Gene therapy with tumor-specific promoter mediated suicide gene plus IL-12 gene enhanced tumor inhibition and prolonged host survival in a murine model of Lewis lung carcinoma

<p>Abstract</p> <p>Background</p> <p>Gene therapy is a promising therapeutic approach for cancer. Targeted expression of desired therapeutic proteins within the tumor is the best approach to reduce toxicity and improve survival. This study is to establish a more effective and less toxic gene therapy of cancer.</p> <p>Methods</p> <p>Combined gene therapy strategy with recombinant adenovirus expressing horseradish peroxidase (HRP) mediated by human telomerase reverse transcriptase (hTERT) promoter (AdhTERTHRP) and murine interleukin-12 (mIL-12) under the control of Cytomegalovirus (CMV) promoter (AdCMVmIL-12) was developed and evaluated against Lewis lung carcinoma (LLC) both <it>in vivo </it>and <it>in vitro</it>. The mechanism of action and systemic toxicities were also investigated.</p> <p>Results</p> <p>The combination of AdhTERTHRP/indole-3-acetic acid (IAA) treatment and AdCMVmIL-12 resulted in significant tumor growth inhibition and survival improvement compared with AdhTERTHRP/IAA alone (tumor volume, 427.4 ± 48.7 mm³<it>vs </it>581.9 ± 46.9 mm³, <it>p </it>= 0.005 on day 15; median overall survival (OS), 51 d <it>vs </it>33 d) or AdCMVmIL-12 alone (tumor volume, 362.2 ± 33.8 mm³<it>vs </it>494.4 ± 70.2 mm³, <it>p </it>= 0.046 on day 12; median OS, 51 d <it>vs </it>36 d). The combination treatment stimulated more CD4⁺and CD8⁺T lymphocyte infiltration in tumors, compared with either AdCMVmIL-12 alone (1.3-fold increase for CD4⁺T cells and 1.2-fold increase for CD8⁺T cells, <it>P </it>< 0.01) or AdhTERTHRP alone (2.1-fold increase for CD4⁺T cells and 2.2-fold increase for CD8⁺T cells, <it>P </it>< 0.01). The apoptotic cells in combination group were significantly increased in comparison with AdCMVmIL-12 alone group (2.8-fold increase, <it>P </it>< 0.01) or AdhTERTHRP alone group (1.6-fold increase, <it>P </it>< 0.01). No significant systematic toxicities were observed.</p> <p>Conclusions</p> <p>Combination gene therapy with AdhTERTHRP/IAA and AdCMVmIL-12 could significantly inhibit tumor growth and improve host survival in LLC model, without significant systemic adverse effects.</p

The Role of Alpha-Lipoic Acid in the Pathomechanism of Acute Ischemic Stroke

Background/Aims: Ischemic stroke results in increased cerebral infarction, neurological deficits and neuroinflammation. The underlying mechanisms involving the anti-inflammatory and neuroprotective properties of α-Lipoic acid (α-LA) remain poorly understood. Herein, we investigated the potential role of α-LA in a middle cerebral artery occlusion (MCAO) rat model and an in vitro lipopolysaccharide (LPS)-induced microglia inflammation model. Methods: In the in vivo study, infarct volume was examined by TTC staining and Garcia score was used to evaluate neurologic recovery. The cytokines were evaluated by enzyme-linked immunosorbent assay, and protein expression of microglia phenotype and NF-κB were measured using western blot. In the in vitro study, the expressions of microglia M1/M2 phenotype were evaluated using qRT-PCR, and immunofluorescence staining was used to assess the nuclear translocation of NF-κB. Results: Both 20 mg/kg and 40 mg/kg of α-LA alleviated infarct size, brain edema, and neurological deficits. Furthermore, α-LA induced the polarization of microglia to the M2 phenotype, modulated the expression of IL-1β, IL-6, TNF-α and IL-10, and attenuated the activation of NF-κB after MCAO. α-LA inhibited the expression of M1 markers, increased activation of the M2 markers, and suppressed the nuclear translocation of NF-κB in LPS-stimulated BV2 microglia. Conclusions: α-LA improved neurological outcome in experimental stroke via modulating microglia M1/M2 polarization. The potential mechanism of α-LA might be mediated by inhibition of NF-κB activation via regulating phosphorylation and nuclear translocation of p65

Mapping Monthly Distribution of Daily Light Integrals Across China

Daily light integral (DLI, mol·m-2·d-1) is the total amount of photosynthetically active radiation received over a 24-hour period. It is a useful light measurement related to plant growth. To provide an estimate of the light quantities delivered to different locations across the country throughout the year, contour maps were developed using solar global-horizontal radiation data recorded from 1973 to 2002 at 45 meteorological observation stations in China. The maps demonstrated the mean daily light integral for each month of the year across the contiguous China. Northern China received the lowest DLI of 5-10 mol·m-2·d-1 in December, while northwestern China had the highest DLI of 45-50 mol·m-2·d-1 in May, June, and July. From October through March, DLI primarily differed between northern and southern China, while from May to August DLI varied between eastern and western China. The DLI changed quickly during the months before and after the vernal and autumnal equinoxes. These contour maps can be used to estimate the necessity and/or amount of supplemental lighting inside greenhouses in various geographical locations

Mapping Monthly Distribution of Daily Light Integrals Across China

Daily light integral( DLI,( mol /( m2·d)) is the total amount of photo synthetically active radiation received over a 24- hour period. It is a useful light measurement related to plant growth. To provide an estimate of the light quantities delivered to different locations across the country throughout the year, contour maps were developed using solar global-horizontal radiation data recorded from 1973 to 2002 at 45 meteorological observation stations in China. The maps demonstrated the mean daily light integral for each month of the year across the contiguous China. Northern China received the lowest DLI of 5 ~ 10 mol /( m2·d) in December, while northwestern China had the highest DLI of 45 ~ 50 mol /( m2·d) in May, June, and July. From October through March, DLI primarily differed between northern and southern China, while from May to August DLI varied between eastern and western China. The DLI changed quickly during the months before and after the vernal and autumnal equinoxes. These contour maps can be used to estimate the necessity and / or amount of supplemental lighting inside greenhouses in various geographical locations

SH3BP1 Regulates Melanoma Progression Through Race1/Wace2 Signaling Pathway

Background: SH3-domain binding protein-1 (SH3BP1), which specifically inactivates Rac1 and its target protein Wave2, has been shown to be an important regulator of cancer metastasis. However, the effects of SH3BP1 in melanoma progression remain unclear. The current study aimed to explore the function of SH3BP1 in melanoma and its possible molecular mechanism. Methods: TCGA database was used to analyze the expression of SH3BP1 in melanoma. Then, reverse transcription–quantitative polymerase chain reaction was performed to detect the expression of SH3BP1 in melanoma tissues and cells. Next, genes related to SH3BP1 were analyzed by LinkedOmics database, and protein interactions were analyzed by STRING database. These genes were further subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. In addition, the signaling pathway of SH3BP1 action was screened by bioinformatics analysis. Finally, the function of SH3BP1 and its mediated signaling pathway in melanoma progression were investigated in vitro and in vivo. Results: SH3BP1 was significantly upregulated in melanoma tissues and cells. The pathways regulated by SH3BP1 are closely related to the occurrence and development of tumors. And we found that overexpression of SH3BP1 promoted the proliferation, migration, and invasion of melanoma cells by increasing Rac1 activity and Wave2 protein levels in vitro. Similarly, overexpression of SH3BP1 facilitated melanoma progression by upregulating Wave2 protein expression in vivo. Conclusion: In summary, this study revealed for the first time that SH3BP1 promoted melanoma progression through Rac1/Wave2 signaling pathway, providing a new therapeutic target for melanoma

A Method for Autonomous Multi-Motion Modes Recognition and Navigation Optimization for Indoor Pedestrian

The indoor navigation method shows great application prospects that is based on a wearable foot-mounted inertial measurement unit and a zero-velocity update principle. Traditional navigation methods mainly support two-dimensional stable motion modes such as walking; special tasks such as rescue and disaster relief, medical search and rescue, in addition to normal walking, are usually accompanied by running, going upstairs, going downstairs and other motion modes, which will greatly affect the dynamic performance of the traditional zero-velocity update algorithm. Based on a wearable multi-node inertial sensor network, this paper presents a method of multi-motion modes recognition for indoor pedestrians based on gait segmentation and a long short-term memory artificial neural network, which improves the accuracy of multi-motion modes recognition. In view of the short effective interval of zero-velocity updates in motion modes with fast speeds such as running, different zero-velocity update detection algorithms and integrated navigation methods based on change of waist/foot headings are designed. The experimental results show that the overall recognition rate of the proposed method is 96.77%, and the navigation error is 1.26% of the total distance of the proposed method, which has good application prospects

An Improved Pedestrian Navigation Method Based on the Combination of Indoor Map Assistance and Adaptive Particle Filter

At present, the traditional indoor pedestrian navigation methods mainly include pedestrian dead reckoning (PDR) and zero velocity update (ZUPT), but these methods have the problem of error divergence during long time navigation. To solve this problem, under the condition of not relying on the active sensing information, combined with the characteristics of particles &ldquo;not going through the wall&rdquo; in the indoor map building structure, an improved adaptive particle filter (PF) based on the particle &ldquo;not going through the wall&rdquo; method is proposed for pedestrian navigation in this paper. This method can restrain the error divergence of the navigation system for a long time. Compared to the traditional pedestrian navigation method, based on the combination of indoor map assistance (MA) and particle filter, a global search method based on indoor MA is used to solve the indoor positioning problem under the condition of the unknown initial position and heading. In order to solve the problem of low operation efficiency caused by the large number of particles in PF, a calculation method of adaptively adjusting the number of particles in the process of particle resampling is proposed. The results of the simulation data and actual test data show that the proposed indoor integrated positioning method can effectively suppress the error divergence problem of the navigation system. Under the condition that the total distance is more than 415.44 m in the indoor environment of about 2600 m2, the average error and the maximum error of the position are less than two meters relative to the reference point

An Improved Pedestrian Navigation Method Based on the Combination of Indoor Map Assistance and Adaptive Particle Filter

At present, the traditional indoor pedestrian navigation methods mainly include pedestrian dead reckoning (PDR) and zero velocity update (ZUPT), but these methods have the problem of error divergence during long time navigation. To solve this problem, under the condition of not relying on the active sensing information, combined with the characteristics of particles “not going through the wall” in the indoor map building structure, an improved adaptive particle filter (PF) based on the particle “not going through the wall” method is proposed for pedestrian navigation in this paper. This method can restrain the error divergence of the navigation system for a long time. Compared to the traditional pedestrian navigation method, based on the combination of indoor map assistance (MA) and particle filter, a global search method based on indoor MA is used to solve the indoor positioning problem under the condition of the unknown initial position and heading. In order to solve the problem of low operation efficiency caused by the large number of particles in PF, a calculation method of adaptively adjusting the number of particles in the process of particle resampling is proposed. The results of the simulation data and actual test data show that the proposed indoor integrated positioning method can effectively suppress the error divergence problem of the navigation system. Under the condition that the total distance is more than 415.44 m in the indoor environment of about 2600 m2, the average error and the maximum error of the position are less than two meters relative to the reference point

BiVO4&ndash;Deposited MIL&ndash;101&ndash;NH2 for Efficient Photocatalytic Elimination of Cr(VI)

In this study, a flower&ndash;like BiVO4/MIL&ndash;101&ndash;NH2 composite is synthesized by a facile and surfactant&ndash;free process. The &ndash;COO&minus;&ndash;Bi3+ ionic bond construction was conductive to enhance the interface affinity between BiVO4 and MIL&ndash;101&ndash;NH2. Due to the highly efficient light capture and sufficient electron traps induced by oxygen vacancies and the formation of a heterostructure, the improved separation and transportation rates of charge carriers are realized. In addition, the MIL&ndash;101&ndash;NH2/BiVO4 composite is favorable for Cr(VI) photocatalytic removal (91.2%). Moreover, FNBV&ndash;3 (Fe/Bi = 0.25) also exhibited an excellent reusability after five cycles