Pyran- and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofurans, respectively, exhibiting diverse physiological and medical bioactivities. However, the biosynthetic mechanisms for their core structures remain poorly understood. Here we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in plants. These included three distinct P. praeruptorum prenyltransferases (PpPT1-3) responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors, and two novel CYP450 cyclases (PpDC and PpOC) crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran scaffolds. Biochemical analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring refactoring. The possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and assessed using site-specific mutagenesis. We identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic process. This study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chemically diverse in terms of enzyme function and catalytic process.

As the first marketed epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib plays an important role in the targeted therapy of malignant tumors such as non-small cell lung cancer, but this drug can cause serious adverse effects such as liver toxicity. If the reaction occurs, the drug must be stopped for liver protection treatment, which greatly affects the treatment process of cancer. However, the mechanism of gefitinib-induced hepatotoxicity is still unclear, and clinical treatment measures are very limited. This article aims to review the molecular mechanism of gefitinib-induced hepatotoxicity and the commonly used clinical therapeutic drugs, so as to provide scientific basis for clinical prevention and rational drug use.

Background and objectiveIt is so far not clear that how myasthenia gravis (MG) affected the prognosis of thymoma patients. The aim of this assay is to compare the postoperative survival between patients with thymoma only and those with both thymoma and MG.MethodsThe Chinese Alliance for Research in Thymomas (ChART) registry recruited patients with thymoma from 18 centers over the country on an intention to treat basis from 1992 to 2012. Two groups were formed according to whether the patient complicated MG. Demographic and clinical data were reviewed, Patients were fol-lowed and their survival status were analyzed.Results There were 1,850 patients included in this study, including 421 with and 1,429 without MG. Complete thymectomy were done in 91.2% patients in MG group and 71.0% in non-MG group (P<0.05). There were more percentage of patients with the histology of thymoma AB, B1, or B2 (P<0.05) in MG group, and more percentage of patients with MG were in Masaoka stage I and II. The 5 year and 10 year OS rates were both higher in MG group (93%vs 88%; 83%vs 81%,P=0.034) respectively. The survival rate was signiifcantly higher in patients with MG when the Masaoka staging was III/IV (P=0.003). Among patients with advanced stage thymoma (stage III, IVa, IVb), the constitu-ent ratios of III, IVa, IVb were similar between MG and Non-MG group. Histologically, however, there were signiifcantly more proportion of AB/B1/B2/B3 in the MG group while there were more C in the non-MG group (P=0.000). Univariate analyses for all patients showed that MG, WHO classiifcation, Masaoka stage, surgical approach, chemotherapy and radiotherapy and resectability were signiifcant factors, and multivariate analysis showed WHO Classiifcation, Masaoka stage, and resectability were strong independent prognostic indicators.ConclusionAlthough MG is not an independent prognostic factor, the sur-vival of patients with thymoma was superior when MG was present, especially in late Masaoka stage patients. Possible reasons included early diagnosis of the tumor, better histologic types, an overall higher R0 resection and less recurrence.

Background and objectiveTo compare the predictive effect of the Masaoka-Koga staging system and the International Association for the Study of Lung Cancer (IASLC)/the International Thymic Malignancies Interest Group (ITMIG) proposal for the new TNM staging on prognosis of thymic malignancies using the Chinese Alliance for Research in Thymomas (ChART) retrospective database.MethodsFrom 1992 to 2012, 2,370 patients in ChART database were ret-rospectively reviewed. Of these, 1,198 patients with complete information on TNM stage, Masaoka-Koga stage, and survival were used for analysis. Cumulative incidence of recurrence (CIR) was assessed in R0 patients. Overall survival (OS) was evalu-ated both in an R0 resected cohort, as well as in all patients (any R status). CIR and OS were ifrst analyzed according to the Masaoka-Koga staging system. Then, they were compared using the new TNM staging proposal.Results Based on Masaoka-Koga staging system, signiifcant difference was detected in CIR among all stages. However, No survival difference was revealed between stage I and II, or between stage II and III. Stage IV carried the highest risk of recurrence and worst survival. According to the new TNM staging proposal, CIR in T1a was signiifcantly lower comparing to all other T categories (P<0.05) and there is a signiifcant difference in OS between T1a and T1b (P=0.004). T4 had the worst OS comparing to all other T categories. CIR and OS were signiifcantly worse in N(+) than in N0 patients. Signiifcant difference in CIR and OS was detected between M0 and M1b, but not between M0 and M1a. OS was almost always statistically different when comparison was made between stages I-IIIa and stages IIIb-IVb. However, no statistical difference could be detected among stages IIIb to IVb.Conclusion Compared with Masaoka-Koga staging, the IASLC/ITMIG TNM staging proposal not only describes the extent of tumor invasion but also provides information on lymphatic involvement and tumor dissemination. Further study using prospectively recorded information on the proposed TNM categories would be helpful to better grouping thymic tumors for predicting prognosis and guiding clinical management.

Background and objectiveTo evaluate the role of preoperative induction therapy on prognosis of local-ly advanced thymic malignancies.MethodsBetween 1994 and 2012, patients received preoperative induction therapies (IT group) in the Chinese Alliance for Research in Thymomas (ChART) database, were compared with those having surgery di-rectly atfer preoperative evaluation (DS group). All tumors receiving induction therapies were locally advanced (clinically stage III-IV) before treatment and those turned out to be in pathological stage I and II were considered downstaged by induction. Clinical pathological characteristics were retrospectively analyzed. To more accurately study the effect of induction therapies, stage IV patients were then excluded. Only stage I-III tumors in the IT group and stage III cases in the DS group were selected for further comparison in a subgroup analysis.Results Only 68 (4%) out of 1,713 patients had induction therapies, with a R0 resection of 67.6%, 5-year recurrence of 44.9%, and 5- and 10-year overall survivals (OS) of 49.7% and 19.9%. Seventeen pa-tients (25%) were downstaged atfer induction. Signiifcantly more thymomas were downstaged than thymic carcinomas (38.7%vs 13.9%,P=0.02). Tumors downstaged atfer induction had signiifcantly higher 5-year OS than those not downstaged (93.8%vs 35.6%,P=0.013). For the subgroup analysis when stage IV patients were excluded, 5-year OS was 85.2% in the DS group and 68.1% in the IT group (P<0.001), although R0 resection were similar (76.4%vs 73.3%,P=0.63). However, 5-year OS in tumors downstaged atfer induction (93.8%) was similar to those in the DS group (85.2%,P=0.438), both signiifcantly higher than those not downstaged atfer induction (35.6%,P<0.001).ConclusionOnly 68 (4%) out of 1,713 patients had induction therapies, with a R0 resection of 67.6%, 5-year recurrence of 44.9%, and 5- and 10-year overall survivals (OS) of 49.7% and 19.9%. Seventeen patients (25%) were downstaged atfer induction. Signiifcantly more thymomas were downstaged than thy-mic carcinomas (38.7%vs 13.9%,P=0.02). Tumors downstaged atfer induction had signiifcantly higher 5-year OS than those not downstaged (93.8%vs 35.6%,P=0.013). For the subgroup analysis when stage IV patients were excluded, 5-year OS was 85.2% in the DS group and 68.1% in the IT group (P<0.001), although R0 resection were similar (76.4%vs 73.3%,P=0.63). However, 5-year OS in tumors downstaged atfer induction (93.8%) was similar to those in the DS group (85.2%,P=0.438), both signiifcantly higher than those not downstaged atfer induction (35.6%,P<0.001).

Background and objectiveVideo-assisted thoracoscopic surgery (VATS) theoretically offers advantages over open thymectomy for clinically early-stage (Masaoka-Koga stage I and II) thymic malignancies. However, longterm outcomes have not been well studied. We compared the postoperative outcomes and survival from a cohort study based on the database of the Chinese Alliance for Research in Thymomas (ChART).MethodsBetween 1994 and 2012, data of 1,117 patients hav-ing surgery for clinically early-stage (Masaoka-Koga stage I and II) tumors were enrolled for the study. Among them, 241 cases underwent VATS thymectomy (VATS group), while 876 cases underwent open thymectomy (Open group). Univariate analyses were used to compare the clinical character and perioperative outcomes between the two groups. And multivariate analysis was performed to determine the independent predictive factors for long-term survival.Results Compared with the Open group, the VATS group had higher percentage of total thymectomy (80.5%vs 73.9%,P=0.028), resection rate (98.8%vs 88.7%,P<0.001) and less recurrence (2.9%vs 16.0%,P<0.001). Five-year overall survival was 92% atfer VATS and 92% atfer open thymectomy, with no signiifcant difference between the two groups (P=0.15). However, 5-year disease free survival were 92% in VATS group and 83% in Open group (P=0.011).Cox proportional hazards model revealed that WHO classiifcation, Masaoka-Koga stage and adjuvant therapy were independent predictive factors for overall survival, while surgical approach had no signiifcant impact on long-term outcome.ConclusionhTis study suggests that VATS thymectomy is an effective approach for clinically early-stage thymic malig-nancies. And it may offer better perioperative outcomes, as well as equal oncological survival.

Background and objectiveTo evaluate the surgical outcomes of tumor resection with or without total thymectomy for thymic epithelial tumors (TETs) using the Chinese Alliance for Research in Thymomas (ChART) retrospec-tive database.Methods Patients without preoperative therapy, who underwent surgery for early-stage (Masaoka-Koga stage I and II) tumors, were enrolled for the study. They were divided into thymectomy and thymomectomy groups according to the resection extent of the thymus. Demographic and surgical outcomes were compared between the two patients groups. Results A total of 1,047 patients were enrolled, with 796 cases in the thymectomy group and 251 cases in the thymomec-tomy group. Improvement rate of myasthenia gravis (MG) was higher atfer thymectomy than atfer thymomectomy (91.6%vs 50.0%,P<0.001). Ten-year overall survival was similar between the two groups (90.9% atfer thymectomy and 89.4% atfer thymomectomy,P=0.732). Overall, recurrence rate was 3.1% atfer thymectomy and 5.4% atfer thymomectomy, with no sig-niifcant difference between the two groups (P=0.149). Stratiifed analysis revealed no signiifcant difference in recurrence rates in Masaoka-Koga stage I tumors (3.2%vs 1.4%,P=0.259). However in patients with Masaoka-Koga stage II tumors, recurrence was signiifcantly less atfer thymectomy group than atfer thymomectomy (2.9%vs 14.5%,P=0.001).Conclusion hTymectomy, instead of tumor resection alone, should still be recommended as the surgical standard for thymic malignancies, especially for stage II tumors and those with concomitant MG.

Background and objectivePostoperative radiotherapy (PORT) for thymic tumor is still controversial. The object of the study is to evaluate the role of PORT for stage I/II/III thymic tumor.MethodsThe database of Chinese Al-liance of Research for Thymomas (ChART) was retrieved for patients with stage I/II/III thymic tumor who underwent surgi-cal therapy without neoajuvant therapy between 1994 and 2012. Univariate and multivariate survival analyses were performed. Cox proportional hazard model was used to determine the hazard ratio for death.Results 1,546 stage I/II/III patients were identiifed from ChART database. Among these patients, 649 (41.98%) underwent PORT. PORT was associated with gender, histologic type (World Health Organization, WHO), surgical extent, complete resection, Masaoka stage and adjuvant che-motherapy. The 5-yr and 10-yr overall survival (OS) rates and disease-free survival (DFS) rate for patients underwent surgery followed by PORT were 90% and 80%, 81% and 63%, comparing with 96% and 95%, 92% and 90% for patients underwent surgery alone (P=0.001,P<0.001) respectively. In univariate analysis, age, histologic type (WHO), Masaoka stage, complete-ness of resection, and PORT were associated with OS. Multivariable analysis showed that histologic type (WHO)(P=0.001), Masaoka stage (P=0.029) and completeness of resection (P=0.003) were independently prognostic factors of OS. In univari-ate analysis, gender, myasthenia gravis, histologic type (WHO), Masaoka stage, surgical approach, PORT and completeness of resection were associated with DFS. Multivariable analysis showed that histologic type (WHO) (P<0.001), Masaoka stage (P=0.005) and completeness of resection (P=0.006) were independently prognostic factors of DFS. Subgroup analysis showed that patients with incomplete resection underwent PORT achieved the better OS and DFS (P=0.010, 0.017, respectively). However, patients with complete resection underwent PORT had the worse OS and DFS (P<0.001,P<0.001, respectively). ConclusionThe current retrospective study indicated that PORT atfer incomplete resection could improve OS and DFS for patients with stage I/II/III thymic tumor. But for those atfer complete resection, PORT may not help improve prognosis on the whole.

Background and objectiveTo study the role of postoperative chemotherapy and its prognostic effect in Masaoka-Koga stage III and IV thymic tumors.Methods Between 1994 and 2012, 1,700 patients with thymic tumors who underwent surgery without neoajuvant therapy were enrolled for the study. Among them, 665 patients in Masaoka-Koga stage III and IV were further analyzed to evaluate the clinical value of postoperative chemotherapy. TheKaplan-Meier method was used to obtain the survival curve of the patients divided into different subgroups, and theCox regression analysis was used to make multivariate analysis on the factors affecting prognosis. A Propensity-Matched Study was used to evaluate the clinical value of chemotherapy.Results Two-hundred-twenty-one patients were treated with postoperative chemotherapy, while the rest 444 cases were not. The two groups showed signiifcant differences (P<0.05) regarding the incidence of myasthenia gravis, World Health Organization (WHO) histological subtypes, pathological staging, resection status and the use of postopera-tive radiotherapy. WHO type C tumors, incomplete resection, and postoperative radiotherapy were signiifcantly related to increased recurrence and worse survival (P<0.05). Five-year and 10-year disease free survivals (DFS) and recurrence rates in patients who underwent surgery followed by postoperative chemotherapy were 51% and 30%, 46% and 68%, comparing with 73% and 58%, 26% and 40% in patients who had no adjuvant chemotherapy atfer surgery (P=0.001,P=0.001, respectively). In propensity-matched study, 158 pairs of patients with or without postoperative chemotherapy (316 patients in total) were se-lected and compared accordingly. Similar 5-year survival rates were detected between the two groups (P=0.332). Conclusion Pathologically higher grade histology, incomplete resection, and postoperative radiotherapy were found to be associated with worse outcomes in advanced stage thymic tumors. At present, there is no evidence to show that postoperative chemotherapy may help improve prognosis in patients with Masaoka-Koga-Koga stage III and IV thymic tumors.

Objective To develop a rapid and reliable method for determination of 210Po using large-area grid ionization chamber α spectrometry.Methods Samples were digested using a microwave digestion system.After preparation of sample source,the concentration of 210Po in clam was detected by large-area grid ionization chamber (φ 25 cm).209Po tracer was used to obtain the recovery.Results Large-area grid ionization chamber could achieve better counting and α spectrum resolution when the optimized thickness was 250 μg/cm2.By spiking 209Po tracer in clam,the minimum detectable activity was 9.870 × 10 4 Bq and the recovery of 210Po was 98％.Conclusions Compared with the traditional method,the developed method can avoid separation process,using less quantity of sample (0.2-0.5 g dry) and simplify the measurement process.This method may be has broad application prospects.