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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
Adopting Weight-Based Dosing With Pharmacy-Level Stewardship Strategies Could Reduce Cancer Drug Spending By Millions
Immune checkpoint inhibitors, a class of drugs used in approximately forty unique cancer indications, are a sizable component of the economic burden of cancer care in the US. Instead of personalized weight-based dosing, immune checkpoint inhibitors are most commonly administered at one-size-fits-all flat doses that are higher than necessary for the vast majority of patients. We hypothesized that personalized weight-based dosing along with common stewardship efforts at the pharmacy level, such as dose rounding and vial sharing, would lead to reductions in immune checkpoint inhibitor use and lower spending. Using data from the Veterans Health Administration (VHA) and Medicare drug prices, we estimated reductions in immune checkpoint inhibitor use and spending that would be associated with pharmacy-level stewardship strategies, in a case-control simulation study of individual patient-level immune checkpoint inhibitor administration events. We identified baseline annual VHA spending for these drugs of approximately 74 million (13.7 percent). We conclude that adoption of pharmacologically justified immune checkpoint inhibitor stewardship measures would generate sizable reductions in spending for these drugs. Combining these operational innovations with value-based drug price negotiation enabled by recent policy changes may improve the long-term financial viability of cancer care in the US
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
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