Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents

The histone acetyltransferases CBP and p300, often referred to as CBP/p300 due to their sequence homology and functional overlap and co-operation, are emerging as critical drivers of oncogenesis in the past several years. CBP/p300 induces histone H3 lysine 27 acetylation (H3K27ac) at target gene promoters, enhancers and super-enhancers, thereby activating gene transcription. While earlier studies indicate that CBP/p300 deletion/loss can promote tumorigenesis, CBP/p300 have more recently been shown to be over-expressed in cancer cells and drug-resistant cancer cells, activate oncogene transcription and induce cancer cell proliferation, survival, tumorigenesis, metastasis, immune evasion and drug-resistance. Small molecule CBP/p300 histone acetyltransferase inhibitors, bromodomain inhibitors, CBP/p300 and BET bromodomain dual inhibitors and p300 protein degraders have recently been discovered. The CBP/p300 inhibitors and degraders reduce H3K27ac, down-regulate oncogene transcription, induce cancer cell growth inhibition and cell death, activate immune response, overcome drug resistance and suppress tumor progression in vivo. In addition, CBP/p300 inhibitors enhance the anticancer efficacy of chemotherapy, radiotherapy and epigenetic anticancer agents, including BET bromodomain inhibitors; and the combination therapies exert substantial anticancer effects in mouse models of human cancers including drug-resistant cancers. Currently, two CBP/p300 inhibitors are under clinical evaluation in patients with advanced and drug-resistant solid tumors or hematological malignancies. In summary, CBP/p300 have recently been identified as critical tumorigenic drivers, and CBP/p300 inhibitors and protein degraders are emerging as promising novel anticancer agents for clinical translation

Synthesis and antibacterial activity against ralstonia solanacearum for novel hydrazone derivatives containing a pyridine moiety

<p>Abstract</p> <p>Background</p> <p><it>Ralstonia solanacearum</it>, one of the most important bacterial diseases on plants, is a devastating, soil-borne plant pathogen with a global distribution and an unusually wide host range. In order to discover new bioactive molecules and pesticides acting on tobacco bacterial wilt, we sought to combine the active structure of hydrazone and pyridine together to design and synthesize a series of novel hydrazone derivatives containing a pyridine moiety.</p> <p>Results</p> <p>A series of hydrazone derivatives containing a pyridine moiety were synthesized. Their structures were characterized by ¹H-NMR, ¹³C-NMR, IR, and elemental analysis. The preliminary biological activity tests showed that compound 3e and 3g exhibited more than 80% activity against <it>Ralstonia solanacearum </it>at 500 mg/L, especially compound 3g displayed relatively good activity to reach 57.0% at 200 mg/L.</p> <p>Conclusion</p> <p>A practical synthetic route to hydrazone derivatives containing a pyridine moiety by the reaction of intermediates 2 with different aldehydes in ethanol at room temperature using 2-chloronicotinic acid and 2-amino-5-chloro-3-methylbenzoic acid as start materials is presented. This study suggests that the hydrazone derivatives containing a substituted pyridine ring could inhibit the growth of <it>Ralstonia solanacearum</it>.</p

Modeling recursive RNA interference.

An important application of the RNA interference (RNAi) pathway is its use as a small RNA-based regulatory system commonly exploited to suppress expression of target genes to test their function in vivo. In several published experiments, RNAi has been used to inactivate components of the RNAi pathway itself, a procedure termed recursive RNAi in this report. The theoretical basis of recursive RNAi is unclear since the procedure could potentially be self-defeating, and in practice the effectiveness of recursive RNAi in published experiments is highly variable. A mathematical model for recursive RNAi was developed and used to investigate the range of conditions under which the procedure should be effective. The model predicts that the effectiveness of recursive RNAi is strongly dependent on the efficacy of RNAi at knocking down target gene expression. This efficacy is known to vary highly between different cell types, and comparison of the model predictions to published experimental data suggests that variation in RNAi efficacy may be the main cause of discrepancies between published recursive RNAi experiments in different organisms. The model suggests potential ways to optimize the effectiveness of recursive RNAi both for screening of RNAi components as well as for improved temporal control of gene expression in switch off-switch on experiments

Spatio-Temporal Characteristics of Global Warming in the Tibetan Plateau during the Last 50 Years Based on a Generalised Temperature Zone - Elevation Model

Temperature is one of the primary factors influencing the climate and ecosystem, and examining its change and fluctuation could elucidate the formation of novel climate patterns and trends. In this study, we constructed a generalised temperature zone elevation model (GTEM) to assess the trends of climate change and temporal-spatial differences in the Tibetan Plateau (TP) using the annual and monthly mean temperatures from 1961-2010 at 144 meteorological stations in and near the TP. The results showed the following: (1) The TP has undergone robust warming over the study period, and the warming rate was 0.318°C/decade. The warming has accelerated during recent decades, especially in the last 20 years, and the warming has been most significant in the winter months, followed by the spring, autumn and summer seasons. (2) Spatially, the zones that became significantly smaller were the temperature zones of -6°C and -4°C, and these have decreased 499.44 and 454.26 thousand sq km from 1961 to 2010 at average rates of 25.1% and 11.7%, respectively, over every 5-year interval. These quickly shrinking zones were located in the northwestern and central TP. (3) The elevation dependency of climate warming existed in the TP during 1961-2010, but this tendency has gradually been weakening due to more rapid warming at lower elevations than in the middle and upper elevations of the TP during 1991-2010. The higher regions and some low altitude valleys of the TP were the most significantly warming regions under the same categorizing criteria. Experimental evidence shows that the GTEM is an effective method to analyse climate changes in high altitude mountainous regions

Model construction of medical endoscope service evaluation system-based on the analysis of Delphi method

Background: Medical endoscope is widely used in clinical practice for the purpose of diagnosis and treatment, occupying around 5% of the medical device market. Evaluating the true service level of medical endoscope is essential and necessary to improve overall performance of medical diagnosis and treatment, and to maintain competitiveness of endoscope manufacturers, however, such a tool is not available in the market. This study develops an Evaluation Index System (EIS) to assess service level of medical endoscope, and to provide suggestions for improving the service level through the Delphi method. Methods: Firstly, the possible factors influencing the service level were identified from literature review. In parallel, the Delphi expert method questionnaire was designed and 25 experts were invited to conduct three rounds of questionnaire, to evaluate and rate the possible factors. Finally, we determined the weights associated with the factors, using the analytic hierarchy process (AHP) and percentage method, and developed the service level EIS. Results: The EIS consists of 3 first-level indicators, 24 s-level indicators and 68 third-level indicators. According to the weights computed using AHP, first-level indicators are ranked as post-sale (0.62), in-sale (0.25) and pre-sale (0.13). Through case verification, the medical endoscope brand Olympus had a total score of 4.17, Shanghai Aohua had a total score of 3.71, and Shanghai Chengyun had a total score of 3.28, which matches its market popularity and ranking in terms of market share. The results obtained from the EIS are consistent with the reality. Conclusions: The EIS established in this study is comprehensive, reliable and reasonable with strong practicality. The EIS can act as a tool for the endoscope users to evaluate potential products and make informed choices. It also provides a measurable basis for endoscope manufacturers and service providers to improve service quality

Graphene Photonics and Optoelectronics

The richness of optical and electronic properties of graphene attracts enormous interest. Graphene has high mobility and optical transparency, in addition to flexibility, robustness and environmental stability. So far, the main focus has been on fundamental physics and electronic devices. However, we believe its true potential to be in photonics and optoelectronics, where the combination of its unique optical and electronic properties can be fully exploited, even in the absence of a bandgap, and the linear dispersion of the Dirac electrons enables ultra-wide-band tunability. The rise of graphene in photonics and optoelectronics is shown by several recent results, ranging from solar cells and light emitting devices, to touch screens, photodetectors and ultrafast lasers. Here we review the state of the art in this emerging field.Comment: Review Nature Photonics, in pres

Vascular endothelial growth factor C promotes cervical cancer metastasis via up-regulation and activation of RhoA/ROCK-2/moesin cascade

<p>Abstract</p> <p>Background</p> <p>The elevated expression of vascular endothelial growth factor C (VEGF-C) is correlated with clinical cervical cancer metastasis and patient survival, which is interpreted by VEGF-C functions to stimulate angiogenesis and lymphatic genesis. However, the direct impact of VEGF-C on cervical cancer cell motility remains largely unknown.</p> <p>Methods</p> <p>In this study, we investigated the effects of VEGF-C on actin cytoskeleton remodeling and on cervical cancer cell migration and invasion and how the actin-regulatory protein, moesin regulated these effects through RhoA/ROCK-2 signaling pathway.</p> <p>Results</p> <p>On cervical carcinoma cell line SiHa cells, exposure of VEGF-C triggered remodeling of the actin cytoskeleton and the formation of membrane ruffles, which was required for cell movement. VEGF-C significantly enhanced SiHa cells horizontal migration and three-dimensional invasion into matrices. These actions were dependent on increased expression and phosphorylation of the actin-regulatory protein moesin and specific moesin siRNA severely impaired VEGF-C stimulated-cell migration. The extracellular small GTPase RhoA/ROCK-2 cascade mediated the increased moesin expression and phosphorylation, which was discovered by the use of Y-27632, a specific inhibitor of Rho kinase and by transfected constitutively active, dominant-negative RhoA as well as ROCK-2 SiRNA. Furthermore, in the surgical cervical specimen from the patients with FIGO stage at cervical intra-epithelial neoplasia and I-II cervical squamous cell carcinoma, the expression levels of moesin were found to be significantly correlated with tumor malignancy and metastasis.</p> <p>Conclusions</p> <p>These results implied that VEGF-C promoted cervical cancer metastasis by upregulation and activation of moesin protein through RhoA/ROCK-2 pathway. Our findings offer new insight into the role of VEGF-C on cervical cancer progression and may provide potential targets for cervical cancer therapy.</p

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets