atherosclerosis, particularly in elderly patients, and it is related to a high cardiovascular risk. DESCRIPTION: It is well established that statin therapy is characterized by crucial benefits on cardiovascular system by limiting atherosclerotic progression and reducing cardiovascular events and mortality. A growing body of evidence support efficacy of statins in LE-PAD due to the ability of both reducing cardiovascular risk and improving walking distance and, hence, quality of life. Consequently, statin therapy should be considered in all LE-PAD patients and new LDL-cholesterol targets should be reached. CONCLUSIONS: Our opinion is that statin therapy remains still underutilized or with inadequate dosage, so therapy of LE-PAD patients should be improved to obtain all the demonstrated benefits of statin

Towards a Comprehensive Asset Integrity Management (AIM) Approach for European Infrastructures

Abstract Transport infrastructure is the backbone of national economies, providing connections for people and goods, access to jobs and services, and enabling trade and economic growth. It is of paramount importance to preserve, maintain and upgrade the infrastructure network so that to sustain the economic growth and an intelligent mobility. Asset Integrity Management (AIM) approaches will therefore represent key tools for facing the infrastructure maintenance issue and for tackling the ageing that characterize already existing assets. This paper, starting from analyzing the current state of the art solutions in assets management (Enevoldsen, I., 2008), proposes a comprehensive AIM approach that aims at replacing current time-based approaches with a performance-based approach that can systematically take into account the dynamic nature of the transport network. This means moving from a deterministic to a probabilistic approach in design, rehabilitation and retrofitting of infrastructures for increasing life-time and reducing maintenance costs. Such approach therefore laid the basis of secure sustainable impact since by improving awareness and reducing uncertainties, it might allow achieving an optimal balance among available resources and planning of investments