PDGF-R inhibition induces glioblastoma cell differentiation via DUSP1/p38MAPK signalling

Glioblastoma (GBM) is the most common and fatal primary brain tumour in adults. Considering that resistance to current therapies leads to limited response in patients, new therapeutic options are urgently needed. In recent years, differentiation therapy has been proposed as an alternative for GBM treatment, with the aim of bringing cancer cells into a post-mitotic/differentiated state, ultimately limiting tumour growth. As an integral component of cancer development and regulation of differentiation processes, kinases are potential targets of differentiation therapies. The present study describes how the screening of a panel of kinase inhibitors (KIs) identified PDGF-Rα/β inhibitor CP-673451 as a potential differentiation agent in GBM. We show that targeting PDGF-Rα/β with CP-673451 in vitro triggers outgrowth of neurite-like processes in GBM cell lines and GBM stem cells (GSCs), suggesting differentiation into neural-like cells, while reducing proliferation and invasion in 3D hyaluronic acid hydrogels. In addition, we report that treatment with CP-673451 improves the anti-tumour effects of temozolomide in vivo using a subcutaneous xenograft mouse model. RNA sequencing and follow-up proteomic analysis revealed that upregulation of phosphatase DUSP1 and consecutive downregulation of phosphorylated-p38MAPK can underlie the pro-differentiation effect of CP-673451 on GBM cells. Overall, the present study identifies a potential novel therapeutic option that could benefit GBM patients in the future, through differentiation of residual GSCs post-surgery, with the aim to limit recurrence and improve quality of life

LMTK3 confers chemo-resistance in breast cancer

Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment. In a mouse model we showed that ectopic overexpression of LMTK3 decreases the efficacy of doxorubicin in reducing tumor growth. Interestingly, breast cancer cells overexpressing LMTK3 delayed the generation of double strand breaks (DSBs) after exposure to doxorubicin, as measured by the formation of γH2AX foci. This effect was at least partly mediated by decreased activity of ataxia-telangiectasia mutated kinase (ATM) as indicated by its reduced phosphorylation levels. In addition, our RNA-seq analyses showed that doxorubicin differentially regulated the expression of over 700 genes depending on LMTK3 protein expression levels. Furthermore, these genes were found to promote DNA repair, cell viability and tumorigenesis processes / pathways in LMTK3-overexpressing MCF7 cells. In human cancers, immunohistochemistry staining of LMTK3 in pre- and postchemotherapy breast tumor pairs from four separate clinical cohorts revealed a significant increase of LMTK3 following both doxorubicin and docetaxel based chemotherapy. In aggregate, our findings show for the first time a contribution of LMTK3 in cytotoxic drug resistance in breast cancer

Androgen receptor signaling regulates the transcriptome of prostate cancer cells by modulating global alternative splicing

Androgen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line antiandrogen therapies, including bicalutamide (CASODEX®) and enzalutamide (XTANDI®). However, the progression-free survival rate for the CRPC patients on antiandrogen therapies is only 8–19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation and inhibition of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes. Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist-mediated switch in IDH1 and PL2G2A isoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many AR-regulated alternatively spliced exons. And, using 2D invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist-driven tumor invasion. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide

Ash formation mechanisms during combustion/co-firing of biomass and coal

In case of PF firing, solid fuels such as coal and biomass undergo various chemical and physical transformations (devolatilization, char oxidation, fragmentation and gas to particle conversion followed by nucleation, coagulation and condensation etc.) just in milliseconds after fuel enters to the furnace. These transformations depend on several operating parameters (temperature, pressure, heating rate etc.) along with several chemical and physical properties (ash, moisture content, density, porosity, mineral matter composition and their association in the fuel matrix, particle size, shape and density etc.). The resultant ash formed during combustion after such parallel transformations in relation with several physical and chemical transformations along with the operating parameters will have different particle sizes and mineralogical composition compare to the original fuel.The scope of this research work is to perform the experimental and modelling work to investigate the ash formation process in terms of particle sizes and their mineralogical composition after combustion. A vast experimental study was planned in the lab scale combustion simulator at ECN with six biomass and two coals (Bark, wood chips, waste wood, saw dust, olive residue, straw, UK and a Polish etc.) under typical PF-firing conditions. Ash release, conversion, size reduction and size distribution alongside with the change in inorganic chemical compositions, are derived at different char burn out levels in the reactor at 20, 90, 210 and 1300 milliseconds of residence times. Several of the past observations made in the literature review are reconfirmed with performed set of experiments. A qualitative predictive tool is also suggested to envisage the extent of first line physical transformations. Based on the extensive data pool at hand, a simple but reliable (R2 >0.95) set of linear correlations have been proposed to predict the elemental release of potassium, sodium, chlorine and sulfur.It is also concluded that such linear expressions can be particularly effective for the prediction of elemental release from the fuels of similar characteristics, such as woody biomass. Mathematical model is developed to predict the particle size after combustion by simplifying Dunn-rankin’s particle population balance model analytically and kinetically. Ash formation modelling has also been attempted. The developed understanding and models can be further used for the investigations of several ash related problems during combustion and co-firing such as slagging, fouling, corrosion and erosion etc

Evaluating the change in central corneal thickness in neonates (term and preterm) in Indian population and the factors affecting it

Background and Aim: Central corneal thickness (CCT) of term and preterm infants in Indian population is not known. We did a prospective noninterventional study to measure the CCT in term and preterm infants. Materials and Methods: An ultrasonic pachymeter was used. The data regarding the date of birth, expected date of delivery, birth weight were recorded. The preterm and the term infants were followed up at 8 weeks, 20 weeks and at 1-year. Results: A total of 85 (170 eyes) children were included in the study. The mean age was 264.6 ± 21.8 days postconception. The mean birth weight and CCT were 1834.4 ± 512.1 g and 595.8 ± 72.4 μ respectively. A comparison of CCT on the basis postgestational age showed a mean thickness of 620.7 ± 88.8 and 574.4 ± 78.3 μ in the 260 days age groups respectively. The difference was statistically significant (Student′s test, P = 0.002). The CCT of preterm infants (<260 days) decreased from a mean value of 620.7 ± 88.8 μ to 534.1 ± 57.6 μ at the end of 1-year. Conclusion: We present the data of CCT in term and preterm infants in Indian population. We believe that the premature babies have slightly thicker corneas than mature term babies

Selection of suitable oxygen carriers for chemical looping air separation: a thermodynamic approach

The increasing demand for oxygen combined with the need for improved economic performance necessitates the search for alternative methods of oxygen production. Chemical looping air separation (CLAS) is one of these alternatives with a relatively small energy footprint. The present paper describes the results of a comprehensive thermodynamic study conducted by our group to identify suitable oxygen carriers for CLAS at medium to low temperatures. The thermodynamic simulations were carried out using Fact-Sage 6.1 for 20 different metal oxides forming 40 oxygen carrier systems. An Ellingham diagram was developed to relate the Gibbs free energy of the relevant reactions to the temperature for all metal oxide systems. Furthermore, the equilibrium partial pressure of oxygen was calculated at elevated temperatures. The mass balance calculations were also performed for identifying the steam/CO₂ requirements for the reduction reactor. On the basis of the comprehensive thermodynamic study, oxides of manganese, cobalt, and copper have been found most suitable for the CLAS process. Additionally, the possibility of carbonate and hydroxide formation during the reduction with CO₂ and steam, respectively, was calculated. The formation of the mixed oxide phases or the spinel structures between the metal oxides and various supports (such as SiO₂ and Al₂O₃) has also been thermodynamically investigated. Several other important factors were also qualitatively assessed. The Cu oxides with SiO₂ and the Co oxides with Al₂O₃ were found to be the most suitable oxygen carriers for CLAS

Effect of flue gas impurities on the performance of a chemical looping based air separation process for oxy-fuel combustion

Integrated Chemical Looping Air Separation (ICLAS) offers an energy efficient and cost effective option for large-scale oxygen generation in oxy-fuel type power plants. Oxygen production in the ICLAS is achieved by reduction of oxidised metal oxides in an environment of steam/recycled flue gas (CO₂-rich) using a dedicated reduction reactor. This paper provides the results of a thermodynamic investigation into the effect of flue gas impurities on the reduction of three metal oxide oxygen carriers (Cu, Mn and Co oxides) under conditions pertinent to an oxy-fuel coal-fired power plant. Relevant calculations were carried out using the Fact-sage 6.1 thermodynamic equilibrium calculation software package. Different gas streams, namely crude/wet, dry, pure CO₂ and steam were considered in the simulations together with the additional hypothetical impure flue gas stream having larger concentrations of CO, SO₂ and NO. Effects of SO₂, NO, CO and O₂ contents of the flue gas on oxygen carrier conversion and oxygen decoupling process were investigated in detail. It was established that the successful reduction of metal oxides in the presence of flue gas impurities can only be achieved at higher temperatures due to increased partial pressure of O₂ and the formation of metal sulphates at temperatures less than 800-900 °C. This may increase the operating and capital costs of the CLAS based oxygen production

Chemical looping air separation (CLAS) for oxygen production: thermodynamic and economic aspects

a number of conventional and emerging air separation technologies are available today for large-scale oxygen production. These technology platforms are often considered as the energy intensive processes. The increasing demand for the oxygen combined with the need of improved economic performance of such production technologies necessitates the search for alternative methods of oxygen production. Chemical Looping Air Separation (CLAS) is one of these alternatives which can possibly run at relatively lower operating temperature and pressure resulting in lower energy footprints. The present paper describes the results of a comprehensive thermodynamic study conducted on twenty different metal oxides for use in the CLAS process. The study was carried out using Fact-sage and an Ellingham diagram was developed relating the Gibbs free energy of the relevant reactions to temperature for all metal oxide systems. Furthermore, the equilibrium partial pressure of oxygen was calculated at elevated temperatures and the steam/CO₂ requirements were determined for the reduction reactor. Based on this thermodynamic scoping study, oxides of manganese, cobalt, copper, lead and chromium have been found most suitable for the CLAS process. Additionally, other factors such as availability of the metal oxides, their physical properties, reaction kinetics, inventory, mechanical strength, health and safety risks, operating and capital costs have also been qualitatively compared

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A feasibility study on a novel stone dust looping process for abatement of ventilation air methane

This paper describes the development of a novel stone dust looping process that relates to the removal of ventilation air methane using stone dust. The working principle behind the stone dust looping process is incredibly simple which involves the catalytic oxidation of methane followed by carbonation and calcination reactions. In the current work, laboratory scale fluidized bed experiments and process simulations were conducted to evaluate the feasibility of the stone dust looping process. The experimental work concluded that oxidation of ventilation air methane in the stone dust looping process can be successfully achieved at temperatures between 500 and 650 °C. The experimental results indicated that oxidation of methane was found to increase at higher temperatures while carbon dioxide capture efficiency showed a declining trend with increasing temperature. Furthermore, higher methane conversion and optimum (thermodynamic) carbon dioxide capture efficiency were observed for lower ventilation air methane flow rates and higher bed inventory. The concentration of methane in ventilation air methane and stone dust particle size did not have a significant effect on methane conversion or carbon dioxide capture. Also, comparison with synthetically prepared CuO and Fe₂O₃ catalysts has been made with CaO for VAM oxidation. CaO was found to be comparable to Fe₂O₃ and superior to CuO. From the process simulations, it was concluded that thermal energy generation in the carbonator was increased with higher methane and carbon dioxide concentrations. However, at the same time for higher methane and carbon dioxide concentrations, a greater CaO flux was required in the carbonator and hence a larger amount of goaf gas was required for the calcination reaction. The higher thermal energy generation in the carbonator was expected to improve the autothermicity of the stone dust looping process at concentrations of methane in the ventilation stream < 0.2 vol.% (thermodynamic limit)