Enzalutamide, a nonsteroidal antiandrogen, significantly prolonged the survival of patients with metastatic castration-resistant prostate cancer (CRPC). However, patients receiving enzalutamide ...frequently develop drug resistance. Rooibos (Aspalathus linearis) is a shrub-like leguminous fynbos plant endemic to the Cedarberg Mountains area in South Africa. We evaluated the possibility of using a pharmaceutical-grade green rooibos extract (GRT, containing 12.78% aspalathin) to suppress the proliferation and survival of enzalutamide-resistant prostate cancer (PCa) cells. Treatment with GRT dose-dependently suppressed the proliferation, survival, and colony formation of enzalutamide-resistant C4-2 MDV3100r cells and PC-3 cells. Non-cancerous human cells were more resistant to GRT treatment. GRT suppressed the expression of proteins involved in phosphoinositide 3-kinase (PI3K)-Akt signaling, androgen receptor (AR), phospho-AR (Ser81), cyclin-dependent kinase 1 (Cdk1), c-Myc and Bcl-2 but increased the expression of apoptotic proteins. Overexpression of c-Myc antagonized the suppressive effects of GRT, while knockdown of c-Myc increased the sensitivity of PCa cells to GRT treatment. Expression level of c-Myc correlated to resistance of PCa cells to GRT treatment. Additionally, immunofluorescence microscopy demonstrated that GRT reduced the abundance of AR proteins both in nucleus and cytoplasm. Treatment with cycloheximide revealed that GRT reduced the stability of AR. GRT suppressed protein expression of AR and AR's downstream target prostate specific antigen (PSA) in C4-2 MDV3100r cells. Interestingly, we observed that AR proteins accumulate in nucleus and PSA expression is activated in the AR-positive enzalutamide-resistant PCa cells even in the absence of androgen. Our results suggested that GRT treatment suppressed the cell proliferation and survival of enzalutamide-resistant PCa cells via inhibition of c-Myc, induction of apoptosis, as well as the suppression of expression, signaling and stability of AR. GRT is a potential adjuvant therapeutic agent for enzalutamide-resistant PCa.
Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly ...understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer's-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer's disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.
Micromechanisms of fracture from acoustic emission Kao, C.-S.; Carvalho, F.C.S.; Labuz, J.F.
International journal of rock mechanics and mining sciences (Oxford, England : 1997),
06/2011, Letnik:
48, Številka:
4
Journal Article
Recenzirano
Acoustic emission (AE) events were located and characterized from a mode I fracture test on Charcoal granite. An AE source was modeled as a displacement discontinuity, a microcrack, with a ...displacement vector
b, normal
n, and area Δ
A. For convenience, the source parameters were recovered through a moment tensor representation, the components of which were estimated by minimizing the error between theoretical and measured displacements at sensor positions, with an appropriate constraint on the moment tensor for the microcrack model. Amplitude sensitivity was obtained through a calibration method with a step-unloading point source, providing the linkage between the AE signal and the measured displacement. The source mechanisms of some 400 events were identified as mixed-mode but shear dominant, with both opening and closing normal displacements. Decomposition of the microcrack volumes
b
i
Δ
A into the global coordinate system of the specimen revealed a positive accumulation of opening volume compatible with the mode I fracture mechanism, while the change in the vertical component agreed with the trend of beam deflection, even during a snap-back response. An out-of-plane, mode III microcrack volume component was also detected, which reflects the nature of the local deviation of the fracture path due to heterogeneity on the grain scale. Microcrack orientations, defined by horizontal and vertical angles called tortuosity and inclination angles, respectively, provided the explanation for the shear-dominant mechanisms on the local scale but opening on the structural level. Thus, shear-type AE events can be consistent with tensile fracture, as microcracks are locally based at various orientations.
► Acoustic emission is modeled as a point source of displacement discontinuity, a microcrack, described by displacement vector
b, normal
n, and area Δ
A. ► From a moment tensor representation of a microcrack, the source mechanisms from a mode I fracture test are identified as shear dominant. ► Decomposition of
b
i
Δ
A reveals a positive accumulation of opening volume compatible with mode I fracture. ► Due to fracture tortuosity, shear-dominant mechanisms on the local scale can be consistent with opening on the global level.
We study the magnetic anisotropic properties of as-grown and annealed Pd/Co/Pd trilayer films based on their atomic and electronic structures using extended X-ray absorption fine structure (EXAFS), ...X-ray absorption near edge structure (XANES) spectroscopy and magnetic circular dichroism (XMCD) measurements. The annealed film exhibits interesting perpendicular magnetic anisotropy (PMA) whereas the as-grown film exhibits in-plane anisotropy. Cross-sectional transmission electron microscopic analysis together with the Co K-edge EXAFS results confirm the formation of an ordered-alloy CoPd phase in the annealed film, whereas the as-grown film has an
hcp
Co-like phase. Co L
3,2
-edge XMCD measurements reveal an enhanced ratio of the Co 3d orbital to spin moments of the annealed film providing evidence of the observed PMA upon annealing.
Strong perpendicular magnetic anisotropy (PMA) is observed in annealed Pd/Co/Pd trilayer film. The effect of temperature on alloy formation, the relationship among the atomic/electronic structures, magnetic moments and PMA has been studied.
Abstract
Second harmonic generation (SHG) microscopy is an effective analytical tool for a detailed investigation of the microscopic structure of non-centrosymmetric molecules. We developed a ...four-channel photon-counting-based Stokes polarimeter integrated to the SHG microscope for spatial characterization of polarization effects in the SH signal. We implemented Stokes-vector-based polarization-resolved SHG imaging to perform quantitative polarimetry, with a view to applications in biomedicine, which can measure the full polarization state of the SH light. In this work, we describe the application of a Stokes-vector-based four-channel photon counting SHG microscope to determine the molecular interpretation of the SH light from collagen in normal, scar, and keloid tissue.
Pancreatic stents can be used to treat a variety of acute and chronic pancreatic lesions. Sporadic successful trials in trauma patients have been reported. To our knowledge, however, a series with ...long-term follow-up has not previously been reported. We treated six patients in a 6-year period and report the long-term results.
From February 1999 to February 2005, six blunt-trauma patients with major pancreatic duct disruption were treated with pancreatic duct stent at a single trauma center. Assessment of injury severity and diagnosis were based on abdominal computed tomography (CT) and proved by endoscopic retrograde pancreatography (ERP), with chart review used to establish mechanism of injury, timing of ERP, and stent placement, as well as the long-term outcome.
Three of the six injuries were classified AAST grade III and three were grade IV; the interval to ERP with stent placement ranged from 8 hours to 22 days after the injury. One patient developed sepsis and died. One patient's stent could be removed early (52 days post-stenting) with mild ductal stricture, whereas the other four were complicated by severe ductal stricture that required repeated and prolonged stenting treatment. Removal of the stents was only possible in three of these four cases (at 12, 19, and 39 months, respectively), with stent dislodgment in the pancreatic duct occurring in another.
Stent therapy may avoid surgery in the acute trauma stage, and may be preserved as another choice for acute grade IV pancreatic injury. However, variant outcome and long-term ductal stricture reveal that the role of pancreatic duct stent is uncertain and may not be suitable for acute grade III pancreatic injury. However, it needs more clinical data to define the value in the acute blunt pancreatic duct injury.
Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular ...disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation.
•Analyzed 17 metabolic and inflammatory traits in >85,500 participants from 14 studies.•Big data evidenced that inflammation is a feature of metabolic syndrome (MetS).•Performed meta-analyses of large GWAS for 8 metabolic and 6 inflammatory traits.•Of the 130 pleiotropic variants identified, 25 are proposed to contribute to MetS.•Pleiotropy across MetS risk factors reflects in its correlated genetic architecture.
In this paper, a uniform material removal (UMR) model is proposed for an automatic mold polishing system (AMPS). Free-form surfaces of mold geometry in IGES format are read and regenerated by the ...AMPS using the NURBS model. The normal vector, the principal curvatures, and the effective contact area are calculated at any point on the surface. The sensitivity of each factor that influences the material removal is determined by Taguchi experiments. The UMR model is based on maintaining constant velocity and contact pressure by controlling the polishing force according to the effective contact area. Three optical molds were polished using two path patterns with and without UMR control for comparison. The experimental results showed that even the conventional constant-force polishing scheme can achieve nearly the same surface roughness; the surface profile error of the mold with UMR control is less than 1/3 of the mold without UMR control. In addition, the actual material removal depth is less than 5.4% of error compared to the predicted value by the UMR model.
More than 80% of advanced prostate cancer (PCa) cases have bone metastasis, with a 5-year survival rate of 25%. Previously, we reported that GRT, a standardized, pharmaceutical-grade aspalathin-rich ...extract (12.78 g aspalathin/100 g extract), prepared from green rooibos produced from the leaves and fine stems of Aspalathus linearis, inhibits the proliferation of PCa cells, meriting this investigation to determine if GRT can suppress the migration and invasion of castration-resistant prostate cancer (CRPC) cells.
In the present study, we investigated whether GRT extract can interfere with the migration and invasion of human CRPC cells.
Transwell assays were used to explore the effects of GRT on the migration and invasion of CRPC cells. Micro-Western Array (MWA) and Western blot analysis were carried out to unravel the underlying molecular mechanism(s).
Treatment with 25–100 μg/ml GRT suppressed the migration and invasion of LNCaP C4-2B and 22Rv1 CRPC cells. MWA and Western blot analysis indicated that GRT treatment suppressed the protein level of yes-associated protein (YAP), macrophage stimulating 1 protein (MST1), phospho-MST1/phospho-MST2 T183/T180, and paxillin, but increased the abundance of E-cadherin. Over-expression of YAP rescued the suppressive effects of GRT on migration and invasion of CRPC cells. Treatment with the major flavonoid of GRT — the C-glucosyl dihydrochalcone, aspalathin — at a concentration of 75–100 μg/ml also reduced the migration and invasion of CRPC cells, and the inhibition was partially rescued by YAP over-expression.
GRT treatment suppresses the migration and invasion of CRPC cells via inhibition of YAP signaling and paxillin.
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We simulate the three-dimensional quantum Heisenberg model with a spatially anisotropic ladder pattern using the first principles Monte Carlo method. Our motivation is to investigate quantitatively ...the newly established universal relation
T
N
/√
c
3
∝ ℳ
s
near the quantum critical point (QCP) associated with dimerization. Here
T
N
,
c
, and ℳ
s
are the Néel temperature, the spinwave velocity, and the staggered magnetization density, respectively. For all the physical quantities considered here, such as
T
N
and ℳ
s
, our Monte Carlo results agree nicely with the corresponding results determined by the series expansion method. In addition, we find it is likely that the effect of a logarithmic correction, which should be present in (3 + 1)-dimensions, to the relation
T
N
/√
c
3
∝ ℳ
s
near the investigated QCP only sets in significantly in the region with strong spatial anisotropy.
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