JAK2 regulates mismatch repair protein‐mediated epigenetic alterations in response to oxidative damage

At sites of chronic inflammation epithelial cells undergo aberrant DNA methylation that contributes to tumorigenesis. Inflammation is associated with an increase in reactive oxygen species (ROS) that cause oxidative DNA damage, which has also been linked to epigenetic alterations. We previously demonstrated that in response to ROS, mismatch repair proteins MSH2 and MSH6 recruit epigenetic silencing proteins DNA methyltransferase 1 (DNMT1) and polycomb repressive complex 2 (PRC2) members to sites of DNA damage, resulting in transcriptional repression of tumor suppressor genes (TSGs). However, it was unclear what signal is unique to ROS that results in the chromatin binding of MSH2 and MSH6. Herein, we demonstrate that in response to hydrogen peroxide (H2O2), JAK2 localizes to the nucleus and interacts with MSH2 and MSH6. Inhibition or knockdown of JAK2 reduces the H2O2‐induced chromatin interaction of MSH2, MSH6, DNMT1, and PRC2 members, reduces H2O2‐induced global increase in trimethylation of lysine 27 of histone H3 (H3K27me3), and abrogates oxidative damage‐induced transcriptional repression of candidate TSGs. Moreover, JAK2 mRNA expression is associated with CpG island methylator phenotype (CIMP) status in human colorectal cancer. Our findings provide novel insight into the connection between kinase activation and epigenetic alterations during oxidative damage and inflammation. Environ. Mol. Mutagen. 2018. © 2018 Wiley Periodicals, Inc

Faecal sludge treatment by vermifiltration: proof of concept

The objective of this study was to determine if composting worms and their cocoons are able to survive in and digest faecal sludge. Eighteen vermifilters with different worm and cocoon densities were set-up, fed with faecal sludge (from portable pour-flush toilets) and ran for 38 days. Samples of the sludge, effluent and vermicompost were analysed for pH, total solids, chemical oxygen demand, faecal coliforms and Ascaris spp. number and viability. Worm and vermicompost mass, and cocoon numbers were assessed at the end of this period. It was found that the composting worms survived in these conditions and cocoons hatched. The validity of the sludge analysis results are questioned in this paper and without these results only estimates of effluent treatment and solids conversion could be made. Although this study was not completely definitive it has shown that worms are capable of converting faecal sludge into vermicompost and cocoons hatch in its presence. This trial was undertaken in India

Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation

Neuropilin-1 (NRP1) regulates developmental and pathological angiogenesis, arteriogenesis, and vascular permeability, acting as a coreceptor for semaphorin 3A (Sema3A) and the 165–amino acid isoform of vascular endothelial growth factor A (VEGF-A165). NRP1 is also the receptor for the CendR peptides, a class of cell- and tissue-penetrating peptides with a specific R-x-x-R carboxyl-terminal motif. Because the cytoplasmic domain of NRP1 lacks catalytic activity, NRP1 is mainly thought to act through the recruitment and binding to other receptors. We report here that the NRP1 intracellular domain mediates vascular permeability. Stimulation with VEGF-A165, a ligand-blocking antibody, and a CendR peptide led to NRP1 accumulation at cell-cell contacts in endothelial cell monolayers, increased cellular permeability in vitro and vascular leakage in vivo. Biochemical analyses, VEGF receptor-2 (VEGFR-2) silencing, and the use of a specific VEGFR blocker established that the effects induced by the CendR peptide and the antibody were independent of VEGFR-2. Moreover, leakage assays in mice expressing a mutant NRP1 lacking the cytoplasmic domain revealed that this domain was required for NRP1-induced vascular permeability in vivo. Hence, these data define a vascular permeability pathway mediated by NRP1 but independent of VEGFR-2 activation

Quantum version of the Monty Hall problem

©2002 The American Physical SocietyA version of the Monty Hall problem is presented where the players are permitted to select quantum strategies. If the initial state involves no entanglement the Nash equilibrium in the quantum game offers the players nothing more than that obtained with a classical mixed strategy. However, if the initial state involves entanglement of the qutrits of the two players, it is advantageous for one player to have access to a quantum strategy while the other does not. Where both players have access to quantum strategies there is no Nash equilibrium in pure strategies, however, there is a Nash equilibrium in quantum mixed strategies that gives the same average payoff as the classical game.A. P. Flitney and D. Abbot

Early epigenetic downregulation of microRNA-192 expression promotes pancreatic cancer progression

Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial–mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149–59. ©2016 AACR

Portal Hypertensive Gastropathy in Chronic Hepatitis C Patients with Bridging Fibrosis and Compensated Cirrhosis: Results from the HALT-C Trial

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72863/1/j.1572-0241.2006.00461.x.pd

Lysine-Specific Demethylase 1 Mediates AKT Activity and Promotes Epithelial-to-Mesenchymal Transition in PIK3CA-Mutant Colorectal Cancer

Activation of the epithelial-mesenchymal transition (EMT) program is a critical mechanism for initiating cancer progression and migration. Colorectal cancers (CRCs) contain many genetic and epigenetic alterations that can contribute to EMT. Mutations activating the PI3K/AKT signaling pathway are observed in >40% of patients with CRC contributing to increased invasion and metastasis. Little is known about how oncogenic signaling pathways such as PI3K/AKT synergize with chromatin modifiers to activate the EMT program. Lysine Specific Demethylase 1 (LSD1) is a chromatin-modifying enzyme that is overexpressed in colorectal cancer (CRC) and enhances cell migration. In this study we determine that LSD1 expression is significantly elevated in CRC patients with mutation of the catalytic subunit of PI3K, PIK3CA, compared to CRC patients with WT PIK3CA. LSD1 enhances activation of the AKT kinase in CRC cells through a non-catalytic mechanism, acting as a scaffolding protein for the transcription-repressing CoREST complex. Additionally, growth of PIK3CA mutant CRC cells is uniquely dependent on LSD1. Knockdown or CRISPR knockout of LSD1 blocks AKT-mediated stabilization of the EMT-promoting transcription factor Snail and effectively blocks AKT-mediated EMT and migration. Overall we uniquely demonstrate that LSD1 mediates AKT activation in response to growth factors and oxidative stress, and LSD1-regulated AKT activity promotes EMT-like characteristics in a subset of PIK3CA mutant cells. Implications Our data supports the hypothesis that inhibitors targeting the CoREST complex may be clinically effective in CRC patients harboring PIK3CA mutations

Impact of Chronic Lung Disease on Very Low Birth Weight infants: a collaborative study of the Italian Group of Neonatal Pneumology

Objective. To evaluate the incidence and risk factors for chronic lung disease in a population of very low birth weight infants. Methods. In a prospective multicentric trial all very low birth weight infants (< 1500 g) accepted in 36 Italian Neonatal Intensive care units were studied from February 89 to January 99. For each patient were recorded maternal history, perinatal events, respiratory disease, infections, patent ductus arteriosus, retinopathy of prematurity, intraventricular haemorrhage and final outcome. Logistic regression analysis was performed in a multivariate assessment of risk factors for chronic lung disease. Results. In the study were included 1634 patients: 1387 infants survived beyond 36 weeks and 6.9% of them still oxygen dependent. The incidence of chronic lung disease was higher among babies with a gestational age of < 28 weeks and weight \ub2 1000 g. The multivariate analysis showed that low birth weight, respiratory distress syndrome, persistent ductus arteriosus and sepsis were the main risk factors. Conclusions. In our study the incidence of chronic lung disease was relatively lo

Valacyclovir in the treatment of acute retinal necrosis

Background: To report the outcome of oral valacyclovir as the sole antiviral therapy for patients with acute retinal necrosis (ARN). Methods: This study reports a retrospective, interventional case series of nine consecutive patients with ten eyes with newly diagnosed ARN treated with oral valacyclovir as the sole antiviral agent. Eight patients received oral valacyclovir 2 g tid (Valtrex, GlaxoSmithKline) and one patient with impaired renal function received oral 1 g tid. The main outcome measures were response to treatment, time to initial response to treatment, time to complete resolution of retinitis, best corrected visual acuity (BCVA) at final follow-up, retinal detachment and development of recurrent or second eye disease. Results: Retinitis resolved in ten of ten (100%) affected eyes. The median time to initial detectable response was seven days and the median time to complete resolution was 21 days. A final BCVA of 20/40 or better was achieved in 6/10 (60%) of eyes. 3/10 eyes (30%) developed a retinal detachment. No patients developed either disease reactivation or second eye involvement over the course of the study (mean follow up 31 weeks, range 7 to 104 weeks). Conclusions: Treatment with oral valacyclovir as the sole antiviral therapy resulted in complete resolution of retinitis. Final BCVA and retinal detachment rate were comparable with previously reported outcomes for intravenous acyclovi

M6 Membrane Protein Plays an Essential Role in Drosophila Oogenesis

We had previously shown that the transmembrane glycoprotein M6a, a member of the proteolipid protein (PLP) family, regulates neurite/filopodium outgrowth, hence, M6a might be involved in neuronal remodeling and differentiation. In this work we focused on M6, the only PLP family member present in Drosophila, and ortholog to M6a. Unexpectedly, we found that decreased expression of M6 leads to female sterility. M6 is expressed in the membrane of the follicular epithelium in ovarioles throughout oogenesis. Phenotypes triggered by M6 downregulation in hypomorphic mutants included egg collapse and egg permeability, thus suggesting M6 involvement in eggshell biosynthesis. In addition, RNAi-mediated M6 knockdown targeted specifically to follicle cells induced an arrest of egg chamber development, revealing that M6 is essential in oogenesis. Interestingly, M6-associated phenotypes evidenced abnormal changes of the follicle cell shape and disrupted follicular epithelium in mid- and late-stage egg chambers. Therefore, we propose that M6 plays a role in follicular epithelium maintenance involving membrane cell remodeling during oogenesis in Drosophila