The current classification methods for traditional Chinese medicine （TCM） visceral syndrome differentiation suffer from excessive generalization， which hinders their clinical application. Based on the analysis of the pattern of "one syndrome corresponding to multiple formulas"， this paper focused on the principle of syndrome-formula correspondence， and proposed that formula-syndromes are the smallest units for refining visceral syndromes. By establishing the correspondence between formula-syndromes and visceral syndromes， this study aims to further clarify the refined categories of syndromes and their treatment patterns， providing a new perspective for the standardization and objectification of TCM syndromes.

Objective:To explore the clinical efficacy of 125I seeds implantation combined with transcatheter arterial chemoembolization (TACE) in the treatment of primary liver cancer. Methods:A retrospective analysis of data from 40 patients with primary liver cancer at the Northern Theater General Hospital from January 2018 to December 2020 (26 males, 14 females, age 41 to 82 years) was performed. Among them, 21 patients were in treatment group and underwent 125I seeds implantation combined with TACE treatment, while 19 patients were in control group and received TACE treatment. Alpha-fetoprotein (AFP) levels between the two groups were compared, effective rate and disease control rate (DCR) of the two groups were analyzed, and overall survival (OS) and progression-free survival (PFS) were observed. Data were analyzed by using Mann-Whitney U test, χ2 test, Kaplan-Meier method and log-rank test. Results:Two months after 125I seeds implantation, the effective rates of treatment group and control group were 76.19%(16/21) and 8/19, respectively ( χ2=4.83, P=0.028); the DCRs were 90.48%(19/21) and 11/19, respectively ( χ2=4.21, P=0.040). AFP levels in both groups decreased significantly, with treatment group showing a greater decrease rate (0.87(0.84, 0.90) and 0.66(0.65, 0.67); z=5.42, P<0.001). No serious adverse reaction was observed in either group. The median OS of treatment group and control group were 18.2 and 10.6 months, respectively ( χ2=10.98, P=0.037); the median PFS of the two groups were 8.4 and 6.1 months, respectively ( χ2=7.54, P=0.041). Conclusion:125I seeds implantation combined with TACE treatment can exert a synergistic and enhancing effect in the treatment of primary liver cancer.

Objective:To explore the efficacy of online pulmonary rehabilitation (PR) management among community-dwelling patients with stable chronic obstructive pulmonary disease (COPD).Methods:This study was a single-center randomized controlled trail with an unblinded design. A total of 130 patients with stable COPD who visited Zhuanqiao Community Health Service Center in Shanghai Minhang District from October 2020 to March 2022 were randomly divided into study group and control group with 65 cases in each group. Both groups received conventional treatment, while patients in study group attended online rehabilitation management, including face-to-face rehabilitation instruction and multiple online guidance. Pulmonary ventilation function including forced vital capacity (FVC), forced expiratory volume in the first second (FEV 1) and percentage of forced expiratory volume in the first second to forced expiratoty volume (FEV 1%pred), modified British Medical Research Council Dyspnea Scale (mMRC), chronic obstructive pulmonary disease assessment test (CAT), score of 6 minutes walking distance (6MWD) and DOSE (dyspnea, degree of airflow obstruction, smoking status, the number of exacerbation) index were measured at baseline and after 8 weeks of rehabilitation, and compared between two groups. Results:The baseline data of the two groups were comparable. After 8 weeks of management, FVC, FEV 1, FEV 1%pred, mMRC, CAT, 6MWD and DOSE index of both groups were improved compared with the baseline level(control group: t=-7.799, -7.581, -9.010, 3.565, 9.887, -16.677, 3.795; study group: t=-12.623, -13.914, -17.644, 7.404, 22.457, -26.826, 7.968; all P<0.05). The FEV 1%pred, CAT and 6MWD in the study group were better than those in the control group ( t=-2.939, 2.277,-2.130, all P<0.05); while there were no significant differences in FVC, FEV 1, mMRC and DOSE index between the two groups( t=-0.162, -1.280, 0.925, 1.939,all P>0.05). Conclusions:The online pulmonary rehabilitation management can better improve lung function, dyspnea symptoms and exercise tolerance of patients with stable COPD, which can be used for rehabilitation training and management of community-dwelling patients.

ObjectiveThis study aims to investigate the effect of modified Baitouwengtang （MBTWD） on tumor growth and the number of tumor-associated macrophages （TAMs） in tumor tissue of MC38 cell tumor-bearing mice with colorectal cancer and explores whether MBTWD mediates the remodeling of TAM phenotype to play an immunologically antitumor effect. MethodFirstly， The C57BL/6 mouse tumor model grafted subcutaneously was established， and then model mice were classified into a model group， positive control group（3 mg·kg^-1）， and MBTWD groups with high and low dosages（23.43、46.86 g·kg^-1）， with 10 mice in each group. In addition， 10 healthy mice were set as the blank group， and the changes in body weight， tumor volume， and survival status of mice in each group were observed. Tumor tissue， spleen， and peripheral blood were collected to calculate the tumor volume change， tumor inhibition rate， and spleen mass. Hematoxylin-eosin （HE） staining was used to observe the morphological changes of tumor tissue， and an immunofluorescence assay was used to detect the expression levels of CD4， CD8， and CD206 in tumor tissues of tumor-bearing mice. The secretion levels of transforming growth factor （TGF）-β， interleukin （IL）-6， and chemokine （C-C Motif） ligand 2 （CCL2） in peripheral serum were measured by using enzyme-linked immunosorbent assay （ELISA）. Secondly， a co-culture model induced by IL-4 in vitro of MC38 cells and murine monocytic macrophage RAW264.7 cells was established. Cell proliferation and activity assay （CCK-8） was used to detect the inhibitory effect of MBTWD containing serum on cell proliferation. A transwell experiment was used to detect the effect of IL-4-induced M2 macrophages on the invasion of MC38 cells. Flow cytometry was used to detect the expression of CD86 on the membrane of M2 macrophages induced by IL-4 with MBTWD containing serum. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect the effect of MBTWD containing serum on the mRNA expression levels of M1 macrophage-related polarization factors CD86， nitric oxide synthase （iNOS）， and IL-12， as well as M2 macrophage-related polarization factors CD206， CD163， and IL-10 after co-cultivation. Finally， the protein expression levels of colony-stimulating factor 1 receptor （CSF1R）， stimulator of interferon genes （STING）， and TANK binding kinase 1 （TBK1） in tumor tissues of tumor-bearing mice were detected by Western blot. ResultIn vivo experimental results show that compared with the model group， the MBTWD can significantly inhibit the tumor growth of tumor-bearing mice. Immunofluorescence experiments show that the MBTWD can increase the number of CD8⁺ T cell infiltration in tumor tissue of tumor-bearing mice， reduce the number of CD206⁺ TAMs infiltration， and down-regulate the secretion levels of cytokines IL-6， TGF-β， and CCL2 in peripheral blood of tumor-bearing mice. The results of in vitro experiments show that the MBTWD containing serum has no obvious inhibitory effect on cell proliferation， but the cell supernatant after co-cultivation with RAW264.7 cells can inhibit the proliferation activity of MC38 cells， and the invasion ability of MC38 cells is enhanced by IL-4-induced M2 macrophages. However， this effect can be inhibited in a concentration-dependent manner by the MBTWD containing serum. At the same time， the results of Real-time PCR show that the MBTWD containing serum can up-regulate the mRNA expression levels of M1 macrophage-related polarization factors CD86， iNOS， and IL-12 and down-regulate those of M2 macrophage-related polarization factors CD206， CD163， and IL-10. Flow cytometry results also confirm that the MBTWD containing serum can increase the number of repolarized CD86⁺ M1 macrophages， indicating that MBTWD can induce M2 macrophages to repolarized M1 macrophages to play an anti-tumor growth role. Finally， Western blot results show that MBTWD can down-regulate the expression of CSF1R protein and up-regulate that of STING and TBK1 proteins in tumor tissue of tumor-bearing mice. ConclusionMBTWD can down-regulate the infiltration number of CD206⁺ TAMs and increase the infiltration of CD8⁺ T cells， thereby playing an immunologically antitumor effect on the growth inhibition of colorectal cancer， which may be related to regulating CSF1R signaling and then activating STING/TBK1 signaling pathway to induce phenotypic remodeling of TAMs.

Objective:To establish and verify a nomogram model based on MRI liver imaging reporting and data system (LI-RADS) features for predicting microvascular invasion (MVI) in hepatocellular carcinoma (HCC) following the Milan criteria.Methods:A retrospective analysis was conducted on data from 118 HCC patients (121 lesions) confirmed by pathology from June 2016 to June 2022 at the Third Affiliated Hospital of Soochow University. Forty-seven HCCs were diagnosed as MVI-positive and 74 HCCs as MVI-negative. The data was randomly divided into the training set (83 patients with 84 HCCs, including 31 MVI-positive and 53 MVI-negative HCCs) and the test set (35 patients with 37 HCCs, including 16 MVI-positive and 21 MVI-negative HCCs) using cross-validation method. HCC imaging features were evaluated based on LI-RADS (version 2018). In the training set, the χ 2 test was used to compare the differences in LI-RADS features between the MVI-positive group and the MVI-negative group. The logistic regression analysis was conducted to identify independent risk factors for predicting MVI-positive and to construct the nomogram model. The receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were used to evaluate the performance and clinical benefits of the nomogram model in predicting MVI tumors. Results:There were statistically significant differences between the MVI-positive group and the MVI-negative group in terms of tumor size, tumor margin, mosaic architecture, and corona enhancement ( P<0.05). Multivariate logistic analysis results showed that HCC maximum diameter>3 cm (OR=1.427, 95%CI 1.314-12.227, P=0.009), nonsmooth tumor margin (OR=3.167, 95%CI 1.227-461.232, P=0.041), mosaic architecture (OR=1.769, 95%CI 1.812-61.434, P=0.022), and corona enhancement (OR=4.015, 95%CI 3.327-836.384, P=0.011) were independent risk factors for predicting MVI-positive tumors. Based on the independent predictors, the constructed nomogram model demonstrated an area under the ROC curve of 0.863 (95%CI 0.768-0.947) and 0.887 (95%CI 0.804-0.987) in the training and test sets for predicting MVI tumors, respectively. DCA showed that the curve of the nomogram model was consistently above the treat-all and treat-none strategies across all reasonable threshold probabilities in the training set, indicating that patients could obtain clinical benefits from the model. Conclusions:The preoperative nomogram model based on MRI LI-RADS features can effectively predict MVI in HCC following the Milan criteria, which could benefit the patients.

Objective:To evaluate the clinical value of CT-guided 125I seeds implantation combining with 89SrCl 2 to relieve pain after failure of external irradiation in patients with bone metastases from prostate cancer. Methods:Clinical data of 48 patients (age 56-85 years) with bone metastases from prostate cancer admitted to General Hospital of the Northern Theater Command from January 2019 to June 2021 were retrospectively analyzed. Patients were treated with 125I seeds implantation combining with 89SrCl 2 (group A) and 89SrCl 2 alone (group B), respectively. Independent-sample t test and repeated measures analysis of variance were used to evaluate the differences of pain level (most severe pain, least pain, mean pain and current pain) scores and bone pain interference scores between 2 groups before and after treatment (before treatment, 3 d, 4 weeks, 8 weeks and 12 weeks after treatment). Prostate specific antigen (PSA), free PSA (fPSA) and alkaline phosphatase (ALP) 12 weeks after treatment of 2 groups were also compared by using independent-sample t test. Results:In group A, a total of 722 seeds were implanted in 39 bone metastases in 23 patients, and the implantation successful rate was 97.44%(38/39). There were 25 patients in group B. In group A, the most severe pain, mean pain and current pain scores decreased with time ( F values: 3.71-22.47, all P<0.05). Except for the scores at 3 d posttreatment, most severe pain, mean pain, and current pain scores at different times showed significant differences with those before treatment (all P<0.05). There were also differences in the most severe pain, mean pain, and current pain scores in group B before and after treatment ( F values: 2.45-2.52, P values: 0.044-0.049), with scores decreasing first (till 8 weeks after treatment) and increasing later. The most severe pain, mean pain, and current pain scores 8 week after treatment were lower than those before treatment (all P<0.05), but all the four scores at 12 weeks were not significantly different from those before treatment ( P values: 0.057-0.693). At 12 weeks after treatment, the differences in the most severe pain, mean pain and current pain scores between 2 groups were statistically significant ( t values: 2.04-3.41, P values: 0.001-0.047). Bone pain interference scores 12 weeks after treatment in group A were higher than those in group B ( t values: 2.04-3.16, P values: 0.022-0.047), and PSA, fPSA and ALP 12 weeks after treatment in group A were significantly lower than those in group B ( t values: 4.38-6.82, P values: 0.012-0.042). Conclusion:CT-guided 125I seeds implantation combined with 89SrCl 2 is feasible and effective for the treatment of bone pain after failed external irradiation in patients with prostate cancer bone metastases, especially for the combination of fulminant pain.

Objective:To explore the value of proton density fat fraction(PDFF) based on histogram analysis for quantification hepatic steatosis and fibrosis in rabbit model and the interference of hepatic fibrosis to the evaluation of hepatic steatosis with PDFF.Methods:From March to November 2020, 135 New Zealand white rabbits were randomly divided into control group ( n=30) and experimental group ( n=105) using a random number table. The volume ratio of CCl 4 and olive oil was 1∶1 to prepare 50% CCl 4 oil solution, and experimental rabbits were subcutaneously injected with the oil solution. An equal dose of normal saline was subcutaneously injected for control group rabbits. At the end of the 4 th, 8 th, and 12 th week, 35 in the experimental group and 10 rabbits in the control group were randomly selected to conduct the mDixon-Quant scanning, and histogram analysis of PDFF was analyzed including volume, mean, median, standard deviation, 25 th, 50 th, 75 th, 90 th quantile, skewness, kurtosis, entropy and inhomogeneity. After the examination, the rabbits were sacrificed and the liver percentage of steatosis (PSH) and fibrosis (POF) were recorded by semi-quantitative analysis. Spearman correlation analysis was used to correlate PDFF with PSH and POF. Multiple linear regression analysis was used to determine independent PDFF histogram parameters for evaluating PSH and POF. A receiver operator characteristic (ROC) curve was used to assess the diagnostic accuracy of PDFF for discriminating mild from moderate-severe hepatic steatosis and mild from moderate-severe hepatic fibrosis with median of PSH or POF for dichotomy, and DeLong test was used to compare the area under the curve (AUC). With the correction of hepatic fibrosis, correlation coefficient and AUC were compared of PDFF for discrimination mild from moderate-severe hepatic steatosis. Results:The PDFF mean, median, standard deviation, 75 th, 90 th showed correlation with PSH ( r=0.558, 0.522, 0.319, 0.723, 0.646, -0.589, all P<0.05). The entropy and 75 th were independent parameters for evaluating PSH (β=2.347, -5.960, P=0.018, 0.001). The PDFF 75 th was the optimal parameter for discriminating mild from moderate-severe hepatic steatosis with AUC=0.915 ( P=0.001). The PDFF volume, mean, median, standard deviation, 75 th, 90 th, entropy showed correlation with POF ( r=0.355, 0.393, 0.376, 0.298, 0.485, 0.426, -0.681, all P<0.05). The entropy, standard deviation and volume (β=-11.041, 1.356, 0.190, P=0.001, 0.026, 0.016) were independent parameters for evaluation of hepatic fibrosis, and the entropy was the optimal parameter for hepatic fibrosis (AUC=0.771, P=0.001). The correlation between PSH and PDFF 75 th was less pronounced when fibrosis was present ( r=0.512, P=0.001) than when fibrosis was absent ( r=0.751, P=0.002). The PDFF 75 th showed a significant difference in discriminating mild hepatic steatosis from moderate-severe hepatic steatosis after correction of POF (AUC=0.895, 0.950, Z=2.970, P=0.025). Conclusions:PDFF based on histogram analysis provided a noninvasive, accurate estimation of quantification for hepatic steatosis and fibrosis. Hepatic fibrosis reduced the correlation between hepatic steatosis and PDFF and the presence of hepatic fibrosis can confound the quantification of hepatic steatosis with PDFF.

Objective:To explore the value of MR elastography (MRE) and shear wave elastography (SWE) for staging liver fibrosis in a rabbit model.Methods:From March to November 2020, 200 healthy New Zealand white rabbits were randomly divided into control group ( n=40) and liver fibrosis group ( n=160) by random number table method. The volume ratio of CCl 4 and olive oil was 1∶1 to prepare 50% CCl 4 oil solution, and the experimental rabbits in the liver fibrosis group were subcutaneously injected with 50% CCl 4 olive oil solution. It was injected once a week at the dose of 0.1 ml/kg in the first to third weeks, once a week at the dose of 0.2 ml/kg in the 4th to 6th weeks. The dose of 0.1 ml/kg was injected twice a week from week 7 to 16. The control group were subcutaneously injected with an equal dose of normal saline. At the end of the 4th, 8th, 12th, and 16th week, 40 and 10 animals in the liver fibrosis group and the control group were randomly selected by random number table method for MRE and SWE, respectively, to obtain the liver elastic stiffness (LS), which were recorded as LS MRE and LS SWE. After the examination, the experimental rabbits were sacrificed and liver tissue of rabbits were taken for histopathological Scheuer staging, and they were divided into F0-F4 groups. One-way ANOVA was used to evaluate the differences of LS MRE and LS SWE in different stages of liver fibrosis. Spearman correlation was used to analyze the correlation between LS and pathological stages. The receiver operating characteristic curve was used to evaluate the efficacy of LS MRE and LS SWE in diagnosing liver fibrosis staging, and the area under the curve (AUC) was compared using the Z test. Results:Totally 162 rabbits were included, which covered F0 ( n=38), F1 ( n=33), F2 ( n=35), F3 ( n=31) and F4 ( n=25). Significant differences of LS MRE and LS SWE values were found among different stages of liver fibrosis ( F=295.29, 102.40, both P<0.001). LS MRE, LS SWE were both positively correlated with liver fibrosis stage ( r=0.93, 0.81, both P<0.001). The AUC of LS MRE for diagnosing liver fibrosis stages ≥F1, ≥F2, ≥F3, and ≥F4 were 0.955, 0.967, 0.996, and 0.980, respectively; the AUC of LS SWE were 0.856, 0.880, 0.974, and 0.953, respectively. The AUC of liver fibrosis stage ≥ F1, ≥ F2 for LS MRE value were greater than LS SWE value ( Z=2.93, 3.29, P=0.003, 0.001), and the AUC of ≥F3, ≥F4 had no significant differences ( Z=1.58, 1.68, P=0.115, 0.093). Conclusion:Both MRE and SWE can accurately predict the stage of liver fibrosis in experimental rabbits, and MRE is better than SWE in diagnosing early liver fibrosis.

Objective:To evaluate the efficacy and safety of 125I seeds implantation for lymph nodes metastasis (LNM) from radioactive iodine-refractory differentiated thyroid carcinoma (RAIR-DTC), and to verify the computer three-dimensional treatment planning system (TPS) from the dosimetry accuracy in assisting seeds implantation to treat LNM. Methods:Retrospective analysis was performed on 17 RAIR-DTC patients with LNM admitted to the General Hospital of Northern Theater Command from December 2016 to January 2019 (8 males, 9 females, median age 58 years). All patients underwent preoperative TPS planning design, CT-guided puncture and 125I seeds implantation (seed activity 14.8-25.9 MBq). The dosimetric results of postoperative validation were compared with those of preoperative planning, including the dosimetric parameters such as target volume before and after surgery and the dose received by 90% and 100% gross tumor volume (GTV) ( D90, D100), the percentage received by 100% and 150% of the prescription dose ( V100, V150), homogeneity index (HI). All patients underwent CT after 6 months to compare the LNM size, serum thyroglobulin (Tg) level, and the improvement of complications before and after treatment. Efficacies were divided into complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). Paired t test or Wilcoxon signed rank test were used to analyze the data. Results:Among 17 patients, a total of 226 125I radioactive seeds were implanted. Among them, 1 achieved CR, 10 achieved PR, 4 were with SD, and 2 were with PD. The diameter of LNM was 1.40(0.65, 3.05) cm before treatment and was 0.40(0.21, 0.91) cm 6 months after treatment ( z=-3.95, P<0.05). The Tg before treatment was 23.50(20.94, 72.92) μg/L and was 8.90(3.20, 40.22) μg/L 6 months after treatment ( z=-5.009, P<0.001). Tg antibody were all negative. There were 90.90% (20/22) of patients had slightly lower D90 than the prescribed dose ((12 378.8±3 182.0) vs (12 497.8±1 686.4) cGy; t=0.251, P>0.05). The postoperative dose parameters D100 and V150 ((6 881.5±1 381.8) cGy, (58.5±18.4)%) were both lower than those of preoperative plan ((8 085.8±2 330.0) cGy, (66.5±17.7)%; t values: 8.913, 3.032, both P<0.05), and the remaining indicators were not significantly different from those of the preoperative plan ( t values: 0.251, 1.493, z values: from -1.604 to -0.593, all P>0.05). Conclusions:According to the TPS preoperative plan, 125I seeds implantation for treating RAIR-DTC LNM can achieve the expected dose distribution, and the short-term tumor local control is effective. It is a safe and effective treatment method.

Over the past 30 years, Yarrowia lipolytica, Kluyveromyces, Pichia, Candida, Hansenula and other non-conventional yeasts have attracted wide attention because of their desirable phenotypes, such as rapid growth, capability of utilizing multiple substrates, and stress tolerance. A variety of synthetic biology tools are being developed for exploitation of their unique phenotypes, making them potential cell factories for the production of recombinant proteins and renewable bio-based chemicals. This review summarizes the gene editing tools and the metabolic engineering strategies recently developed for non-conventional yeasts. Moreover, the challenges and future perspectives for developing non-conventional yeasts into efficient cell factories for the production of useful products through metabolic engineering are discussed.
Gene Editing ; Metabolic Engineering ; Pichia/genetics* ; Synthetic Biology ; Yarrowia/genetics* ; Yeasts