New mouse xenograft model modulated by tumor-associated fibroblasts for human multi-drug resistance in cancer

We developed an MDR tumor model that is modulated by tumor-associated fibroblasts. Studies on proliferation of tumor cell lines including paclitaxel-sensitive and resistant cell lines were performed. The expressions of P-gp and α-smooth muscle actin (α-SMA) antigen were evaluated by immunohistochemistry and western blot analysis. Quantitative P-gp analyses of different cell lines were accomplished by nanoUPLC-MS/MS. Tumor cell colony formation assay and established xenograft model was used to investigate the relationship between P-gp expression, fibroblast levels and tumorigenesis. The mouse xenograft model was developed after co-inoculation with MDR tumor cells and NIH/3T3 fibroblast cells. There was no correlation between tumorigenesis in vivo and the growth rate of cells in vitro. The proliferation among different cell lines had no significant differences, but the P-gp expression and tumor growth in the xenograft model were fairly different. P-gp determination and α-SMA immunofluorescence staining clarified the relationship between P-gp expression, fibroblast levels and tumorigenesis. It was more difficult for tumor cells with higher P-gp levels to recruit fibroblasts in vivo, resulting in lower tumorigenesis due to the lack of structural and chemical support during tumor progression. In the established paclitaxel-resistant mouse xenograft model, no obvious antitumor effect was observed after Taxol treatment, but a significant decrease in tumor size for the group treated with gemcitabine sensitive to the model. The results show that the added fibroblasts do not disturb the applicability of the model in MDR. Therefore, this mouse xenograft MDR model could serve as an effective tool for MDR research

Patient-derived glioblastoma cultures as a tool for small-molecule drug discovery

There is a compelling need for new therapeutic strategies for glioblastoma multiforme (GBM). Preclinical target and therapeutic discovery for GBMs is primarily conducted using cell lines grown in serum-containing media, such as U-87 MG, which do not reflect the gene expression profiles of tumors found in GBM patients. To address this lack of representative models, we sought to develop a panel of patient-derived GBM models and characterize their genomic features, using RNA sequencing (RNA-seq) and growth characteristics, both when grown as neurospheres in culture, and grown orthotopically as xenografts in mice. When we compared these with commonly used GBM cell lines in the Cancer Cell Line Encyclopedia (CCLE), we found these patient-derived models to have greater diversity in gene expression and to better correspond to GBMs directly sequenced from patient tumor samples. We also evaluated the potential of these models for targeted therapy, by using the genomic characterization to identify small molecules that inhibit the growth of distinct subsets of GBMs, paving the way for precision medicines for GBM

Improving Performance of All-Polymer Solar Cells Through Backbone Engineering of Both Donors and Acceptors

All-polymer solar cells (APSCs), composed of semiconducting donor and acceptor polymers, have attracted considerable attention due to their unique advantages compared to polymer-fullerene-based devices in terms of enhanced light absorption and morphological stability. To improve the performance of APSCs, the morphology of the active layer must be optimized. By employing a random copolymerization strategy to control the regularity of the backbone of the donor polymers (PTAZ-TPDx) and acceptor polymers (PNDI-Tx) the morphology can be systematically optimized by tuning the polymer packing and crystallinity. To minimize effects of molecular weight, both donor and acceptor polymers have number-average molecular weights in narrow ranges. Experimental and coarse-grained modeling results disclose that systematic backbone engineering greatly affects the polymer crystallinity and ultimately the phase separation and morphology of the all-polymer blends. Decreasing the backbone regularity of either the donor or the acceptor polymer reduces the local crystallinity of the individual phase in blend films, affording reduced short-circuit current densities and fill factors. This two-dimensional crystallinity optimization strategy locates a PCE maximum at highest crystallinity for both donor and acceptor polymers. Overall, this study demonstrates that proper control of both donor and acceptor polymer crystallinity simultaneously is essential to optimize APSC performance

A Small Molecule that Binds and Inhibits the ETV1 Transcription Factor Oncoprotein

Members of the ETS transcription factor family have been implicated in several cancers, where they are often dysregulated by genomic derangement. ETS variant 1 (ETV1) is an ETS factor gene that undergoes chromosomal translocation in prostate cancers and Ewing\u27s sarcomas, amplification in melanomas, and lineage dysregulation in gastrointestinal stromal tumors. Pharmacologic perturbation of ETV1 would be appealing in these cancers; however, oncogenic transcription factors are often deemed “undruggable” by conventional methods. Here, we used small-molecule microarray (SMM) screens to identify and characterize drug-like compounds that modulate the biological function of ETV1. We identified the 1,3,5-triazine small molecule BRD32048 as a top candidate ETV1 perturbagen. BRD32048 binds ETV1 directly, modulating both ETV1-mediated transcriptional activity and invasion of ETV1-driven cancer cells. Moreover, BRD32048 inhibits p300-dependent acetylation of ETV1, thereby promoting its degradation. These results point to a new avenue for pharmacological ETV1 inhibition and may inform a general means to discover small molecule perturbagens of transcription factor oncoproteins

A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein

Members of the ETS transcription factor family have been implicated in several cancers, where they are often dysregulated by genomic derangement. ETS variant 1 (ETV1) is an ETS factor gene that undergoes chromosomal translocation in prostate cancers and Ewing sarcomas, amplification in melanomas, and lineage dysregulation in gastrointestinal stromal tumors. Pharmacologic perturbation of ETV1 would be appealing in these cancers; however, oncogenic transcription factors are often deemed “undruggable” by conventional methods. Here, we used small-molecule microarray screens to identify and characterize drug-like compounds that modulate the biologic function of ETV1. We identified the 1,3,5-triazine small molecule BRD32048 as a top candidate ETV1 perturbagen. BRD32048 binds ETV1 directly, modulating both ETV1-mediated transcriptional activity and invasion of ETV1-driven cancer cells. Moreover, BRD32048 inhibits p300-dependent acetylation of ETV1, thereby promoting its degradation. These results point to a new avenue for pharmacologic ETV1 inhibition and may inform a general means to discover small molecule perturbagens of transcription factor oncoproteins.National Cancer Institute (U.S.) (Initiative for Chemical Genetics Contract N01-CO-12400)National Cancer Institute (U.S.) (Cancer Target Discovery and Development Network RC2 CA148399

Dengue Virus Inhibits Immune Responses in Aedes aegypti Cells

The ability of many viruses to manipulate the host antiviral immune response often results in complex host-pathogen interactions. In order to study the interaction of dengue virus (DENV) with the Aedes aegypti immune response, we have characterized the DENV infection-responsive transcriptome of the immune-competent A. aegypti cell line Aag2. As in mosquitoes, DENV infection transcriptionally activated the cell line Toll pathway and a variety of cellular physiological systems. Most notably, however, DENV infection down-regulated the expression levels of numerous immune signaling molecules and antimicrobial peptides (AMPs). Functional assays showed that transcriptional induction of AMPs from the Toll and IMD pathways in response to bacterial challenge is impaired in DENV-infected cells. In addition, Escherichia coli, a Gram-negative bacteria species, grew better when co-cultured with DENV-infected cells than with uninfected cells, suggesting a decreased production of AMPs from the IMD pathway in virus-infected cells. Pre-stimulation of the cell line with Gram-positive bacteria prior to DENV infection had no effect on DENV titers, while pre-stimulation with Gram-negative bacteria resulted in an increase in DENV titers. These results indicate that DENV is capable of actively suppressing immune responses in the cells it infects, a phenomenon that may have important consequences for virus transmission and insect physiology

The Wnt and BMP Families of Signaling Morphogens at the Vertebrate Neuromuscular Junction

The neuromuscular junction has been extensively employed in order to identify crucial determinants of synaptogenesis. At the vertebrate neuromuscular synapse, extracellular matrix and signaling proteins play stimulatory and inhibitory roles on the assembly of functional synapses. Studies in invertebrate species have revealed crucial functions of early morphogens during the assembly and maturation of the neuromuscular junction. Here, we discuss growing evidence addressing the function of Wnt and Bone morphogenetic protein (BMP) signaling pathways at the vertebrate neuromuscular synapse. We focus on the emerging role of Wnt proteins as positive and negative regulators of postsynaptic differentiation. We also address the possible involvement of BMP pathways on motor neuron behavior for the assembly and/or regeneration of the neuromuscular junction

Tools to Support Policy Decisions Related to Treatment Strategies and Surveillance of Schistosomiasis Japonica towards Elimination

Immunodiagnostic assays are widely applied in the field to control schistosomiasis in P.R. China as the prevalence and infection intensity of schistosome infections decrease. Field evaluations are urgently needed before they can be adopted to support policy decisions of the national programme for the control and elimination of schistosomiasis in P.R. China. We carried out a large scale cross-sectional survey in field settings with different transmission situations to validate immunodiagnostic tools that can be used to formulate new schistosomiasis elimination strategy in P.R. China. Regarding stool examination as gold reference, the validity and screening efficacy of each immunodiagnostic kit were calculated and compared with each other. The association of the prevalence of schistosomiasis and antibody positive rates determined by immunoassays were analyzed using Pearson's correlation coefficient values. The study indicates that which test to use with the elimination strategy is dependent on the purpose of testing, the endemic status of community and the resources available. And more sensitive methods need to be explored and used to target infected individuals for treatment or to eliminate schistosomiasis

The Relationship between Emotional Intelligence and Cool and Hot Cognitive Processes: A Systematic Review

Although emotion and cognition were considered to be separate aspects of the psyche in the past, researchers today have demonstrated the existence of an interplay between the two processes. Emotional intelligence (EI), or the ability to perceive, use, understand, and regulate emotions, is a relatively young concept that attempts to connect both emotion and cognition. While EI has been demonstrated to be positively related to well-being, mental and physical health, and non-aggressive behaviors, little is known about its underlying cognitive processes. The aim of the present study was to systematically review available evidence about the relationship between EI and cognitive processes as measured through “cool” (i.e., not emotionally laden) and “hot” (i.e., emotionally laden) laboratory tasks. We searched Scopus and Medline to find relevant articles in Spanish and English, and divided the studies following two variables: cognitive processes (hot vs. cool) and EI instruments used (performance-based ability test, self-report ability test, and self-report mixed test). We identified 26 eligible studies. The results provide a fair amount of evidence that performance-based ability EI (but not self-report EI tests) is positively related with efficiency in hot cognitive tasks. EI, however, does not appear to be related with cool cognitive tasks: neither through self-reporting nor through performance-based ability instruments. These findings suggest that performance-based ability EI could improve individuals’ emotional information processing abilities.This research was financed by the Spanish Ministry of Economy (PSI2012-37490) and the Innovation and Development Agency of Andalusia,Spain(SEJ-07325)