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Systems biology analysis of gene expression across solid tumors identifies a 27 signature that centers on EZH2, the key component of polycomb repressive complex 2. Our study demonstrates that targeting the 27 gene network by the c...
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Systems biology analysis of gene expression across solid tumors identifies a 27 signature that centers on EZH2, the key component of polycomb repressive complex 2. Our study demonstrates that targeting the 27 gene network by the combination of BIRC5 and EZH2 inhibitors achieves remarkable anticancer synergy that is independent of the histone methyltransferase activity of EZH2.Globlal gene expression analysis in combination with pathway analysis shows that combination of YM155, the BIRC5 inhibitor, with EZH2 inhibitors induces unfolded protein response.
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Since ALWRs are anticipated to provide an enhanced margin of safety and newer nuclear power plants have a higher standard of severe accident safety performance than the existing plant designs, recent efforts aimed at simplifying t...
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Since ALWRs are anticipated to provide an enhanced margin of safety and newer nuclear power plants have a higher standard of severe accident safety performance than the existing plant designs, recent efforts aimed at simplifying the concept of EPZ for ALWR standard plant designs had been made by a group of utility companies through the EPRI in the U.S. In Korea, similar efforts have been made for the APR1400, which is a 1,400 MW-sized PWR of an advanced concept developed in Korea. This is possible due to a large enhancement in the performance of various accident mitigation features adopted in its design. The technical assessment shows that radius of the EPZ area of the APR1400 can be reduced to 700 m . However, even though the reduction in the EPZ area is well accepted through an extensive technical assessment process, it has been found that public acceptance appears to be a completely different matter. Therefore, this study performed a public poll to assess the degree of public acceptance to a reduction in the EPZ area and to identify the means of implementing the simplification of EPZ that would be most acceptable to the public.
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Retinoblastoma (RB) is the most common intraocular malignant tumour in infants, and chemotherapy has been the primary therapy method in recent years. PRMT5 is an important member of the protein arginine methyl-transferase family, ...
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Retinoblastoma (RB) is the most common intraocular malignant tumour in infants, and chemotherapy has been the primary therapy method in recent years. PRMT5 is an important member of the protein arginine methyl-transferase family, which plays an important role in various tumours. Our study showed that PRMT5 was overexpressed in retinoblastoma and played an important role in retinoblastoma cell growth. EPZ015666 is a novel PRMT5 inhibitor, and we found that it inhibited retinoblastoma cell proliferation and led to cell cycle arrest at the G1 phase. At the same time, EPZ015666 regulated cell cycle related protein (P53, P21, P27, CDK2) expression. In brief, our study showed that PRMT5 promoted retinoblastoma growth, the PRMT5 inhibitor EPZ015666 inhibited retinoblastoma in vitro by regulating P53-P21/P27-CDK2 signaling pathways and slowed retinoblastoma growth in a xenograft model.
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Recent studies of the impact of China's rise on the economies of sub-Saharan Africa generally find that the resource-rich countries of the sub-continent will gain while those that compete with China in export markets will invariab...
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Recent studies of the impact of China's rise on the economies of sub-Saharan Africa generally find that the resource-rich countries of the sub-continent will gain while those that compete with China in export markets will invariably lose. Mauritius, with no exploitable natural resources, and facing acute Chinese competition in its traditional markets, is a most likely candidate to suffer China's onslaught. This paper argues that China's economic rise can benefit Mauritius. Analyzing the impact of China through the channels of trade, aid and investment, we show that preference erosion, not China's emergence, is to blame for the drastic loss of jobs in the clothing industry. This industry, however, has proved resilient since exports are back on a rising trend. On the other hand, Chinese aid to finance construction and infrastructure projects has been a welcome relief, even when it has been tied to the use of Chinese labour and inputs. The most significant benefits of China's engagement are likely to occur in the area of investment as China strategically uses Mauritius as a platform to penetrate the African market.
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Acute myeloid leukemia (AML) is a malignant disorder of hematopoietic progenitor cells with a poor prognosis of 26% of patients surviving 5 years after diagnosis. Poor bioavailability and solubility are significant factors limitin...
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Acute myeloid leukemia (AML) is a malignant disorder of hematopoietic progenitor cells with a poor prognosis of 26% of patients surviving 5 years after diagnosis. Poor bioavailability and solubility are significant factors limiting the efficacy of chemopreventive agents. In AML, the epigenetic regulator polycomb group of protein member EZH2 is highly expressed and is essential for the survival of leukemic cells. An EZH2-specific inhibitor, EPZ011989, encapsulated in human serum albumin nanoparticles (HSANPs) was synthesized for the first time via the desolvation method. The noncovalent interactions between EPZ011989 and HSANPs in nanocomposites facilitating the efficient loading and sustainable release of the drug showed enhanced cellular uptake and nuclear localization of EPZ011989-loaded HSANPs in human AML cell lines. The reduction of cell viability, colony formation inhibition, cell cycle arrest at the G2/M phase, and cell proliferation assay promoting apoptosis through the loss of mitochondrial homeostasis exerting antileukemic activity were evident. The real-time polymerase chain reaction (PCR) and western blot-based studies showed that the present nanoformulation reduces the level of PcG proteins, including EZH2, BMI-1, etc. This downregulation is associated with reduced H3K27me3 and H2AK119ub modifications conferring chromatin compaction. The immunoprecipitation study showed the physical interaction of EZH2 and c-Myb can be linked to the regulation of leukemogenesis. Further investigation revealed the mechanism of EZH2 and c-Myb downregulation via ubiquitination and proteasomal degradation pathway, confirmed by using proteasome inhibitor, suggesting the key role of proteasomal degradation machinery. Moreover, c-Myb interacted with the EZH2 promoter, which is evident by the chromatin immunoprecipitation assay and siRNA silencing. Furthermore, the formulation of EPZ011989 in HSANPs improved its biodistribution in vivo and showed excellent aqueous dispersibility and biocompatibility. In vivo studies further showed that EPZ011989-loaded HSANPs reduce the expression of CD11b(+) and CD45(+) markers in immunophenotyping from peripheral blood and bone marrow in engrafted nude mice. Targeted depletion of EZH2 alleviated the disease progression in nude mice and prolonged their survival. The findings provide valuable experimental evidence for the targeted epigenetic therapy of AML. The present results demonstrate an epigenetic regulation-based superior antileukemic therapy.
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An EPZ is basically no more than a device whereby imports, to be used in the production of exports, can be acquired by manufacturers on a bonded duty-free basis. They are literally industrial zones with special incentives to attra...
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An EPZ is basically no more than a device whereby imports, to be used in the production of exports, can be acquired by manufacturers on a bonded duty-free basis. They are literally industrial zones with special incentives to attract foreign investors in which imported materials undergo some degree of processing before being exported again. The logic behind these zones was the creation of an area in which domestic policies do not hold and in which, therefore, a government could implement policies designed to enable individual firms to invest profitably on the basis of a country's comparative advantage. However, although there is significant literature on the impact of EPZs on host countries, nevertheless, the evidence has mainly been concerned with their benefits and costs and has stopped short of formal benefit-cost analysis. In essence, what the empirical studies have lacked, including those done on the Mauritius Export Processing Zone (MEPZ), has been an analytical framework within which the benefits and costs of EPZs can be identified conceptually and quantified empirically. In this respect, the objective of the current paper is to formally attempt to calculate the net contribution of the MEPZ using a modified version of the enclave model put forward by Warr (1988). The results show that although Mauritius has been able to attain its objective of reducing employment and raising foreign exchange through the creation of the EPZ, yet overall the EPZ has cost more to the economy than the benefits it has conferred to the economy. This is principally because of the incentives that were given to the producers working in the EPZ sector. The costs of these incentives were higher than the overall returns obtained from the sector. The two variables that negatively contributed to the sector were domestic borrowings and electricity usage.
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Rapid economic globalization presents major challenges to the sustainable development of 'development zones' in many countries. Development zones in China evolved from the concept of Export Processing Zones (EPZs) in the western w...
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Rapid economic globalization presents major challenges to the sustainable development of 'development zones' in many countries. Development zones in China evolved from the concept of Export Processing Zones (EPZs) in the western world. After China's accession to the World Trade Organisation, however, they have lost their special preferential status to the overseas investors in terms of promotion of industrialization and inward investment. With the changing global and national circumstances, spatial, economic and social transformations are taking place in these development zones. Given the vast number of development zones in China, the successful integration of these development zones into the regional and urban contexts will have great implications on the economic and social development of China. Based upon a case study of Guangzhou Development District (GDD) which is one of the earliest development zones of China, this paper examines the evolution of development zones in the mainland with particular reference to the development problems associated with their urbanisation in recent years. Although this paper primarily focuses on GDD, the findings and discussion will provide insights for other development zones of China in reviewing their development strategies as most of them are sharing similar development problems.
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Protein arginine methyltransferase 5 (PRMT5) is an arginine methylation methyltransferase that regulates various physiological processes. Abnormal PRMT5 activity has been reported in inflammation and various types of cancers. Beca...
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Protein arginine methyltransferase 5 (PRMT5) is an arginine methylation methyltransferase that regulates various physiological processes. Abnormal PRMT5 activity has been reported in inflammation and various types of cancers. Because osteoclast differentiation is characterized by the activation of inflammation-related pathways, we speculated that PRMT5 may play a role in this process. In the present study, we found that PRMT5 was upregulated during osteoclast differentiation. Knockdown of PRMT5 with siRNA in bone marrow mononuclear cells (BMMs) resulted in inhibition of receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclast formation. Consistent with the PRMT5 knockdown results, the PRMT5 inhibitor EPZ015666 (EPZ) suppressed osteoclast differentiation and bone resorption. Intraperitoneal administration of EPZ prevented ovariectomy-induced bone loss. Moreover, RANKL-induced NF-kB and MAPK activation was inhibited by EPZ. Expression microarrays showed that the expression of several osteoclast formation-related genes was altered by EPZ treatment, including chemokine C-X-C motif ligand 10 (CXCL10). Administration of recombinant CXCL10 partially reversed the osteoclastogenesis inhibition effect of the PRMT5 inhibitor. Intriguingly, RSAD2, which is a reported antiviral protein, was apparently suppressed when PRMT5 was inhibited. Knockdown of RSAD2 with siRNA in BMMs led to inhibition of osteoclast differentiation. Subsequent ChIP-qPCR identified that both PRMT5 inhibition and knockdown resulted in decreased H3R8 or/and H4R3 methylation at CXCL10 and RSAD2 promotors. In conclusion, our study found that PRMT5 is an activator of osteoclast differentiation and inhibition of PRMT5 partially suppressed osteoclastogenesis through downregulation of CXCL10 and RSAD2. (C) 2017 The Authors. Published by Elsevier Inc.
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Neuroblastoma is predominantly characterised by chromosomal rearrangements. Next to V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma Derived Homolog (MYCN) amplification, chromosome 7 and 17q gains are frequently observed...
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Neuroblastoma is predominantly characterised by chromosomal rearrangements. Next to V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma Derived Homolog (MYCN) amplification, chromosome 7 and 17q gains are frequently observed. We identified a neuroblastoma patient with a regional 7q36 gain, encompassing the enhancer of zeste homologue 2 (EZH2) gene. EZH2 is the histone methyltransferase of lysine 27 of histone H3 (H3K27me3) that forms the catalytic subunit of the polycomb repressive complex 2. H3K27me3 is commonly associated with the silencing of genes involved in cellular processes such as cell cycle regulation, cellular differentiation and cancer. High EZH2 expression correlated with poor prognosis and overall survival independent of MYCN amplification status. Unexpectedly, treatment of 3 EZH2-high expressing neuroblastoma cell lines (IMR32, CHP134 and NMB), with EZH2-specific inhibitors (GSK126 and EPZ6438) resulted in only a slight G1 arrest, despite maximum histone methyltransferase activity inhibition. Furthermore, colony formation in cell lines treated with the inhibitors was reduced only at concentrations much higher than necessary for complete inhibition of EZH2 histone methyltransferase activity. Knockdown of the complete protein with three independent shRNAs resulted in a strong apoptotic response and decreased cyclin D1 levels. This apoptotic response could be rescued by overexpressing EZH2ASET, a truncated form of wild-type EZH2 lacking the SET transactivation domain necessary for histone methyltransferase activity. Our findings suggest that high EZH2 expression, at least in neuroblastoma, has a survival function independent of its methyltransferase activity. This important finding highlights the need for studies on EZH2 beyond its methyltransferase function and the requirement for compounds that will target EZH2 as a complete protein. (C) 2017 Elsevier Ltd. All rights reserved.
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Synthesis of 3,3-Disubstituted Oxindoles was achieved by one-pot multicomponent condensation of isatin, malononitrile and indole in presence of Envirocat EPZ-G as a heterogeneous environmental friendly catalyst.This is an environm...
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Synthesis of 3,3-Disubstituted Oxindoles was achieved by one-pot multicomponent condensation of isatin, malononitrile and indole in presence of Envirocat EPZ-G as a heterogeneous environmental friendly catalyst.This is an environmentally benign method and reusability of the catalyst is beneficial over the others.
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