Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model.

Prodrug activator gene therapy mediated by murine leukemia virus (MLV)-based retroviral replicating vectors (RRV) was previously shown to be highly effective in killing glioma cells both in culture and in vivo. To avoid receptor interference and enable dual vector co-infection with MLV-RRV, we have developed another RRV based on gibbon ape leukemia virus (GALV) that also shows robust replicative spread in a wide variety of tumor cells. We evaluated the potential of GALV-based RRV as a cancer therapeutic agent by incorporating yeast cytosine deaminase (CD) and E. coli nitroreductase (NTR) prodrug activator genes into the vector. The expression of CD and NTR genes from GALV-RRV achieved highly efficient delivery of these prodrug activator genes to RG-2 glioma cells, resulting in enhanced cytotoxicity after administering their respective prodrugs 5-fluorocytosine and CB1954 in vitro. In an immune-competent intracerebral RG-2 glioma model, GALV-mediated CD and NTR gene therapy both significantly suppressed tumor growth with CB1954 administration after a single injection of vector supernatant. However, NTR showed greater potency than CD, with control animals receiving GALV-NTR vector alone (i.e., without CB1954 prodrug) showing extensive tumor growth with a median survival time of 17.5 days, while animals receiving GALV-NTR and CB1954 showed significantly prolonged survival with a median survival time of 30 days. In conclusion, GALV-RRV enabled high-efficiency gene transfer and persistent expression of NTR, resulting in efficient cell killing, suppression of tumor growth, and prolonged survival upon CB1954 administration. This validates the use of therapeutic strategies employing this prodrug activator gene to arm GALV-RRV, and opens the door to the possibility of future combination gene therapy with CD-armed MLV-RRV, as the latter vector is currently being evaluated in clinical trials

Functional Effects of let-7g Expression in Colon Cancer Metastasis.

MicroRNA regulation is crucial for gene expression and cell functions. It has been linked to tumorigenesis, development and metastasis in colorectal cancer (CRC). Recently, the let-7 family has been identified as a tumor suppressor in different types of cancers. However, the function of the let-7 family in CRC metastasis has not been fully investigated. Here, we focused on analyzing the role of let-7g in CRC. The Cancer Genome Atlas (TCGA) genomic datasets of CRC and detailed data from a Taiwanese CRC cohort were applied to study the expression pattern of let-7g. In addition, in vitro as well as in vivo studies have been performed to uncover the effects of let-7g on CRC. We found that the expression of let-7g was significantly lower in CRC specimens. Our results further supported the inhibitory effects of let-7g on CRC cell migration, invasion and extracellular calcium influx through store-operated calcium channels. We report a critical role for let-7g in the pathogenesis of CRC and suggest let-7g as a potential therapeutic target for CRC treatment

Measurements of Natural Carbonate Rare Earth Elements in Femtogram Quantities by Inductive Coupled Plasma Sector Field Mass Spectrometry

A rapid and precise standard-bracketing method has been developed for measuring femtogram quantity rare earth element (REE) levels in natural carbonate samples by inductively coupled plasma sector field mass spectrometry that does not require chemical separation steps. A desolvation nebulization system was used to effectively reduce polyatomic interference and enhance sensitivity. REE/Ca ratios are calculated directly from the intensities of the ion beams of 46Ca, 139La, 140Ce, 141Pr, 146Nd, 147Sm, 153Eu, 160Gd, 159Tb, 163Dy, 165Ho, 166Er, 169Tm, 172Yb, and 175Lu using external matrix-matched synthetic standards to correct for instrumental ratio drifting and mass discrimination. A routine measurement time of 3 min is typical for one sample containing 20-40 ppm Ca. Replicate measurements made on natural coral and foraminiferal samples with REE/Ca ratios of 2-242 nmol/mol show that external precisions of 1.9-6.5% (2 RSD) can be achieved with only 10-1000 fg of REEs in 10-20 μg of carbonate. We show that different sources for monthly resolved coral ultratrace REE variability can be distinguished using this method. For natural slow growth-rate carbonate materials, such as sclerosponges, tufa, and speleothems, the high sample throughput, high precision, and high temporal resolution REE records that can be produced with this procedure have the potential to provide valuable time-series records to advance our understanding of paleoclimatic and paleoenvironmental dynamics on different time scales

Konsep Demokrasi Politik Dalam Islam

Coexistence of chronic rhinosinusitis (CRS) with asthma appears to impair asthma control. Type-2 innate lymphoid cells (ILC2s) respond to the cytokines of thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33, thus contributing to airway diseases such as CRS and asthma. We investigate whether the augmented Th2-cytokines in CRS might be related to sinonasal tract ILC2s corresponding to enhanced IL-25, IL-33 and TSLP release in severe asthmatics, and be involved in asthma control. Twenty-eight asthmatics (12 non-severe and 16 severe) with CRS receiving nasal surgery were enrolled. The predicted FEV1 inversely associated with CRS severity of CT or endoscopy scores. Higher expression of Th2-driven cytokines (IL-4, IL-5, IL-9, and IL-13), TSLP, IL-25 and IL-33 in nasal tissues was observed in severe asthma. Severe asthmatics had higher ILC2 cell counts in their nasal tissues. ILC2 counts were positively correlated with Th2-cytokines. Nasal surgery significantly improved asthma control and lung function decline in severe asthma and CRS. The higher expression of IL-33/ILC2 axis-directed type 2 immune responses in nasal tissue of CRS brought the greater decline of lung function in severe asthma. ILC2-induced the upregulated activity of Th2-related cytokines in asthmatics with CRS may contribute to a recalcitrant status of asthma control

Play as You Like: Timbre-enhanced Multi-modal Music Style Transfer

Style transfer of polyphonic music recordings is a challenging task when considering the modeling of diverse, imaginative, and reasonable music pieces in the style different from their original one. To achieve this, learning stable multi-modal representations for both domain-variant (i.e., style) and domain-invariant (i.e., content) information of music in an unsupervised manner is critical. In this paper, we propose an unsupervised music style transfer method without the need for parallel data. Besides, to characterize the multi-modal distribution of music pieces, we employ the Multi-modal Unsupervised Image-to-Image Translation (MUNIT) framework in the proposed system. This allows one to generate diverse outputs from the learned latent distributions representing contents and styles. Moreover, to better capture the granularity of sound, such as the perceptual dimensions of timbre and the nuance in instrument-specific performance, cognitively plausible features including mel-frequency cepstral coefficients (MFCC), spectral difference, and spectral envelope, are combined with the widely-used mel-spectrogram into a timber-enhanced multi-channel input representation. The Relativistic average Generative Adversarial Networks (RaGAN) is also utilized to achieve fast convergence and high stability. We conduct experiments on bilateral style transfer tasks among three different genres, namely piano solo, guitar solo, and string quartet. Results demonstrate the advantages of the proposed method in music style transfer with improved sound quality and in allowing users to manipulate the output

Aciculatin inhibits lipopolysaccharide-mediated inducible nitric oxide synthase and cyclooxygenase-2 expression via suppressing NF-κB and JNK/p38 MAPK activation pathways

<p>Abstract</p> <p>Objectives</p> <p>Natural products have played a significant role in drug discovery and development. Inflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) have been suggested to connect with various inflammatory diseases. In this study, we explored the anti-inflammatory potential of aciculatin (8-((2<it>R</it>,4<it>S</it>,5<it>S</it>,6<it>R</it>)-tetrahydro-4,5-dihydroxy-6-methyl-2<it>H</it>-pyran-2-yl)-5-hydroxy-2-(4-hydroxyphenyl)-7-methoxy-4<it>H</it>-chromen-4-one), one of main components of <it>Chrysopogon aciculatis</it>, by examining its effects on the expression and activity of iNOS and COX-2 in lipopolysaccharide (LPS)-activated macrophages.</p> <p>Methods</p> <p>We used nitrate and prostaglandin E₂(PGE₂) assays to examine inhibitory effect of aciculatin on nitric oxide (NO) and PGE₂levels in LPS-activated mouse RAW264.7 macrophages and further investigated the mechanisms of aciculatin suppressed LPS-mediated iNOS/COX-2 expression by western blot, RT-PCR, reporter gene assay and confocal microscope analysis.</p> <p>Results</p> <p>Aciculatin remarkably decreased the LPS (1 μg/mL)-induced mRNA and protein expression of iNOS and COX-2 as well as their downstream products, NO and PGE₂respectively, in a concentration-dependent manner (1-10 μM). Such inhibition was found, via immunoblot analyses, reporter gene assays, and confocal microscope observations that aciculatin not only acts through significant suppression of LPS-induced NF-κB activation, an effect highly correlated with its inhibitory effect on LPS-induced IκB kinase (IKK) activation, IκB degradation, NF-κB phosphorylation, nuclear translocation and binding of NF-κB to the κB motif of the iNOS and COX-2 promoters, but also suppressed phosphorylation of JNK/p38 mitogen-activated protein kinases (MAPKs).</p> <p>Conclusion</p> <p>Our results demonstrated that aciculatin exerts potent anti-inflammatory activity through its dual inhibitory effects on iNOS and COX-2 by regulating NF-κB and JNK/p38 MAPK pathways.</p