METH-2 silencing and promoter hypermethylation in NSCLC

The antiangiogenic factor METH-2 (ADAMTS-8) was identified in a previous dual-channel cDNA microarray analysis to be at least two-fold under-represented in 85% (28 out of 33) of primary non-small-cell lung carcinomas (NSCLCs). This observation has been validated in an independent series of NSCLCs and adjacent normal tissues by comparative multiplex RT—PCR, and METH-2 mRNA expression was dramatically reduced in all 23 tumour samples analysed. Immunohistochemical analysis of the same sample set demonstrated that METH-2 was strongly expressed in 14 out of 19 normal epithelial sites examined but only one out of 20 NSCLCs. DNA methylation analysis of the proximal promoter region of this gene revealed abnormal hypermethylation in 67% of the adenocarcinomas and 50% of squamous cell carcinomas, indicating that epigenetic mechanisms are involved in silencing this gene in NSCLC. No homozygous deletions of METH-2 were found in lung cancer cell lines. Allelic imbalance in METH-2 was assessed by an intronic single nucleotide polymorphism (SNP) assay and observed in 44% of informative primary samples. In conclusion, the downregulation of METH-2 expression in primary NSCLC, often associated with promoter hypermethylation, is a frequent event, which may be related to the development of the disease

Lower crustal crystallization and melt evolution at mid-ocean ridges

Author Posting. © The Author(s), 2012. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Geoscience 5 (2012): 651–655, doi:10.1038/ngeo1552.Mid-ocean ridge magma is produced when Earth’s mantle rises beneath the ridge axis and melts as a result of the decrease in pressure. This magma subsequently undergoes cooling and crystallization to form the oceanic crust. However, there is no consensus on where within the crust or upper mantle crystallization occurs1-5. Here we provide direct geochemical evidence for the depths of crystallization beneath ridge axes of two spreading centres located in the Pacific Ocean: the fast-spreading-rate East Pacific Rise and intermediate-spreading-rate Juan de Fuca Ridge. Specifically, we measure volatile concentrations in olivine-hosted melt inclusions to derive vapour-saturation pressures and to calculate crystallisation depth. We also analyse the melt inclusions for major and trace element concentrations, allowing us to compare the distributions of crystallisation and to track the evolution of the melt during ascent through the oceanic crust. We find that most crystallisation occurs within a seismically-imaged melt lens located in the shallow crust at both ridges, but over 25% of the melt inclusions have crystallisation pressures consistent with formation in the lower oceanic crust. Furthermore, our results suggest that melts formed beneath the ridge axis can be efficiently mixed and undergo olivine crystallisation in the mantle, prior to ascent into the ocean crust.This research was supported by the National Science Foundation (EAR-0646694) and the WHOI Deep Ocean Exploration Institute/Ocean Ridge Initiative.2013-02-1

Hot Gas in Galaxy Groups: Recent Observations

Galaxy groups are the least massive systems where the bulk of baryons begin to be accounted for. Not simply the scaled-down versions of rich clusters following self-similar relations, galaxy groups are ideal systems to study baryon physics, which is important for both cluster cosmology and galaxy formation. We review the recent observational results on the hot gas in galaxy groups. The first part of the paper is on the scaling relations, including X-ray luminosity, entropy, gas fraction, baryon fraction and metal abundance. Compared to clusters, groups have a lower fraction of hot gas around the center (e.g., r < r_2500), but may have a comparable gas fraction at large radii (e.g., r_2500 < r < r_500). Better constraints on the group gas and baryon fractions require sample studies with different selection functions and deep observations at r > r_500 regions. The hot gas in groups is also iron poor at large radii (0.3 r_500 - 0.7 r_500). The iron content of the hot gas within the central regions (r < 0.3 r_500) correlates with the group mass, in contrast to the trend of the stellar mass fraction. It remains to be seen where the missing iron in low-mass groups is. In the second part, we discuss several aspects of X-ray cool cores in galaxy groups, including their difference from cluster cool cores, radio AGN heating in groups and the cold gas in group cool cores. Because of the vulnerability of the group cool cores to radio AGN heating and the weak heat conduction in groups, group cool cores are important systems to test the AGN feedback models and the multiphase cool core models. At the end of the paper, some outstanding questions are listed.Comment: 31 pages, 9 figures, to appear in the focus issue on "Galaxy Clusters", New Journal of Physics, http://iopscience.iop.org/1367-2630/focus/Focus%20on%20Galaxy%20Cluster

Non-O157 Shiga Toxin–producing Escherichia coli Associated with Venison

News reports of “E. coli outbreaks” usually refer to Shiga toxin–producing E. coli O157. But there are other types of Shiga toxin–producing E. coli, often called STEC,about which less is known. For these other types of STEC, what is the source? What are the risk factors? An outbreak among 29 high school students in Minnesota provided some answers. The source of this outbreak was a white-tailed deer that had been butchered and eaten at the school. The risk factors for infection were handling raw or eating undercooked venison. To prevent this type of STECinfection, people should handle and cook venison with the same caution recommended for other meats

Expression of ADAMTS-8, a secreted protease with antiangiogenic properties, is downregulated in brain tumours

Angiogenesis and extracellular matrix degradation are key events in tumour progression, and factors regulating stromal–epithelial interactions and matrix composition are potential targets for the development of novel anti-invasive/antiangiogenic therapies. Here, we examine the expression of ADAMTS-8, a secreted protease with antiangiogenic properties, in brain tissues. Using quantitative RT–polymerase chain reaction (PCR), high, equivalent expression of ADAMTS-8 was found in normal whole brain, cerebral cortex, frontal lobe, cerebellum and meninges. ADAMTS-8 expression in 34 brain tumours (including 22 high-grade gliomas) and four glioma cell lines indicated at least two-fold reduction in mRNA compared to normal whole brain in all neoplastic tissues, and no detectable expression in 14 out of 34 (41%) tumours or four out of four (100%) cell lines. In contrast, differential expression of TSP1 and VEGF was seen in nine out of 15 (60%) and seven out of 13 (54%) tumours, with no relationship in the expression of these genes. Immunohistochemistry and Western analysis indicated downregulation of ADAMTS-8 protein in >77% tumours. Methylation-specific PCR analysis of ADAMTS-8 indicated promoter hypermethylation in one out of 24 brain tumours (a metastasis) and three out of four glioma cell lines suggesting an alternative mechanism of downregulation. These data suggest a role for ADAMTS-8 in brain tumorigenesis, warranting further investigation into its role in regulation of tumour angiogenesis and local invasion

The brain monitoring with information technology (BrainIT) collaborative network: EC feasibility study results

The BrainIT group works collaboratively on developing standards for collection and analyses of data from brain injured patients towards providing a more efficient infrastructure for assessing new health technology. Materials and methods Over a 2 year period, core dataset data (grouped by nine categories) were collected from 200 head-injured patients by local nursing staff. Data were uploaded by the BrainIT web and random samples of received data were selected automatically by computer for validation by data validation (DV) research nurse staff against gold standard sources held in the local centre. Validated data was compared with original data sent and percentage error rates calculated by data category. Findings Comparisons, 19,461, were made in proportion to the size of the data received with the largest number checked in laboratory data (5,667) and the least in the surgery data (567). Error rates were generally less than or equal to 6%, the exception being the surgery data class where an unacceptably high error rate of 34% was found. Conclusions The BrainIT core dataset (with the exception of the surgery classification) is feasible and accurate to collect. The surgery classification needs to be revised

Clinical course, characteristics and prognostic indicators in patients presenting with back and leg pain in primary care. The ATLAS study protocol

Low-back related leg pain with or without nerve root involvement is associated with a poor prognosis compared to low back pain (LBP) alone. Compared to the literature investigating prognostic indicators of outcome for LBP, there is limited evidence on prognostic factors for low back-related leg pain including the group with nerve root pain. This 1 year prospective consultation-based observational cohort study will describe the clinical, imaging, demographic characteristics and health economic outcomes for the whole cohort, will investigate differences and identify prognostic indicators of outcome (i.e. change in disability at 12 months), for the whole cohort and, separately, for those classified with and without nerve root pain. In addition, nested qualitative studies will provide insights on the clinical consultation and the impact of diagnosis and treatment on patients' symptom management and illness trajectory

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Channeling by Proximity: The Catalytic Advantages of Active Site Colocalization Using Brownian Dynamics

Nature often colocalizes successive steps in a metabolic pathway. Such organization is predicted to increase the effective concentration of pathway intermediates near their recipient active sites and to enhance catalytic efficiency. Here, the pathway of a two-step reaction is modeled using a simple spherical approximation for the enzymes and substrate particles. Brownian dynamics are used to simulate the trajectory of a substrate particle as it diffuses between the active site zones of two different enzyme spheres. The results approximate distances for the most effective reaction pathways, indicating that the most effective reaction pathway is one in which the active sites are closely aligned. However, when the active sites are too close, the ability of the substrate to react with the first enzyme was hindered, suggesting that even the most efficient orientations can be improved for a system that is allowed to rotate or change orientation to optimize the likelihood of reaction at both sites

Search for charged Higgs decays of the top quark using hadronic tau decays

We present the result of a search for charged Higgs decays of the top quark, produced in $p\bar{p}$ collisions at $\surd s =$ 1.8 TeV. When the charged Higgs is heavy and decays to a tau lepton, which subsequently decays hadronically, the resulting events have a unique signature: large missing transverse energy and the low-charged-multiplicity tau. Data collected in the period 1992-1993 at the Collider Detector at Fermilab, corresponding to 18.7$\pm$0.7~pb$^{-1}$, exclude new regions of combined top quark and charged Higgs mass, in extensions to the standard model with two Higgs doublets.Comment: uuencoded, gzipped tar file of LaTeX and 6 Postscript figures; 11 pp; submitted to Phys. Rev.