Development of Fibrous Bioactive Glass-based Composites for Bone Tissue Engineering Applications

信州大学博士（工学）学位論文・平成24年9月30日授与（甲第571号）・高 春霞Thesis高 春霞. Development of Fibrous Bioactive Glass-based Composites for Bone Tissue Engineering Applications. 信州大学, 2012, 129p, 博士論文doctoral thesi

Design and development of a photoswitchable DFG-out kinase inhibitor

We report the synthesis and characterisation of a photoswitchable DFG-out kinase inhibitor. Photocontrol of the target kinase in both enzymatic and living cell assays is demonstrated

Prognostic influence of PD-1/PD-L1 suppressors in combination with chemotherapeutic agents for non-small cell pulmonary carcinoma: system review and meta-analysis

BackgroundLung cancer is a common malignant tumor, which is seriously harmful to human life and health. Nowadays, it has gradually become one of the best treatments for non-small cell lung cancer (NSCLC) to combine immunotherapy and chemotherapy, and its clinical efficacy is preliminary. Nevertheless, substantial differences exist between various studies and various indicators. Despite their unconvincing results, high-quality research evidence is needed to support them. In this case, further correlative studies are necessary to investigate the prognostic outcomes of PD-1/PD-L1 suppressors in combination with chemotherapeutic drugs in NSCLC.MethodsThe online public databases were searchable for the clinical trials that consisted of NSCLC patients who had concluded their chemotherapy and who had accepted PD-1/PD-L1 suppressors. The time-span of the search spanned from the beginning to the end of the database. Two investigators retrieved the data independently. RevMan 5.3 statistical software was utilized for the assessment of bias risk. The software followed the Cochrane Handbook 5.3 guidelines.ResultsThere were seven clinically controlled studies with 2781 NSCLC samples finally included in this study. A meta-analysis of the post-treatment overall response rate (ORR) was undertaken. A remarkably higher ORR rate was observed in the study group (p<0.05). Study participants had a noticeably longer PFS (HR=0.61, 95% CI=0.54-0.70, P<0.00001). Study participants had markedly longer overall survival (OS) (HR=0.651, 95% CI=0.52-0.82, P<0.05). The incidence of adverse events (AEs) of Grade 3 or above was not clinically clearly different (P>0.05), as demonstrated by the incidence of AEs. The funnel plots were separately charted in accordance with ORR rate, PFE, OS, and Grade 3 AEs. The majority of the funnel plots were symmetrical and a minority of funnel plots were asymmetrical, indicating the heterogeneity of research and the limited evidence available may lead to some publication bias in the contained literature.ConclusionThe combined PD-1/PD-L1 inhibitors with conventional chemotherapy can dramatically elevate the prognosis of NSCLC patients, obviously enhancing the ORR rate and prolonging their PFS and OS. Furthermore, it was found that adding PD-1/PD-L1 inhibitors to conventional chemotherapy did not result in any additional adverse effects

Synthesis and Photophysical Characterization of Azoheteroarenes

A set of azoheteroarenes have been synthesized with Buchwald-Hartwig coupling and microwave-assisted O2oxidation as the key steps. Several compounds exhibit good to excellent photoswitching properties (high switching efficiency, good fatigue resistance, and thermal stability of Z-isomer) relevant for photocontrolled applications, which pave the way for use in photopharmacology

An analysis of microbiota-targeted therapies in patients with avian influenza virus subtype H7N9 infection

BACKGROUND: Selective prophylactic decontamination of the digestive tract is a strategy for the prevention of secondary nosocomial infection in patients with avian influenza virus subtype H7N9 infection. Our aim was to summarize the effectiveness of these therapies in re-establishing a stable and diverse microbial community, and reducing secondary infections. METHODS: Comprehensive therapies were dependent on the individual clinical situation of subjects, and were divided into antiviral treatment, microbiota-targeted therapies, including pro- or pre-biotics and antibiotic usage, and immunotherapy. Quantitative polymerase chain reaction and denaturing gradient gel electrophoresis (DGGE) were used for real-time monitoring of the predominant intestinal microbiome during treatment. Clinical information about secondary infection was confirmed by analyzing pathogens isolated from clinical specimens. RESULTS: Different antibiotics had similar effects on the gut microbiome, with a marked decrease and slow recovery of the Bifidobacterium population. Interestingly, most fecal microbial DGGE profiles showed the relative stability of communities under the continual suppression of the same antibiotics, and significant changes when new antibiotics were introduced. Moreover, we found no marked increase in C-reactive protein, and no cases of bacteremia or pneumonia, caused by probiotic use in the patients, which confirmed that the probiotics used in this study were safe for use in patients with H7N9 infection. Approximately 72% of those who subsequently suffered exogenous respiratory infection by Candida species or multidrug-resistant Acinetobacter baumannii and Klebsiella pneumoniae were older than 60 years. The combination of probiotics and prebiotics with antibiotics seemed to fail in these patients. CONCLUSIONS: Elderly patients infected with the influenza A (H7N9) virus are considered a high-risk group for developing secondary bacterial infection. Microbiota restoration treatment reduced the incidence of enterogenous secondary infection, but not exogenous respiratory infection. The prophylactic effects of microbiota restoration strategies for secondary infection were unsatisfactory in elderly and critically ill patients

Design and development of photoswitchable DFG-Out RET kinase inhibitors

REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase that is required for development of multiple human tissues, but which is also an important contributor to human cancers. RET activation through rearrangement or point mutations occurs in thyroid and lung cancers. Furthermore, activation of wild type RET is an increasingly recognized mechanism promoting tumor growth and dissemination of a much broader group of cancers. RET is therefore an attractive therapeutic target for small-molecule kinase inhibitors. Non-invasive control of RET signaling with light offers the promise of unveiling its complex spatiotemporal dynamics in vivo. In this work, photoswitchable DFG-out RET kinase inhibitors based on heterocycle-derived azobenzenes were developed, enabling photonic control of RET activity. Based on the binding mode of DFG-out kinase inhibitors and using RET kinase as the test model, we developed a photoswitchable inhibitor with a quinoline “head” constituting the azoheteroarene. This azo compound was further modified by three different strategies to increase the difference in biological activity between the E-isomer and the light enriched Z-isomer. Stilbene-based derivatives were used as model compounds to guide in the selection of substituents that could eventually be introduced to the corresponding azo compounds. The most promising quinoline-based compound showed more than a 15-fold difference in bioactivity between the two isomers in a biochemical assay. However, the same compound showed a decreased Z/E (IC50) ratio in the cellular assay, tentatively assigned to stability issues. The corresponding stilbene compound gave a Z/E (IC50) ratio well above 100, consistent with that measured in the biochemical assay. Ultimately, a 7-azaindole based photoswitchable DFG-out kinase inhibitor was shown to display more than a 10-fold difference in bioactivity between the two isomers, in both a biochemical and a cell-based assay, as well as excellent stability even under reducing conditions