Irradiation-induced localization of IL-12-expressing mesenchymal stem cells to enhance the curative effect in murine metastatic hepatoma

Irradiation in conjunction with gene therapy is considered for efficient cancer treatment. Mesenchymal stem cells (MSCs), due to their irradiation-promotable tumor tropism, are ideal delivery vehicles for gene therapy. In this study, we investigated whether treatment with radiation and interleukin (IL)-12-expressing MSCs (MSCs/IL-12) exerts improved antitumor effects on murine metastatic hepatoma. HCa-I and Hepa 1-6 cells were utilized to generate heterotopic murine hepatoma models. Tumor-bearing mice were treated with irradiation or MSCs/IL-12 alone, or a combination. Monocyte chemoattractant protein-1 (MCP-1/CCL2) expression was assessed in irradiated hepatoma tissues to confirm a chemotactic effect. Combination treatment strategies were established and their therapeutic efficacies were evaluated by monitoring tumor growth, metastasis and survival rate. IL-12 expression was assessed and the apoptotic activity and immunological alterations in the tumor microenvironment were examined. MCP-1/CCL2 expression and localization of MSCs/IL-12 increased in the irradiated murine hepatoma cells. The antitumor effects, including suppression of pulmonary metastasis and survival rate improvements, were increased by the combination treatment with irradiation and MSCs/IL-12. IL-12 expression was increased in tumor cells, causing proliferation of cluster of differentiation 8(+) T-lymphocytes and natural killer cells. The apoptotic activity increased, indicating that the cytotoxicity of immune cells was involved in the antitumor effect of the combined treatment. Treatment with irradiation and MSCs/IL-12 showed effectiveness in treating murine metastatic hepatoma. IL-12-induced proliferation of immune cells played an important role in apoptosis of tumor cells. Our results suggest that treatment with irradiation and MSCs/IL-12 may be a useful strategy for enhancing antitumor activity in metastatic hepatoma. What's new? Mesenchymal stem cells (MSCs) are promising gene-delivery vehicles, with the potential to improve antitumor effects when used in combination with existing therapies. In the present study, the combined use of interleukin (IL)-12-expressing MSCs (MSCs/IL-12) and radiation therapy increased antitumor activity in murine metastatic hepatoma, a model that is representative of human metastatic hepatocellular carcinoma (HCC), which affects nearly half of HCC patients. Treatment with MSCs/IL-12 resulted in increased IL-12 expression in tumor cells and immune cell proliferation. Immune cell cytotoxicity, evidenced by increased apoptotic activity, appeared to play a role in MSCs/IL-12 augmentation of antitumor effects.1178Ysciescopu

Metronidazole-induced encephalopathy in a patient with infectious colitis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Encephalopathy is a rare disease caused by adverse effects of antibiotic drugs such as metronidazole. The incidence of metronidazole-induced encephalopathy is unknown, although several previous studies have addressed metronidazole neurotoxicity. Here, we report the case of a patient with reversible cerebellar dysfunction on magnetic resonance imaging, induced by prolonged administration of metronidazole for the treatment of infectious colitis.</p> <p>Case presentation</p> <p>A 71-year-old Asian man, admitted to our hospital with hematochezia, underwent Hartmann's operation for the treatment of colorectal cancer three years ago. He was diagnosed with an infectious colitis by colonoscopy. After taking metronidazole, he showed drowsiness and slow response to verbal commands. Brain magnetic resonance imaging showed obvious bilateral symmetric hyperintensities within his dentate nucleus, tectal region of the cerebellum, and splenium of corpus callosum in T2-weighted images and fluid attenuated inversion recovery images. Our patient's clinical presentation and magnetic resonance images were thought to be most consistent with metronidazole toxicity. Therefore, we discontinued metronidazole, and his cerebellar syndrome resolved. Follow-up magnetic resonance imaging examinations showed complete resolution of previously noted signal changes.</p> <p>Conclusion</p> <p>Metronidazole may produce neurologic side effects such as cerebellar syndrome, and encephalopathy in rare cases. We show that metronidazole-induced encephalopathy can be reversed after cessation of the drug. Consequently, careful consideration should be given to patients presenting with complaints of neurologic disorder after the initiation of metronidazole therapy.</p

Nanosilver Colloids-Filled Photonic Crystal Arrays for Photoluminescence Enhancement

For the improved surface plasmon-coupled photoluminescence emission, a more accessible fabrication method of a controlled nanosilver pattern array was developed by effectively filling the predefined hole array with nanosilver colloid in a UV-curable resin via direct nanoimprinting. When applied to a glass substrate for light emittance with an oxide spacer layer on top of the nanosilver pattern, hybrid emission enhancements were produced from both the localized surface plasmon resonance-coupled emission enhancement and the guided light extraction from the photonic crystal array. When CdSe/ZnS nanocrystal quantum dots were deposited as an active emitter, a total photoluminescence intensity improvement of 84% was observed. This was attributed to contributions from both the silver nanoparticle filling and the nanoimprinted photonic crystal array

An Antireflective Nanostructure Array Fabricated by Nanosilver Colloidal Lithography on a Silicon Substrate

An alternative method is presented for fabricating an antireflective nanostructure array using nanosilver colloidal lithography. Spin coating was used to produce the multilayered silver nanoparticles, which grew by self-assembly and were transformed into randomly distributed nanosilver islands through the thermodynamic action of dewetting and Oswald ripening. The average size and coverage rate of the islands increased with concentration in the range of 50–90 nm and 40–65%, respectively. The nanosilver islands were critically affected by concentration and spin speed. The effects of these two parameters were investigated, after etching and wet removal of nanosilver residues. The reflection nearly disappeared in the ultraviolet wavelength range and was 17% of the reflection of a bare silicon wafer in the visible range

Measuring the value of air quality: application of the spatial hedonic model

This study applies a hedonic model to assess the economic benefits of air quality improvement following the 1990 Clean Air Act Amendment at the county level in the lower 48 United States. An instrumental variable approach that combines geographically weighted regression and spatial autoregression methods (GWR-SEM) is adopted to simultaneously account for spatial heterogeneity and spatial autocorrelation. SEM mitigates spatial dependency while GWR addresses spatial heterogeneity by allowing response coefficients to vary across observations. Positive amenity values of improved air quality are found in four major clusters: (1) in East Kentucky and most of Georgia around the Southern Appalachian area; (2) in a few counties in Illinois; (3) on the border of Oklahoma and Kansas, on the border of Kansas and Nebraska, and in east Texas; and (4) in a few counties in Montana. Clusters of significant positive amenity values may exist because of a combination of intense air pollution and consumer awareness of diminishing air quality

The Potential for pathogenicity was present in the ancestor of the Ascomycete subphylum Pezizomycotina

<p>Abstract</p> <p>Background</p> <p>Previous studies in Ascomycetes have shown that the function of gene families of which the size is considerably larger in extant pathogens than in non-pathogens could be related to pathogenicity traits. However, by only comparing gene inventories in extant species, no insights can be gained into the evolutionary process that gave rise to these larger family sizes in pathogens. Moreover, most studies which consider gene families in extant species only tend to explain observed differences in gene family sizes by gains rather than by losses, hereby largely underestimating the impact of gene loss during genome evolution.</p> <p>Results</p> <p>In our study we used a selection of recently published genomes of Ascomycetes to analyze how gene family gains, duplications and losses have affected the origin of pathogenic traits. By analyzing the evolutionary history of gene families we found that most gene families with an enlarged size in pathogens were present in an ancestor common to both pathogens and non-pathogens. The majority of these families were selectively maintained in pathogenic lineages, but disappeared in non-pathogens. Non-pathogen-specific losses largely outnumbered pathogen-specific losses.</p> <p>Conclusions</p> <p>We conclude that most of the proteins for pathogenicity were already present in the ancestor of the Ascomycete lineages we used in our study. Species that did not develop pathogenicity seemed to have reduced their genetic complexity compared to their ancestors. We further show that expansion of gained or already existing families in a species-specific way is important to fine-tune the specificities of the pathogenic host-fungus interaction.</p

Structural and functional analyses of minimal phosphopeptides targeting the polo-box domain of polo-like kinase 1

Polo-like kinase-1 (Plk1) has a pivotal role in cell proliferation and is considered a potential target for anticancer therapy. The noncatalytic polo-box domain (PBD) of Plk1 forms a phosphoepitope binding module for protein-protein interaction. Here, we report the identification of minimal phosphopeptides that specifically interact with the PBD of human PLK1, but not those of the closely related PLK2 and PLK3. Comparative binding studies and analyses of crystal structures of the PLK1 PBD in complex with the minimal phosphopeptides revealed that the C-terminal SpT dipeptide functions as a high-affinity anchor, whereas the N-terminal residues are crucial for providing specificity and affinity to the interaction. Inhibition of the PLK1 PBD by phosphothreonine mimetic peptides was sufficient to induce mitotic arrest and apoptotic cell death. The mode of interaction between the minimal peptide and PBD may provide a template for designing therapeutic agents that target PLK1.National Institutes of Health (U.S.) (Grant R01 GM60594)National Cancer Institute (U.S.)National Institutes of Health (U.S.) (Contract N01-CO-12400)National Institutes of Health (U.S.) (HHSN261200800001E

Epithelial Cells Derived from Swine Bone Marrow Express Stem Cell Markers and Support Influenza Virus Replication In Vitro

The bone marrow contains heterogeneous population of cells that are involved in the regeneration and repair of diseased organs, including the lungs. In this study, we isolated and characterized progenitor epithelial cells from the bone marrow of 4- to 5-week old germ-free pigs. Microscopically, the cultured cells showed epithelial-like morphology. Phenotypically, these cells expressed the stem cell markers octamer-binding transcription factor (Oct4) and stage-specific embryonic antigen-1 (SSEA-1), the alveolar stem cell marker Clara cell secretory protein (Ccsp), and the epithelial cell markers pan-cytokeratin (Pan-K), cytokeratin-18 (K-18), and occludin. When cultured in epithelial cell growth medium, the progenitor epithelial cells expressed type I and type II pneumocyte markers. Next, we examined the susceptibility of these cells to influenza virus. Progenitor epithelial cells expressed sialic acid receptors utilized by avian and mammalian influenza viruses and were targets for influenza virus replication. Additionally, differentiated type II but not type I pneumocytes supported the replication of influenza virus. Our data indicate that we have identified a unique population of progenitor epithelial cells in the bone marrow that might have airway reconstitution potential and may be a useful model for cell-based therapies for infectious and non-infectious lung diseases

A Type 2C Protein Phosphatase FgPtc3 Is Involved in Cell Wall Integrity, Lipid Metabolism, and Virulence in Fusarium graminearum

Type 2C protein phosphatases (PP2Cs) play important roles in regulating many biological processes in eukaryotes. Currently, little is known about functions of PP2Cs in filamentous fungi. The causal agent of wheat head blight, Fusarium graminearum, contains seven putative PP2C genes, FgPTC1, -3, -5, -5R, -6, -7 and -7R. In order to investigate roles of these PP2Cs, we constructed deletion mutants for all seven PP2C genes in this study. The FgPTC3 deletion mutant (ΔFgPtc3-8) exhibited reduced aerial hyphae formation and deoxynivalenol (DON) production, but increased production of conidia. The mutant showed increased resistance to osmotic stress and cell wall-damaging agents on potato dextrose agar plates. Pathogencity assays showed that ΔFgPtc3-8 is unable to infect flowering wheat head. All of the defects were restored when ΔFgPtc3-8 was complemented with the wild-type FgPTC3 gene. Additionally, the FgPTC3 partially rescued growth defect of a yeast PTC1 deletion mutant under various stress conditions. Ultrastructural and histochemical analyses showed that conidia of ΔFgPtc3-8 contained an unusually high number of large lipid droplets. Furthermore, the mutant accumulated a higher basal level of glycerol than the wild-type progenitor. Quantitative real-time PCR assays showed that basal expression of FgOS2, FgSLT2 and FgMKK1 in the mutant was significantly higher than that in the wild-type strain. Serial analysis of gene expression in ΔFgPtc3-8 revealed that FgPTC3 is associated with various metabolic pathways. In contrast to the FgPTC3 mutant, the deletion mutants of FgPTC1, FgPTC5, FgPTC5R, FgPTC6, FgPTC7 or FgPTC7R did not show aberrant phenotypic features when grown on PDA medium or inoculated on wheat head. These results indicate FgPtc3 is the key PP2C that plays a critical role in a variety of cellular and biological functions, including cell wall integrity, lipid and secondary metabolisms, and virulence in F. graminearum