Molecular testing for the clinical diagnosis of fibrolamellar carcinoma.

Fibrolamellar carcinoma has a distinctive morphology and immunophenotype, including cytokeratin 7 and CD68 co-expression. Despite the distinct findings, accurate diagnosis of fibrolamellar carcinoma continues to be a challenge. Recently, fibrolamellar carcinomas were found to harbor a characteristic somatic gene fusion, DNAJB1-PRKACA. A break-apart fluorescence in situ hybridization (FISH) assay was designed to detect this fusion event and to examine its diagnostic performance in a large, multicenter, multinational study. Cases initially classified as fibrolamellar carcinoma based on histological features were reviewed from 124 patients. Upon central review, 104 of the 124 cases were classified histologically as typical of fibrolamellar carcinoma, 12 cases as 'possible fibrolamellar carcinoma' and 8 cases as 'unlikely to be fibrolamellar carcinoma'. PRKACA FISH was positive for rearrangement in 102 of 103 (99%) typical fibrolamellar carcinomas, 9 of 12 'possible fibrolamellar carcinomas' and 0 of 8 cases 'unlikely to be fibrolamellar carcinomas'. Within the morphologically typical group of fibrolamellar carcinomas, two tumors with unusual FISH patterns were also identified. Both cases had the fusion gene DNAJB1-PRKACA, but one also had amplification of the fusion gene and one had heterozygous deletion of the normal PRKACA locus. In addition, 88 conventional hepatocellular carcinomas were evaluated with PRKACA FISH and all were negative. These findings demonstrate that FISH for the PRKACA rearrangement is a clinically useful tool to confirm the diagnosis of fibrolamellar carcinoma, with high sensitivity and specificity. A diagnosis of fibrolamellar carcinoma is more accurate when based on morphology plus confirmatory testing than when based on morphology alone

Human Cytomegalovirus Long Non-coding RNA1.2 Suppresses Extracellular Release of the Pro-inflammatory Cytokine IL-6 by Blocking NF-κB Activation.

Long non-coding RNAs (lncRNAs) are transcripts of >200 nucleotides that are not translated into functional proteins. Cellular lncRNAs have been shown to act as regulators by interacting with target nucleic acids or proteins and modulating their activities. We investigated the role of RNA1.2, which is one of four major lncRNAs expressed by human cytomegalovirus (HCMV), by comparing the properties of parental virus in vitro with those of deletion mutants lacking either most of the RNA1.2 gene or only the TATA element of the promoter. In comparison with parental virus, these mutants exhibited no growth defects and minimal differences in viral gene expression in human fibroblasts. In contrast, 76 cellular genes were consistently up- or down-regulated by the mutants at both the RNA and protein levels at 72 h after infection. Differential expression of the gene most highly upregulated by the mutants (Tumor protein p63-regulated gene 1-like protein; TPRG1L) was confirmed at both levels by RT-PCR and immunoblotting. Consistent with the known ability of TPRG1L to upregulate IL-6 expression via NF-κB stimulation, RNA1.2 mutant-infected fibroblasts were observed to upregulate IL-6 in addition to TPRG1L. Comparable surface expression of TNF receptors and responsiveness to TNF-α in cells infected by the parental and mutant viruses indicated that activation of signaling by TNF-α is not involved in upregulation of IL-6 by the mutants. In contrast, inhibition of NF-κB activity and knockdown of TPRG1L expression reduced the extracellular release of IL-6 by RNA1.2 mutant-infected cells, thus demonstrating that upregulation of TPRG1L activates NF-κB. The levels of MCP-1 and CXCL1 transcripts were also increased in RNA1.2 mutant-infected cells, further demonstrating the presence of active NF-κB signaling. These results suggest that RNA1.2 plays a role in manipulating intrinsic NF-κB-dependent cytokine and chemokine release during HCMV infection, thereby impacting downstream immune responses

Luminous and Dark Matter in the Milky Way

(Abridged) Axisymmetric models of the Milky Way exhibit strong interrelations between the Galactic constants (R_0 and T_0), the stellar columndensity (S_*) and the shape of the dark matter (DM) halo. Here we present analytical relations that can be used to investigate the effects of the uncertain gaseous velocity dispersion on the HI flaring constraints. The contribution of cosmic rays and magnetic fields to the pressure gradients is small. A significantly flattened dark matter halo is only possible if R_0 <~ 6.8 kpc. If R_0 is larger than ~7 kpc, or T_0 >~ 170 km/s, we can rule out two DM candidates that require a highly flattened DM halo: 1) decaying massive neutrinos; and 2) a disk of cold molecular hydrogen. It is only possible to construct self-consistent models of the Galaxy based on the IAU-recommended values for the Galactic constants in the unlikely case that the the stellar columndensity is smaller than ~18 M_sun/pc^2. If we assume that the halo is oblate and S_* = 35 +/- 5 M_sun/pc^2, R_0 <~ 8 kpc and T_0 <~ 200 km/s. Combining the best kinematical and star-count estimates of S_*, we conclude that: 25 <~ S_* <~ 45 M_sun/pc^2. Kuijken & Gilmore's (1991) determination of the columndensity of matter with |z|<=1.1 kpc is robust and valid over a wide range of Galactic constants. Our mass models show that the DM density in the Galactic centre is uncertain by a factor 1000. In the Solar neighbourhood we find: rho_DM ~0.42 GeV/c^2/cm^3 or (11 +/- 5) mM_sun/pc^3 -- roughly 15% of rho_tot.Comment: Accepted for publication in MNRA

Early detection of doxorubicin-induced cardiotoxicity in rats by its cardiac metabolic signature assessed with hyperpolarized MRI.

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects culminating in congestive heart failure (HF). There are currently no clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline. Mitochondrial dysfunction is thought to be a key factor driving functional decline, though real-time metabolic fluxes have never been assessed in DOX-cardiotoxicity. Hyperpolarized magnetic resonance imaging (MRI) can assess real-time metabolic fluxes in vivo. Here we show that cardiac functional decline in a clinically relevant rat-model of DOX-HF is preceded by a change in oxidative mitochondrial carbohydrate metabolism, measured by hyperpolarized MRI. The decreased metabolic fluxes were predominantly due to mitochondrial loss and additional mitochondrial dysfunction, and not, as widely assumed hitherto, to oxidative stress. Since hyperpolarized MRI has been successfully translated into clinical trials this opens up the potential to test cancer patients receiving DOX for early signs of cardiotoxicity

Changes in the red giant and dusty environment of the recurrent nova RS Ophiuchi following the 2006 eruption

We present near-infrared spectroscopy of the recurrent nova RS Ophiuchi (RS Oph) obtained on several occasions after its latest outburst in 2006 February. The 1–5 μm spectra are dominated by the red giant, but the H i, He i and coronal lines present during the eruption are present in all our observations. From the fits of the computed infrared spectral energy distributions to the observed fluxes, we find Teff= 4200 ± 200 K for the red giant. The first overtone CO bands at 2.3 μm, formed in the atmosphere of the red giant, are variable. The spectra clearly exhibit an infrared excess due to dust emission longward of 5 μm; we estimate an effective temperature for the emitting dust shell of 500 K, and find that the dust emission is also variable, being beyond the limit of detection in 2007. Most likely, the secondary star in RS Oph is intrinsically variable

The Milky Way's circular velocity curve between 4 and 14 kpc from APOGEE data

We measure the Milky Way's rotation curve over the Galactocentric range 4 kpc <~ R <~ 14 kpc from the first year of data from the Apache Point Observatory Galactic Evolution Experiment (APOGEE). We model the line-of-sight velocities of 3,365 stars in fourteen fields with b = 0 deg between 30 deg < l < 210 deg out to distances of 10 kpc using an axisymmetric kinematical model that includes a correction for the asymmetric drift of the warm tracer population (\sigma_R ~ 35 km/s). We determine the local value of the circular velocity to be V_c(R_0) = 218 +/- 6 km/s and find that the rotation curve is approximately flat with a local derivative between -3.0 km/s/kpc and 0.4 km/s/kpc. We also measure the Sun's position and velocity in the Galactocentric rest frame, finding the distance to the Galactic center to be 8 kpc < R_0 < 9 kpc, radial velocity V_{R,sun} = -10 +/- 1 km/s, and rotational velocity V_{\phi,sun} = 242^{+10}_{-3} km/s, in good agreement with local measurements of the Sun's radial velocity and with the observed proper motion of Sgr A*. We investigate various systematic uncertainties and find that these are limited to offsets at the percent level, ~2 km/s in V_c. Marginalizing over all the systematics that we consider, we find that V_c(R_0) 99% confidence. We find an offset between the Sun's rotational velocity and the local circular velocity of 26 +/- 3 km/s, which is larger than the locally-measured solar motion of 12 km/s. This larger offset reconciles our value for V_c with recent claims that V_c >~ 240 km/s. Combining our results with other data, we find that the Milky Way's dark-halo mass within the virial radius is ~8x10^{11} M_sun.Comment: submitted to Ap

The Mass and Structure of the Pleiades Star Cluster from 2MASS

We present the results of a large scale search for new members of the Pleiades star cluster using 2MASS near-infrared photometry and proper motions derived from POSS plates digitized by the USNO PMM program. The search extends to a 10 degree radius around the cluster, well beyond the presumed tidal radius, to a limiting magnitude of R ~ 20, corresponding to ~ 0.07 M_sun at the distance and age of the Pleiades. Multi-object spectroscopy for 528 candidates verifies that the search was extremely effective at detecting cluster stars in the 1 - 0.1 M_sun mass range using the distribution of H_alpha emission strengths as an estimate of sample contamination by field stars. When combined with previously identified, higher mass stars, this search provides a sensitive measurement of the stellar mass function and dynamical structure of the Pleiades. The degree of tidal elongation of the halo agrees well with current N body simulation results. Tidal truncation affects masses below ~ 1 M_sun. The cluster contains a total mass ~ 800 M_sun. Evidence for a flatter mass function in the core than in the halo indicates the depletion of stars in the core with mass less than ~ 0.5 M_sun, relative to stars with mass \~1 - 0.5 M_sun, and implies a preference for very low mass objects to populate the halo or escape. The overall mass function is best fitted with a lognormal form that becomes flat at ~ 0.1 M_sun. Whether sufficient dynamical evaporation has occurred to detectably flatten the initial mass function, via preferential escape of very low mass stars and brown dwarfs, is undetermined, pending better membership information for stars at large radial distances.Comment: 19 pages, 14 figures, 2 tables, accepted by AJ, to appear April 200

Cardiorespiratory fitness is associated with hard and light intensity physical activity but not time spent sedentary in 10–14 year old schoolchildren: the HAPPY study

Sedentary behaviour is a major risk factor for developing chronic diseases and is associated with low cardiorespiratory fitness in adults. It remains unclear how sedentary behaviour and different physical activity subcomponents are related to cardiorespiratory fitness in children. The purpose of this study was to assess how sedentary behaviour and different physical activity subcomponents are associated with 10–14 year-old schoolchildren's cardiorespiratory fitness