Studies on the Roles of PDGFRA and EGFR in the Classification and Identification of Therapeutic Targets for Human Gliomas

Glioma is the most common type of primary tumor in the adult central nervous system (CNS). However, the current classification of gliomas is highly subjective and even inaccurate in some cases, which leads to clinical confusion and hinders the development of targeted therapies. EGFR and PDGFRA play crucial roles in glia development and glioma pathogenesis. In this thesis we aim to establish a glial genesis-guided molecular classification scheme for gliomas based on the genes co-expressed with EGFR or PDGFRA and to clarify the clinical relevance and the mechanism of PDGFRA expression in different glioma subtypes. We also aim to investigate the role of cell surface PDGFRA expression in regulating glioma cell proliferation. In order to establish a glial genesis-guided classification scheme, we identified 69 genes co-expressed with EGFR (EM) or PDGFRA (PM) as classifiers. Using these 69 classifiers, gliomas are clarified into EM (highly expressing EM genes), PM (highly expressing PM genes), and EMlowPMlow (lowly expressing both EM and PM genes) subtypes in a morphology-independent manner. Our results showed that besides their distinct patterns of genomic alterations, EM gliomas were associated with higher age at diagnosis, poorer prognosis, stronger expression of neural stem cell genes and astrogenesis genes, while PM and EMlowPMlow gliomas were associated with younger age at diagnosis and better prognosis. PM gliomas were enriched in the expression of oligodendrogenesis genes, whereas EMlowPMlow gliomas were enriched in the signatures of mature neurons and oligodendrocytes. These findings constitute a framework for improving molecular diagnosis and identifying therapeutic targets to combat gliomas. To investigate the clinical relevance of PDGFRA in gliomas, the clinical outcomes of gliomas with the top 25% of PDGFRA expression levels (PDGFRA-high) were compared with the gliomas with lowest 25% of PDGFRA expression levels (PDGFRA-low). We found that PDGFRA-high gliomas contained nearly all morphological subtypes, which was associated with frequent IDH1 mutation, 1p LOH, 19q LOH, less EGFR amplification, younger age at disease onset and better survival compared to PDGFRA-low gliomas. We also found that the PDGFRA expression can be induced and maintained by fibroblast growth factor 2 (FGF2) in primary glioma cells. FGF2-dependent maintenance of PDGFRA expression was concordant with the maintenance of a subset of gliogenic genes and higher rates of cell proliferation. Our findings suggest a role of FGF2 in regulating PDGFRA expression in the subset of gliomas. To investigate the role of cell surface expression of PDGFRA in regulating cell proliferation, we compared the growth rate of primary glioma cells having high cell surface PDGFRA expression level with the glioma cells having low cell surface PDGFRA expression level. We demonstrated that glioma cell proliferation correlated with the extent of surface expression of PDGFRA in both glioma cell lines and their corresponding tumor samples. We also found that MEK inhibitor U0126 treatment can decrease the surface PDGFRA expression and result in deviation of PDGFRA from endosomal trafficking and recycling compartment to the Golgi network in a reversible, dose- and time-dependent manner without affecting total PDGFRA expression. U0126 mediated down-regulation of PDGFRA surface expression correlated with diminished cell proliferation. Our findings suggested that the trafficking of PDGFRA in glioma cells is regulated by ERK activity and can potentially be manipulated to combat glioma growth

Sex-Related Differences in Vocal Responses to Pitch Feedback Perturbations During Sustained Vocalization

The present study assessed the effect of sex on voice fundamental frequency (F0) responses to pitch feedback perturbations during sustained vocalization. Sixty-four native-Mandarin speakers heard their voice pitch feedback shifted at ±50, ±100, or ±200 cents for 200 ms, five times during each vocalization. The results showed that, as compared to female speakers, male speakers produced significantly larger but slower vocal responses to the pitch-shifted stimuli. These findings reveal a modulation of vocal response as a function of sex, and suggest that there may be a differential processing of vocal pitch feedback perturbations between men and wome

Study on microstructure and properties of Mg-alloy surface alloying layer fabricated by EPC

AZ91D surface alloying was investigated through evaporative pattern casting (EPC) technology. Aluminum powder (0.074 to 0.104 mm) was used as the alloying element in the experiment. An alloying coating with excellent properties was fabricated, which mainly consisted of adhesive, co-solvent, suspending agent and other ingredients according to desired proportion. Mg-alloy melt was poured under certain temperature and the degree of negative pressure. The microstructure of the surface layer was examined by means of scanning electron microscopy. It has been found that a large volume fraction of network new phases were formed on the Mg-alloy surface, the thickness of the alloying surface layer increased with the alloying coating increasing from 0.3 mm to 0.5 mm, and the microstructure became compact. Energy dispersive X-ray (EDX) analysis was used to determine the chemical composition of the new phases. It showed that the new phases mainly consist of β-Mg17Al12, in addition to a small quantity of inter-metallic compounds and oxides. A micro-hardness test and a corrosion experiment to simulate the effect of sea water were performed. The result indicated that the highest micro-hardness of the surface reaches three times that of the matrix. The corrosion rate of alloying samples declines to about a fifth of that of the as-cast AZ91D specimen

Dynamics of Vocalization-Induced Modulation of Auditory Cortical Activity at Mid-utterance

Background: Recent research has addressed the suppression of cortical sensory responses to altered auditory feedback that occurs at utterance onset regarding speech. However, there is reason to assume that the mechanisms underlying sensorimotor processing at mid-utterance are different than those involved in sensorimotor control at utterance onset. The present study attempted to examine the dynamics of event-related potentials (ERPs) to different acoustic versions of auditory feedback at mid-utterance. Methodology/Principal findings: Subjects produced a vowel sound while hearing their pitch-shifted voice (100 cents), a sum of their vocalization and pure tones, or a sum of their vocalization and white noise at mid-utterance via headphones. Subjects also passively listened to playback of what they heard during active vocalization. Cortical ERPs were recorded in response to different acoustic versions of feedback changes during both active vocalization and passive listening. The results showed that, relative to passive listening, active vocalization yielded enhanced P2 responses to the 100 cents pitch shifts, whereas suppression effects of P2 responses were observed when voice auditory feedback was distorted by pure tones or white noise. Conclusion/Significance: The present findings, for the first time, demonstrate a dynamic modulation of cortical activity as a function of the quality of acoustic feedback at mid-utterance, suggesting that auditory cortical responses can be enhanced or suppressed to distinguish self-produced speech from externally-produced sounds

Perceived corporate social responsibility performance in professional football and its impact on fan-based patronage intentions: An example from Chinese football

Purpose This paper analyzes fans' perceptions of the CSR activities of a professional football club, specifically whether or not perceived CSR performances are then likely to influence patronage intentions of the fans in relation to the football club. Methodology The paper uses the example of a professional football club in China as a case study for data analysis. Based on a sample of 451home team fans, analysis was conducted through calculation of descriptive statistics, and exploratory factor analysis (EFA). Regression analysis was conducted to determine the impact of perceived CSR performance on fan’s patronage intentions. Findings The results revealed factor 3(“CSR to customer and employee”), and factor 4 (“Community development and youth education”) were significantly predictive of all the three patronage intention variables, i.e. repeat purchase, Word of Mouth, and merchandise consumption. In addition, factor 2 (“charity”) would also affect merchandise consumption intention, but have no effect on any other dimensions. Originality/Value A scale measuring perceived CSR performance in professional football clubs by the fans in the Chinese context has been developed. In addition, we have identified that the two main CSR factors that would influence fans’ patronage intentions, i.e. "CSR to the customer and employee" and "community development and youth education". Thus, if football clubs are to use CSR strategically to leverage spend then it is these two areas that they should focus on explicitly in relation to CSR activities. This paper adds value to an area that is currently under-researched in respect of CSR activities in Chinese professional football

Real-Time Pricing Strategy Based on the Stability of Smart Grid for Green Internet of Things

The ever increasing demand of energy efficiency and the strong awareness of environment have led to the enhanced interests in green Internet of things (IoTs). How to efficiently deliver power, especially, with the smart grid based on the stability of network becomes a challenge for green IoTs. Therefore, in this paper we present a novel real-time pricing strategy based on the network stability in the green IoTs enabled smart grid. Firstly, the outage is analyzed by considering the imbalance of power supply and demand as well as the load uncertainty. Secondly, the problem of power supply with multiple-retailers is formulated as a Stackelberg game, where the optimal price can be obtained with the maximal profit for retailers and users. Thirdly, the stability of price is analyzed under the constraints. In addition, simulation results show the efficiency of the proposed strategy

Pyrethroid insecticides: Isoform-dependent hydrolysis, induction of cytochrome P450 3A4 and evidence on the involvement of the pregnane X receptor

Pyrethroids account for more than one-third of the insecticides currently marketed in the world. In mammals, these insecticides undergo extensive metabolism by carboxylesterases and cytochrome P450s (CYPs). In addition, some pyrethroids are found to induce the expression of CYPs. The aim of this study was to determine whether pyrethroids induce carboxylesterases and CYP3A4, and whether the induction is correlated inversely with their hydrolysis. Human liver microsomes were pooled and tested for the hydrolysis of 11 pyrethroids. All pyrethroids were hydrolyzed by the pooled microsomes, but the hydrolytic rates varied by as many as 14 fold. Some pyrethroids such as bioresmethrin were preferably hydrolyzed by carboxylesterase HCE1, whereas others such as bifenthrin preferably by HCE2. In primary human hepatocytes, all pyrethroids except tetramethrin significantly induced CYP3A4. In contrast, insignificant changes were detected on the expression of carboxylesterases. The induction of CYP3A4 was confirmed in multiple cell lines including HepG2, Hop92 and LS180. Overall, the magnitude of the induction was correlated inversely with the rates of hydrolysis, but positively with the activation of the pregnane X receptor (PXR). Transfection of a carboxylesterase markedly decreased the activation of PXR, and the decrease was in agreement with carboxylesterase-based preference for hydrolysis. In addition, human PXR variants as well as rat PXR differed from human PXR (wild-type) in responding to certain pyrethroids (e.g., lambda-cyhalothrin), suggesting that induction of PXR target genes by these pyrethroids varies depending on polymorphic variants and the PXR species identity

The effects of apoptosis vulnerability markers on the myocardium in depression after myocardial infarction

Background : There is an increased incidence of major depressive disorder (MDD) in individuals after myocardial infarction (MI), but the pathophysiological processes mediating this association are unclear. Our previous study demonstrated an increase in pro-apoptotic pathways in the myocardium and hippocampus in MDD, which was reversed by venlafaxine. This study aimed to attempt to confirm the effects of apoptosis vulnerability markers on the myocardium in a model of depression after myocardial infarction. Methods : Rats were divided into four groups: sham (N = 8), depression (N = 8, chronic mild unpredictable stress and separation were used in the depression group), MI (N = 13) and post-MI depression (N = 7). The rats in all four groups underwent the same open field and sucrose preference behavioral tests. Evan Blue staining was used to determine the area at risk of myocardial infarction in the left ventricle, and 2,3,5-triphenyl tetrazolium chloride (1.5% TTC) dye was used to detect the size of the myocardial infarction. The expression of bax and bcl-2 protein in the myocardium was investigated by immunohistochemistry, and the mRNA expression of bax, bcl-2 and caspase-3 in the myocardium was investigated by real time RT-PCR. Apoptosis was estimated in the myocardium by measuring the Bax:Bcl-2 ratio. Results : In the depression and post-MI depression rats, there were significantly decreased movements and total sucrose consumption, modeling behavioral deficits and an anhedonic-like state. In terms of myocardial infarction size, no difference was seen between the MI and post-MI depression groups. There was an up-regulated Bax:Bcl-2 ratio in the depression, MI and post-MI depression groups. Furthermore, in the latter group, there was a greater up-regulated Bax:Bcl-2 ratio. However, caspase-3 did not differ among the four groups. Conclusions : These results of this animal model suggest that active pro-apoptotic pathways may be involved in the nexus between myocardial infarction and depression. This mechanism may be germane to understanding this relationship in humans