Aberrant DNA hypermethylation of the ITIH5 tumor suppressor gene in acute myeloid leukemia

Epigenetic mechanisms such as DNA hypermethylation and modifications of histone amino acids are known to play an important role in the control of gene expression both in normal human development and tumorigenesis. Hypermethylation of CpG islands within promoter regions of tumor suppressor genes is associated with transcriptional inactivation and represents, in addition to genetic aberrations, an important mechanism of gene silencing in the pathogenesis of human cancer. Inter-α-trypsine inhibitors (ITIs) are a family of serine protease inhibitors consisting of one light chain (bikunin) and two heavy chains (ITI heavy chains, ITIHs). ITIHs stabilize the extracellular matrix (ECM) by interacting with hyaluronic acid, which is a major ECM component. Hypermethylation in the upstream region of the promoter-associated CpG island of ITIH5, the most recently described member of the ITIH family, has been previously detected in breast cancer and was associated with an adverse outcome. In this study, we determined the DNA methylation status of the promoter region near the transcription start site of the ITIH5 tumor suppressor gene in leukemia cell lines and primary samples from patients with acute myeloid leukemia (AML) as well as the potential use of demethylating agents to restore a demethylated state of the promoter. Aberrant ITIH5 promoter hypermethylation occurred in 15 of 104 (14.4%) diagnostic AML samples. There were no statistically significant correlations between the ITIH5 methylation status and clinical prognostic parameters. Our results indicate that aberrant ITIH5 promoter hypermethylation is a novel epigenetic event in AML

Trends in utilization and costs of BRCA testing among women aged 18–64 years in the United States, 2003–2014

Purpose We examined 12-year trends in BRCA testing rates and costs in the context of clinical guidelines, national policies, and other factors. Methods We estimated trends in BRCA testing rates and costs from 2003 to 2014 for women aged 18–64 years using private claims data and publicly reported revenues from the primary BRCA testing provider. Results The percentage of women with zero out-of-pocket payments for BRCA testing increased during 2013–2014, after 7 years of general decline, coinciding with a clarification of Affordable Care Act coverage of BRCA genetic testing. Beginning in 2007, family history accounted for an increasing proportion of women with BRCA tests compared with personal history, coinciding with BRCA testing guidelines for primary care settings and direct-to-consumer advertising campaigns. During 2013–2014, BRCA testing rates based on claims grew at a faster rate than revenues, following 3 years of similar growth, consistent with increased marketplace competition. In 2013, BRCA testing rates based on claims increased 57%, compared with 11% average annual increases over the preceding 3 years, coinciding with celebrity publicity. Conclusion The observed trends in BRCA testing rates and costs are consistent with possible effects of several factors, including the Affordable Care Act, clinical guidelines and celebrity publicity

Involvement of EphB1 Receptors Signalling in Models of Inflammatory and Neuropathic Pain

EphB receptors tyrosine kinases and ephrinB ligands were first identified as guidance molecules involved in the establishment of topographical mapping and connectivity in the nervous system during development. Later in development and into adulthood their primary role would switch from guidance to activity-dependent modulation of synaptic efficacy. In sensory systems, they play a role in both the onset of inflammatory and neuropathic pain, and in the establishment of central sensitisation, an NMDA-mediated form of synaptic plasticity thought to underlie most forms of chronic pain. We studied wild type and EphB1 knockout mice in a range of inflammatory and neuropathic pain models to determine 1), whether EphB1 expression is necessary for the onset and/or maintenance of persistent pain, regardless of origin; 2), whether in these models cellular and molecular changes, e.g. phosphorylation of the NR2B subunit of the NMDA receptor, increased c-fos expression or microglial activation, associated with the onset of pain, are affected by the lack of functional EphB1 receptors. Differences in phenotype were examined behaviourally, anatomically, biochemically and electrophysiologically. Our results establish firstly, that functional EphB1 receptors are not essential for the development of normal nociception, thermal or mechanical sensitivity. Secondly, they demonstrate a widespread involvement of EphB1 receptors in chronic pain. NR2B phosphorylation, c-fos expression and microglial activation are all reduced in EphB1 knockout mice. This last finding is intriguing, since microglial activation is supposedly triggered directly by primary afferents, therefore it was not expected to be affected. Interestingly, in some models of long-term pain (days), mechanical and thermal hyperalgesia develop both in wild type and EphB1 knockout mice, but recovery is faster in the latter, indicating that in particular models these receptors are required for the maintenance, rather than the onset of, thermal and mechanical hypersensitivity. This potentially makes them an attractive target for analgesic strategies

Post-Training Dephosphorylation of eEF-2 Promotes Protein Synthesis for Memory Consolidation

Memory consolidation, which converts acquired information into long-term storage, is new protein synthesis-dependent. As protein synthesis is a dynamic process that is under the control of multiple translational mechanisms, however, it is still elusive how these mechanisms are recruited in response to learning for memory consolidation. Here we found that eukaryotic elongation factor-2 (eEF-2) was dramatically dephosphorylated within 0.5–2 hr in the hippocampus and amygdala of mice following training in a fear-conditioning test, whereas genome-wide microarrays did not reveal any significant change in the expression level of the mRNAs for translational machineries or their related molecules. Moreover, blockade of NMDA receptors with MK-801 immediately following the training significantly impeded both the post-training eEF-2 dephosphorylation and memory retention. Notably, with an elegant sophisticated transgenic strategy, we demonstrated that hippocampus-specific overexpression of eEF-2 kinase, a kinase that specifically phosphorylates and hence inactivates eEF-2, significantly inhibited protein synthesis in the hippocampus, and this effects was more robust during an “ongoing” protein synthesis process. As a result, late phase long-term potentiation (L-LTP) in the hippocampus and long-term hippocampus-dependent memory in the mice were significantly impaired, whereas short-term memory and long-term hippocampus-independent memory remained intact. These results reveal a novel translational underpinning for protein synthesis pertinent to memory consolidation in the mammalian brain

Rule-Based Cell Systems Model of Aging using Feedback Loop Motifs Mediated by Stress Responses

Investigating the complex systems dynamics of the aging process requires integration of a broad range of cellular processes describing damage and functional decline co-existing with adaptive and protective regulatory mechanisms. We evolve an integrated generic cell network to represent the connectivity of key cellular mechanisms structured into positive and negative feedback loop motifs centrally important for aging. The conceptual network is casted into a fuzzy-logic, hybrid-intelligent framework based on interaction rules assembled from a priori knowledge. Based upon a classical homeostatic representation of cellular energy metabolism, we first demonstrate how positive-feedback loops accelerate damage and decline consistent with a vicious cycle. This model is iteratively extended towards an adaptive response model by incorporating protective negative-feedback loop circuits. Time-lapse simulations of the adaptive response model uncover how transcriptional and translational changes, mediated by stress sensors NF-κB and mTOR, counteract accumulating damage and dysfunction by modulating mitochondrial respiration, metabolic fluxes, biosynthesis, and autophagy, crucial for cellular survival. The model allows consideration of lifespan optimization scenarios with respect to fitness criteria using a sensitivity analysis. Our work establishes a novel extendable and scalable computational approach capable to connect tractable molecular mechanisms with cellular network dynamics underlying the emerging aging phenotype

Selenium and Lung Cancer: A Systematic Review and Meta Analysis

Selenium is a natural health product widely used in the treatment and prevention of lung cancers, but large chemoprevention trials have yielded conflicting results. We conducted a systematic review of selenium for lung cancers, and assessed potential interactions with conventional therapies.Two independent reviewers searched six databases from inception to March 2009 for evidence pertaining to the safety and efficacy of selenium for lung cancers. Pubmed and EMBASE were searched to October 2009 for evidence on interactions with chemo- or radiation-therapy. In the efficacy analysis there were nine reports of five RCTs and two biomarker-based studies, 29 reports of 26 observational studies, and 41 preclinical studies. Fifteen human studies, one case report, and 36 preclinical studies were included in the interactions analysis. Based on available evidence, there appears to be a different chemopreventive effect dependent on baseline selenium status, such that selenium supplementation may reduce risk of lung cancers in populations with lower baseline selenium status (serum<106 ng/mL), but increase risk of lung cancers in those with higher selenium (≥ 121.6 ng/mL). Pooling data from two trials yielded no impact to odds of lung cancer, OR 0.93 (95% confidence interval 0.61-1.43); other cancers that were the primary endpoints of these trials, OR 1.51 (95%CI 0.70-3.24); and all-cause-death, OR 0.93 (95%CI 0.79-1.10). In the treatment of lung cancers, selenium may reduce cisplatin-induced nephrotoxicity and side effects associated with radiation therapy.Selenium may be effective for lung cancer prevention among individuals with lower selenium status, but at present should not be used as a general strategy for lung cancer prevention. Although promising, more evidence on the ability of selenium to reduce cisplatin and radiation therapy toxicity is required to ensure that therapeutic efficacy is maintained before any broad clinical recommendations can be made in this context

Pharmacologically Reversible, Loss of Function Mutations in the tm2 and tm4 Inner Pore Helices of Trek-1 k2p Channels

A better understanding of the gating of TREK two pore domain potassium (K2P) channels and their activation by compounds such as the negatively charged activator, flufenamic acid (FFA) is critical in the search for more potent and selective activators of these channels. Currents through wild-type and mutated human K2P channels expressed in tsA201 cells were measured using whole-cell patch-clamp recordings in the presence and absence of FFA. Mutation of the TM2.6 residue of TREK-1 to a phenylalanine (G171F) and a similar mutation of TM4.6 (A286F) substantially reduced current through TREK-1 channels. In complementary experiments, replacing the natural F residues at the equivalent position in TRESK channels, significantly enhanced current. Known, gain of function mutations of TREK-1 (G137I, Y284A) recovered current through these mutated channels. This reduction in current could be also be reversed pharmacologically, by FFA. However, an appropriate length MTS (MethaneThioSulfonate) cross-linking reagent (MTS14) restricted the activation of TREK-1_A286C channels by repeated application of FFA. This suggests that the cross-linker stabilises the channel in a conformation which blunts FFA activation. Pharmacologically reversible mutations of TREK channels will help to clarify the importance of these channels in pathophysiological conditions such as pain and depression

Ubiquitous molecular substrates for associative learning and activity-dependent neuronal facilitation.

Recent evidence suggests that many of the molecular cascades and substrates that contribute to learning-related forms of neuronal plasticity may be conserved across ostensibly disparate model systems. Notably, the facilitation of neuronal excitability and synaptic transmission that contribute to associative learning in Aplysia and Hermissenda, as well as associative LTP in hippocampal CA1 cells, all require (or are enhanced by) the convergence of a transient elevation in intracellular Ca2+ with transmitter binding to metabotropic cell-surface receptors. This temporal convergence of Ca2+ and G-protein-stimulated second-messenger cascades synergistically stimulates several classes of serine/threonine protein kinases, which in turn modulate receptor function or cell excitability through the phosphorylation of ion channels. We present a summary of the biophysical and molecular constituents of neuronal and synaptic facilitation in each of these three model systems. Although specific components of the underlying molecular cascades differ across these three systems, fundamental aspects of these cascades are widely conserved, leading to the conclusion that the conceptual semblance of these superficially disparate systems is far greater than is generally acknowledged. We suggest that the elucidation of mechanistic similarities between different systems will ultimately fulfill the goal of the model systems approach, that is, the description of critical and ubiquitous features of neuronal and synaptic events that contribute to memory induction

Viral Etiologies of Hospitalized Acute Lower Respiratory Infection Patients in China, 2009-2013

Our findings could serve as robust evidence for public health authorities in drawing up further plans to prevent and control ALRIs associated with viral pathogens. RSV is common in young children and prevention measures could have large public health impact. Influenza was most common in adults and influenza vaccination should be implemented on a wider scale in China