61 research outputs found
HER receptor-mediated dynamic signalling in breast cancer cells
The dynamics of cell signalling are critical to cell fate decisions. Human Epidermal
growth factor Receptors (HERs)-mediated Ras/Raf/MEK/ERK and PI3K/Akt
signalling cascades relay extracellular signals from the plasma membrane to targets
in the nucleus and cytoplasm and play pivotal roles in cell fate determination
including proliferation, differentiation and cell survival. Both pathways, once
activated, are further regulated by complex feedback loops which may exert either
positive or negative effects on cascade components and can result in signalling
oscillation. In this study, heregulin (HRG) - and epidermal growth factor (EGF)-
stimulated oscillation of both p-ERK1/2 and p-Akt expression in breast cancer cell
lines was demonstrated. The oscillation was cell line dependent and was observed in
MCF-7 and MCF-7/HER2-18 cells but not in BT474 cells. The oscillation was
augmented by cycloheximide implicating transcriptional involvement. Gene
expression analysis identified 29 genes as possible candidates involved in the
transcriptional feedback regulation. Apart from the feedback regulation, feedforward
regulation was also observed. To expedite the analyses In-cell Western and
Reverse Phase Protein Array (RPPA) assays were developed. A scheme of
transcriptional feedback loops regulating the oscillation in the ERK1/2 pathway is
proposed, including negative feedback loops to ERK1/2 from DUSPs, early positive
and late negative feedback loops to MEK1/2 and positive feedback loops to HER-3
from AREG, HB-EGF, CYR61 and CTGF. Two HER-2-targeted inhibitory
monoclonal antibodies were investigated – trastuzumab and pertuzumab.
Trastuzumab not only inhibited the growth of HER-2 over-expressing MCF-7/HER2-
18 cells and BT474 cells but also that of EGF-driven MCF-7 cells which expressed
low/moderate HER-2 levels. Pertuzumab blocked the growth of both MCF-7 and
MCF-7/HER2-18 driven by either EGF or HRG. When used in combination with
trastuzumab, pertuzumab had much more potent activity in inhibiting cell growth and
signalling than either single drug. Trastuzumab and pertuzumab had opposing effects
on immediate p-ERK1/2 signalling and trastuzumab’s effects on signalling could be
mimicked by the PI3K inhibitor LY294002. PTPN13, a non-receptor type tyrosine
protein phosphatase, is a proposed tumour suppressor in breast cancer. This was
investigated as a candidate regulator of the signalling oscillation and although not observed as a transcriptional modulator of the oscillation, its high expression level
was observed to be associated with cell growth inhibition in MCF-7/HER2-18 cells
by trastuzumab. Moreover, immunohistochemical analysis of 121 clinical tumours
which had received trastuzumab treatment revealed the correlation between the
expression level of PTPN13 and the mutation status of PIK3CA. In conclusion, the
observed oscillation may contribute to the elucidation of the complex regulation of
signalling pathways, which is vital to the different cell fate decision made through
the same core pathway. The synergy between trastuzumab and pertuzumab supports
the clinical use of the combination treatment and suggested PI3K/Akt pathway as the
major pathway in controlling tumour growth
Systems analysis of drug-induced receptor tyrosine kinase reprogramming following targeted mono- and combination anti-cancer therapy
The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers. One route to overcome this resistance is combination therapy. We describe the results of a joint in silico, in vitro, and in vivo investigations on the efficacy of trastuzumab, pertuzumab and their combination to target the HER2 receptors. Computational modelling revealed that these two drugs alone and in combination differentially suppressed RTK network activation depending on RTK co-expression. Analyses of mRNA expression in SKOV3 ovarian tumour xenograft showed up-regulation of HER3 following treatment. Considering this in a computational model revealed that HER3 up-regulation reprograms RTK kinetics from HER2 homodimerisation to HER3/HER2 heterodimerisation. The results showed synergy of the trastuzumab and pertuzumab combination treatment of the HER2 overexpressing tumour can be due to an independence of the combination effect on HER3/HER2 composition when it changes due to drug-induced RTK reprogramming
Impacts of air pollutants from rural Chinese households under the rapid residential energy transition
Rural residential energy consumption in China is experiencing a rapid transition towards clean energy, nevertheless, solid fuel combustion remains an important emission source. Here we quantitatively evaluate the contribution of rural residential emissions to PM2.5 (particulate matter with an aerodynamic diameter less than 2.5 μm) and the impacts on health and climate. The clean energy transitions result in remarkable reductions in the contributions to ambient PM2.5, avoiding 130,000 (90,000-160,000) premature deaths associated with PM2.5 exposure. The climate forcing associated with this sector declines from 0.057 ± 0.016 W/m2 in 1992 to 0.031 ± 0.008 W/m2 in 2012. Despite this, the large remaining quantities of solid fuels still contributed 14 ± 10 μg/m3 to population-weighted PM2.5 in 2012, which comprises 21 ± 14% of the overall population-weighted PM2.5 from all sources. Rural residential emissions affect not only rural but urban air quality, and the impacts are highly seasonal and location dependent
Manipulating Multiple Order Parameters via Oxygen Vacancies: The case of Eu0.5Ba0.5TiO3-{\delta}
Controlling functionalities, such as magnetism or ferroelectricity, by means
of oxygen vacancies (VO) is a key issue for the future development of
transition metal oxides. Progress in this field is currently addressed through
VO variations and their impact on mainly one order parameter. Here we reveal a
new mechanism for tuning both magnetism and ferroelectricity simultaneously by
using VO. Combined experimental and density-functional theory studies of
Eu0.5Ba0.5TiO3-{\delta}, we demonstrate that oxygen vacancies create Ti3+ 3d1
defect states, mediating the ferromagnetic coupling between the localized Eu
4f7 spins, and increase an off-center displacement of Ti ions, enhancing the
ferroelectric Curie temperature. The dual function of Ti sites also promises a
magnetoelectric coupling in the Eu0.5Ba0.5TiO3-{\delta}.Comment: Accepted by Physical Review B, 201
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Significant contrasts in aerosol acidity between China and the United States
Aerosol acidity governs several key processes in aerosol physics and chemistry, thus affecting aerosol mass and composition and ultimately climate and human health. Previous studies have reported aerosol pH values separately in China and the United States (USA), implying different aerosol acidity between these two countries. However, there is debate about whether mass concentration or chemical composition is the more important driver of differences in aerosol acidity. A full picture of the pH difference and the underlying mechanisms responsible is hindered by the scarcity of simultaneous measurements of particle composition and gaseous species, especially in China. Here we conduct a comprehensive assessment of aerosol acidity in China and the USA using extended ground-level measurements and regional chemical transport model simulations. We show that aerosols in China are significantly less acidic than in the USA, with pH values 1–2 units higher. Based on a proposed multivariable Taylor series method and a series of sensitivity tests, we identify major factors leading to the pH difference. Compared to the USA, China has much higher aerosol mass concentrations (gas + particle, by a factor of 8.4 on average) and a higher fraction of total ammonia (gas + particle) in the aerosol composition. Our assessment shows that the differences in mass concentrations and chemical composition play equally important roles in driving the aerosol pH difference between China and the USA – increasing the aerosol mass concentrations (by a factor of 8.4) but keeping the relative component contributions the same in the USA as the level in China increases the aerosol pH by ∼ 1.0 units and further shifting the chemical composition from US conditions to China's that are richer in ammonia increases the aerosol pH by ∼ 0.9 units. Therefore, China being both more polluted than the USA and richer in ammonia explains the aerosol pH difference. The difference in aerosol acidity highlighted in the present study implies potential differences in formation mechanisms, physicochemical properties, and toxicity of aerosol particles in these two countries.
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HER receptor-mediated dynamic signalling in breast cancer cells
The dynamics of cell signalling are critical to cell fate decisions. Human Epidermal growth factor Receptors (HERs)-mediated Ras/Raf/MEK/ERK and PI3K/Akt signalling cascades relay extracellular signals from the plasma membrane to targets in the nucleus and cytoplasm and play pivotal roles in cell fate determination including proliferation, differentiation and cell survival. Both pathways, once activated, are further regulated by complex feedback loops which may exert either positive or negative effects on cascade components and can result in signalling oscillation. In this study, heregulin (HRG) - and epidermal growth factor (EGF)- stimulated oscillation of both p-ERK1/2 and p-Akt expression in breast cancer cell lines was demonstrated. The oscillation was cell line dependent and was observed in MCF-7 and MCF-7/HER2-18 cells but not in BT474 cells. The oscillation was augmented by cycloheximide implicating transcriptional involvement. Gene expression analysis identified 29 genes as possible candidates involved in the transcriptional feedback regulation. Apart from the feedback regulation, feedforward regulation was also observed. To expedite the analyses In-cell Western and Reverse Phase Protein Array (RPPA) assays were developed. A scheme of transcriptional feedback loops regulating the oscillation in the ERK1/2 pathway is proposed, including negative feedback loops to ERK1/2 from DUSPs, early positive and late negative feedback loops to MEK1/2 and positive feedback loops to HER-3 from AREG, HB-EGF, CYR61 and CTGF. Two HER-2-targeted inhibitory monoclonal antibodies were investigated – trastuzumab and pertuzumab. Trastuzumab not only inhibited the growth of HER-2 over-expressing MCF-7/HER2- 18 cells and BT474 cells but also that of EGF-driven MCF-7 cells which expressed low/moderate HER-2 levels. Pertuzumab blocked the growth of both MCF-7 and MCF-7/HER2-18 driven by either EGF or HRG. When used in combination with trastuzumab, pertuzumab had much more potent activity in inhibiting cell growth and signalling than either single drug. Trastuzumab and pertuzumab had opposing effects on immediate p-ERK1/2 signalling and trastuzumab’s effects on signalling could be mimicked by the PI3K inhibitor LY294002. PTPN13, a non-receptor type tyrosine protein phosphatase, is a proposed tumour suppressor in breast cancer. This was investigated as a candidate regulator of the signalling oscillation and although not observed as a transcriptional modulator of the oscillation, its high expression level was observed to be associated with cell growth inhibition in MCF-7/HER2-18 cells by trastuzumab. Moreover, immunohistochemical analysis of 121 clinical tumours which had received trastuzumab treatment revealed the correlation between the expression level of PTPN13 and the mutation status of PIK3CA. In conclusion, the observed oscillation may contribute to the elucidation of the complex regulation of signalling pathways, which is vital to the different cell fate decision made through the same core pathway. The synergy between trastuzumab and pertuzumab supports the clinical use of the combination treatment and suggested PI3K/Akt pathway as the major pathway in controlling tumour growth.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Complete mitochondrial DNA and phylogenetic study of qionglai native black chicken
The complete mitochondrial genome sequence of the qionglai black chicken was measured by PCR-based methods, the molecular characterization and phyletic evolution analyzed in detail. Our result showed that the entire mitochondrial genome of the qionglai black chicken is a circular molecule consisting of 16,785 bp (GenBank accession number: KT958484). The contents of A, T, C, and G were 30.25%, 23.74%, 32.54% and 13.48%in the mitochondrial genome, respectively. The complete mitochondrial genome of the qionglai blackchicken contains a typical structure, including 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and 1 control region (D-loop region). The phyletic evolution analysis shown that this chicken was evolution between the red jungle fowl and the special egg chicken white loghorn chicken.This complete mitochondrial genome sequence provides essential information in understanding phylogenetic relationships among Gallusgallus domesticus mitochondrial genomes and the breeding of native chic
Complete mitochondrial DNA and phylogenetic study of qionglai native black chicken
The complete mitochondrial genome sequence of the qionglai black chicken was measured by PCR-based methods, the molecular characterization and phyletic evolution analyzed in detail. Our result showed that the entire mitochondrial genome of the qionglai black chicken is a circular molecule consisting of 16,785 bp (GenBank accession number: KT958484). The contents of A, T, C, and G were 30.25%, 23.74%, 32.54% and 13.48%in the mitochondrial genome, respectively. The complete mitochondrial genome of the qionglai blackchicken contains a typical structure, including 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and 1 control region (D-loop region). The phyletic evolution analysis shown that this chicken was evolution between the red jungle fowl and the special egg chicken white loghorn chicken.This complete mitochondrial genome sequence provides essential information in understanding phylogenetic relationships among Gallusgallus domesticus mitochondrial genomes and the breeding of native chic
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