Metallopanstimulin as a marker for head and neck cancer

BACKGROUND: Metallopanstimulin (MPS-1) is a ribosomal protein that is found in elevated amounts in the sera of patients with head and neck squamous cell carcinoma (HNSCC). We used a test, denoted MPS-H, which detects MPS-1 and MPS-1-like proteins, to determine the relationship between MPS-H serum levels and clinical status of patients with, or at risk for, HNSCC. PATIENTS AND METHODS: A total of 125 patients were prospectively enrolled from a university head and neck oncology clinic. Participants included only newly diagnosed HNSCC patients. Two control groups, including 25 non-smokers and 64 smokers, were studied for comparison. A total of 821 serum samples collected over a twenty-four month period were analyzed by the MPS-H radioimmunoassay. RESULTS: HNSCC, non-smokers, and smokers had average MPS-H values of 41.5 ng/mL, 10.2 ng/mL, and 12.8 ng/mL, respectively (p = 0.0001). CONCLUSION: We conclude that MPS-1 and MPS-1-like proteins are elevated in patients with HNSCC, and that MPS-H appears to be a promising marker of presence of disease and response to treatment in HNSCC patients

On the Importance of Countergradients for the Development of Retinotopy: Insights from a Generalised Gierer Model

During the development of the topographic map from vertebrate retina to superior colliculus (SC), EphA receptors are expressed in a gradient along the nasotemporal retinal axis. Their ligands, ephrin-As, are expressed in a gradient along the rostrocaudal axis of the SC. Countergradients of ephrin-As in the retina and EphAs in the SC are also expressed. Disruption of any of these gradients leads to mapping errors. Gierer's (1981) model, which uses well-matched pairs of gradients and countergradients to establish the mapping, can account for the formation of wild type maps, but not the double maps found in EphA knock-in experiments. I show that these maps can be explained by models, such as Gierer's (1983), which have gradients and no countergradients, together with a powerful compensatory mechanism that helps to distribute connections evenly over the target region. However, this type of model cannot explain mapping errors found when the countergradients are knocked out partially. I examine the relative importance of countergradients as against compensatory mechanisms by generalising Gierer's (1983) model so that the strength of compensation is adjustable. Either matching gradients and countergradients alone or poorly matching gradients and countergradients together with a strong compensatory mechanism are sufficient to establish an ordered mapping. With a weaker compensatory mechanism, gradients without countergradients lead to a poorer map, but the addition of countergradients improves the mapping. This model produces the double maps in simulated EphA knock-in experiments and a map consistent with the Math5 knock-out phenotype. Simulations of a set of phenotypes from the literature substantiate the finding that countergradients and compensation can be traded off against each other to give similar maps. I conclude that a successful model of retinotopy should contain countergradients and some form of compensation mechanism, but not in the strong form put forward by Gierer

The Josephson heat interferometer

The Josephson effect represents perhaps the prototype of macroscopic phase coherence and is at the basis of the most widespread interferometer, i.e., the superconducting quantum interference device (SQUID). Yet, in analogy to electric interference, Maki and Griffin predicted in 1965 that thermal current flowing through a temperature-biased Josephson tunnel junction is a stationary periodic function of the quantum phase difference between the superconductors. The interplay between quasiparticles and Cooper pairs condensate is at the origin of such phase-dependent heat current, and is unique to Josephson junctions. In this scenario, a temperature-biased SQUID would allow heat currents to interfere thus implementing the thermal version of the electric Josephson interferometer. The dissipative character of heat flux makes this coherent phenomenon not less extraordinary than its electric (non-dissipative) counterpart. Albeit weird, this striking effect has never been demonstrated so far. Here we report the first experimental realization of a heat interferometer. We investigate heat exchange between two normal metal electrodes kept at different temperatures and tunnel-coupled to each other through a thermal `modulator' in the form of a DC-SQUID. Heat transport in the system is found to be phase dependent, in agreement with the original prediction. With our design the Josephson heat interferometer yields magnetic-flux-dependent temperature oscillations of amplitude up to ~21 mK, and provides a flux-to-temperature transfer coefficient exceeding ~ 60mK/Phi_0 at 235 mK [Phi_0 2* 10^(-15) Wb is the flux quantum]. Besides offering remarkable insight into thermal transport in Josephson junctions, our results represent a significant step toward phase-coherent mastering of heat in solid-state nanocircuits, and pave the way to the design of novel-concept coherent caloritronic devices.Comment: 4+ pages, 3 color figure

Cochrane corner: PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease

In this synopsis we describe findings from a recent Cochrane review on PCSK9 inhibitors for cardiovascular disease prevention. Compared against placebo, PCSK9 inhibitors show a substantial reduction in atherogenic lipid particles (LDL-C, Apo-B and Lp(a)), and protective effects on: CVD, MI, stroke, and elevated creatinine. There is however only limited, and lower quality, evidence comparing PCSK9 inhibitors against active treatments such as statins or ezetimibe. Furthermore, the current evidence is limited by the relatively short follow-up (at most a median follow-up of 26 months) which likely also relates to the observed beneficial safety profile, showing no clear signals on adverse events such as influenza, myalgia, T2DM or cancers

Ultra-Sensitive Hot-Electron Nanobolometers for Terahertz Astrophysics

The background-limited spectral imaging of the early Universe requires spaceborne terahertz (THz) detectors with the sensitivity 2-3 orders of magnitude better than that of the state-of-the-art bolometers. To realize this sensitivity without sacrificing operating speed, novel detector designs should combine an ultrasmall heat capacity of a sensor with its unique thermal isolation. Quantum effects in thermal transport at nanoscale put strong limitations on the further improvement of traditional membrane-supported bolometers. Here we demonstrate an innovative approach by developing superconducting hot-electron nanobolometers in which the electrons are cooled only due to a weak electron-phonon interaction. At T<0.1K, the electron-phonon thermal conductance in these nanodevices becomes less than one percent of the quantum of thermal conductance. The hot-electron nanobolometers, sufficiently sensitive for registering single THz photons, are very promising for submillimeter astronomy and other applications based on quantum calorimetry and photon counting.Comment: 19 pages, 3 color figure

PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease

Background Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Therefore, additional LDL-C reduction may be warranted, especially for patients who are unresponsive to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) may further reduce LDL-C, potentially reducing CVD risk as well. Objectives Primary To quantify short-term (24 weeks), medium-term (one year), and long-term (five years) effects of PCSK9 inhibitors on lipid parameters and on the incidence of CVD. Secondary To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of type 2 diabetes, cognitive function, and cancer. Additionally, to determine if specific patient subgroups were more or less likely to benefit from the use of PCSK9 inhibitors. Search methods We identified studies by systematically searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and Web of Science. We also searched Clinicaltrials.gov and the International Clinical Trials Registry Platform and screened the reference lists of included studies. We identified the studies included in this review through electronic literature searches conducted up to May 2016, and added three large trials published in March 2017. Selection criteria All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up time of at least 24 weeks were eligible. Data collection and analysis Two review authors independently reviewed and extracted data. When data were available, we calculated pooled effect estimates. Main results We included 20 studies with data on 67,237 participants (median age 61 years; range 52 to 64 years). Twelve trials randomised participants to alirocumab, three trials to bococizumab, one to RG7652, and four to evolocumab. Owing to the small number of trials using agents other than alirocumab, we did not differentiate between types of PCSK9 inhibitors used. We compared PCSK9 inhibitors with placebo (thirteen RCTs), ezetimibe (two RCTs) or ezetimibe and statins (five RCTs). Compared with placebo, PCSK9 inhibitors decreased LDL-C by 53.86% (95% confidence interval (CI) 58.64 to 49.08; eight studies; 4782 participants; GRADE: moderate) at 24 weeks; compared with ezetimibe, PCSK9 inhibitors decreased LDL-C by 30.20% (95% CI 34.18 to 26.23; two studies; 823 participants; GRADE: moderate), and compared with ezetimibe and statins, PCSK9 inhibitors decreased LDL-C by 39.20% (95% CI 56.15 to 22.26; five studies; 5376 participants; GRADE: moderate). Compared with placebo, PCSK9 inhibitors decreased the risk of CVD events, with a risk difference (RD) of 0.91% (odds ratio (OR) of 0.86, 95% CI 0.80 to 0.92; eight studies; 59,294 participants; GRADE: moderate). Compared with ezetimibe and statins, PCSK9 inhibitors appeared to have a stronger protective effect on CVD risk, although with considerable uncertainty (RD 1.06%, OR 0.45, 95% CI 0.27 to 0.75; three studies; 4770 participants; GRADE: very low). No data were available for the ezetimibe only comparison. Compared with placebo, PCSK9 probably had little or no effect on mortality (RD 0.03%, OR 1.02, 95% CI 0.91 to 1.14; 12 studies; 60,684 participants; GRADE: moderate). Compared with placebo, PCSK9 inhibitors increased the risk of any adverse events (RD 1.54%, OR 1.08, 95% CI 1.04 to 1.12; 13 studies; 54,204 participants; GRADE: low). Similar effects were observed for the comparison of ezetimibe and statins: RD 3.70%, OR 1.18, 95% CI 1.05 to 1.34; four studies; 5376 participants; GRADE: low. Clinical event data were unavailable for the ezetimibe only comparison. Authors' conclusions Over short-term to medium-term follow-up, PCSK9 inhibitors reduced LDL-C. Studies with medium-term follow-up time (longest median follow-up recorded was 26 months) reported that PCSK9 inhibitors (compared with placebo) decreased CVD risk but may have increased the risk of any adverse events (driven by SPIRE-1 and -2 trials). Available evidence suggests that PCSK9 inhibitor use probably leads to little or no difference in mortality. Evidence on relative efficacy and safety when PCSK9 inhibitors were compared with active treatments was of low to very low quality (GRADE); follow-up times were short and events were few. Large trials with longer follow-up are needed to evaluate PCSK9 inhibitors versus active treatments as well as placebo. Owing to the predominant inclusion of high-risk patients in these studies, applicability of results to primary prevention is limited. Finally, estimated risk differences indicate that PCSK9 inhibitors only modestly change absolute risks (often to less than 1%)

Distant X-ray Galaxies: Insights from the Local Population

A full understanding of the origin of the hard X-ray background requires a complete and accurate census of the distant galaxies that produce it. Unfortunately, distant X-ray galaxies tend to be very faint at all wavelengths, which hinders efforts to perform this census. This chapter discusses the insights that can be obtained through comparison of the distant population to local X-ray galaxies, whose properties are well characterized. Such comparisons will ultimately aid investigations into the cosmic evolution of supermassive black holes and their environments.Comment: 19 pages, 10 figures, to appear as Chapter 7 in "Supermassive Black Holes in the Distant Universe" (2004), ed. A. J. Barger, Kluwer Academic Publishers, in pres

The VMC survey XXVIII. Improved measurements of the proper motion of the Galactic globular cluster 47 Tucanae

We use deep multi-epoch point-spread function (PSF) photometry taken with the Visible and Infrared Survey Telescope for Astronomy (VISTA) to measure and analyze the proper motions of stars within the Galactic globular cluster 47 Tucanae (47 Tuc, NGC 104). The observations are part of the ongoing near-infrared VISTA survey of the Magellanic Cloud system (VMC). The data analyzed in this study correspond to one VMC tile, which covers a total sky area of 1.77 deg(2). Absolute proper motions with respect to similar to 9070 background galaxies are calculated from a linear regression model applied to the positions of stars in 11 epochs in the K-s filter. The data extend over a total time baseline of about 17 months. We found an overall median proper motion of the stars within 47 Tuc of (mu alpha cos(delta), mu(delta)) = (+5.89 +/- 0.02 (statistical) +/- 0.13 (systematic), -2.14 +/- 0.02 (statistical) +/- 0.08 (systematic)) mas yr(-1), based on the measurements of similar to 35 000 individual sources between 5’ and 42’ from the cluster center. We compared our result to the proper motions from the newest US Naval Observatory CCD Astrograph Catalog (UCAC5), which includes data from the Gaia data release 1. Selecting cluster members (similar to 2700 stars), we found a median proper motion of (mu(alpha)cos(delta), mu(delta)) = (+5.30 +/- 0.03 (statistical) +/- 0.70 (systematic), -2.70 +/- 0.03 (statistical) +/- 0.70 (systematic)) mas yr(-1). Comparing the results with measurements in the literature, we found that the values derived from the VMC data are consistent with the UCAC5 result, and are close to measurements obtained using the Hubble Space Telescope. We combined our proper motion results with radial velocity measurements from the literature and reconstructed the orbit of 47 Tuc, finding that the cluster is on an orbit with a low ellipticity and is confined within the inner similar to 7.5 kpc of the Galaxy. We show that the use of an increased time baseline in combination with PSF-determined stellar centroids in crowded regions significantly improves the accuracy of the method. In future works, we will apply the methods described here to more VMC tiles to study in detail the kinematics of the Magellanic Clouds

An elliptically symmetric angular Gaussian distribution

We define a distribution on the unit sphere Sd−1 called the elliptically symmetric angular Gaussian distribution. This distribution, which to our knowledge has not been studied before, is a subfamily of the angular Gaussian distribution closely analogous to the Kent subfamily of the general Fisher–Bingham distribution. Like the Kent distribution, it has elliptical contours, enabling modelling of rotational asymmetry about the mean direction, but it has the additional advantages of being simple and fast to simulate from, and having a density and hence likelihood that is easy and very quick to compute exactly. These advantages are especially beneficial for computationally intensive statistical methods, one example of which is a parametric bootstrap procedure for inference for the directional mean that we describe