Summary
Background
Pioglitazone is a safe and effective option to manage patients with type 2 diabetes and nonalcoholic steatohepatitis (NASH). However, there is marked variability in treatment ...response.
Aim
To evaluate the relationship between concentrations of pioglitazone and its active metabolites and treatment outcomes in patients with NASH.
Methods
Pioglitazone concentrations were measured in patients with NASH treated with pioglitazone 45 mg/day for 18 months; liver biopsy samples were obtained at baseline and after treatment. The primary outcome was a ≥2‐point reduction in NAFLD activity score (NAS) with at least one‐point improvement in more than one liver histology category and without worsening of fibrosis. A novel marker, the pioglitazone exposure index, was calculated to consider the concentrations of pioglitazone as well as the two active metabolites.
Results
The response to pioglitazone was concentration‐dependent as evidenced by the significant relationship between both pioglitazone concentration and pioglitazone exposure index with changes in NAS (r=.48, P=.0002 and r=.51, P<.0001, respectively), steatosis (r=.41, P=.002 and r=.46, P=.0005), and inflammation (r=.44, P=.0009 and r=.40, P=.0003). The pioglitazone exposure index was also associated with a change in ballooning (P=.04). The pioglitazone exposure index was higher in patients with NASH resolution (2.85±1.38 vs 1.78±1.48, P=.018). A predictive model for the primary outcome was developed that incorporated baseline NAS and pioglitazone exposure index (AUC=0.77).
Conclusions
This study demonstrates the importance of pioglitazone exposure to variable response in patients with NASH, and indicates potential factors that may identify patients most likely to benefit from chronic pioglitazone treatment.
Linked ContentThis article is linked to Srinivas paper. To view this article visit https://doi.org/10.1111/apt.14169.
Recently, driver tyrosine kinase gene mutations have been detected in malignant tumors, including lung tumors. Notwithstanding their attractiveness as targets for molecular therapy, limited ...information is available regarding BRAF-mutated lung carcinomas.
BRAF mutation status was determined in 2001 surgically resected nonsmall-cell lung cancer (NSCLC) cases using high-resolution melting analysis (HRMA) followed by Sanger sequencing and/or deep sequencing using next generation sequencer.
BRAF mutations were detected in 26 (1.3%) of 2001 NSCLC cases (25 adenocarcinomas and 1 squamous cell carcinoma). In the 26 cases, 13 mutation genotypes were identified, including V600E (8 of 26; 30.8%), G469A (6 of 26; 23.1%), K601E (4 of 26; 15.4%), and other residual mutations (1 of 26; 0.04%). Of the 13 genotypes, 4 genotypes (G464E, G596R, A598T, and G606R) had not been previously reported in lung cancer. The overall survival rate was not significantly different between patients with wild-type BRAF and those with V600E or non-V600E BRAF mutations (P = 0.49 and P = 0.15, respectively). Histomorphological analysis revealed that focal clear cell changes were present in 75% of V600E-mutated tumors. All V600E BRAF-mutated tumors were negative for other driver gene alterations including epidermal growth factor receptor (EGFR) and KRAS mutations and the anaplastic lymphoma kinase gene translocation, whereas five tumors with non-V600E BRAF mutations (four G469A and one G464E/G466R) showed concomitant EGFR mutations.
The frequency of BRAF mutations in lung cancer was low in an Asian cohort. Furthermore, BRAF mutation status lacked prognostic significance in this patient population.
In order to investigate the electronic properties of the semiconducting van der Waals ferromagnet Cr2Ge2Te6 (CGT), where ferromagnetic layers are bonded through van der Waals forces, we have ...performed angle-resolved photoemission spectroscopy measurements and density-functional theory (DFT+U) calculations. The valence-band maximum at the Γ point is located ∼0.2eV below the Fermi level, consistent with the semiconducting property of CGT. Comparison of the experimental density of states with the DFT calculation has suggested that Coulomb interaction between the Cr 3d electrons Ueff∼1.1eV. The DFT+U calculation indicates that magnetic coupling between Cr atoms within the layer is ferromagnetic if Coulomb Ueff is smaller than 3.0 eV and that the interlayer coupling is ferromagnetic below Ueff∼1.0eV. We therefore conclude that, for Ueff deduced by the experiment, the intralayer Cr-Cr coupling is ferromagnetic and the interlayer coupling is near the boundary between ferromagnetic and antiferromagnetic, which means experimentally deduced Ueff is consistent with the theoretical ferromagnetic condition.
Stratospheric sudden warming (SSW) is a dramatic phenomenon of the winter stratosphere in which the distribution of chemical constituents, associated chemical tendency, and transport of chemical ...constituents differ significantly inside and outside of the polar vortex. In this study, the chemical constituent distributions in the major SSW of 2009/2010 were simulated by the Model for Interdisciplinary Research on Climate 3.2‐Chemistry‐Climate Model (CCM) nudged toward the European Center for Medium‐Range Weather Forecasts‐Interim Re‐Analysis data. The results were compared with Superconducting Submillimeter‐Wave Limb‐Emission Sounder (SMILES) and Microwave Limb Sounder (MLS) observations. In addition, ozone tendency due to ozone transport and chemical ozone loss in the high‐latitude lower stratosphere before and after the SSW was analyzed for the period from 1 January 2010 to 11 February 2010. The evolution and distribution of ozone and HCl inside/outside the polar vortex associated with the vortex shift to the midlatitudes in January are quite similar between SMILES and MLS. Those of ClO are also similar, considering the difference in the local time for the measurement. Analyses of the nudged CCM run indicate that inside the polar vortex at 50 hPa, the ozone concentration increased moderately owing to partial cancelation between the large negative ozone tendency due to chemical ozone destruction and large positive ozone tendency due to horizontal ozone influx from outside of the vortex as well as downward advection. In the region of a high ozone concentration with the same area as that of the polar vortex at 50 hPa, the large increase in ozone was primarily due to a downward advection of ozone. SMILES and MLS observations, nudged CCM simulations, and ozone tendency analyses revealed a highly longitudinal dependent ozone tendency at high latitudes during the SSW.
Key Points
O3, HCl, and ClO during the 2009/2010 SSW are compared between SMILES and MLS
O3, HCl, and ClO from a REF‐C1SD simulation by a nudged CCM are compared with SMILES and MLS
O3 tendency inside/outside the Arctic polar vortex during the SSW from the simulation is analyzed
Amplification and overexpression of the miR-17-92 microRNAs (miRNA) cluster at 13q31.3 has recently reported, with pointers to functional involvement in the development of B-cell lymphomas and lung ...cancers. In the present study, we show that inhibition of miR-17-5p and miR-20a with antisense oligonucleotides (ONs) can induce apoptosis selectively in lung cancer cells overexpressing miR-17-92, suggesting the possibility of 'OncomiR addiction' to expression of these miRNAs in a subset of lung cancers. In marked contrast, antisense ONs against miR-18a and miR-19a did not exhibit such inhibitory effects, whereas inhibition of miR-92-1 resulted in only modest reduction of cell growth, showing significant distinctions among miRNAs of the miR-17-92 cluster in terms of their roles in cancer cell growth. During the course of this study, we also found that enforced expression of a genomic region, termed C2, residing 3' to miR-17-92 in the intron 3 of C13orf25 led to marked growth inhibition in association with double stranded RNA-dependent protein kinase activation. Finally, this study also revealed that the vast majority of C13orf25 transcripts are detected as Drosha-processed cleavage products on Northern blot analysis and that a novel polyadenylation site is present 3' to the miR-17-92 cluster and 5' to the C2 region. Taken together, the present findings contribute towards better understanding of the oncogenic roles of miR-17-92, which might ultimately lead to the future translation into clinical applications.
Background and Objectives
Disruption of transcriptional regulation is a confounding factor associated with a wide range of human inflammatory diseases. To investigate mechanistic links between ...transcription factor DEC1 and pathways underlying inflammation, wild‐type and DEC1 knockout (KO) C57BL/6 mice were treated with Porphyromonas gingivalis (or carboxymethyl cellulose as a control) to induce periodontal inflammation. It provoked an inflammatory response within the oral environment, which showed robust variation in alveolar bone resorption and expression of inflammatory cytokines.
Material and Methods
Male DEC1KO mice and their wild‐type littermates were used for the experimental periodontitis model. Measurement of alveolar bone resorption, micro‐computed tomography, isolation of gingival mononuclear cells (GMCs), flow cytometry and immunohistochemical analysis were used in this study. Human gingival fibroblast cells (HGF‐1) were used for DEC1 over‐expression and short interference RNA (siRNA) studies and quantitative real‐time polymerase chain reaction and western blot analysis were performed.
Results
Micro‐computed tomography analysis demonstrated that P. gingivalis caused a decrease in bone area of wild‐type mice compared with DEC1KO mice. Expression of inflammatory and immune markers in GMCs was significantly decreased in DEC1KO mice after treatment with P. gingivalis. Conversely, interleukin (IL)‐4 and IL‐10 mRNAs were significantly increased in GMCs isolated from DEC1KO mice. The results show that treatment of DEC1KO mice with P. gingivalis decreased the numbers of CD11b+F4/80+ and CD4+RANKL+ T cells. Moreover, expression of CD4, F4/80, RANKL and cathepsin K in inflammatory cell infiltrates was significantly reduced in DEC1KO mice treated with P. gingivalis compared with controls. Furthermore, over‐expression of DEC1 in HGF‐1 cells increased the expression of IL‐1β and tumor necrosis factor‐α mRNAs and their expression levels reached a maximum in response to treatment with lipopolysaccharide. Inhibition of DEC1 by short interference RNA interference suppressed the P. gingivalis‐derived lipopolysaccharide‐induced expression of IL‐1β, tumor necrosis factor‐α and toll‐like receptor4.
Conclusion
These results suggest that transcription factor DEC1 can modulate P. gingivalis‐induced periodontitis in the oral mucosa.
Paclitaxel (PTX) is one of the most effective anticancer agents. In clinical practice, however, high incidences of adverse reactions of the drug, for example, neurotoxicity, myelosuppression, and ...allergic reactions, have been reported. NK105, a micellar nanoparticle formulation, was developed to overcome these problems and to enhance the antitumour activity of PTX. Via the self-association process, PTX was incorporated into the inner core of the micelle system by physical entrapment through hydrophobic interactions between the drug and the well-designed block copolymers for PTX. NK105 was compared with free PTX with respect to their in vitro cytotoxicity, in vivo antitumour activity, pharmacokinetics, pharmacodynamics, and neurotoxicity. Consequently, the plasma area under the curve (AUC) values were approximately 90-fold higher for NK105 than for free PTX because the leakage of PTX from normal blood vessels was minimal and its capture by the reticuloendothelial system minimised. Thus, the tumour AUC value was 25-fold higher for NK105 than for free PTX. NK105 showed significantly potent antitumour activity on a human colorectal cancer cell line HT-29 xenograft as compared with PTX (P<0.001) because the enhanced accumulation of the drug in the tumour has occurred, probably followed by its effective and sustained release from micellar nanoparticles. Neurotoxicity was significantly weaker with NK105 than with free PTX. The neurotoxicity of PTX was attenuated by NK105, which was demonstrated by both histopathological (P<0.001) and physiological (P<0.05) methods for the first time. The present study suggests that NK105 warrants a clinical trial for patients with metastatic solid tumours.
Dental fluorosis is caused by chronic high-level fluoride (F–) exposure during enamel development, and fluorosed enamel has a higher than normal protein content. Matrix metalloproteinase 20 cleaves ...enamel matrix proteins during the secretory stage, and KLK4 further cleaves these proteins during the maturation stage so that the proteins can be reabsorbed from the hardening enamel. We show that transforming growth factor β1 (TGF-β1) can induce Klk4 expression, and we examine the effect of F– on TGF-β1 and KLK4 expression. We found that in vivo F– inhibits Klk4 but not Mmp20 transcript levels. LacZ-C57BL/6-Klk4+/LacZ mice have LacZ inserted in frame at the Klk4 translation initiation site so that the endogenous Klk4 promoter drives LacZ expression in the same temporal/spatial way as it does for Klk4. KLK4 protein levels in rat enamel and β-galactosidase staining in LacZ-C57BL/6-Klk4+/LacZ mouse enamel were both significantly reduced by F– treatment. Since TGF-β1 induces KLK4 expression, we tested and found that F– significantly reduced Tgf-β1 transcript levels in rat enamel organ. These data suggest that F–-mediated downregulation of TGF-β1 expression contributes to reduced KLK4 protein levels in fluorosed enamel and provides an explanation for why fluorosed enamel has a higher than normal protein content.
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