Objective To establish a method of LC-MS/MS for determining cordycepin(Cor)and 3′-deoxyinosine(3′-Deo)concentration in rat plasma,and to study their pharmacokinetics in rats.Methods Protein was precipitated with methanol using 2-chloadenosine(2-Chl)as an internal standard.The chromatography was performed on Kinetex C18(3 mm×100 mm,2.6 μm,Phenomenex,USA)with gradient elution in aqueous(5 mmol·L-1 ammonium acetate)-methanol solution as mobile phase.ESI ion source was used for mass spectrometry,and positive ion multiple reaction monitoring(MRM)was used for scanning detection.The pharmacokinetics of Cor and 3′-Deo after oral administration of Cor(10 mg·kg-1)were studied in rats.Results Cor at 0.5-100 ng·mL-1 and 3′-Deo at 1-200 ng·mL-1 had good linearity,and the lower limits of quantification were 0.5 and 1 ng·mL-1,respectively.After oral administration of Cor in rats,the plasma concentration of Cor was low,which was mainly converted into the metabolite 3′-Deo.The Cmax of Cor and 3′-Deo were(5.4±3.4)and(142.0±50.0)ng·mL-1,and AUC0-360min min were(658.4±459.3)and(18 034.9±4 981.1)ng·min·mL-1,respectively.Conclusion The method is simple,sensi-tive,and accurate,which is suitable for determining Cor and 3′-Deo concentration in plasma and the pharmacokinetic study.

Uncovering the risk factors of pulmonary hypertension and its mechanisms is crucial for the prevention and treatment of the disease.In the current study,we showed that experimental periodontitis,which was established by ligation of molars followed by orally smearing subgingival plaques from patients with periodontitis,exacerbated hypoxia-induced pulmonary hypertension in mice.Mechanistically,periodontitis dysregulated the pulmonary microbiota by promoting ectopic colonization and enrichment of oral bacteria in the lungs,contributing to pulmonary infiltration of interferon gamma positive(IFNγ+)T cells and aggravating the progression of pulmonary hypertension.In addition,we identified Prevotella zoogleoformans as the critical periodontitis-associated bacterium driving the exacerbation of pulmonary hypertension by periodontitis,and the exacerbation was potently ameliorated by both cervical lymph node excision and IFNγ neutralizing antibodies.Our study suggests a proof of concept that the combined prevention and treatment of periodontitis and pulmonary hypertension are necessary.

Objective:To investigate the effects of estimated dose of radiation to immune cells (EDRIC) on overall survival (OS), local progression-free survival (LPFS) and distant metastasis-free survival (DMFS) in limited-stage small-cell lung cancer (LS-SCLC) with different tumor burdens.Methods:Clinical data of 216 patients with LS-SCLC who initially received conventional fractionated radiotherapy of the chest for radical treatment in Tianjin Medical University Cancer Institute and Hospital from 2013 to 2019 were retrospectively analyzed. EDRIC was calculated based on the model developed by Jin et al. and tumor burdens were assessed by gross tumor volume (GTV) or clinical stage. The study endpoints were OS, LPFS and DMFS, which were calculated from the date of diagnosis. The optimal cut-off value of EDRIC was calculated by R language. The correlation between EDRIC and tumor burdens was analyzed using Spearman's correlations. Survival analysis was performed by Cox proportional hazards regression model and Kaplan-Meier curve. Results:The median follow-up time for the whole group was 47.8 months, and the median OS and DMFS was 34.6 months and 18.5 months, respectively, while the median LPFS did not reach. The optimal cut-off value of EDRIC was 6.8 Gy. Cox multivariate analysis showed that EDRIC was an independent prognostic factor affecting OS and DMFS. EDRIC was weakly correlated with GTV or clinical stage. Stratified by the median GTV, OS ( P=0.021) and DMFS ( P=0.030) were significantly shortened and LPFS had a tendency of shortening ( P=0.107) when EDRIC>6.8 Gy compared with those when EDRIC ≤ 6.8 Gy in the GTV ≤ 34.6 cm 3 group; EDRIC had little effect on OS, LPFS, and DMFS ( P=0.133, 0.420, 0.374) in the GTV>34.6 cm 3 group. Stratified by clinical stage, OS ( P=0.003) and DMFS ( P=0.032) were significantly shortened and LPFS ( P=0.125) tended to shorten when EDRIC>6.8 Gy in stage I, II and IIIA groups; EDRIC exerted slight effect on OS, LPFS, and DMFS ( P=0.377, 0.439, 0.484) in stage IIIB and IIIC groups. Conclusion:EDRIC is an important factor affecting prognosis and exerts more significant impact on prognosis in patients with smaller tumor burden.

Objective:To evaluate the value of whole-brain radiotherapy (WBRT) combined with simultaneous integrated boost (SIB) and WBRT plus sequential stereotactic radiosurgery (SRS) in the treatment of small-cell lung cancer (SCLC) patients with brain metastases (BM).Methods:A retrospective analysis was performed among 135 SCLC patients with BM who were admitted to Tianjin Medical University Cancer Institute and Hospital from 2007 to 2023. They all received cisplatin- or carboplatin-based first-line chemotherapy and WBRT with 94 patients receiving thoracic radiotherapy after chemotherapy. All patients were divided into the WBRT+SIB ( n=66) and WBRT+SRS groups ( n=69) according to the treatment methods. After propensity score matching (PSM), 63 patients were assigned into each group. The primary endpoints were overall survival (OS) and brain metastasis-related local control (BMRLC) rates. Categorical data, such as gender and age, were compared by Chi-square test. OS and BMRLC were calculated by Kaplan-Meier method. The survival curves between two groups were compared by log-rank test. The risk factors of OS and BMRLC were assessed by multivariate Cox regression models. Results:In all the patients, the median follow-up time was 24.9 (range 6.30-109.57) months. The 2-year OS and BMRLC rates were 49.0% and 85.0%, respectively. Cerebral necrosis occurred in 2 patients. Multivariate analysis revealed that shorter time interval of BM after diagnosis (≤10 months) ( P=0.041), control of extracranial progression ( P=0.029), and lower diagnosis-specific graded prognostic assessment (DS-GPA) (≥2) ( P=0.006) significantly improved OS. After PSM, the 2-year OS rate in the WBRT+SIB group was significantly higher than that in the WBRT+SRS group ( P=0.041), while the 2-year BMRLC rate was not significantly improved ( P=0.203). In the DS-GPA<2 subgroup, the OS in the WBRT+SIB group was significantly higher than that in the WBRT+SRS group ( P=0.016), whereas no significant difference was observed in BMRLC between two groups ( P=0.205). In the DS-GPA≥2 subgroup, no significant difference was found in OS between two groups ( P=0.266), while BMRLC in the WBRT+SIB group was significantly lower compared with that in the WBRT+SRS group ( P=0.027). Conclusions:WBRT+SIB is more suitable for SCLC patients with BM than WBRT+SRS. However, WBRT+SRS yields higher local control for DS-GPA≥2 patients.

Objective:To explore the potential of dosiomics in predicting the incidence of radiation pneumonitis by extracting dosiomic features of definitive radiotherapy for lung cancer, and building a machine learning model.Methods:The clinical data, dose files of radiotherapy, planning CT and follow-up CT of 314 patients with lung cancer undergoing definitive radiotherapy were collected retrospectively. According to the clinical data and follow-up CT, the radiation pneumonia was graded, and the dosiomic features of the whole lung were extracted to establish a machine learning model. Dosiomic features associated with radiation pneumonia by LASSO-LR with 1000 bootstrap and AIC backward method with 1000 bootstraps were selected. Training cohort and validation cohort were randomly divided on the basis of 7:3.Logistic regression was used to establish the prediction model, and ROC curve and calibration curve were adopted to evaluate the performance of the model.Results:A total of 120 dosiomic features were extracted. After LASSO-LR dimensionality reduction, 12 features were selected into the "feature pool".After AIC, 6 dosiomic features were finally selected for model construction. The AUC of training cohort was 0.77(95% CI: 0.65 to 0.87), and the AUC of validation cohort was 0.72 (95% CI: 0.64 to 0.81). Conclusion:The dosiomics prediction model has the potential to predict the incidence of radiation pneumonia, but it still needs to include multicenter data and prospective data.

The internal organs and meridians were associated with Yin and Yang, five elements, six qi, and time and space, based on the holistic view of heaven, earth and human, according to Huangdi Neijing. The syndrome differentiation system of six meridians and Zang Fu meridians were established by Shanghan Zabing Lun, on the basis of the three Yin, three Yang, six meridians, and five Zang system in Huangdi Neijing. We put forward the concept of the six meridians syndrome differentiation system of circular motion, considering that the six meridians syndrome differentiation system actually implies the theory of circular motion. The syndrome differentiation system was constructed with the circular model of one qi circulating around the road, rising left and falling right, corresponding up and down, and maintaining conservation in the middle as the core, integrating Yin and Yang, five elements, six qi, Zang Fu and meridians, qi, blood and body fluid, and the integration of heaven, earth and human, focusing on "disease location and disease nature", taking classical prescriptions as the main treatments, and cooperating with external treatments such as acupuncture and moxibustion. We organically combined the circular motion with the syndrome differentiation of the six meridians, systematically interpreted the physiological bases, pathological changes, progressive patterns, and the treatments, based on syndrome differentiation, by inheriting the classical thinking mode of Hetu, Luoshu,Zhouyi, Huangdi Neijing, ShennongHerbal Classic, and Shanghan Zabing Lun.

Objective:To compare the incidence of radiation pneumonitis (RP) between lung cancer patients from the European, American and Asian regions.Methods:The studies related to lung cancer and RP were searched from PubMed, Embase, and Cochrane library. According to the different places where the studies were conducted, the searched studies were divided into two types: Asian studies and European, American and Australian studies. The incidence of RP between two regions was summarized. Studies related to dosimetry parameters were searched from PubMed database.Results:A total of 3, 190 patients from 14studies were included. Meta-analysis results showed that the incidence of ≥ grade 3 RP was similar in patients from Asia and Europe, America and Australia (4.9% vs. 4.6%, P=0.895), whereas the incidence of grade 5 RP in Asia was significantly higher than that in Europe, America and Australia (1.5% vs. 0.2%, P=0.002). Moreover, the lung irradiation dose received by the patients in the Asian group was relatively low. Lung V 20Gy dose limitation standard was reported in 21studies. Further analysis found no statistical significance in lung V 20Gy dose limitation standard between two regions ( P=0.440), and the standard in Asian studies is likely to be even stricter. Conclusions:The incidence of RP after chemoradiotherapy in lung cancer patients in Asia is relatively higher compared with those in Europe, America and Australia. The differences in dose limitation standard should be noted when the thoracic radiation regimen based solely on the data from foreign studies is applied to the patients in Asia.

Objective:To investigate the role of concurrent chemoradiotherapy in the treatment of limited-stage small cell lung cancer (LS-SCLC) and the impact of the number of chemotherapy cycle during radiotherapy (RT) on clinical prognosis.Methods:Patients with LS-SCLC treated with definitive radiotherapy from May, 2008 to September, 2016 were included in the study. The primary endpoint was overall survival (OS), which was calculated from the start of treatment to the date of death or last follow-up. The effect of the number of concurrent chemotherapy cycle and other clinical factors on clinical efficacy was analyzed. Survival analysis was performed with Kaplan- Meier method, and multivariate analysis was performed with Cox regression model. Results:Three hundred and seventeen patients were eligible for the analysis. Among them, 129 patients received sequential chemoradiotherapy and 188 patients received concurrent chemoradiotherapy. Among patients receiving concurrent chemoradiotherapy, 86 patients received 1 cycle of concurrent chemotherapy and 102 cases of 2 cycles of concurrent chemotherapy. The median follow-up time was 22.47 months. Multivariate survival analysis showed that only clinical stage, timing of RT administration and prophylactic cranial irradiation (PCI) were the independent prognostic factor for OS. The median OS in patients who received 1 cycle and 2 cycles of concurrent chemotherapy during RT were 33.8 months and 30.4 months ( P=0.400). No matter in elder patients or in younger patients, in early RT group or in late RT group and application of PCI or not, the number of concurrent chemotherapy cycle exerted no significant impact on OS. The incidence of grade 3 or above adverse events was 20% in the 1-cycle concurrent chemotherapy group, and 13.7% in the 2-cycle concurrent chemotherapy group. Conclusions:Concurrent chemoradiotherapy is the standard treatment of LS-SCLC. Two cycles of concurrent chemotherapy during RT is not necessarily superior to 1 cycle of concurrent chemotherapy. The optimal number of concurrent chemotherapy cycle during RT need to be studied in a large prospective randomized clinical trial.

Objective:To evaluate the survival outcome and toxicity of hypofractionated radiotherapy (45 Gy/15f) in patients with locally advanced/advanced non-small cell lung cancer (NSCLC) who are ineligible for conventional fractionated radiotherapy.Methods:The early efficacy, survival and toxicity of inoperable patients ( n=64) with locally advanced/advanced NSCLC patients admitted to Cancer Hospital of Tianjin Medical University from 2014 to 2018 were retrospectively analyzed. Hypofractionated radiotherapy (45 Gy/15f) were performed by using intensity-modulated radiotherapy or volumetric-modulated arc therapy technologies on Pinnacle 9 planning system. Results:The median follow-up time was 26 months. The early efficacy was available in 58 patients: complete response for 2 cases (3%), partial response for 22(38%), stable disease for 28(44%) and progressive disease for 6(9%), respectively. The local control rate was 90%. The median time to progression (TTP) and the median overall survival (OS) for all patients was 8.2 months and 21.0 months, respectively. The 1-, 2-and 3-year TTP rate was 37%, 28%, 14% and the OS rate was 66%, 43% and 27%, respectively. The incidence of esophagitis was 17%( n=11), 19%( n=12) for radiation pneumonitis and 20%( n=13) for myelosuppression. No grade ≥3 esophagitis or pneumonia was found. Conclusion:Hypofractionated radiotherapy (45 Gy/15f) is efficacious and safe for patients with locally advanced/advanced NSCLC, which yields controllable adverse events.

Objective:To analyze and explore the common radiomics features of radiation pneumonitis (RP) in patients with lung cancer and esophageal cancer, and then establish a prediction model that can predict the occurrence of RP in two types of cancer after radiotherapy.Methods:Clinical data of 100 patients with stage Ⅲ lung cancer and 100 patients with stage Ⅲ esophageal cancer who received radical radiotherapy were retrospectively analyzed. The RP was graded by imaging data and clinical information during follow-up, and the planning CT images were collected. The whole lung was used as the volume of interest to extract radiomics features. The radiomics features, clinical and dosimetric parameters related to RP were analyzed, and the model was constructed by machine learning.Results:A total of 1691 radiomics features were extracted from CT images. After ANOVA and LASSO dimensionality reduction in lung cancer and esophageal cancer patients, 8 and 6 radiomics features associated with RP were identified, and 5 of them were the same. Using the random forest to construct the prediction model, lung cancer and esophageal cancer were alternately used as the training and validation sets. The AUC values of esophageal cancer and lung cancer as the independent validation set were 0.662 and 0.645.Conclusions:It is feasible to construct a common prediction model of RP in patients with lung cancer and esophageal cancer. Nevertheless, it is necessary to further expand the sample size and include clinical and dosimetric parameters to increase its accuracy, stability and generalization ability.