Dysregulation of cell surface proteolysis has been strongly implicated in tumorigenicity and metastasis. In this study, we delineated the role of hepatocyte growth factor activator inhibitor-2 ...(HAI-2) in prostate cancer (PCa) cell migration, invasion, tumorigenicity and metastasis using a human PCa progression model (103E, N1, and N2 cells) and xenograft models. N1 and N2 cells were established through serial intraprostatic propagation of 103E human PCa cells and isolation of the metastatic cells from nearby lymph nodes. The invasion capability of these cells was revealed to gradually increase throughout the serial isolations (103E<N1<N2). In this series of cells, the expression of HAI-2 but not HAI-1 was significantly decreased throughout the progression and occurred in parallel with increased activation of matriptase. The expression level and activity of matriptase increased whereas the HAI-2 protein level decreased over the course of orthotopic tumor growth in mice, which was consistent with the immunohistochemical profiles of matriptase and HAI-2 in archival PCa specimens. Knockdown of matriptase reduced the PCa cell invasion induced by HAI-2 knockdown. HAI-2 overexpression or matriptase silencing in N2 cells downregulated matriptase activity and significantly decreased tumorigenicity and metastatic capability in orthotopically xenografted mice. These results suggest that during the progression of human PCa, matriptase activity is primarily controlled by HAI-2 expression. The imbalance between HAI-2 and matriptase expression led to matriptase activation, thereby increasing cell migration, invasion, tumorigenicity and metastasis.
Colistin and polymyxin B remain part of the last line of antibiotics for multidrug-resistant Gram-negative bacteria, such as carbapenem-resistant
Current joint EUCAST-CLSI recommendations are for ...broth microdilution (BMD) to be performed for MIC testing of colistin. Commercial susceptibility testing methods were evaluated and compared against the reference BMD, using a susceptibility breakpoint of ≤2 mg/liter for both colistin and polymyxin B. Seventy-six
were included, of which 21 were
positive (18
isolates, 2
isolates, and 1
isolate). Rates of essential agreement (EA) of colistin test results between BMD and Vitek 2, Sensititre, and Etest were 93.4%, 89.5%, and 75.0%, respectively. Rates of EA of polymyxin B test results between BMD and Vitek 2, Sensititre, and Etest were 96.1%, 96.1%, and 48.7%, respectively. A positive MIC correlation with a categorical agreement of >90% was achieved for Sensititre (colistin Spearman's ρ = 0.863, and polymyxin B Spearman's ρ = 0.877) and Vitek 2 (polymyxin B only Spearman's ρ = 0.8917). Although a positive MIC correlation (Spearman's ρ = 0.873) with the reference method was achieved for colistin testing with Vitek 2, categorical agreement was <90%, with very major error rates of 36%. Correlation with the Etest MIC was lower, with very major error rates of 12% (colistin) and 26.1% (polymyxin B). MicroScan (colistin) categorical agreement was 88.2%, with a very major error rate of 4%. Colistin MICs for 15 of the 21
-positive isolates were >2 mg/liter, and polymyxin MICs for 17 of them were >2 mg/liter by broth microdilution. The use of a lower breakpoint of ≤1 mg/liter further improves detection of
for all testing methods. However, further data on the correlation between MICs and clinical outcome are required to determine the most suitable breakpoint to guide clinical management.
Future weak-lensing measurements of cosmic shear will reach such high accuracy that second-order effects in weak-lensing modeling, such as the influence of baryons on structure formation, become ...important. We use a controlled set of high-resolution cosmological simulations to quantify this effect by comparing pure N-body dark matter runs with corresponding hydrodynamic simulations, carried out both in nonradiative form and in dissipative form with cooling and star formation. In both hydrodynamic simulations, the clustering of the gas is suppressed while that of dark matter is boosted at scales k > 1 h Mpc super(-1). Despite this counterbalance between dark matter and gas, the clustering of the total matter is suppressed by up to 1% at 1 h Mpc super(-1) k 10 h Mpc super(-1), while for k - 20 h Mpc super(-1) it is boosted, up to 2% in the nonradiative run and 10% in the run with star formation. The stellar mass formed in the latter is highly biased relative to the dark matter in the pure TV-body simulation. Using our power spectrum measurements to predict the effect of baryons on the weak-lensing signal at scales corresponding to multipole moments 100 < l < 10,000, we find that baryons may change the lensing power spectrum by less than 0.5% at l < 1000, but by 1% to 10% at 1000 < l < 10,000. The size of the effect exceeds the predicted accuracy of fixture lensing power spectrum measurements and will likely be detected. Precise determinations of cosmological parameters with weak lensing, and studies of small-scale fluctuations and clustering, therefore rely on properly including baryonic physics.
A total of 1,281 specimens from 1,024 patients were screened. Phylogenetic analysis classified 44 of these isolates as Klebsiella quasipneumoniae subsp.
(44/1,281 3.4%) and the remaining three as
...subsp.
The most common specimen source was urine (21/47 44.7%) followed by blood (14/47 29.8%).
isolates were nonclonal. Carbapenemase-encoding genes (
and
) were detected in only two isolates (2/47 4.3%).
appears to cause a spectrum of infections similar to those of K. pneumoniae, although higher rates of susceptibility to many commonly tested antimicrobials and low prevalence of virulence genes were demonstrated.
Simulating the evolution of the local universe is important for studying galaxies and the intergalactic medium in a way free of cosmic variance. Here we present a method to reconstruct the initial ...linear density field from an input nonlinear density field, employing the Hamiltonian Markov Chain Monte Carlo (HMC) algorithm combined with Particle-mesh (PM) dynamics. The HMC+PM method is applied to cosmological simulations, and the reconstructed linear density fields are then evolved to the present day with iV-body simulations. These constrained simulations accurately reproduce both the amplitudes and phases of the input simulations at various z. Using a PM model with a grid cell size of 0.75 h super(-1) Mpc and 40 time steps in the HMC can recover more than half of the phase information down to a scale k ~ 0.85 h Mpc super(-1) at high z and to k ~ 3.4 h Mpc super(-1) at z = 0, which represents a significant improvement over similar reconstruction models in the literature, and indicates that our model can reconstruct the formation histories of cosmic structures over a large dynamical range. Adopting PM models with higher spatial and temporal resolutions yields even better reconstructions, suggesting that our method is limited more by the availability of computer resource than by principle. Dynamic models of structure evolution adopted in many earlier investigations can induce non-Gaussianity in the reconstructed linear density field, which in turn can cause large systematic deviations in the predicted halo mass function. Such deviations are greatly reduced or absent in our reconstruction.
Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine ...degrading enzyme—arginine deiminase—conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy.
Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4–5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives.
A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion.
ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway.
www.clinicaltrials.gov (NCT 01287585).
The metallic interface between insulating LaAlO3 and SrTiO3 opens up the field of oxide electronics. With more than a decade of researches on this heterostructure, the origin of the interfacial ...conductivity, however, remains unsettled. Here we resolve this long-standing puzzle by atomic-scale observation of electron-gas formation for screening hidden lattice instabilities, rejuvenated near the interface by epitaxial strain. Using atomic-resolution imaging and electron spectroscopy, the generally accepted notions of polar catastrophe and cation intermixing for the metallic interface are discounted. Instead, the conductivity onset at the critical thickness of 4-unit cell LaAlO3 on SrTiO3 substrate is accompanied with head-to-head ferroelectric-like polarizations across the interface due to strain-rejuvenated ferroelectric-like instabilities in the materials. The divergent depolarization fields of the head-to-head polarizations cast the interface into an electron reservoir, forming screening electron gas in SrTiO3 with LaAlO3 hosting complementary localized holes. The ferroelectric-like polarizations and electron-hole juxtaposition reveal the cooperative nature of metallic LaAlO3/SrTiO3.
A common imaging finding in brain abscess and necrotic glioblastoma is a T2 hypointense margin. The features of this hypointense rim on SWI have not been previously described, to our knowledge. We ...aimed to differentiate abscesses from glioblastomas by assessing the morphology of their lesion margin by using SWI.
T2WI and SWI were performed in 12 abscesses and 20 rim-enhancing glioblastomas. On T2WI and SWI, the prevalence and the border types (complete versus incomplete) of hypointense rims were qualitatively assessed. On SWI, the contour (smooth versus irregular) and the location of hypointense rims relative to the contrast-enhancing rims as well as the prevalence of the "dual rim sign," defined as 2 concentric rims at lesion margins with the outer one being hypointense and the inner one hyperintense relative to cavity contents, were also analyzed.
Prevalence and the border types of the hypointense rims on T2WI were not different between abscesses and glioblastomas. On SWI, there were significantly more hypointense rims that were complete (P < .001) and smooth (P < .001), having the same location as the contrast-enhancing rims (P < .001) for abscesses. A dual rim sign was present in 9 of 12 abscesses but absent in all glioblastomas (P < .001).
SWI may be helpful in differentiating pyogenic abscesses from necrotic glioblastomas. The dual rim sign is the most specific imaging feature distinguishing the 2.
Micro-Arc oxidation (MAO) coatings with actively protective functionality by incorporating 2-aminobenzimidazole (2-ABi) loaded halloysite nanotubes (HNTs) was presented. The coatings were ...characterized by SEM, EDX and XRD. Corrosion behavior was evaluated by EIS, PDP and salt spray test. With the SEM and EDX analysis, the existence of HNT or 2ABi-loaded HNT was confirmed. The OCP evolution, EIS complex spectra and the result of salt spray test showed the enhanced corrosion resistance of 2-ABi-HNT MAO coating owing to the self-healing effect, suggesting 2-ABi has good potential as corrosion inhibitor for Mg alloys.
•Several characteristics on three different kinds of MAO coatings on Mg alloys were simultaneously presented and compared.•2-ABi molecules were successfully loaded into the HNTand the 2-ABi-HNT-MAO films showed higher corrosion resistance.•Confirm that 2-ABi has a good self-healing function and has a long-term protective effect on MAO coatings.
The first measurements from the CIBER experiment of extragalactic background light (EBL) in near-infrared (NIR) band exhibit a higher intensity than those inferred through γ-ray observations. Recent ...theoretical-EBL intensities are typically consistent with the very high energy (VHE) γ-ray observations. Yet, it is possible that the excess NIR radiation is a new component of EBL and not in tension with the TeV spectra of distant blazars, since the hypothetical axionlike particle (ALP) may lead to a reduced opacity of the Universe for VHE γ-rays. In order to probe whether the excess component arises mainly from EBL, thirteen observed spectra in high energy and VHE ranges from ten distant TeV BL Lac objects are fitted by four theoretical spectra which involve theoretical EBL (Gilmore et al.), Gilmore's EBL model including photon/ALP coupling, Gilmore's EBL with CIBER excess and the latter including photon/ALP coupling respectively. We find the goodness of fit for the model with CIBER excess can be improved with a significance of 7.6σ after including the photon/ALP coupling. Thus, the ALP/photon mixing mechanism can effectively alleviate the tension; However, the Gilmore EBL model, on the whole, is more compatible with the observed spectra compared to those with ALP, although individual blazars such as PKS 1424 + 240 and 1ES 1101-232 prefer the ALP-model. Our results suggest that the recent EBL models can solely explain the VHE γ-ray observations, and assuming the existence of the ALP to alleviate the tension is not required in a statistical sense, thus the excess over the EBL models is less likely to be a new EBL component.
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