To elucidate the biosynthesis of a fungicidal dimeric anhydride zopfiellin, the putative biosynthetic gene cluster was identified. We conducted heterologous expression of candidate genes for the synthesis of maleic anhydride and its dimerization and identified the two isomeric dimers with 9-membered rings as products. Notably, α-ketoglutarate-dependent dioxygenase ZopK oxidized one of the dimers, giving the 8-membered ring of zopfiellin. The mechanism of oxidative rearrangement is proposed by analyzing the incorporation of 13C-labeled precursors.
Conidiogenone, a diterpene with a unique structure, is known to induce the conidiation of Penicillium cyclopium. The biosynthetic pathway of (−)-conidiogenone has been fully elucidated by the heterologous expression of biosynthetic genes in Aspergillus oryzae and by in vitro enzyme assay with 13C-labeled substrates. After construction of deoxyconidiogenol by the action of bifunctional terpene synthase, one cytochrome P450 catalyzes two rounds of oxidation to furnish conidiogenone. Notably, similar biosynthetic genes are conserved among more than 10 Penicillium sp., suggesting that conidiogenone is a common conidiation inducer in this genus. The cyclization mechanism catalyzed by terpene synthase, which involves successive 1,2-alkyl shifts, was fully elucidated using 13C-labeled geranylgeranyl pyrophosphate (GGPP) as substrate. During the structural analysis of deoxyconidiogenol, we observed broadening of some of the 13C signals measured at room temperature, which has not been observed with other structurally related compounds. Careful examination using techniques including 13C NMR studies at −80 °C, conformational analysis and prediction of the 13C chemical shifts using density functional theory gave insights into this intriguing phenomenon.
Introduction: Treatment for Multiple Myeloma (MM) with new therapeutic agents has dramatically improved outcomes and increased the number of survivors. Although venous thromboembolism (VTE) is common in MM, the pathophysiological interplay between VTE and MM, including risk factors related to the patient, disease, and modern treatments, is complex and incompletely understood. Objectives: To evaluate real-world data on the risk factors of VTE and outcomes of patients with MM using a nationwide claims database. Methods: This study involved the retrospective observational analysis of the Japan Medical Data Center (JMDC, Tokyo, Japan) database, an anonymized patient-level claims database younger than 75 years old. We identified cases with diagnosis and treatment of MM with codes provided by JMDC. Patients with a tentative diagnosis code of MM [C90] were included. Cases with a history of VTE or a pre-diagnostic history of fewer than six months were excluded. Propensity score (PS) was calculated using logistic regression based on age, gender, and cardiovascular risk factors. Results: We identified 2,023 eligible cases (mean age 53.6 ± 11.8 years) between January 2015 and December 2020. After 1:1 PS matching, the number of patients, mean age (years), follow-up (months) were as follows: MM group (n=280, 58.7 ± 8.1, 18.6 ± 14.8), Control group (n=280, 58.5 ± 8.1, 24.4 ± 18.4). Kaplan-Meier analysis indicated that the rate of VTE within 60 months was significantly higher among MM than in Control (25.7% vs 2.5%, Log-rank p<.001). Within the MM group, multivariable Cox proportional hazard model showed that lenalidomide had a risk of VTE (Hazard Ratio 1.16 [95% Confidence Interval: 1.19-7.69]) among modern therapies (stem cell transplantation 37.1%, elotuzumab 6.4%, daratumumab 16.8%, bortezomib 88.9%, carfilzomib 21.8%, ixazomib 11.8%, thalidomide 3.9%, lenalidomide 78.9%, and pomalidomide 15.4%). Conclusions: Patients who underwent modern MM therapies, including immunomodulatory agents, had significantly higher VTE risk than PS-matched Control. Therefore, further studies using real-world data to improve prevention, early detection, and treatment of MM-related VTE are warranted.
ObjectivesFollow-up invasive coronary angiography (FUICA) after percutaneous coronary intervention (PCI) has been shown to increase the rate of early coronary revascularisation without reducing the incidence of subsequent myocardial infarction or death. However, no studies have evaluated the cost-effectiveness of FUICA in patients after coronary stenting. Therefore, this study aimed to evaluate the cost-effectiveness of FUICA after PCI.DesignRetrospective observational cohort study.Setting497 hospitals.Participants and interventionsOverall, 558 patients who underwent coronary artery stenting between April 2014 and March 2015 were matched and included in the invasive angiographic follow-up (AF) group (n=279), in which patients underwent FUICA 6–12 months after PCI, or in the clinical follow-up alone group (CF; n=279) using propensity scores.Primary and secondary outcome measuresThe primary endpoint was the composite outcome of death, myocardial infarction, urgent coronary revascularisation, stroke or hospitalisation for the heart failure. The secondary endpoints included all-cause death, non-fatal myocardial infarction, urgent revascularisation, coronary artery bypass grafting, stroke, hospitalisation for the heart failure and any coronary revascularisation after a minimum of 6 months of follow-up.ResultsCosts were calculated as direct medical expenses based on medical fee billing information. The cumulative 3-year incidence of the primary endpoint was 5.3% in the AF group and 4.7% in the CF group (HR 1.02; 95% CI 0.47 to 2.20; p=0.98). The total incremental cost at the 3-year endpoint in the AF group was US$1874 higher than that in the CF group (US$8947±US$5684 vs US$7073±US$6360; p≤0.001).ConclusionsFUICA increased the costs but did not improve clinical benefits. Thus, FUICA is not economically more attractive than CF alone.Trial registration numberUMIN000039768.
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