Our previous study reported that Epstein-Barr virus(EBV)-encoded latent membrane protein 1 (LMP1) could induce development of CD44(+/High) stem-like cells in nasopharyngeal carcinoma (NPC). However, ...the molecular mechanisms that underlie modulation of cancer stem cells (CSCs) in NPC remain unclear. Here, we show that LMP1 induced CSC-like properties through promotion of the expression of epithelial-mesenchymal transition-like cellular markers and through alterations in differentiation markers. Furthermore, LMP1 activated and triggered phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, which subsequently stimulated expression of CSC markers, development of side population and tumor sphere formation. This suggests that PI3K/AKT pathway has an important role in the induction and maintenance of CSC properties in NPC. Similarly, PI3K/AKT pathway was also activated by phosphorylase in LMP1-induced CD44(+/High) cells. In addition, LMP1 greatly increased expression of miR-21 and downregulated expression of the miR-21 target, PTEN. Overexpression of miR-21 by transfection of miR-21 mimics into LMP1-transformed cells led to phosphorylase-mediated activation of the PI3K/AKT pathway and induction of CSCs. On the contrary, phosphorylation of the PI3K/AKT pathway and the expression of CSC were reversed by an miR-21 inhibitor. The specific inhibitor (Ly294002) of PI3K/AKT pathway significantly decreased expression of miR-21 and CSC markers and upregulated the expression of PTEN, which indicates that miR-21 and PTEN are the downstream effectors of PI3K/AKT and that expression of these two effectors are related to the development of NPC CSCs. Taken together, our novel findings indicate that LMP1, PI3K/AKT, miR-21 and PTEN constitute a positive feedback loop and have a key role in LMP1-induced CSCs in NPC.
The extragalactic background light (EBL) is of fundamental importance both for understanding the entire process of galaxy evolution and for γ-ray astronomy, but the overall spectrum of the EBL ...between 0.1 and 1000 μm has never been determined directly from galaxy spectral energy distribution (SED) observations over a wide redshift range. The evolving, overall spectrum of the EBL is derived here utilizing a novel method based on observations only. This is achieved from the observed evolution of the rest-frame K-band galaxy luminosity function up to redshift 4, combined with a determination of galaxy-SED-type fractions. These are based on fitting Spitzer Wide-Area Infrared Extragalactic Survey (SWIRE) templates to a multiwavelength sample of about 6000 galaxies in the redshift range from 0.2 to 1 from the All-wavelength Extended Groth Strip International Survey (AEGIS). The changing fractions of quiescent galaxies, star-forming galaxies, starburst galaxies and active galactic nucleus (AGN) galaxies in that redshift range are estimated, and two alternative extrapolations of SED types to higher redshifts are considered. This allows calculation of the evolution of the luminosity densities from the ultraviolet (UV) to the infrared (IR), the evolving star formation rate density of the Universe, the evolving contribution to the bolometric EBL from the different galaxy populations including AGN galaxies and the buildup of the EBL. Our EBL calculations are compared with those from a semi-analytic model, another observationally based model and observational data. The EBL uncertainties in our modelling based directly on the data are quantified, and their consequences for attenuation of very-high-energy γ-rays due to pair production on the EBL are discussed. It is concluded that the EBL is well constrained from the UV to the mid-IR, but independent efforts from IR and γ-ray astronomy are needed in order to reduce the uncertainties in the far-IR.
Due to the poor self-regeneration of brain tissue, stem cell transplantation therapy is purported to enable the replacement of lost neurons after traumatic brain injury (TBI). The main challenge of ...brain regeneration is whether the transplanted cells can survive and carry out neuronal functions in the lesion area. The brain is a complex neuronal network consisting of various types of cells that significantly influence on each other, and the survival of the implanted stem cells in brain is critically influenced by the surrounding cells. Although stem cell-based therapy is developing rapidly, most previous studies just focus on apply single type of stem cells as cell source. Here, we found that co-culturing human umbilical cord mesenchymal stem cells (hUC-MSCs) directly with the activated astrocytes benefited to the proliferation and neuron differentiation of hUC-MSCs in vitro. In this study, hUC-MSCs and the activated astrocytes were seeded in RADA16-BDNF peptide scaffold (R-B-SPH scaffold), a specifical self-assembling peptide hydrogel, in which the environment promoted the differentiation of typical neuron-like cells with neurites extending in three-dimensional directions. Moreover, the results showed co-culture of hUC-MSCs and activated astrocytes promoted more BDNF secretion which may benefit to both neural differentiation of ectogenic hUC-MSCs and endogenic neurogenesis. In order to promote migration of the transplanted hUC-MSCs to the host brain, the hUC-MSCs were forced with CXC chemokine receptor 4 (CXCR4). We found that the moderate-sized lesion cavity, but not the large cavity caused by TBI was repaired via the transplantation of hUC-MSCs
and activated astrocytes embedded in R-B-SPH scaffolds. The functional neural repair for TBI demonstrated in this study is mainly due to the transplantation system of double cells, hUC-MSCs and activated astrocytes. We believe that this novel cell transplantation system offers a promising treatment option for cell replacement therapy for TBI.
In this reach, we specifically linked RGIDKRHWNSQ, a functional peptide derived from BDNF, to the C-terminal of RADARADARADARADA (RADA16) to structure a functional self-assembling peptide hydrogel scaffold, RADA16-BDNF (R-B-SPH scaffold) for the better transplantation of the double cell unit. Also, the novel scaffold was used as cell-carrier for transplantation double cell unit (hUC-MSCs/astrocyte) for treating traumatic brain injury. The results of this study showing that R-B-SPH scaffold was pliancy and flexibility to fit the brain lesion cavity and promotes the outgrowth of axons and dendrites of the neurons derived from hUC-MSCs in vitro and in vivo, indicating the 3D R-B-SPH scaffold provided a suitable microenvironment for hUC-MSC survival, proliferation and differentiation. Also, our results showing the double-cells transplantation system (hUC-MSCs/astrocyte) may be a novel cell-based therapeutic strategy for neuroregeneration after TBI with potential value for clinical application.
Background
The Child–Pugh (CP) score is used widely to assess liver function and predict postoperative outcomes in patients with hepatocellular carcinoma (HCC). Recently, the albumin–bilirubin (ALBI) ...score has been validated as a predictor of overall survival in these patients. This study aimed to compare the ability of the ALBI and CP scores to predict outcomes in patients with HCC after liver resection with curative intent.
Methods
Consecutive patients who underwent liver resection with curative intent for HCC between January 2007 and July 2013 were included in this retrospective study. The performance of the ALBI score in predicting postoperative liver failure (PHLF) and long‐term survival was compared with that of the CP score.
Results
A total of 1242 patients were enrolled. Of these, 166 (13·4 per cent) experienced PHLF. The area under the receiver operating characteristic (ROC) curve of the ALBI score for predicting PHLF was greater than that of the CP score (0·723 versus 0·607; P < 0·001). Similar to findings for CP grade, the incidence and severity of PHLF increased with increasing ALBI grade. The ALBI grade stratified patients into at least two distinct overall survival cohorts (P < 0·001), whereas the CP grade did not. The ALBI grade also classified patients with CP grade A disease into two distinct overall survival cohorts (P < 0·001), and overall survival rates in the group with poorer survival were similar to those in the majority of patients with CP grade B disease. Both CP and ALBI scores had low power in predicting disease‐free survival.
Conclusion
The ALBI grade predicted PHLF and overall survival in patients with HCC undergoing liver resection with curative intent more accurately than the CP grade.
ALBI score may be better
We present new observational determinations of the evolution of the 2–10 keV X-ray luminosity function (XLF) of active galactic nuclei (AGN). We utilize data from a number of surveys including both ...the 2 Ms Chandra Deep Fields and the AEGIS-X 200 ks survey, enabling accurate measurements of the evolution of the faint end of the XLF. We combine direct, hard X-ray selection and spectroscopic follow-up or photometric redshift estimates at z < 1.2 with a rest-frame UV colour pre-selection approach at higher redshifts to avoid biases associated with catastrophic failure of the photometric redshifts. Only robust optical counterparts to X-ray sources are considered using a likelihood ratio matching technique. A Bayesian methodology is developed that considers redshift probability distributions, incorporates selection functions for our high-redshift samples and allows robust comparison of different evolutionary models. We statistically account for X-ray sources without optical counterparts to correct for incompleteness in our samples. We also account for Poissonian effects on the X-ray flux estimates and sensitivities and thus correct for the Eddington bias. We find that the XLF retains the same shape at all redshifts, but undergoes strong luminosity evolution out to z∼ 1, and an overall negative density evolution with increasing redshift, which thus dominates the evolution at earlier times. We do not find evidence that a luminosity-dependent density evolution, and the associated flattening of the faint-end slope, is required to describe the evolution of the XLF. We find significantly higher space densities of low-luminosity, high-redshift AGN than in prior studies, and a smaller shift in the peak of the number density to lower redshifts with decreasing luminosity. The total luminosity density of AGN peaks at z= 1.2 ± 0.1, but there is a mild decline to higher redshifts. We find that >50 per cent of black hole growth takes place at z > 1, with around half in LX < 1044 erg s−1 AGN.
Flavonoids display a wide range of pharmacological properties including anti‐inflammatory. Anti‐mutagenic, anti‐carcinogenic and anti‐cancer effects. Here, we evaluated the effects of eight ...flavonoids on the tumour cell proliferation, cellular protein phosphorylation, and matrix metalloproteinase (MMPs) secretion.
Of the flavonoids examined, luteolin (Lu) and quercetin (Qu) were the two most potent agents, and significantly inhibited A431 cell proliferation with IC50 values of 19 and 21 μM, respectively.
The epidermal growth factor (EGF) (10 nM) promoted growth of A431 cells (+25±4.6%) and mediated epidermal growth factor receptor (EGFR) tyrosine kinase activity and autophosphorylation of EGFR were inhibited by Lu and Qu. At concentration of 20 μM, both Lu and Qu markedly decreased the levels of phosphorylation of A431 cellular proteins, including EGFR.
A431 cells treated with Lu or Qu exhibited protuberant cytoplasmic blebs and progressive shrinkage morphology. Lu and Qu also time‐dependently induced the appearance of a ladder pattern of DNA fragmentation, and this effect was abolished by EGF treatment.
The addition of EGF only marginally diminished the inhibitory effect of luteolin and quercetin on the growth rate of A431 cells, treatment of cellular proteins with EGF and luteolin or quercetin greatly reduced protein phosphorylation, indicating Lu and Qu may act effectively to inhibit a wide range of protein kinases, including EGFR tyrosine kinase.
EGF increased the levels of matrix metalloproteinase‐2 (MMP‐2) and matrix metalloproteinase‐9 (MMP‐9), while Lu and Qu appeared to suppress the secretion of these two MMPs in A431 cells.
Examination of the relationship between the chemical structure and inhibitory effects of eight flavonoids reveal that the double bond between C2 and C3 in ring C and the OH groups on C3′ and C4′ in ring B are critical for the biological activities.
This study demonstrates that the inhibitory effects of Lu and Qu, and the stimulatory effects of EGF, on tumour cell proliferation, cellular protein phosphorylation, and MMP secretion may be mediated at least partly through EGFR. This study supports the idea that Lu and Qu may have potential as anti‐cancer and anti‐metastasis agents.
British Journal of Pharmacology (1999) 128, 999–1010; doi:10.1038/sj.bjp.0702879
ABSTRACT The Spitzer-Cosmic Assembly Deep Near-infrared Extragalactic Legacy Survey (S-CANDELS; PI G.Fazio) is a Cycle 8 Exploration Program designed to detect galaxies at very high redshifts ( ). To ...mitigate the effects of cosmic variance and also to take advantage of deep coextensive coverage in multiple bands by the Hubble Space Telescope (HST) Multi-cycle Treasury Program CANDELS, S-CANDELS was carried out within five widely separated extragalactic fields: the UKIDSS Ultra-deep Survey, the Extended Chandra Deep Field South, COSMOS, the HST Deep Field North, and the Extended Groth Strip. S-CANDELS builds upon the existing coverage of these fields from the Spitzer Extended Deep Survey (SEDS), a Cycle 6 Exploration Program, by increasing the integration time from SEDS' 12 hr to a total of 50 hr but within a smaller area, 0.16 deg2. The additional depth significantly increases the survey completeness at faint magnitudes. This paper describes the S-CANDELS survey design, processing, and publicly available data products. We present Infrared Array Camera (IRAC) dual-band catalogs reaching to a depth of 26.5 AB mag. Deep IRAC counts for the roughly 135,000 galaxies detected by S-CANDELS are consistent with models based on known galaxy populations. The increase in depth beyond earlier Spitzer/IRAC surveys does not reveal a significant additional contribution from discrete sources to the diffuse Cosmic Infrared Background (CIB). Thus it remains true that only roughly half of the estimated CIB flux from COBE/DIRBE is resolved.
Of several dozen galaxies observed spectroscopically that are candidates for having a redshift (z) in excess of seven, only five have had their redshifts confirmed via Lyman α emission, at z = 7.008, ...7.045, 7.109, 7.213 and 7.215 (refs 1-4). The small fraction of confirmed galaxies may indicate that the neutral fraction in the intergalactic medium rises quickly at z > 6.5, given that Lyman α is resonantly scattered by neutral gas. The small samples and limited depth of previous observations, however, makes these conclusions tentative. Here we report a deep near-infrared spectroscopic survey of 43 photometrically-selected galaxies with z > 6.5. We detect a near-infrared emission line from only a single galaxy, confirming that some process is making Lyman α difficult to detect. The detected emission line at a wavelength of 1.0343 micrometres is likely to be Lyman α emission, placing this galaxy at a redshift z = 7.51, an epoch 700 million years after the Big Bang. This galaxy's colours are consistent with significant metal content, implying that galaxies become enriched rapidly. We calculate a surprisingly high star-formation rate of about 330 solar masses per year, which is more than a factor of 100 greater than that seen in the Milky Way. Such a galaxy is unexpected in a survey of our size, suggesting that the early Universe may harbour a larger number of intense sites of star formation than expected.
Neurons in the prefrontal cortex exhibit diverse behavioural correlates, an observation that has been attributed to cell-type diversity. To link identified neuron types with network and behavioural ...functions, we recorded from the two largest genetically defined inhibitory interneuron classes, the perisomatically targeting parvalbumin (PV) and the dendritically targeting somatostatin (SOM) neurons in anterior cingulate cortex of mice performing a reward foraging task. Here we show that PV and a subtype of SOM neurons form functionally homogeneous populations showing a double dissociation between both their inhibitory effects and behavioural correlates. Out of several events pertaining to behaviour, a subtype of SOM neurons selectively responded at reward approach, whereas PV neurons responded at reward leaving and encoded preceding stay duration. These behavioural correlates of PV and SOM neurons defined a behavioural epoch and a decision variable important for foraging (whether to stay or to leave), a crucial function attributed to the anterior cingulate cortex. Furthermore, PV neurons could fire in millisecond synchrony, exerting fast and powerful inhibition on principal cell firing, whereas the inhibitory effect of SOM neurons on firing output was weak and more variable, consistent with the idea that they respectively control the outputs of, and inputs to, principal neurons. These results suggest a connection between the circuit-level function of different interneuron types in regulating the flow of information and the behavioural functions served by the cortical circuits. Moreover, these observations bolster the hope that functional response diversity during behaviour can in part be explained by cell-type diversity.
Immunity acquired from infection or vaccination protects humans from symptomatic hepatitis E. However, whether the risk of hepatitis E virus (HEV) infection is reduced by the immunity remains ...unknown. To understand this issue, a cohort with 12 409 participants randomized to receive the hepatitis E vaccine Hecolin® or placebo were serologically followed up for 2 years after vaccination. About half (47%) of participants were initially seropositive. A total of 139 infection episodes, evidenced by four-fold or greater rise of anti-HEV level or positive seroconversion, occurred in participants who received three doses of treatment. Risk of infection was highest among the baseline seronegative placebo group participants (2.04%). Pre-existing immunity and vaccine-induced immunity lower the risk significantly, to 0.52% and 0.30%, respectively. In conclusion, both vaccine-induced and naturally acquired immunity can effectively protect against HEV infection.
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