PI3K (phosphoinositide 3-kinase)/AKT and RAS/MAPK (mitogen-activated protein kinase) pathway coactivation in the prostate epithelium promotes both epithelial-mesenchymal transition (EMT) and ...metastatic castration-resistant prostate cancer (mCRPC), which is currently incurable. To study the dynamic regulation of the EMT process, we developed novel genetically defined cellular and in vivo model systems from which epithelial, EMT and mesenchymal-like tumor cells with Pten deletion and Kras activation can be isolated. When cultured individually, each population has the capacity to regenerate all three tumor cell populations, indicative of epithelial-mesenchymal plasticity. Despite harboring the same genetic alterations, mesenchymal-like tumor cells are resistant to PI3K and MAPK pathway inhibitors, suggesting that epigenetic mechanisms may regulate the EMT process, as well as dictate the heterogeneous responses of cancer cells to therapy. Among differentially expressed epigenetic regulators, the chromatin remodeling protein HMGA2 is significantly upregulated in EMT and mesenchymal-like tumors cells, as well as in human mCRPC. Knockdown of HMGA2, or suppressing HMGA2 expression with the histone deacetylase inhibitor LBH589, inhibits epithelial-mesenchymal plasticity and stemness activities in vitro and markedly reduces tumor growth and metastasis in vivo through successful targeting of EMT and mesenchymal-like tumor cells. Importantly, LBH589 treatment in combination with castration prevents mCRPC development and significantly prolongs survival following castration by enhancing p53 and androgen receptor acetylation and in turn sensitizing castration-resistant mesenchymal-like tumor cells to androgen deprivation therapy. Taken together, these findings demonstrate that cellular plasticity is regulated epigenetically, and that mesenchymal-like tumor cell populations in mCRPC that are resistant to conventional and targeted therapies can be effectively treated with the epigenetic inhibitor LBH589.
The Low-Frequency Array radio telescope discovered the 707 Hz binary millisecond pulsar (MSP) J0952−0607 in a targeted radio pulsation search of an unidentified Fermi gamma-ray source. This source ...shows a weak energy flux of Fγ = 2.6 × 10−12 erg cm−2 s−1 in the energy range between 100 MeV and 100 GeV. Here we report the detection of pulsed gamma-ray emission from PSR J0952−0607 in a very sensitive gamma-ray pulsation search. The pulsar's rotational, binary, and astrometric properties are measured over 7 years of Fermi-Large Area Telescope data. For this we take into account the uncertainty on the shape of the gamma-ray pulse profile. We present an updated radio-timing solution now spanning more than 2 years and show results from optical modeling of the black-widow-type companion based on new multiband photometric data taken with HiPERCAM on the Gran Telescopio Canarias on La Palma and ULTRACAM on the New Technology Telescope at ESO La Silla (based on observations collected at the European Southern Observatory, Chile; programme 0101.D-0925, PI: Clark, C. J.). PSR J0952−0607 is now the fastest-spinning pulsar for which the intrinsic spin-down rate has been reliably constrained ( ). The inferred surface magnetic field strength of is among the 10 lowest of all known pulsars. This discovery is another example of an extremely fast spinning black-widow pulsar hiding within an unidentified Fermi gamma-ray source. In the future such systems might help to pin down the maximum spin frequency and the minimum surface magnetic field strength of MSPs.
Background
The role of routine prophylactic central neck dissection (pCND) in clinically lymph node-negative (cN0) papillary thyroid microcarcinoma (PTMC) patients remains controversial. This ...retrospective study aimed to identify the clinical and pathologic factors of central lymph node metastasis (CLNM) and recurrence in PTMC patients.
Methods
A total of 371 cN0 PTMC patients from two hospitals were retrospectively analyzed. All patients underwent thyroidectomy plus pCND between January 2010 and January 2018. Clinicopathological features were collected, univariate and multivariate analyses were performed to determine the risk factors of CLNM. A scoring model was constructed on the basis of the results of independent risk factors of CLNM. The Cox proportional hazards model was used to analyze the risk factors of recurrence.
Results
CLNM occurred in 123 (33.2%) patients. Multivariate analysis showed male, tumor size > 0.75 cm, multifocality, extrathyroidal extension (ETE) and tumor in the middle/lower pole were independent risk predictors of CLNM (
P
< 0.05). A seven-point risk-scoring model was established to predict the stratified CLNM in cN0 PTMC patients. Multivariate Cox regression model showed ETE, vascular invasion and CLNM were independent risk predictors of recurrence (
P
< 0.05).
Conclusion
Our study suggested that routine pCND should be performed for cN0 PTMC patients with score ≥ 3 according to the risk-scoring model. Moreover, patients with risk factors of recurrence should consider more complete treatment and more frequent follow-up.
Recent developments in the instrumentation and data analysis of synchrotron small‐angle X‐ray scattering (SAXS) on biomolecules in solution have made biological SAXS (BioSAXS) a mature and popular ...tool in structural biology. This article reports on an advanced endstation developed at beamline 13A of the 3.0 GeV Taiwan Photon Source for biological small‐ and wide‐angle X‐ray scattering (SAXS–WAXS or SWAXS). The endstation features an in‐vacuum SWAXS detection system comprising two mobile area detectors (Eiger X 9M/1M) and an online size‐exclusion chromatography system incorporating several optical probes including a UV–Vis absorption spectrometer and refractometer. The instrumentation and automation allow simultaneous SAXS–WAXS data collection and data reduction for high‐throughput biomolecular conformation and composition determinations. The performance of the endstation is illustrated with the SWAXS data collected for several model proteins in solution, covering a scattering vector magnitude q across three orders of magnitude. The crystal‐model fittings to the data in the q range ∼0.005–2.0 Å−1 indicate high similarity of the solution structures of the proteins to their crystalline forms, except for some subtle hydration‐dependent local details. These results open up new horizons of SWAXS in studying correlated local and global structures of biomolecules in solution.
A new endstation for biological small‐ and wide‐angle X‐ray scattering is detailed, which provides development opportunities for studying correlated local and global structures of biomolecules in solution.
Global satellite observations of temperature and geopotential height (GPH) from the Microwave Limb Sounder (MLS) on the EOS Aura spacecraft are discussed. The precision, resolution, and accuracy of ...the data produced by the MLS version 2.2 processing algorithms are quantified, and recommendations for data screening are made. Temperature precision is 1 K or better from 316 hPa to 3.16 hPa, degrading to ∼3 K at 0.001 hPa. The vertical resolution is 3 km at 31.6 hPa, degrading to 6 km at 316 hPa and to ∼13 km at 0.001 hPa. Comparisons with analyses (Goddard Earth Observing System version 5.0.1 (GEOS‐5), European Centre for Medium‐range Weather Forecasts (ECMWF), Met Office (MetO)) and other observations (CHAllenging Minisatellite Payload (CHAMP), Atmospheric Infrared Sounder/Advanced Microwave Sounder Unit (AIRS/AMSU), Sounding of the Atmosphere using Broadband Radiometry (SABER), Halogen Occultation Experiment (HALOE), Atmospheric Chemistry Experiment (ACE), radiosondes) indicate that MLS temperature has persistent, pressure‐dependent biases which are between −2.5 K and +1 K between 316 hPa and 10 hPa. The 100‐hPa MLS v2.2 GPH surface has a bias of ∼150 m relative to the GEOS‐5 values. These biases are compared to modeled systematic uncertainties. GPH biases relative to correlative measurements generally increase with height owing to an overall cold bias in MLS temperature relative to correlative temperature measurements in the upper stratosphere and mesosphere.
Records suggest that the Permo-Triassic mass extinction (PTME) involved one of the most severe terrestrial ecosystem collapses of the Phanerozoic. However, it has proved difficult to constrain the ...extent of the primary productivity loss on land, hindering our understanding of the effects on global biogeochemistry. We build a new biogeochemical model that couples the global Hg and C cycles to evaluate the distinct terrestrial contribution to atmosphere-ocean biogeochemistry separated from coeval volcanic fluxes. We show that the large short-lived Hg spike, and nadirs in δ
Hg and δ
C values at the marine PTME are best explained by a sudden, massive pulse of terrestrial biomass oxidation, while volcanism remains an adequate explanation for the longer-term geochemical changes. Our modelling shows that a massive collapse of terrestrial ecosystems linked to volcanism-driven environmental change triggered significant biogeochemical changes, and cascaded organic matter, nutrients, Hg and other organically-bound species into the marine system.
Various synchrotron radiation-based spectroscopic and microscopic techniques are used to elucidate the room-temperature ferromagnetism of carbon-doped ZnO-nanowires (ZnO-C:NW) via a mild C
ion ...implantation method. The photoluminescence and magnetic hysteresis loops reveal that the implantation of C reduces the number of intrinsic surface defects and increases the saturated magnetization of ZnO-NW. The interstitial implanted C ions constitute the majority of defects in ZnO-C:NW as confirmed by the X-ray absorption spectroscopic studies. The X-ray magnetic circular dichroism spectra of O and C K-edge respectively indicate there is a reduction in the number of unpaired/dangling O 2p bonds in the surface region of ZnO-C:NW and the C 2p-derived states of the implanted C ions strongly affect the net spin polarization in the surface and bulk regions of ZnO-C:NW. Furthermore, these findings corroborate well with the first-principles calculations of C-implanted ZnO in surface and bulk regions, which highlight the stability of implanted C for the suppression and enhancement of the ferromagnetism of the ZnO-C:NW in the surface region and bulk phase, respectively.
ABSTRACT Hot dust-obscured galaxies (hot DOGs), selected from Wide-Field Infrared Survey Explorer's all-sky infrared survey, host some of the most powerful active galactic nuclei known and may ...represent an important stage in the evolution of galaxies. Most known hot DOGs are located at , due in part to a strong bias against identifying them at lower redshift related to the selection criteria. We present a new selection method that identifies 153 hot DOG candidates at , where they are significantly brighter and easier to study. We validate this approach by measuring a redshift z = 1.009 and finding a spectral energy distribution similar to that of higher-redshift hot DOGs for one of these objects, WISE J1036+0449 ( ). We find evidence of a broadened component in Mg ii, which would imply a black hole mass of and an Eddington ratio of . WISE J1036+0449 is the first hot DOG detected by the Nuclear Spectroscopic Telescope Array, and observations show that the source is heavily obscured, with a column density of . The source has an intrinsic 2-10 keV luminosity of , a value significantly lower than that expected from the mid-infrared/X-ray correlation. We also find that other hot DOGs observed by X-ray facilities show a similar deficiency of X-ray flux. We discuss the origin of the X-ray weakness and the absorption properties of hot DOGs. Hot DOGs at could be excellent laboratories to probe the characteristics of the accretion flow and of the X-ray emitting plasma at extreme values of the Eddington ratio.
This paper provides an analysis for the performance evaluation of a piezoelectric energy harvesting system using the synchronized switch harvesting on inductor (SSHI) electronic interface. In ...contrast with estimates based on a variety of approximations in the literature, an analytic expression of harvested power is derived explicitly and validated numerically for the SSHI system. It is shown that the electrical response using an ideal SSHI interface is similar to that using the standard interface in a strongly coupled electromechanical system operated at short circuit resonance. On the other hand, if the SSHI circuit is not ideal, the performance degradation is evaluated and classified according to the relative strength of coupling. It is found that the best use of the SSHI harvesting circuit is for systems in the mid-range of electromechanical coupling. The degradation in harvested power due to the non-perfect voltage inversion is not pronounced in this case, and a new finding shows that the reduction in power is much less sensitive to frequency deviations than that using the standard technique.
Previous results from our trial showed that adding oxaliplatin to radiotherapy (RT) increased survival in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) at 2 years. Here, we ...present the data of long-term efficacy and late toxic effects.
Between January 2001 and January 2003, 115 Patients with nonkeratinizing/undifferentiated locoregionally advanced NPC were randomly to receive either RT alone (n = 56) or plus concurrent oxaliplatin 70 mg/m2 weekly for six cycles (n = 59).
After a median follow-up of 114 months (range 18–139 months), the 5-year overall survival (OS) and metastasis-free survival (MFS) rates in the concurrent chemoradiotherapy (CCRT) group were significantly higher than those observed in the RT-alone group (OS, 73.2% versus 60.2%, P = 0.028; MFS, 74.7% versus 63.0%, P = 0.027). However, CCRT did not improve locoregional failure-free survival significantly. Subgroup analyses showed that the superiorities of CCRT mainly existed in the T3-4N0-1 stage subgroup (OS: HR = 0.394, P = 0.034). The grade 3/4 late toxic effects were similar in the two groups.
The long-term follow-up data confirms the role of CCRT as a treatment of locoregionally advanced NPC. Oxaliplatin can be considered as an alternative optional therapeutic regimen for these patients due to its high efficiency and low toxic effect.
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