Establishment of induced pluripotent stem cell model of Aicardi-Goutières Syndrome mutated in TREX1 / 中华预防医学杂志

To establish and identify induced pluripotent stem cells (iPSCs) derived from patients with Aicardi-Goutières syndrome (AGS) with TREX1 gene 667G>A mutation, and obtain a specific induced pluripotent stem cell model for Aicardi-Goutières syndrome (AGS-iPSCs). A 3-year-old male child with Aicardi-Goutieres syndrome was admitted to Zhongshan People's Hospital in December 2020. After obtaining the informed consent of the patient's family members, 5 ml peripheral blood samples from the patient were collected, and mononuclear cells were isolated. Then,the peripheral blood mononuclear cells(PBMCs) were transduced with OCT3/4, SOX2, c-Myc and Klf4 by using Sendai virus, and PBMCs were reprogrammed into iPSCs. The pluripotency and differentiation ability of the cells were identified by cellular morphological analysis, real-time PCR, alkaline phosphatase staining (AP), immunofluorescence, teratoma formation experiments in mice. The results showed that the induced pluripotent stem cell line of Aicardi-Goutieres syndrome was successfully constructed and showed typical embryonic stem-like morphology after stable passage, RT-PCR showed mRNA expression of stem cell markers, AP staining was positive, OCT4, SOX2, NANOG, SSEA4, TRA-1-81 and TRA-1-60 pluripotency marker proteins were strongly expressed. In vivo teratoma formation experiments showed that iPSCs differentiate into the ectoderm (neural tube like tissue), mesoderm (vascular wall tissue) and endoderm (glandular tissue). Karyotype analysis also confirmed that iPSCs still maintained the original karyotype (46, XY). In conclusion, induced pluripotent stem cell line for Aicardi-Goutières syndrome was successfully established using Sendai virus, which provided an important model platform for studying the pathogenesis of the disease and for drug screening.

CD301b+ macrophage: the new booster for activating bone regeneration in periodontitis treatment / 国际口腔科学杂志·英文版

Periodontal bone regeneration is a major challenge in the treatment of periodontitis. Currently the main obstacle is the difficulty of restoring the regenerative vitality of periodontal osteoblast lineages suppressed by inflammation, via conventional treatment. CD301b+ macrophages were recently identified as a subpopulation that is characteristic of a regenerative environment, but their role in periodontal bone repair has not been reported. The current study indicates that CD301b+ macrophages may be a constituent component of periodontal bone repair, and that they are devoted to bone formation in the resolving phase of periodontitis. Transcriptome sequencing suggested that CD301b+ macrophages could positively regulate osteogenesis-related processes. In vitro, CD301b+ macrophages could be induced by interleukin 4 (IL-4) unless proinflammatory cytokines such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) were present. Mechanistically, CD301b+ macrophages promoted osteoblast differentiation via insulin-like growth factor 1 (IGF-1)/thymoma viral proto-oncogene 1 (Akt)/mammalian target of rapamycin (mTOR) signaling. An osteogenic inducible nano-capsule (OINC) consisting of a gold nanocage loaded with IL-4 as the "core" and mouse neutrophil membrane as the "shell" was designed. When injected into periodontal tissue, OINCs first absorbed proinflammatory cytokines in inflamed periodontal tissue, then released IL-4 controlled by far-red irradiation. These events collectively promoted CD301b+ macrophage enrichment, which further boosted periodontal bone regeneration. The current study highlights the osteoinductive role of CD301b+ macrophages, and suggests a CD301b+ macrophage-targeted induction strategy based on biomimetic nano-capsules for improved therapeutic efficacy, which may also provide a potential therapeutic target and strategy for other inflammatory bone diseases.

Advances of Immunotherapy Resistance and Coping Strategies in Non-small Cell Lung Cancer / 中国肺癌杂志

Immunotherapy has significantly improved clinical outcomes of non-small cell lung cancer (NSCLC), however, along with the popularization of immunotherapy, immune resistance has become an unavoidable problem. Immunotherapy can induce extensive cellular and molecular alterations in the tumor microenvironment. Considering the mechanisms of immune resistance are not yet fully understood and the efficacy of standard chemotherapy regimens is limited, more effective coping strategies based on resistance mechanisms are urgently needed. In this review, we intend to summarize the known mechanisms of immune resistance and feasible strategies, so as to provide a foundation for clinicians to develop more individualized and precise regimens and finally improve patients' prognosis.
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CiteSpace knowledge map of research hotspots and frontiers of Polygalae Radix / 中国中药杂志

In this study, the Web of Science and China National Knowledge Infrastructure(CNKI) were searched comprehensively for the literature about the research on Polygalae Radix. After manual screening, 1 207 Chinese articles and 263 English articles were included in this study. Excel was used to draw the line chart of the annual number of relevant publications. CiteSpace 6.1.R3 was used for the visual analysis of author cooperation, publishing institutions, keyword co-occurrence, keyword clustering, and bursts in the research on Polygalae Radix. The results showed that the number of articles published in Chinese and English increased linearly, which indicated the rising research popularity of Polygalae Radix. WANG J and LIU X were the authors publishing the most articles in Chinese and English, respectively. Shanxi University of Chinese Medicine and Chinese Academy of Medical Sciences were the research institutions with the largest number of Chinese and English publications in this field, respectively. The institutions publishing the relevant articles in English formed a system with the Chinese Academy of Medical Sciences as the core. According to the keywords, the research hotspots of Polygalae Radix included variety selection and breeding, quality standard, extraction and identification of active chemical components, prescription compatibility, processing, clinical medication rules, and pharmacological mechanism. The research frontiers were the molecular mechanisms of Polygalae Radix and its active components in exerting the protective effect on brain nerve, regulating receptor pathways, alleviating anxiety and Alzheimer's disease, as well as data mining and clinical medication summary. This study has reference significance for the topic selection and frontier identification of the future research on Polygalae Radix.

Efficacy of first-line tyrosine kinase inhibitors plus immune checkpoint inhibitors in metastatic fumarate hydratase-deficient renal cell carcinoma / 中华泌尿外科杂志

Objective:To evaluate the efficacy of first-line tyrosine kinase inhibitors (TKI) plus immune checkpoint inhibitors (ICI) in metastatic fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC).Methods:The data of 87 metastatic FH-deficient RCC patients from West China Hospital ( n=44), Renji Hospital ( n=27) and Sun Yat-sen University Cancer Center (n=16) from Mar 2019 to Aug 2022 were retrospectively analyzed. The median age was 37(30, 47) years, the male to female ratio was 1.9∶1. The median size of tumor was 7.5(5.0, 10.0) cm. Sixty-one patients (70.1%) had germline FH mutations, and 26 patients (29.9%) had somatic FH mutations. Forty-nine patients (56.3%) metastasis disease at initial diagnosis, and 38 patients (43.7%) had metachronous metastasis. The most common site of metastasis was lymph node (41/87, 47.1%), followed by bone (33/87, 37.9%), liver (22/87, 25.3%), and lung (14/87, 16.1%). Fifteen patients (17.2%) had weak expression of FH protein and 59 patients (67.8%) had positive PD-L1 expression. The most common treatments were sintilimab plus axitinib (52/87, 59.8%), followed by pembrolizumab plus cabozantinib (7/87, 8.0%), tirelizumab plus axitinib (6/87, 6.9%), pembrolizumab plus axitinib (5/87, 5.7%), and toripalimab plus axitinib (4/87, 4.6%). Thirteen patients (13/87, 14.9%) received other ICI plus TKI combination treatments. Statistical analysis was conducted using R 4.2.3 software. Kaplan Meier survival curve was used to evaluate survival data, and log-rank test was used to compare differences between treatment groups. Results:The overall objective response rate (ORR) and disease control rate (DCR) of first-line TKI + ICI were 39.1% and 89.7%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 16.5 months and 71.0 months, respectively. For first-line sintilimab plus axitinib, the ORR and DCR were 44.2% and 92.3%, respectively. The median PFS was 17.3 months and the median OS was not reached for this combination treatment. The efficacy of first-line tirelizumab plus axitinib was inferior to other treatment strategies (median PFS: 4.0 vs. 16.6 months, P<0.001; median OS: 22.0 vs. 71.0 months, P=0.043). Subgroup analyses further showed that the efficacy of ICI+ TKI combination therapy was consistent in patients with different clinicopathologic and genomic features. However, patients with liver metastasis had shorter OS than those without liver metastasis (median OS: 26.3 vs. 71.0 months, P=0.021). Conclusion:First-line TKI + ICI is effective for metastatic FH-deficient RCC and can significantly prolong the survival of the patients.

Comprehensive interpretation of RCC abstracts, ASCO-GU 23 / 中华泌尿外科杂志

The ASCO-GU 23 conference was held offline as scheduled after the pandemic. A total of 167 abstracts in the field of renal cell carcinoma has been posted during the conference, covering the first PET/CT diagnostic technology targeting tumors in renal cell carcinoma, risk stratified interpretation of the previous clinical trial results, and exploring the value of tumor and serum biomarkers for precise classification therapy, as well as providing evidence for the therapeutic scheme sequencing.

Advance in renal cell carcinoma in 2022 ASCO-GU / 中华泌尿外科杂志

ASCO-GU is one of the landmark meetings of urogenital cancer. Within 2022 meeting, the extended follow up result of adjuvant pembrolizumab after nephrectomy in renal cell carcinoma as well as the efficacy and safety of neoadjuvant Axitinib and avelumab for local advanced renal cell carcinoma have been released. There were also explorations in local therapy for oligometastasis, novel combination system therapy and regiments alterations. The further research protocol of immunostimulatory IL-2 cytokine prodrug and PARP inhibitor for metastatic RCC were also disclosed.

Monitoring of sunitinib blood concentration and analysis of its safety and efficacy in Chinese patients with metastatic renal cell carcinoma / 中华泌尿外科杂志

Objective:To investigate the safety and efficacy of individualized sunitinib schedule for patients with metastatic renal cell carcinoma (mRCC) according to the monitoring results of plasma drug concentration.Methods:The clinical data of patients with mRCC who received sunitinib treatment in our center from January 2014 to December 2020 were retrospectively analyzed, including 20 patients who underwent monitoring of plasma drug concentration (monitoring group), and 45 patients, matched by propensity score matching, received sunitinib but did not undergo monitoring of plasma drug concentration during the same period (unmonitored group). In the monitoring group, there were 12 males and 8 females. The mean age was 52.9 years, and ECOG score ≤1 in 16 cases (80%). Three patients were in the IMDC favorable-risk group, 15 patients were in the intermediate-risk group, and 2 patients were in the high-risk group. There were 18 cases of clear cell carcinoma and 2 cases of non-clear cell carcinoma, 5 cases of ISUP grade 1-2 and 11 cases of grade 3-4. In the unmonitored group, there were 31 males and 14 females. The mean age was 57.7 years, and 30 patients had ECOG score ≤1, 15 cases ≥2. There were 10 cases in IMDC favorable-risk group, 23 cases in intermediate-risk group, and 12 cases in high-risk group. Thirty-seven cases were clear cell carcinoma and 8 cases were non-clear cell carcinoma, 8 cases were in ISUP grade 1-2 and 28 cases in grade 3-4. There were no statistically significant differences between the two groups in the above parameters ( P>0.05). The monitoring group used the regimen of taking sunitinib for 4 weeks and stopping for 2 weeks (4/2 week) in the first cycle. The blood concentration of sunitinib was monitored before the first cycle and on days 4, 7, 10, 14, 21 and 28, and personalized medication plan was formulated according to the curve of the blood concentration. The 4/2 week scheme was adopted in the undetected monitoring group.The two groups were compared in the incidence of adverse events (AEs), progression-free survival (PFS), overall survival (OS), tumor treatment response and other clinical outcomes. Results:In the monitoring group, 90% (18/20) of patients receiving sunitinib had a steady-state plasma concentration of more than 150ng/ml, of which 10 patients (50%) had a plasma concentration of 150-200 ng/ml and 8 patients (40%) had a plasma concentration of more than 200 ng/ml. Meanwhile, all patients with plasma concentration higher than 150 ng/ml developed severe AEs (grade 3 and above) after treatment. The other two patients' plasma concentration were 100-150 ng/ml, and did not have severe AEs.All patients in the monitoring group received individualized medication schedule adjustment according to the plasma drug concentration and the occurrence point of severe AEs, ensuring that the peak plasma drug concentration was maintained at about 100-150 ng/ml. Among them, 6 patients were changed to take 2 weeks and stop for 1 week (2/1 week schedule), 4 patients were changed to take 10 days and stop for 5 days (10/5 d schedule), 7 patients were changed to take 7 days and stop for 3 days (7/3 d schedule), and 3 patients were changed to take 5 days and stop for 2 days (5/2 d schedule). The incidence of severe AEs significantly decreased from 90% (18/20) to 35% (7/20), and the difference was statistically significant ( P=0.003), while the incidence of grade 3 and higher AEs was 55.6% (25/45) in the standard group, which was statistically significant compared with the incidence of severe AEs before adjustment in the monitoring group ( P=0.006). Further analysis of the efficacy difference between the two groups showed that the overall objective response rate in the monitoring group (40%, 8/20) was higher than that in the standard group (20%, 9/45), although the difference was not statistically significant ( P=0.09). Median PFS and OS were significantly longer in the monitored group than in the standard group (PFS: 23 vs. 10 months, P=0.002; OS: not reached vs.25 months, P=0.005). Conclusions:The bioavailability of sunitinib is high in mRCC patients, which may lead to higher plasma drug concentration, adjustment of medication regimen based on blood concentration monitoring significantly improved patient safety and clinical outcomes. However, further validation by larger-scale, multi-center and prospective studies is needed.

Pathogenesis of Gouty Arthritis and Intervention with Chinese Medicines： A Review / 中国实验方剂学杂志

Gouty arthritis （GA） is the metabolic rheumatism caused by purine metabolism disorder， which can be acute or chronic. The main manifestations of GA include recurrent redness， swelling， heat pain， and dysfunction of the affected joints. According to the theory of modern medicine， GA is closely associated with the increase in uric acid， the participation of inflammatory cytokines， the weakening of antioxidant response， apoptosis， and the imbalance of intestinal flora and bone metabolism， whereas the specific pathogenesis remains unclear. GA is characterized by easy diagnosis， difficult treatment， and high recurrence rate， which seriously affects the life quality of patients. Colchicine， corticosteroids， non-steroidal anti-inflammatory drugs， and selective cyclooxygenase-2 inhibitors are the commonly used western medicines for this disease， which demonstrate remarkable short-term therapeutic effect. However， long-term use of these medicines will bring serious adverse reactions. Chinese medicines， with high safety and causing few adverse reactions， have a variety of active components which can act on multiple pathways and targets to exert synergistic effects， thus attracting wide attention. This paper systematically reviews the literature reporting the Chinese medicines in improving antioxidant response， reducing chondrocyte apoptosis， and regulating intestinal flora and bone metabolism， aiming to further clarify the pathogenesis of GA and provide a scientific basis for the clinical application of Chinese medicines in the prevention and treatment of GA.

Predictors of efficacy of corticosteroid switching from abiraterone plus prednisone to dexamethasone in patients with metastatic castration-resistant prostate cancer / 亚洲男科学杂志(英文版)

Corticosteroid switching can reverse abiraterone resistance in some patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we investigated the potential biomarkers for predicting the efficacy of corticosteroid switching during treatment with abiraterone acetate (AA). We retrospectively analyzed 101 mCRPC patients receiving corticosteroid switching from West China Hospital and Sun Yat-Sen University Cancer Center between January 2016 and December 2018. All cases received AA plus prednisone as first-line therapy during mCRPC. Primary end points were biochemical progression-free survival (bPFS) and overall survival (OS). The risk groups were defined based on multivariate analysis. A total of 42 (41.6%) and 25 (24.8%) patients achieved 30% and 50% decline in prostate-specific antigen (PSA), respectively, after corticosteroid switching. The median bPFS and median OS on AA plus dexamethasone were 4.9 (95% confidence interval [CI]: 3.7-6.0) months and 18.8 (95% CI: 16.2-30.2) months, respectively. Aldo-keto reductase family 1 member C3 (AKR1C3) expression (hazard ratio [HR]: 2.15, 95% Cl: 1.22-3.80, P = 0.008) and baseline serum alkaline phosphatase (ALP; HR: 4.95, 95% Cl: 2.40-10.19, P < 0.001) were independent predictors of efficacy before corticosteroid switching in the multivariate analysis of bPFS. Only baseline serum ALP >160 IU l-1 (HR: 3.41, 95% Cl: 1.57-7.38, P = 0.002) together with PSA level at switch ≥50 ng ml-1 (HR: 2.59, 95% Cl: 1.22-5.47, P = 0.013) independently predicted poorer OS. Based on the predictive factors in multivariate analysis, we developed two risk stratification tools to select candidates for corticosteroid switching. Detection of serum ALP level, PSA level, and tissue AKR1C3 expression in mCRPC patients could help make clinical decisions for corticosteroid switching.

Analysis and interpretation of genetic testing results from 249 Chinese high to very-high risk non-metastatic prostate cancer patients / 中华泌尿外科杂志

Objective:To analyze germline genetic testing in Chinese high-to very-high-risk non-metastatic prostate cancer patients.Methods:This study included 249 Chinese patients with high- to very-high-risk non-metastatic prostate cancer for germline genetic testing, in Fudan University Shanghai Cancer Center, West China Hospital and Cancer Center of Sun Yat-sen University, from January 2018 to December 2022. High risk and very-high risk are termed according to National Comprehensive Cancer Network (NCCN) Prostate Cancer Guideline (2022 V1). The mean age of the patients was (66.7±9.2) years old and median PSA level was 28.50 (ranging 2.43 - 1481.11) ng/ml. Within these 249 patients, 84 (33.7%) were T 1-2, 98 (39.3%) were T 3-4, while 67 (26.9%) were unclear in T stage. Additionally, 51 patients (20.5%) were classified into International Society of Urological Pathology(ISUP) grade group 1-3 group and 198 patients (79.5%) were in ISUP 4-5 group. Focusing on 16 genetic susceptibility genes for prostate cancer, we interpret the germline genetic testing data in accordance with the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guideline, clarify the germline pathogenic mutation rate and elucidate the clinicopathological characteristics of germline pathogenic mutation carriers. Results:Among Chinese high-to very-high-risk non-metastatic prostate cancer patients, 7.2% (18/249) had germline pathogenic mutations. Patients with mutations had a significantly higher proportion of first-degree relatives with a history of malignancy than those without mutations (50% vs. 13%, P<0.001), but there was no difference in age of onset [(68.2±9.3)years vs. (66.6±9.2) years], PSA level (median: 40.68 ng/ml vs. 28.00 ng/ml), T stage [T 3-4: 38.9%(7/18)vs. 39.4%(91/231)] and ISUP grade [group 4-5: 88.9%(16/18) vs. 78.8%(182/231)]. Germline pathogenic mutations were observed in BRCA2 (7 patients, 38.9%), MSH2 (3 patients, 16.7%), PALB2 (2 patients, 11.1%), ATM (2 patients, 11.1%), RAD51C (1 patient, 5.6%), PMS2 (1 patient, 5.6%), MSH6 (1 patient, 5.6%) and HOXB13 (1 patient, 5.6%). By comparing with normal controls of East-Asian population, germline pathogenic mutations in BRCA2 ( OR=11.1, 95% CI 4.8-25.6, P<0.001) and MSH2 ( OR= 43.5, 95% CI 8.5-200.0, P<0.001) can significantly increase the risk of developing high- to very-high-risk prostate cancer in Chinese males. Conclusions:This study identified a germline pathogenic mutation rate of 7.2% in 249 Chinese patients with high- or very-high-risk non-metastatic prostate cancer. Carrying germline BRCA2 or MSH2 pathogenic mutations can significantly increase the risk of high- or very-high-risk prostate cancer in Chinese men.

The clinical exploration of corticosteroid switch of abiraterone acetate in patients with metastatic castration-resistant prostate cancer / 中华泌尿外科杂志

The terminal stage of prostate cancer is metastatic castration-resistant prostate cancer (mCRPC) with poor prognosis and high mortality. Abiraterone acetate (AA), as a new generation drug for endocrine therapy, has been demonstrated to prolonged overall survival signicantly in mCRPC patients. In addition, a corticosteroid drug must be administered during treatment to avoid side effects of abiraterone. It has been found that a corticosteroid switch from prednisone to dexamethasone could delay the development of resistance, significantly prolong the progression-free survival rate of patients, with well tolerance. But the specific mechanism and long-term clinical benefit still need further study. This emerging treatment paradigm provides new ideas for treatment options for patients with mCRPC, however, caution is still needed in clinical practice, and it is recommended to determine the treatment plan after considering all aspects of the patients.

Prognostic factors of salvage radiotherapy after radical prostatectomy / 中华泌尿外科杂志

Objective:To investigate the prognosis after salvage radiotherapy with or without hormone therapy for prostate cancer.Methods:From May 2014 to December 2020, 248 patients undergoing salvage radiotherapy due to prostate-specific antigen (PSA)persistence or biochemical progression after radical prostatectomy at Sun Yat-sen University Cancer Center (n=157) and West China Hospital, Sichuan University (n=91) were analyzed. Median age was 66 (45-78) years old. Median PSA was 23.50 (0.18-845.00) ng/ml. The number of PSA persistence and biochemical progression were 143 (59%) and 105 (42%). The number of pT 2, pT 3a, pT 3b, pT 4, and unknown T stage was 99, 49, 78, 15 and 7 cases.The number of N 0, N 1 and unknown N stage was 153, 44 and 51 cases. 165 cases had positive surgical margin. Gleason score of 6, 7, 8, >8 score and unknown was in 12, 104, 34, 90 and 8 patients. Early and late salvage radiotherapy was performed in 117 and 131 patients, and 70 patients (28%) were CRPC. Hormone therapy was used combined with radiotherapy in 182 patients (73%). PSA decline after radiotherapy was compared with Chi-squre test. Kaplan-Meier method and log-rank test were used to compare progression free-survival (PFS)after radiotherapy. Univariate and multivariate analyses of PFS were performed using Cox proportional hazards model. Early salvage radiotherapy was defined as PSA≤0.5 ng/ml before radiotherapy, and late salvage radiotherapy was defined as PSA>0.5ng/ml. Results:PSA response (PSA decline ≥50%) rate was 94% (233/248), and 82% (203/248) patients had PSA decline ≥ 90%. Twelve (5%) patients had rising PSA after completing radiotherapy, but only 4 (2%) had real progression. The median PFS was 69 months (95% CI 68-70), and 3-year and 5-year PFS rate were 80% and 67%. PFS of PSA persistence and biochemical progression were similar ( HR =0.71, 95% CI 0.37-1.37, P=0.311). Compared with late salvage radiotherapy, early salvage radiotherapy had better PFS [69 (95% CI 68-70) vs. 59 (95% CI 44-74) months, P<0.001]. Compared with hormone sensitive, castration-resistant was associated with worse PFS (5-year PFS rate 74% vs. 51%, P<0.001). In multivariate analysis, Gleason score>8, castration-resistant and late salvage radiotherapy were unfavorable prognostic factors. Conclusions:In patients receiving salvage radiotherapy with or without hormone therapy for PSA persistence and biochemical progression after radical prostatectomy, high PSA level before radiotherapy and castration resistant is associated with poor prognosis.

Explore Mechanism of Modified Si Junzitang in Improving Acidic Microenvironment and Reversing Gastric Precancerous Lesions Based on MCT4/CD147 / 中国实验方剂学杂志

Objective:To observe the effect of modified Si Junzitang on the level of lactic acid in gastric mucosa and the expression of Carboxylic acid transporter 1（MCT1）， monocarboxylic acid transporter 4（MCT4）， and extracellular matrix metalloproteinase inducer （CD147）in rats with gastric precancerous lesions（GPL）. Method:Seventy-four SD male rats were randomly divided into normal group （12 rats） and model group （62 rats）. <italic>N</italic>-methyl-<italic>N'</italic>-nitro-<italic>N</italic>-nitrosoguanidine（MNNG）-ammonia compound method was used to establish GPL rat models， and at the 9^th week， the model rats were randomly divided into model group， folic acid group（2.7 mg·kg^-1）， modified Si Junzitang high， medium and low dose groups（12.6， 6.3， 3.15 g·kg^-1）， with 12 rats in each group. After intragastric administration for 12 weeks， the general conditions of the rats were observed. Hematoxylin-eosin（HE）staining was used to observe the histopathological changes of gastric mucosa in rats， chemical colorimetry was used to detect the content of lactic acid in gastric mucosa； immunohistochemistry and real-time polymerase chain reaction（Real-time PCR）were used to detect MCT1， MCT4， CD147 protein and mRNA expression in gastric mucosal tissues. Result:Modified Si Junzitang significantly improved the pathological manifestations in GPL rats such as gastric mucosal epithelial gland structure， disorder of arrangement and cell atypia. Compared with the normal group， the lactic acid content of the gastric mucosa tissue in the model group increased significantly（<italic>P</italic><0.01）， and the protein and mRNA expressions of MCT1， MCT4， CD147 significantly increased（<italic>P</italic><0.05， <italic>P</italic><0.01）. Compared with the model group， the lactic acid content in each dose group of modified Si Junzitang was significantly reduced（<italic>P</italic><0.05， <italic>P</italic><0.01）， and the protein expression levels of MCT4 and CD147 were also significantly reduced in each dose group of modified Si Junzitang（<italic>P</italic><0.05， <italic>P</italic><0.01）. The mRNA expression of MCT4 was significantly reduced in the middle and high dose groups（<italic>P</italic><0.05， <italic>P</italic><0.01）， and the mRNA expression of CD147 was significantly reduced in the high dose group（<italic>P</italic><0.05）. Modified Si Junzitang showed no significant regulatory effect on MCT1. Conclusion:Modified Si Junzitang can significantly improve the abnormal histopathology of gastric mucosal epithelium in GPL model rats. Its mechanism may be related to down-regulating the overexpression of MCT4 and CD147， inhibiting lactic acid outflow， and improving the acidic microenvironment of gastric mucosal epithelium.

Progress of Liquid Biopsy in the Diagnosis and Treatment of Lung Cancer with Malignant Pleural Effusion / 中国肺癌杂志

Lung cancer is the malignancy with the highest mortality rate worldwide. Malignant pleural effusion (MPE) caused by advanced lung cancer severely affects the quality of life and prognosis of patients. Tumor-associated genetic testing is the basis for making precise treatment decisions. There are some risks of tissue biopsy, and it is difficult to sample repeatedly. Due to its non-invasive and can reflect the full profile of tumor gene characteristics, liquid biopsy is increasingly used in the diagnosis and treatment of lung cancer. Because of the extremely low DNA level of circulating tumor, the sensitivity and specificity of liquid biopsy based on blood samples are limited. Tumor cells is enriched in MPE. The detection of cell-free DNA, extracellular vesicles and microRNA in MPE will be helpful to the diagnose, treatment and assess prognosis of patients with lung cancer. This review aims to discuss the research progress of liquid biopsy based on MPE in the diagnosis and treatment of lung cancer patients.
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Comparison of the prognosis of subgroup of renal cell carcinoma of different pathological types / 中华泌尿外科杂志

Objective:To study and compare the prognosis of different pathological subtypes of renal cell carcinoma (RCC).Methods:Clinicopathological and prognostic data of 1 346 cases of postoperative renal cell carcinoma during July 2002 to June 2014 in West China Hospital were collected retrospectively.There were 839 males and 507 females, aged (55.1±13.4)years, including 1 120 cases of clear cell RCC, 62 cases of papillary RCC, 79 cases of chromophobe RCC and 85 cases of the other pathological types respectively. ECOG 0 and ≥1 were 911 and 435 cases, with; T 1, T 2, T 3 and T 4 of 1 019, 177, 102 and 48 cases respectively; WHO nuclear grade for well, intermediate, poor differentiation and unknown were 587, 530, 85 and 144 cases separately.Tumor size <5cm, 5-10cm, ≥10cm and unknown were 685, 541, 104 and 16 cases.Combined with necrosis or sacromatoid differentiation were 200/1 146 and 27/1 319 cases separately. Meanwhile, data of 80 439 cases from Surveillance, Epidemiology, and End Results Program (SEER) were also collected.There were 51 371 males and 29 068 females, aged (60.9±12.4) years; , with 66 261, 8 680, 5 022 and 476 cases of White, Black, Asian, American native, or unknown race separately. There were 62 600 of clear cell RCC, 12 170 of papillary RCC, 4 354 of chromophobe RCC and 1 315 of other pathological types, with T 1, T 2, T 3 and T 4 of 55 332, 8 687, 15 516 and 904 cases respectively; WHO nuclear grade for well, intermediate and poor differentiation were 52 323, 22 700 and 5 416 cases separately.Tumor size <5cm, 5-10cm, ≥10cm were 46 741, 25 760 and 7 938 cases respectively. Kaplan-Meier survival analysis were performed on these two group of cases, with different factors between subgroups (gender, age, pathological types, tumor stage, size and nuclear grade) evaluated by log-rank test. To evaluate accuracy of outcome prediction models of SSIGN, Leibovich and UISS score, concordance index of these models were evaluated. Results:In 1 346 cases of our cohort, those with chromophobe RCC were well prognostic, survival were relatively better in clear cell RCC than that of papillary RCC, and worst prognosis were demonstrated in those with other types of RCC (5 year overall survival rate: 97.5%, 87.9%, 79.7% and 68.4% separately). Poor prognosis were seen in those older than 50 years, with poor T stage or nuclear grade, large tumor size and tumors with necrosis or sacromatoid differentiation ( P<0.05). In 80 439 seer cases, the best prognosis was also seen in chromophobe RCC and the worst in other type of RCC separately (5 year overall survival rate: 96.3% and 85.3%). In addition, longer survival was seen in papillary RCC than clear cell RCC (5 year overall survival rate: 92.5% and 88.9%). However, similar results with our cohort were seen in Asian and American native subgroup of SEER cases (95.1%, 88.6%, 86.7%, 80.2% for chromophobe, clear cell, papillary and other types of RCC respectively). Poor prognosis were seen in those older than 50 years, males, Asian/ American Indian, poor T stage or nuclear grade and large tumor size ( P<0.05). Concordance index for SSIGN, Leibovich and UISS models in our cohort were 0.763-0.781, 0.725-0.752 and 0.641-0.660, respectively. The chromophobe RCC subgroup was relative better based on predictive value of prognosis models(c-index of UISS of 0.670-0.781, SSIGN and Leibovich of 0.733-0.903). Conclusions:In Asian RCC population, prognosis of chromophobe RCC is best, clear cell RCC is slightly better than papillary RCC, and the prognosis of other types of RCC is the worst. Concordance index of SSIGN and Leibovich in our cohort were higher than that of UISS, and the use value for predictive model was better in the chromophobe RCC subgroup.

Study on the effect of changing operator on the detection rate of colorectal polyps during surgery / 中国医师进修杂志

Objective:To study the effect of changing operator on the detection rate of colorectal polyps during surgery in patients who had been diagnosed with colorectal polyps by electronic colonoscopy for the first time.Methods:From June 2016 to June 2019, the patients who had been diagnosed with colorectal polyps by electronic colonoscopy for the first time, they were performed by electronic colonoscopy for the second time after 3 months by 5 doctors in the No.946 Hospital of PLA who had engaged in endoscopic work longer and been with rich experience. The results of the electronic colonoscopy were recorded and compared.Results:Fived hundred and seventy-six patients were found have colorectal polyps through electronic colonoscopy for the first time. Among them, 423 patients came to the hospital within 3 months and were eligibled for the research. The detection rate of newly detected polyps by the same operator was 22.7%(96/423), after changing the operator, the detection rate became 24.3% (103/423), but there was no significant difference ( P>0.05). The detection rates of newly detected polyps were respectively 20.8% (220/1 059) and 25.9%(294/1 133), the proportion of newly detected polyps with diameter ≤ 5 mm was respectively 73.6%(162/220) and 82.0%(241/294), the ratio of flat polyps to total newly detected polyps was 71.8%(158/220) and 79.9%(235/294), and there were significant differences ( P<0.05). The proportion of polyps in sigmoid colon was respectively 35.0% (77/220) and 39.1%(115/294), and there was no significant difference ( P>0.05). Conclusions:For patients with colorectal polyps detected by electronic colonoscopy, the operator should be changed during surgery, so that more missed polyps can be detected during surgery, especially flat polyps with diameter ≤ 5 mm. The operator should be changed to improve the detection rate and reduce the probability of missed diagnosis.

Activated PKB/GSK-3β synergizes with PKC-δ signaling in attenuating myocardial ischemia/reperfusion injury via potentiation of NRF2 activity: Therapeutic efficacy of dihydrotanshinone-I

@#Disrupted redox status primarily contributes to myocardial ischemia/reperfusion injury (MIRI). NRF2, the endogenous antioxidant regulator, might provide therapeutic benefits. Dihydrotanshinone-I (DT) is an active component in Salvia miltiorrhiza with NRF2 induction potency. This study seeks to validate functional links between NRF2 and cardioprotection of DT and to investigate the molecular mechanism particularly emphasizing on NRF2 cytoplasmic/nuclear translocation. DT potently induced NRF2 nuclear accumulation, ameliorating post-reperfusion injuries via redox alterations. Abrogated cardioprotection in NRF2-deficient mice and cardiomyocytes strongly supports NRF2-dependent cardioprotection of DT. Mechanistically, DT phosphorylated NRF2 at Ser40, rendering its nuclear-import by dissociating from KEAP1 and inhibiting degradation. Importantly, we identified PKC-δ-(Thr505) phosphorylation as primary upstream event triggering NRF2-(Ser40) phosphorylation. Knockdown of PKC-δ dramatically retained NRF2 in cytoplasm, convincing its pivotal role in mediating NRF2 nuclear-import. NRF2 activity was further enhanced by activated PKB/GSK-3β signaling via nuclear-export signal blockage independent of PKC-δ activation. By demonstrating independent modulation of PKC-δ and PKB/GSK-3β/Fyn signaling, we highlight the ability of DT to exploit both nuclear import and export regulation of NRF2 in treating reperfusion injury harboring redox homeostasis alterations. Coactivation of PKC and PKB phenocopied cardioprotection of DT in vitro and in vivo, further supporting the potential applicability of this rationale. Graphical abstract

Recent progress of virtual reality simulation in endoscopy training / 中华医学教育探索杂志

There are two methods of endoscopic teaching including traditional apprenticeship mode and simulation training. Although the apprenticeship model has some advantages in the docking of experience, there are many shortcomings. Virtual reality simulation training is learner-centered in endoscopic teaching, which is a safe and effective training method and an important supplement to the apprenticeship model. In the process of simulation training, paying attention to feedback, obtaining non-technical ability, dealing with emergencies in endoscopic operation and optimizing ergonomics are the directions of future research. This paper will briefly summarize the research progress of virtual reality simulation training in endoscope teaching.

Mechanism of Yupingfeng Granule on CU Rats Based on IL-23/IL-17 Inflammation Axis / 中国实验方剂学杂志

Objective::To study the effect of Yupingfeng granule on the degranulation of skin mast cells in chronic urticaria (CU) rats and the intervention mechanism of interleukin-23(IL-23), interleukin-17(IL-17) inflammation axis. Method::Totally 60 SPF SD rats were selected and randomly divided into normal group (normal saline), model group (normal saline), and loratadine group (0.9 mg·kg-1·d-1), high-dose Yupingfeng granules group (4.05 g·kg-1·d-1), middle-dose group (2.7 g·kg-1·d-1), low-dose group (1.35 g·kg-1·d-1). The CU rat model was reproduced through intraperitoneal injection of ovalbumin with aluminum hydroxide suspension and DTP vaccine. Histopathological changes of rat skin were observed by hematoxylin-eosin (HE) staining. Degranulation of mast cells in rat skin was determined by toluidine blue staining. IL-23 and IL-17 protein expressions in skin tissue were determined by immunohistochemistry (IHC). IL-23 and IL-17 mRNA transcription levels in skin tissue were determined by real-time fluorescence quantitative polymerase chain reaction (Real-time PCR). Result::Yupingfeng granules can significantly alleviate the pathological manifestations of dermal edema, collagen beam distance, inflammatory cell infiltration of CU rats, and reduce the degranulation reaction of skin tissue mast cells in CU rats. The IL-23, IL-17 mRNA and protein expressions of the skin of model group were significantly increased compared with the normal group (P<0.05, P<0.01). Compared with the model group, Yupingfeng granules can significantly down-regulate IL-23 mRNA and protein expressions of CU rats (P<0.05, P<0.01). Yupingfeng granules had no significant regulatory effect on IL-17. Conclusion::Yupingfeng granule can significantly reduce the degranulation of mast cells in skin tissue of CU rats, and improve the pathological manifestations, such as dermal edema, serous exudation and inflammatory cell infiltration. The mechanism may be related to inhibiting the secretion of IL-23 pro-inflammatory cytokines and improving CU lesions.