DAPK1 Promoter Methylation and Cervical Cancer Risk: A Systematic Review and a Meta-Analysis.

Objective: The Death-Associated Protein Kinase 1 (DAPK1) gene has been frequently investigated in cervical cancer (CC). The aim of the present study was to carry out a systematic review and a meta-analysis in order to evaluate DAPK1 promoter methylation as an epigenetic marker for CC risk. Methods A systematic literature search was carried out. The Cochrane software package Review Manager 5.2 was used. The fixed-effects or random-effects models, according to heterogeneity across studies, were used to calculate odds ratios (ORs) and 95% Confidence Intervals (CIs). Furthermore, subgroup analyses were conducted by histological type, assays used to evaluate DAPK1 promoter methylation, and control sample source. Results: A total of 20 papers, published between 2001 and 2014, on 1929 samples, were included in the meta-analysis. DAPK1 promoter methylation was associated with an increased CC risk based on the random effects model (OR: 21.20; 95%CI = 11.14–40.35). Omitting the most heterogeneous study, the between study heterogeneity decreased and the association increased (OR: 24.13; 95% CI = 15.83–36.78). The association was also confirmed in all the subgroups analyses. Conclusions: A significant strong association between DAPK1 promoter methylation and CC was shown and confirmed independently by histological tumor type, method used to evaluate methylation and source of control samples. Methylation markers may have value in early detection of CC precursor lesions, provide added reassurances of safety for women who are candidates for less frequent screens, and predict outcomes of women infected with human papilloma virus

Probabilistic inversions of electrical resistivity tomography data with a machine learning-based forward operator

Casting a geophysical inverse problem into a Bayesian setting is often discouraged by the computational workload needed to run many forward modeling evaluations. Here we present probabilistic inversions of electrical resistivity tomography data in which the forward operator is replaced by a trained residual neural network that learns the non-linear mapping between the resistivity model and the apparent resistivity values. The use of this specific architecture can provide some advantages over standard convolutional networks as it mitigates the vanishing gradient problem that might affect deep networks. The modeling error introduced by the network approximation is properly taken into account and propagated onto the estimated model uncertainties. One crucial aspect of any machine learning application is the definition of an appropriate training set. We draw the models forming the training and validation sets from previously defined prior distributions, while a finite element code provides the associated datasets. We apply the approach to two probabilistic inversion frameworks: a Markov Chain Monte Carlo algorithm is applied to synthetic data, while an ensemble-based algorithm is employed for the field measurements. For both the synthetic and field tests, the outcomes of the proposed method are benchmarked against the predictions obtained when the finite element code constitutes the forward operator. Our experiments illustrate that the network can effectively approximate the forward mapping even when a relatively small training set is created. The proposed strategy provides a forward operator three that is orders of magnitude faster than the accurate but computationally expensive finite element code. Our approach also yields most likely solutions and uncertainty quantifications comparable to those estimated when the finite element modeling is employed. The presented method allows solving the Bayesian electrical resistivity tomography with a reasonable computational cost and limited hardware resources

Machine learning-accelerated gradient-based Markov Chain Monte Carlo inversion applied to electrical resistivity tomography

Expensive forward model evaluations and the curse of dimensionality usually hinder applications of Markov chain Monte Carlo algorithms to geophysical inverse problems. Another challenge of these methods is related to the definition of an appropriate proposal distribution that simultaneously should be inexpensive to manipulate and a good approximation of the posterior density. Here we present a gradient-based Markov chain Monte Carlo inversion algorithm that is applied to cast the electrical resistivity tomography into a probabilistic framework. The sampling is accelerated by exploiting the Hessian and gradient information of the negative log-posterior to define a proposal that is a local, Gaussian approximation of the target posterior probability. On the one hand, the computing time to run the many forward evaluations needed for both the data likelihood evaluation and the Hessian and gradient computation is decreased by training a residual neural network to predict the forward mapping between the resistivity model and the apparent resistivity value. On the other hand, the curse of dimensionality issue and the computational effort related to the Hessian and gradient manipulation are decreased by compressing data and model spaces through a discrete cosine transform. A non-parametric distribution is assumed as the prior probability density function. The method is first demonstrated on synthetic data and then applied to field measurements. The outcomes provided by the presented approach are also benchmarked against those obtained when a computationally expensive finite-element code is employed for forward modelling, with the results of a gradient-free Markov chain Monte Carlo inversion, and also compared with the predictions of a deterministic inversion. The implemented approach not only guarantees uncertainty assessments and model predictions comparable with those achieved by more standard inversion strategies, but also drastically decreases the computational cost of the probabilistic inversion, making it similar to that of a deterministic inversion

Enhancing the significance of gravitational wave bursts through signal classification

The quest to observe gravitational waves challenges our ability to discriminate signals from detector noise. This issue is especially relevant for transient gravitational waves searches with a robust eyes wide open approach, the so called all- sky burst searches. Here we show how signal classification methods inspired by broad astrophysical characteristics can be implemented in all-sky burst searches preserving their generality. In our case study, we apply a multivariate analyses based on artificial neural networks to classify waves emitted in compact binary coalescences. We enhance by orders of magnitude the significance of signals belonging to this broad astrophysical class against the noise background. Alternatively, at a given level of mis-classification of noise events, we can detect about 1/4 more of the total signal population. We also show that a more general strategy of signal classification can actually be performed, by testing the ability of artificial neural networks in discriminating different signal classes. The possible impact on future observations by the LIGO-Virgo network of detectors is discussed by analysing recoloured noise from previous LIGO-Virgo data with coherent WaveBurst, one of the flagship pipelines dedicated to all-sky searches for transient gravitational waves

Exploring the role of fallopian ciliated cells in the pathogenesis of high-grade serous ovarian cancer

High-grade serous epithelial ovarian cancer (HGSOC) is the fifth leading cause of cancer death in women and the first among gynecological malignancies. Despite an initial response to standard chemotherapy, most HGSOC patients relapse. To improve treatment options, we must continue investigating tumor biology. Tumor characteristics (e.g., risk factors and epidemiology) are valuable clues to accomplish this task. The two most frequent risk factors for HGSOC are the lifetime number of ovulations, which is associated with increased oxidative stress in the pelvic area caused by ovulation fluid, and a positive family history due to genetic factors. In the attempt to identify novel genetic factors (i.e., genes) associated with HGSOC, we observed that several genes in linkage with HGSOC are expressed in the ciliated cells of the fallopian tube. This finding made us hypothesize that ciliated cells, despite not being the cell of origin for HGSOC, may take part in HGSOC tumor initiation. Specifically, malfunction of the ciliary beat impairs the laminar fluid flow above the fallopian tube epithelia, thus likely reducing the clearance of oxidative stress caused by follicular fluid. Herein, we review the up-to-date findings dealing with HGSOC predisposition with the hypothesis that fallopian ciliated cells take part in HGSOC onset. Finally, we review the up-to-date literature concerning genes that are located in genomic loci associated with epithelial ovarian cancer (EOC) predisposition that are expressed by the fallopian ciliated cells

Immunopositivity for Histone MacroH2A1 Isoforms Marks Steatosis-Associated Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Prevention and risk reduction are important and the identification of specific biomarkers for early diagnosis of HCC represents an active field of research. Increasing evidence indicates that fat accumulation in the liver, defined as hepatosteatosis, is an independent and strong risk factor for developing an HCC. MacroH2A1, a histone protein generally associated with the repressed regions of chromosomes, is involved in hepatic lipid metabolism and is present in two alternative spliced isoforms, macroH2A1.1 and macroH2A1.2. These isoforms have been shown to predict lung and colon cancer recurrence but to our knowledge, their role in fatty-liver associated HCC has not been investigated previously

Effects of the peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals

Aims/hypothesis: Glitazones are powerful insulin sensitisers prescribed for the treatment of type 2 diabetes. Their use is, however, associated with fluid retention and an increased risk of congestive heart failure. We previously demonstrated that pioglitazone increases proximal sodium reabsorption in healthy volunteers. This study examines the effects of pioglitazone on renal sodium handling in individuals prone to insulin resistance, i.e. those with diabetes and/or hypertension. Methods: In this double-blind randomised placebo-controlled four-way crossover study, we examined the effects of pioglitazone (45mg daily during 6weeks) or placebo on renal, systemic and hormonal responses to changes in sodium intake in 16 individuals, eight with type 2 diabetes and eight with hypertension. Results: Pioglitazone was associated with a rapid increase in body weight and an increase in diurnal proximal sodium reabsorption, without any change in renal haemodynamics or in the modulation of the renin-angiotensin aldosterone system to changes in salt intake. A compensatory increase in brain natriuretic peptide levels was observed. In spite of sodium retention, pioglitazone dissociated the blood-pressure response to salt and abolished salt sensitivity in salt-sensitive individuals. Conclusions/interpretation: Pioglitazone increases diurnal proximal sodium retention in diabetic and hypertensive individuals. These effects cause fluid retention and may contribute to the increased incidence of congestive heart failure with glitazones. Trial registration:: ClinicalTrial.gov NCT01090752 Funding:: Hypertension Research Foundation Lausann

Loss of histone macroH2A1 in hepatocellular carcinoma cells promotes paracrine-mediated chemoresistance and CD4+CD25+FoxP3+ regulatory T cells activation

Rationale: Loss of histone macroH2A1 induces appearance of cancer stem cells (CSCs)-like cells in hepatocellular carcinoma (HCC). How CSCs interact with the tumor microenvironment and the adaptive immune system is unclear. Methods: We screened aggressive human HCC for macroH2A1 and CD44 CSC marker expression. We also knocked down (KD) macroH2A1 in HCC cells, and performed integrated transcriptomic and secretomic analyses. Results: Human HCC showed low macroH2A1 and high CD44 expression compared to control tissues. MacroH2A1 KD CSC-like cells transferred paracrinally their chemoresistant properties to parental HCC cells. MacroH2A1 KD conditioned media transcriptionally reprogrammed parental HCC cells activated regulatory CD4+/CD25+/FoxP3+ T cells (Tregs). Conclusions: Loss of macroH2A1 in HCC cells drives cancer stem-cell propagation and evasion from immune surveillance