Pituitary tumor transforming gene-1 haplotypes and risk of pituitary adenoma: a case-control study

<p>Abstract</p> <p>Background</p> <p>It has been suggested that pituitary adenoma results from accumulation of multiple genetic and/or epigenetic aberrations, which may be identified through association studies. As pituitary tumor transforming gene-1 (<it>PTTG1</it>)/securin plays a critical role in promoting genomic instability in pituitary neoplasia, the present study explored the association of <it>PTTG1 </it>haplotypes with the risk of pituitary adenoma.</p> <p>Methods</p> <p>We genotyped five <it>PTTG1 </it>haplotype-tagging SNPs (htSNP) by PCR-RFLP assays in a case-control study, which included 280 Han Chinese patients diagnosed with pituitary adenoma and 280 age-, gender- and geographically matched Han Chinese controls. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium status of the htSNPs.</p> <p>Results</p> <p>No significant differences in allele and genotype frequencies of the htSNPs were observed between pituitary adenoma patients and controls, indicating that none of the individual <it>PTTG1 </it>SNPs examined in this study is associated with the risk of pituitary adenoma. In addition, no significant association was detected between the reconstructed <it>PTTG1 </it>haplotypes and pituitary adenoma cases or the controls.</p> <p>Conclusions</p> <p>Though no significant association was found between <it>PTTG1 </it>haplotypes and the risk of pituitary adenoma, this is the first report on the association of individual <it>PTTG1 </it>SNPs or <it>PTTG1 </it>haplotypes with the risk of pituitary adenoma based on a solid study; it will provide an important reference for future studies on the association between genetic alterations in <it>PTTG1 </it>and the risk of pituitary adenoma or other tumors.</p

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Expression of HA of HPAI H5N1 Virus at US2 Gene Insertion Site of Turkey Herpesvirus Induced Better Protection than That at US10 Gene Insertion Site

Herpesvirus of turkey (HVT) is being widely used as a vector for development of recombinant vaccines and US2 and US10 genes are often chosen as insertion sites for targeted gene expression. However, the different effects of the two genes for generation of recombinant HVT vaccines were unknown. In order to compare the effects of inserted genes in the two sites on the efficacy of the recombinant vaccines, host-protective haemagglutinin (HA) gene of the highly pathogenic avian influenza virus (HPAIV) H5N1 was inserted into either US2 or US10 gene locus of the HVT. The resulting US2 (rHVT-US2-HA) or US10 (rHVT-US10-HA) recombinant HVT viruses were used to infect chicken embryo fibroblasts. Plaques and the growth kinetics of rHVT-US2-HA-infected chicken embryo fibroblasts were similar to those of parental HVT whereas rHVT-US10-HA infected chicken embryo fibroblasts had different growth kinetics and plaque formation. The viremia levels in rHVT-US10-HA virus-infected chickens were significantly lower than those of rHVT-US2-HA group on 28 days post infection. The vaccine efficacy of the two recombinant viruses against H5N1 HPAIV and virulent Marek's disease virus was also evaluated in 1-day-old vaccinated chickens. rHVT-US2-HA-vaccinated chickens were better protected with reduced mortality than rHVT-US10-HA-vaccinated animals following HPAIV challenge. Furthermore, the overall hemaglutination inhibition antibody titers of rHVT-US2-HA-vaccinated chickens were higher than those of rHVT-US10-HA-vaccinated chickens. Protection levels against Marek's disease virus challenge following vaccination with either rHVT-US2-HA or rHVT-US10-HA, however, were similar to those of the parental HVT virus. These results, for the first time, indicate that US2 gene provides a favorable foreign gene insertion site for generation of recombinant HVT vaccines

Review on catalytic cleavage of C-C inter-unit linkages in lignin model compounds: Towards lignin depolymerisation

Lignin depolymerisation has received considerable attention recently due to the pressing need to find sustainable alternatives to fossil fuel feedstock to produce chemicals and fuels. Two types of interunit linkages (C–C and C–O linkages) link several aromatic units in the structure of lignin. Between these two inter-unit linkages, the bond energies of C–C linkages are higher than that of C–O linkages, making them harder to break. However, for an efficient lignin depolymerisation, both types of inter-unit linkages have to be broken. This is more relevant because of the fact that many delignification processes tend to result in the formation of additional C–C inter-unit bonds. Here we review the strategies reported for the cleavage of C–C inter-unit linkages in lignin model compounds and lignin. Although a number of articles are available on the cleavage of C–O inter-unit linkages, reports on the selective cleavage of C–C inter-unit linkages are relatively less. Oxidative cleavage, hydrogenolysis, two-step redox-neutral process, microwave assisted cleavage, biocatalytic and photocatalytic methods have been reported for the breaking of C–C inter-unit linkages in lignin. Here we review all these methods in detail, focused only on the breaking of C–C linkages. The objective of this review is to motivate researchers to design new strategies to break this strong C–C inter-unit bonds to valorise lignins, technical lignins in particular

Regulation of hTERT by BCR-ABL at multiple levels in K562 cells

<p>Abstract</p> <p>Background</p> <p>The cytogenetic characteristic of Chronic Myeloid Leukemia (CML) is the formation of the Philadelphia chromosome gene product, BCR-ABL. Given that BCR-ABL is the specific target of Gleevec in CML treatment, we investigated the regulation of the catalytic component of telomerase, hTERT, by BCR-ABL at multiple levels in K562 cells.</p> <p>Methods</p> <p>Molecular techniques such as over expression, knockdown, real-time PCR, immunoprecipitation, western blotting, reporter assay, confocal microscopy, telomerase assays and microarray were used to suggest that hTERT expression and activity is modulated by BCR-ABL at multiple levels.</p> <p>Results</p> <p>Our results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited <it>hTERT </it>at mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells (BCR-ABL negative cells). We also demonstrated that the transcription factor STAT5a plays a critical role in <it>hTERT </it>gene regulation in K562 cells. Knockdown of STAT5a, but not STAT5b, resulted in a marked downregulation of <it>hTERT </it>mRNA level, TA and hTERT protein level in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec.</p> <p>Conclusions</p> <p>Our data reveal that BCR-ABL can regulate TA at multiple levels, including transcription, post-translational level, and proper localization. Thus, suppression of cell growth and induction of apoptosis by Gleevec treatment may be partially due to TA inhibition. Additionally, we have identified STAT5a as critical mediator of the <it>hTERT </it>gene expression in BCR-ABL positive CML cells, suggesting that targeting STAT5a may be a promising therapeutic strategy for BCR-ABL positive CML patients.</p

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Plasmid-encapsulated polyethylene glycol-grafted polyethylenimine nanoparticles for gene delivery into rat mesenchymal stem cells

Xiao-Ai Chen1,5*, Li-Jun Zhang2*, Zhi-Jie He3, Wei-Wei Wang4, Bo Xu1, Qian Zhong1, Xin-Tao Shuai4, Li-Qun Yang4, Yu-Bin Deng11Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; 2Futian Affiliated Hospital, Guangdong Medical College, Shenzhen, China; 3Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; 4Institute of Polymer Science, School of Chemistry and Chemical Engineering, BME Center, State Key Laboratory of Optoelectronic Materials and Technologies, Sun Yat-sen University, Guangzhou, China; 5Yunnan Cancer Hospital, The Third Affiliated Hospital, Kunming Medical College, Kunming, China*Both authors contributed equally to this workBackground: Mesenchymal stem cell transplantation is a promising method in regenerative medicine. Gene-modified mesenchymal stem cells possess superior characteristics of specific tissue differentiation, resistance to apoptosis, and directional migration. Viral vectors have the disadvantages of potential immunogenicity, carcinogenicity, and complicated synthetic procedures. Polyethylene glycol-grafted polyethylenimine (PEG-PEI) holds promise in gene delivery because of easy preparation and potentially targeting modification.Methods: A PEG8k-PEI25k graft copolymer was synthesized. Agarose gel retardation assay and dynamic light scattering were used to determine the properties of the nanoparticles. MTT reduction, wound and healing, and differentiation assays were used to test the cytobiological characteristics of rat mesenchymal stem cells, fluorescence microscopy and flow cytometry were used to determine transfection efficiency, and atomic force microscopy was used to evaluate the interaction between PEG-PEI/plasmid nanoparticles and mesenchymal stem cells.Results: After incubation with the copolymer, the bionomics of mesenchymal stem cells showed no significant change. The mesenchymal stem cells still maintained high viability, resettled the wound area, and differentiated into adipocytes and osteoblasts. The PEG-PEI completely packed plasmid and condensed plasmid into stable nanoparticles of 100&amp;ndash;150 nm diameter. After optimizing the N/P ratio, the PEG-PEI/plasmid microcapsules delivered plasmid into mesenchymal stem cells and obtained an optimum transfection efficiency of 15%&amp;ndash;21%, which was higher than for cationic liposomes.Conclusion: These data indicate that PEG-PEI is a valid gene delivery agent and has better transfection efficiency than cationic liposomes in mesenchymal stem cells.Keywords: stem cells, gene delivery, nanoparticles, atomic force microscop