コバルト触媒による〔2+2+2〕ピリジン環化反応を用いた複素芳香環化合物の合成

金沢大学薬学部酒石酸より誘導したジインに適当な芳香族ニトリルを連結しようと試みた。また酒石酸よりアルキンとニトリルを繋ぐ化合物を合成することも試みた。これらの合成法を検討していたところ、第7回有機合成指向有機金属化学国際会議(神戸)においてInstiturt fur Organische Chemie der Universitat,Gottingen(Germany)のProf.U.Grothらによる同様な研究(Intramolecular Cobalt-Mediated〔2+2+2〕-Cycloadditions of Enediynestowards Linear An-nelated Polycycles)が報告された。本研究の複素環の合成は彼等の研究と同様の概念に基づいて行われているので、これ以上の検討を断念した。そこで、研究のもう1つの概念である(R^*,R^*)-隣接ジオールによるコンホメーション制御による反応場の設計を目的とする研究を続けた。その結果、酒石酸由来の嵩高い保護基で保護した隣接ジオールに連結されたアルキンとアルカンのパラジウム触媒による分子内エン-イン環化反応において、反応の促進および立体選択性の発現を見い出した。また同様に、保護した隣接ジオールに連結されたアルケンと水酸基のオキシパラデーションによるピラン環の構築で、高い立体選択性の発現が見い出された。このようなコンホメーション制御による反応場の設計は今後の環化反応の研究における有用な知見を与えるものと期待できる。また、これらの合成手法を利用して複素環化合物の合成を行えることが期待できる。研究課題/領域番号:05771921, 研究期間(年度):1993出典：研究課題「コバルト触媒による〔2+2+2〕ピリジン環化反応を用いた複素芳香環化合物の合成」課題番号05771921（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-05771921/）を加工して作

B型肝炎・C型肝炎を背景とする肝細胞癌に対する抗ウイルス療法と予後改善効果に関する研究

学位の種別:課程博士University of Tokyo(東京大学

Efficacy of the Pulse Pressure Generator during Cardiopulmonary Bypass Training Using the Extracorporeal Circulation Simulator

Objective: Cardiopulmonary bypass during cardiac surgery is an essential procedure, and the perfusionist needs to have sufficient education and training. Simulation training is suitable in such cases. We have developed a simulation system for cardiopulmonary bypass training (extracorporeal circulation simulator [ECCSIM]) and reported its efficacy. ECCSIM had no pulse pressure generator, so some perfusionists have mentioned that the operational feeling during training differs from that in real clinical cases. In this study, we have developed a new pulse pressure generator and examined the efficacy of this system during cardiopulmonary bypass training using ECCSIM. Materials and Methods: Results were observed as wave patterns during simulation of extracorporeal circulation with and without pulse pressure flow. Operational feeling during training of extracorporeal circulation was compared using a questionnaire survey, based on the Japanese version of the NASA Task Load Index (NASA-TLX), a subjective index, completed by seven perfusionists. Results: With the addition of pulse pressure flow, fluctuation of arterial flow at low speed with the centrifugal pump increased, and operation of extracorporeal circulation became unstable. The questionnaire survey, including ‘Operational feeling of centrifugal pump’, ‘Feeling of afterload’, and ‘Display of pressure monitor’, showed results similar to that of the clinical situation using pulse pressure flow. The difficulty of simulator operation in extracorporeal circulation was significantly greater in the group with pulse pressure flow. Mental/physical load examined with NASA-TLX increased with pulse pressure flow. Conclusion: Using a new pulse pressure generator with ECCSIM was effective in extracorporeal circulation training

Polaprezinc Protects Mice against Endotoxin Shock

Polaprezinc (PZ), a chelate compound consisting of zinc and l-carnosine (Car), is an anti-ulcer drug developed in Japan. In the present study, we investigated whether PZ suppresses mortality, pulmonary inflammation, and plasma nitric oxide (NO) and tumor necrosis factor (TNF)-α levels in endotoxin shock mice after peritoneal injection of lipopolysaccharide (LPS), and how PZ protects against LPS-induced endotoxin shock. PZ pretreatment inhibited the decrease in the survival rate of mice after LPS injection. PZ inhibited the increases in plasma NO as well as TNF-α after LPS. Compatibly, PZ suppressed LPS-induced inducible NO synthase mRNA transcription in the mouse lungs. PZ also improved LPS-induced lung injury. However, PZ did not enhance the induction of heat shock protein (HSP) 70 in the mouse lungs after LPS. Pretreatment of RAW264 cells with PZ suppressed the production of NO and TNF-α after LPS addition. This inhibition likely resulted from the inhibitory effect of PZ on LPS-mediated nuclear factor-κB (NF-κB) activation. Zinc sulfate, but not Car, suppressed NO production after LPS. These results indicate that PZ, in particular its zinc subcomponent, inhibits LPS-induced endotoxin shock via the inhibition of NF-κB activation and subsequent induction of proinflammatory products such as NO and TNF-α, but not HSP induction

Geranylgeranylacetone Ameliorates Inflammatory Response to Lipopolysaccharide (LPS) in Murine Macrophages: Inhibition of LPS Binding to The Cell Surface

We investigated whether pretreatment with geranylgeranylacetone (GGA), a potent heat shock protein (HSP) inducer, could inhibit proinflammatory cytokine liberation and nitric oxide (NO) production in lipopolysaccharide (LPS)-treated murine macrophages. The levels of NO and tumor necrosis factor-α (TNF-α) released from murine macrophage RAW 264 cells were increased dose- and time-dependently following treatment with LPS (1 µg/ml). GGA (80 µM) treatment 2 h before LPS addition significantly suppressed TNF-α and NO productions at 12 h and 24 h after LPS, respectively, indicating that GGA inhibits activation of macrophages. However, replacement by fresh culture medium before LPS treatment abolished the inhibitory effect of GGA on NO production in LPS-treated cells. Furthermore, GGA inhibited both HSP70 and inducible NO synthase expressions induced by LPS treatment despite an HSP inducer. When it was examined whether GGA interacts with LPS and/or affects expression of Toll-like receptor 4 (TLR4) and CD14 on the cell surface, GGA inhibited the binding of LPS to the cell surface, while GGA did not affect TLR4 and CD14 expressions. These results indicate that GGA suppresses the binding of LPS to the cell surface of macrophages, resulting in inhibiting signal transduction downstream of TLR4

Lenvatinib for Anaplastic Thyroid Cancer

Background: Lenvatinib has been approved by regulatory agencies in Japan, the United States, and the European Union for treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thyroid cancer, however, is a clinically diverse disease that includes anaplastic thyroid cancer (ATC), the subtype associated with the highest lethality. Effective therapy for ATC is an unmet need. Patients and methods: This phase 2, single-arm, open-label study in patients with thyroid cancer, including ATC, RR-DTC, and medullary thyroid cancer was conducted from 3 September 2012 to 9 July 2015. Patients received lenvatinib 24 mg daily until disease progression or development of unacceptable toxicity. The primary endpoint was safety, and the secondary endpoint was efficacy, as assessed by progression-free survival (PFS), overall survival (OS), and objective response rate. Results: At data cutoff, 17 patients with ATC were enrolled. All experienced >= 1 treatment-emergent adverse event (TEAE). The most frequent TEAEs were decreased appetite (82%), hypertension (82%), fatigue (59%), nausea (59%), and proteinuria (59%). Of note, only one patient required lenvatinib withdrawal because of a TEAE, and this TEAE was considered unrelated to lenvatinib. The median PFS was 7.4 months [95% confidence interval (CI): 1.7-12.9], the median OS was 10.6 months (95% CI: 3.8-19.8), and the objective response rate was 24%. Conclusion: In this study, lenvatinib demonstrated manageable toxicities with dose adjustments and clinical activity in patients with ATC. This clinical activity of lenvatinib warrants further investigation in ATC

Comorbid depressive disorders and left-side dominant occlusal discomfort in patients with phantom bite syndrome

Background: Phantom bite syndrome (PBS) is characterised by occlusal discomfort without corresponding dental abnormalities. Despite repeated, failed dental treatments, patients with PBS persist in seeking bite correction. PBS has been regarded as a mental disorder. However, we have reported that PBS patients with a dental trigger tend to have less psychiatric history than those without. Hence, the symptoms of PBS cannot be explained by a mental disorder alone, and it is unclear if mental disorders affect occlusal sensation. Objective: To elucidate the pathophysiology of PBS, we analysed the dental history, PBS symptom laterality and psychiatric history of patients. Methods: In this retrospective study, we reviewed outpatients with PBS who presented at our clinic between April 2012 and March 2017. Their medical records were reviewed for demographic data, medical history and laterality of occlusal discomfort. Results: Approximately half of the 199 enrolled patients had bilateral occlusal discomfort. In the others, the side with occlusal discomfort generally tended to be the one that had received dental treatment. There was no significant relationship between the side chiefly affected by occlusal discomfort and whether dental treatment had been received; however, the affected side differed depending on whether the patient had comorbid psychiatric disorders (P = .041). Conclusions: The distributions of the side with symptoms of PBS were different between those with and without comorbid psychiatric disorders, suggesting that psychiatric disorders might affect occlusal sensation due to a subtle dysfunction in brain areas central to sensory integration. Central dysfunction might play an important role in PBS

Sarcopenia, intramuscular fat deposition, and visceral adiposity independently predict the outcomes of hepatocellular carcinoma

Background & AimsObesity defined by body mass index (BMI) significantly increases the risk of hepatocellular carcinoma (HCC). In contrast, not only obesity but also underweight is associated with poor prognosis in patients with HCC. Differences in body composition rather than BMI were suggested to be true determinants of prognosis. However, this hypothesis has not been demonstrated conclusively.MethodsWe measured skeletal muscle index (SMI), mean muscle attenuation (MA), visceral adipose tissue index, subcutaneous adipose tissue index, and visceral to subcutaneous adipose tissue area ratios (VSR) via computed tomography in a large-scale retrospective cohort of 1257 patients with different stages of HCC, and comprehensively analyzed the impact of body composition on the prognoses.ResultsAmong five body composition components, low SMI (called sarcopenia), low MA (called intramuscular fat [IMF] deposition), and high VSR (called visceral adiposity) were significantly associated with mortality, independently of cancer stage or Child-Pugh class. A multivariate analysis revealed that sarcopenia (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.18–1.96; p=0.001), IMF deposition (HR, 1.34; 95% CI, 1.05–1.71; p=0.020), and visceral adiposity (HR, 1.35; 95% CI, 1.09–1.66; p=0.005) but not BMI were significant predictors of survival. The prevalence of poor prognostic body composition components was significantly higher in underweight and obese patients than in normal weight patients.ConclusionsSarcopenia, IMF deposition, and visceral adiposity independently predict mortality in patients with HCC. Body composition rather than BMI is a major determinant of prognosis in patients with HCC

Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study

Treating advanced or recurrent melanoma remains a challenge. Cancer cells canevade the immune system by blocking T-cell activation through overexpressionof the inhibitory receptor programmed death 1 (PD-1) ligands. The PD-1 inhibitornivolumab blocks the inhibitory signal in T cells, thus overcoming the immuneresistance of cancer cells. Nivolumab has shown promising anticancer activity invarious cancers. We carried out a single-arm, open-label, multicenter, phase IIstudy to investigate the efficacy and safety of nivolumab in previously untreatedJapanese patients with advanced melanoma. Twenty-four patients with stage III/IV or recurrent melanoma were enrolled and received i.v. nivolumab 3 mg/kgevery 2 weeks until disease progression or unacceptable toxicity. The primaryendpoint was overall response rate evaluated by an independent radiologyreview committee. The independent radiology review committee-assessed overallresponse rate was 34.8% (90% confidence interval, 20.8–51.9), and the overallsurvival rate at 18 months was 56.5% (90% confidence interval, 38.0–71.4). Treatment-related adverse events (AEs) of grade 3 or 4 only occurred in three patients(12.5%). Two patients discontinued nivolumab because of AEs, but all AEs wereconsidered manageable by early diagnosis and appropriate treatment. Subgroupanalyses showed that nivolumab was clinically beneficial and tolerable regardlessof BRAF genotype, and that patients with treatment-related select AEs and withvitiligo showed tendency for better survival. In conclusion, nivolumab showedfavorable efficacy and safety profiles in Japanese patients with advanced orrecurrent melanoma, with or without BRAF mutations. (Trial registration no.JapicCTI-142533.

Long-term follow-up on the use of vascularized fibular graft for the treatment of congenital pseudarthrosis of the tibia

<p>Abstract</p> <p>Background</p> <p>Congenital pseudoarthrosis of the tibia (CPT) is one of the most difficult conditions to treat.</p> <p>Methods</p> <p>Five girls and 3 boys with CPT were treated by vascularized fibular grafting (VFG). The average age at VFG was 7.0 years (range: 1.9–11.5 years) with an average follow-up term of 11.7 years (range: 4.9–19.6 years). Five of the children had undergone multiple operations before VFG, while the other 3 had no such history.</p> <p>Results</p> <p>Bone consolidation was obtained in all cases after an average term of 6.6 months (range: 4–10 months); this was with the first VFG in 7 cases but with the second VFG in 1 case. Complication of stress fracture and ankle pain occurred in 1 and 3 cases, respectively, only in cases undergoing multiple operations. Leg-length discrepancy was more prominent in the patients with multiple previous operations (mean: 7.5 cm), than in the cases with no prior surgery (mean: 0.7 cm).</p> <p>Conclusion</p> <p>The long-term results of VFG for CPT were excellent, especially in the cases, with no prior surgery. VFG should be considered as a primary treatment option for CPT.</p