Comparison of aspirin treatment strategies for primary prevention of cardiovascular diseases: A decision-analytic Markov modelling study / 北京大学学报(医学版)

OBJECTIVE@#To compare the expected population impact of benefit and risk of aspirin treatment strategies for the primary prevention of cardiovascular diseases recommended by different guidelines in the Chinese Electronic Health Records Research in Yinzhou (CHERRY) study.@*METHODS@#A decision-analytic Markov model was used to simulate and compare different strategies of aspirin treatment, including: Strategy ①: Aspirin treatment for Chinese adults aged 40-69 years with a high 10-year cardiovascular risk, recommended by the 2020 Chinese Guideline on the Primary Prevention of Cardiovascular Diseases; Strategy ②: Aspirin treatment for Chinese adults aged 40-59 years with a high 10-year cardiovascular risk, recommended by the 2022 United States Preventive Services Task Force Recommendation Statement on Aspirin Use to Prevent Cardiovascular Disease; Strategy ③: Aspirin treatment for Chinese adults aged 40-69 years with a high 10-year cardiovascular risk and blood pressure well-controlled (< 150/90 mmHg), recommended by the 2019 Guideline on the Assessment and Management of Cardio-vascular Risk in China. The high 10-year cardiovascular risk was defined as the 10-year predicted risk over 10% based on the 2019 World Health Organization non-laboratory model. The Markov model simulated different strategies for ten years (cycles) with parameters mainly from the CHERRY study or published literature. Quality-adjusted life year (QALY) and the number needed to treat (NNT) for each ischemic event (including myocardial infarction and ischemic stroke) were calculated to assess the effectiveness of the different strategies. The number needed to harm (NNH) for each bleeding event (including hemorrhagic stroke and gastrointestinal bleeding) was calculated to assess the safety. The NNT for each net benefit (i.e., the difference of the number of ischemic events could be prevented and the number of bleeding events would be added) was also calculated. One-way sensitivity analysis on the uncertainty of the incidence rate of cardiovascular diseases and probabilistic sensitivity analysis on the uncertainty of hazard ratios of interventions were conducted.@*RESULTS@#A total of 212 153 Chinese adults, were included in this study. The number of people who were recommended for aspirin treatment Strategies ①-③ was 34 235, 2 813, and 25 111, respectively. The Strategy ③ could gain the most QALY of 403 [95% uncertainty interval (UI): 222-511] years. Compared with Strategy ①, Strategy ③ had similar efficiency but better safety, with the extra NNT of 4 (95%UI: 3-4) and NNH of 39 (95%UI: 19-132). The NNT per net benefit was 131 (95%UI: 102-239) for Strategy ①, 256 (95%UI: 181-737) for Strategy ②, and 132 (95%UI: 104-232) for Strategy ③, making Strategy ③ the most favorable option with a better QALY and safety, along with similar efficiency in terms of net benefit. The results were consistent in the sensitivity analyses.@*CONCLUSION@#The aspirin treatment strategies recommended by the updated guidelines on the primary prevention of cardiovascular diseases showed a net benefit for high-risk Chinese adults from developed areas. However, to balance effectiveness and safety, aspirin is suggested to be used for primary prevention of cardiovascular diseases with consideration for blood pressure control, resulting in better intervention efficiency.

Research on applying genetic and environmental risk score in risk-adapted colorectal cancer screening / 中华流行病学杂志

Objective: To evaluate the effectiveness of a risk-adapted colorectal cancer screening strategy constructed utilizing genetic and environmental risk score (ERS). Methods: A polygenic risk score (PRS) was constructed based on 20 previously published single nucleotide polymorphisms for colorectal cancer in East Asian populations, using 2 160 samples with MassARRAY test results from a multicenter randomized controlled trial of colorectal cancer screening in China. The ERS was calculated using the Asia-Pacific Colorectal Screening Score system. Logistic regression was used to analyze the association between PRS alone and PRS combined with ERS and colorectal neoplasms risk, respectively. We also designed a risk-adapted screening strategy based on PRS and ERS (high-risk participants undergo a single colonoscopy, low-risk participants undergo an annual fecal immunochemical test, and those with positive results undergo further diagnostic colonoscopy) and compared its effectiveness with the all-acceptance colonoscopy strategy. Results: The high PRS group had a 26% increased risk of colorectal neoplasms compared with the low PRS group (OR=1.26, 95%CI: 1.03-1.54, P=0.026). Participants with the highest PRS and ERS were 3.03 times more likely to develop advanced colorectal neoplasms than those with the lowest score (95%CI: 1.87-4.90, P<0.001). As the risk-adapted screening simulation reached the third round, the detection rate of the PRS combined with ERS strategy was not statistically different from the all-acceptance colonoscopy strategy (8.79% vs. 10.46%, P=0.075) and had a higher positive predictive value (14.11% vs. 10.46%, P<0.001) and lower number of colonoscopies per advanced neoplasms detected (7.1 vs. 9.6, P<0.001). Conclusion: The risk-adapted screening strategy combining PRS and ERS helps achieve population risk stratification and better effectiveness than the traditional colonoscopy-based screening strategy.

The Methodology and Practices of Real-world Study of Acupuncture and Moxibustion / 中山大学学报(医学科学版)

Real-world study is based on evidence in real clinical medical environments. The results of real-world study have high clinical applicability and strong extrapolation， and are more in line with the characteristics of acupuncture and moxibustion. Therefore， real-world study is receiving more and more attention from the clinical research community. In this article， we briefly analyze the compatibility between real-world study and clinical research of acupuncture and moxibustion，and discuss the implementation of real-world research methodology of acupuncture and moxibustion. In addition， the shortcomings and countermeasures of real-world study on acupuncture and moxibustion in China are also summarized. At the end， we provide an outlook on the application of real-world study in clinical research of acupuncture and moxibustion.

Papillary carcinoma in a thyroglossal duct remnant: a case report / 临床耳鼻咽喉头颈外科杂志

This case report has described a case of papillary carcinoma of thyroglossal duct in a young male. This patient was admitted with a mass in the anterior neck for 2 years. Preoperative Bultrasonography, CT and MR showed a subcutaneous cystic mass with irregular calcification shadow in the central region of the neck without obvious enhancement. Initial diagnosis was thyroglossal duct cyst, and was excised by Sistrunk under general anesthesia. The postoperative pathological examination showed thyroglossal duct cyst combined with thyroid papillary carcinoma, which was confirmed by immunohistochemistry as thyroglossal duct papillary carcinoma.

Regulation of Baicalin on Growth of Extranodal NK/T Cell Lymphoma Cells through FOXO3/CCL22 Signaling Pathway / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect of baicalin on the growth of extranodal NK/T cell lymphoma (ENKTCL) cells and its related mechanism.@*METHODS@#Normal NK cells and human ENKTCL cells lines SNK-6 and YTS were cultured, then SNK-6 and YTS cells were treated with 5, 10, 20 μmol/L baicalin and set control. Cell proliferation and apoptosis was detected by Edu method and FCM method, respectively, and expressions of BCL-2, Bax, FOXO3 and CCL22 proteins were detected by Western blot. Interference plasmids were designed and synthesized. FOXO3 siRNA interference plasmids and CCL22 pcDNA overexpression plasmids were transfected with PEI transfection reagent. Furthermore, animal models were established for validation.@*RESULTS@#In control group and 5, 10, 20 μmol/L baicalin group, the proliferation rate of SNK-6 cells was (56.17±2.96)%, (51.92±4.63)%, (36.42±1.58)%, and (14.60±2.81)%, respectively, while that of YTS cells was (58.85±2.98)%, (51.38±1.32)%, (34.75±1.09)%, and (15.45±1.10)%, respectively. In control group and 5, 10, 20 μmol/L baicalin group, the apoptosis rate of SNK-6 cells was (5.93±0.74)%, (11.78±0.34)%, (28.46±0.44)%, and (32.40±0.37)%, respectively, while that of YTS cells was (7.93±0.69)%, (16.29±1.35)%, (33.91±1.56)%, and (36.27±1.06)%, respectively. Compared with control group, the expression of BCL-2 protein both in SNK-6 and YTS cells decreased significantly (P<0.001), and the expression of Bax protein increased in SNK-6 cells only when the concentration of baicalin was 20 μmol/L (P<0.001), while that in YTS cells increased in all three concentrations(5, 10, 20 μmol/L) of baicalin (P<0.001). The expression of FOXO3 protein decreased while CCL22 protein increased in ENKTCL cell lines compared with human NK cells (P<0.001), but the expression of FOXO3 protein increased (P<0.01) and CCL22 protein decreased after baicalin treatment (P<0.001). Animal experiments showed that baicalin treatment could inhibit tumor growth. The expression of CCL22 protein in ENKTCL tissue of nude mice treated with baicalin decreased compared with control group (P<0.01), while the FOXO3 protein increased (P<0.05). In addition, FOXO3 silencing resulted in the decrease of FOXO3 protein expression and increase of CCL22 protein expression (P<0.01, P<0.001).@*CONCLUSION@#Baicalin can inhibit proliferation and promote apoptosis of ENKTCL cell lines SNK-6 and YTS, up-regulate the expression of Bax protein, down-regulate the expression of BCL-2 protein, and down-regulate the expression of CCL22 protein mediated by FOXO3. Animal experiment shown that the baicalin can inhibit tumor growth. Baicalin can inhibit the growth and induce apoptosis of ENKTCL cells through FOXO3/CCL22 signaling pathway.

Correlation between spinous process deviation and lumbar disc herniation in young patients / 中国骨伤

OBJECTIVE@#To explore the relationship between spinous process deviation and lumbar disc herniation in young patients.@*METHODS@#From March 2015 to January 2022, 30 treated young (under the age of 30) patients with lumbar disc herniation were included as the young group. In addition 30 middle-aged patients (quinquagenarian group) with lumbar disc herniation and 30 patients with non-degenerative spinal diseases (young non-degenerative group) were selected as control groups. The angle of the spinous process deviation was measured on CT and statistically analyzed by various groups. All the data were measured twice and the average value was taken and recorded.@*RESULTS@#The average angle of spinous process deviation in the degenerative lumbar vertebra of young patients were (3.89±3.77) degrees, similar to the (3.72±2.98) degrees of quinquagenarian patients(P=0.851). The average angle of s spinous process deviation young non-degenerative group were (2.20±2.28) degrees, significantly less than young group(P=0.040). The spinous process deviation angle of the superior vertebral of the degenerative lumbar in the young group was (4.10±3.44) degrees, which similar to the (3.47±2.87) degrees in the quinquagenarian group (P=0.447). A total of 19 young patients had the opposite deviation direction of the spinous process of the degenerative lumbar vertebra and upper vertebra, while only 7 quinquagenarian patients had this condition(P=0.02). The type of lumbar disc herniation in young patients had no significant relationship with the direction of spinous process deflection of the degenerative or upper lumbar vertebra (P>0.05).@*CONCLUSION@#Spinous process deviation is a risk factor of young lumbar disc herniation patients. If the deviation directions of adjacent lumbar spinous processes are opposite, it will increase the incidence of lumbar disc herniation in young patients. There was no significant correlation between the type of disc herniation and the deviation direction of the spinous process of the degenerative or upper lumbar vertebra. People with such anatomical variation can strengthen the stability of spine and prevent lumbar disc herniation through reasonable exercise.

Improving acupuncture research: progress, guidance, and future directions / 中国针灸

This paper makes an interpretation of the collection Acupuncture: how to improve the evidence base published by BMJ & BMJ Open. Studies show that the quality of randomized controlled trial (RCT) of acupuncture is low, and multivariable Meta-regression analysis fails to confirm most factors commonly believed to influence the effect of acupuncture. The methodological challenges in design and conduct of RCT in acupuncture were analyzed, and a consensus on how to design high-quality acupuncture RCT was developed. The number of acupuncture systematic reviews was huge but the evidence was underused in clinical practice and health policy, and a large number of western clinical practice guidelines recommended acupuncture therapy, but the usefulness of recommendations needed to be improved. In view of the problems in clinical research on acupuncture mentioned in this collection, combined with the analysis of the purpose of clinical research on acupuncture, perspectives, study types, as well as the relationship between evidence and clinical decision-making, a five-stage study paradigm of clinical research on acupuncture is proposed.

Application of discrete event simulation model in analysis on cost-effectiveness of epidemiology screening / 中华流行病学杂志

Discrete event simulation (DES) model is based on individual data, by which discrete events over time are simulated to reflect disease progression. The effects of individual characteristics on disease progression could be considered in the DES model. Moreover, unlike state-transition models, DES model without setting of fixed cycle can contribute to more accurate estimation of event time, especially in the evaluation of the long-term effectiveness of screening strategies for complex diseases in which time dimension needs to be considered. This article introduces the general principles, construction steps, analytic methods and other relevant issues of the DES model. Based on a research case of estimating the cost-effectiveness of screening for abdominal aortic aneurysms in women aged 65 years and above in the United Kingdom, key points in applications of the DES model in analysis on effectiveness of complex disease screening are discussed in detail, including model construction and analysis and interpretation of the results. DES model can predict occurring time of discrete events accurately by establishing the distribution function of their occurring time and is increasingly used to evaluate the screening strategies for complex diseases in which time dimension needs to be considered. In the construction of DES model, it is necessary to pay close attention to the clear presentation of model structure and simulation process and follow the relevant reporting specification to conduct cost-effectiveness analysis to ensure the transparency and repeatability of the research.

Advances in diagnosis and treatment of Wolfram syndrome and related molecular mechanism / 中华预防医学杂志

Wolfram syndrome is a rare genetic spectrum disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, accompanied by other variable clinical manifestations. At present, the prognosis of this syndrome is very poor, the specific molecular mechanism is not clear, effective treatments are lacking to delay, prevent or reverse the development of Wolfram syndrome, and many patients die prematurely due to severe neurological dysfunction. This increases the urgency of the research on the pathogenic molecular mechanism related to Wolfram syndrome and the development of new therapies. This article summarizes the research progress on the pathogenic molecular mechanism and treatment status of Wolfram syndrome, in order to provide reference for the further mechanism research, prevention and treatment of Wolfram syndrome.

Impeding the combination of astrocytic ASCT2 and NLRP3 by talniflumate alleviates neuroinflammation in experimental models of Parkinson's disease

Alanine-serine-cysteine transporter 2 (ASCT2) is reported to participate in the progression of tumors and metabolic diseases. It is also considered to play a crucial role in the glutamate-glutamine shuttle of neuroglial network. However, it remains unclear the involvement of ASCT2 in neurological diseases such as Parkinson's disease (PD). In this study, we demonstrated that high expression of ASCT2 in the plasma samples of PD patients and the midbrain of MPTP mouse models is positively correlated with dyskinesia. We further illustrated that ASCT2 expressed in astrocytes rather than neurons significantly upregulated in response to either MPP+ or LPS/ATP challenge. Genetic ablation of astrocytic ASCT2 alleviated the neuroinflammation and rescued dopaminergic (DA) neuron damage in PD models in vitro and in vivo. Notably, the binding of ASCT2 to NLRP3 aggravates astrocytic inflammasome-triggered neuroinflammation. Then a panel of 2513 FDA-approved drugs were performed via virtual molecular screening based on the target ASCT2 and we succeed in getting the drug talniflumate. It is validated talniflumate impedes astrocytic inflammation and prevents degeneration of DA neurons in PD models. Collectively, these findings reveal the role of astrocytic ASCT2 in the pathogenesis of PD, broaden the therapeutic strategy and provide a promising candidate drug for PD treatment.

Guide growth with transphyseal medial malleolus screw for the treatment of ankle valgus deformity in children / 中华骨科杂志

Objective:To explore the effectiveness of medial malleolus screw epiphyseodesis for pediatric ankle valgus correction and calculate the correction rate, and analyse the influence factors on deformity correction and the risk factors of deformity recurrence after screw removal.Methods:Medical records and radiographs of patients undergoing screw hemiepiphyseodesis of the medial physis of the distal tibia for ankle valgus between Jan 2011 and Dec 2020, at a single pediatric orthopedic department were retrospectively analyzed. A total of 41 patients (49 ankles) were included in following study, including 28 male patients and 13 female patients; with 24 left sides and 25 right sides. Median age at surgery was 10.75 (4.5, 13.9) years, and median follow-up time was 27 (12, 64) months. According to the clinical diagnosis: hereditary multiple exostoses were 23 ankles, fibula hemimelia were 5 ankles, tibia hemimelia were 2 ankles, endochondromatosis were 5 ankles, neurofibromatosis were 5 ankles, traumatic fracture were 6 ankles, and fibrous dysplasia were 3 ankles. The lateral distal tibial angle (LDTA) was measured on ankle weight-bearing X-ray to evaluate the deformity correction. Malhotra classification was used to describe shortening of the fibula at the ankle.Results:Eventually effective correction were obtained in 36 ankles, with an overall effective rate of 73.5%. Screw type (partial-thread or full-thread), screw length (whether to the contralateral cortex), washer used, clinical diagnosis, and age are not independent risk factors for effective correction. Multiple linear regression analysis ( R 2=0.67) was applied for postoperative correction amplitude in effective correction cases, and the length of correction time ( P<0.001), clinical diagnosis ( P=0.013) and preoperative LDTA ( P=0.002) were significant predictive factors after adjusting for age differences. One-way ANOVA were used to compare data between different clinical diagnosis, showed a significant difference in the mean postoperative correction rate ( F=5.05, P=0.003). Conclusion:Medial malleolus screw epiphyseodesis is an effective and reliable method for the treatment of ankle valgus deformity in children; different clinical diagnosis can produce significant differences in the correction rate of ankle valgus deformity.

Application guidelines and research progress of biomarkers for Alzheimer's disease / 中华预防医学杂志

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. It is expected that the incidence of AD will increase exponentially in the coming decades. The clinical and research application of AD biomarkers has gone through a long process. At present, the clinical diagnostic criteria for AD mainly include the IWG-2 criteria developed by International Working Group (IWG), the NIA-AA criteria formulated by the National Institute on Aging and Alzheimer's Association (NIA-AA) and the "Guidelines for the Diagnosis and Treatment of Alzheimer's Disease in China (2020 version)" released by the Professional Committee on Alzheimer's Disease and Related Diseases of the Chinese Geriatric Health Care Association (Alzheimer's Disease Chinese, ADC). Cerebrospinal fluid biomarkers such as Aβ42, T-tau and P-tau are recognized as central biomarkers for AD, besides, the development of new molecules in other pathophysiological pathway that can be used as biomarkers for the diagnosis of AD have made great progress in the last decade. This article elaborates studies of the application guidelines of AD biomarkers and highlights the research progress of biomarkers in AD pathophysiological pathway.

Effectiveness of different screening strategies for type 2 diabete on preventing cardiovascular diseases in a community-based Chinese population using a decision-analytic Markov model / 北京大学学报(医学版)

OBJECTIVE@#To evaluate the effectiveness of different screening strategies for type 2 diabetes to prevent cardiovascular disease in a community-based Chinese population from economically developed areas based on the Chinese electronic health records research in Yinzhou (CHERRY) study.@*METHODS@#A Markov model was used to simulate different systematic diabetes screening strategies, including: (1) screening among Chinese adults aged 40-70 years recommended by the 2020 Chinese Guideline for the prevention and Treatment of Type 2 Diabetes (Strategy 1); (2) screening among Chinese adults aged 35 to 70 years recommended by the 2022 American Diabetes Association Standard of Medical Care in Diabetes (Strategy 2); and (3) screening among Chinese adults aged 35-70 years with overweight or obesity recommended by the 2021 United States Preventive Services Task Force Recommendation Statement on Screening for Prediabetes and Type 2 Diabetes (Strategy 3). According to the guidelines, individuals who were screened positively (fasting plasma glucose ≥ 7.0 mmol/L) would be introduced to intensive glycemic targets management (glycated hemoglobin < 7.0%).The Markov model simulated different screening scenarios for ten years (cycles) with parameters mainly from the CHERRY study or published literature. Number of cardiovascular disease events or deaths could be prevented and number needed to screen (NNS) were calculated to compare the effectiveness of the different strategies. One-way sensitivity analysis on the sensitivity of screening methods and probabilistic sensitivity analysis on uncertainties of diabetes incidence, the sensitivity of screening methods, and intensive glycemic management effects were conducted.@*RESULTS@#Totally 289 245 Chinese adults aged 35-70 years without cardiovascular diseases or diagnosed diabetes at baseline were enrolled. In terms of the number of cardiovascular disease events could be prevented, Strategy 1 for systematic diabetes screening among the adults aged 35-70 years was 222 (95%UI: 180-264), Strategy 2 for systematic diabetes screening among the adults aged 40-70 years was 227 (95%UI: 185-271), and Strategy 3 for systematic diabetes screening among the adults aged 35-70 years with obesity or overweight (body mass index ≥ 24 kg/m2) was 131 (95%UI: 98-164), compared with opportunistic screening. NNS per cardiovascular disease event for the strategies 1, 2 and 3 were 1 184 (95%UI: 994-1 456), 1 274 (95%UI: 1 067-1 564) and 814 (95%UI: 649-1 091), respectively. Compared with Strategy 1, NNS per cardiovascular disease event for Strategy 2 increased by 90 (95%UI: -197-381) with similar effectiveness of cardiovascular prevention; however, NNS per cardiovascular disease event for Strategy 3 was reduced by 460 (95%UI: 185-724) in contrast to the Strategy 2, suggesting that the Strategy 3 was more efficient. The results were consistent in multiple sensitivity analyses.@*CONCLUSION@#Systematic screening for diabetes based on the latest guidelines in economically developed areas of China can reduce cardiovascular events and deaths. However, merely lowering the starting age of screening from 40 to 35 years seems ineffective for preventing cardiovascular disease, while screening strategy for Chinese adults aged 35-70 years with overweight or obesity is recommended to improve efficiency.

Effectiveness of statin treatment strategies for primary prevention of cardiovascular diseases in a community-based Chinese population: A decision-analytic Markov model / 北京大学学报(医学版)

OBJECTIVE@#To evaluate the effectiveness of statin treatment strategies based on risk assessment for the primary prevention of cardiovascular diseases by the Western guidelines in a community-based Chinese population from economically developed areas using data from the Chinese electronic health records research in Yinzhou (CHERRY) study.@*METHODS@#A Markov model was used to evaluate the effectiveness of the following statin treatment strategies, including: (1) usual care without cardiovascular risk assessment(Strategy 0); (2) using the World Health Organization (WHO) non-laboratory-based risk charts with statin treatment for high-risk group (risk ≥ 20%) (Strategy 1); (3) using the WHO laboratory-based risk charts with statin treatment for high-risk group (risk ≥ 20%) (Strategy 2); and (4) using the Prediction for Atherosclerotic cardiovascular disease Risk in China (China-PAR) model with statin treatment for high-risk group (risk ≥ 10%, Strategy 3). According to the guidelines, adults in the medium-risk group received lifestyle intervention, and adults in the high-risk group received life-style intervention and statin treatment under these strategies. The Markov model simulated different strategies for ten years (cycles) using parameters from the CHERRY study, published data, meta-analyses and systematic reviews for Chinese. The number of cardiovascular events or deaths, as well as the number need to treat (NNT) with statin per cardiovascular event or death prevented, were calculated to compare the effectiveness of different strategies. One-way sensitivity analysis on the uncertainty of incidence rate of cardiovascular diseases, and probabilistic sensitivity analysis on the uncertainty of hazard ratios of interventions were conducted.@*RESULTS@#Totally 225 811 Chinese adults aged 40-79 years without cardiovascular diseases at baseline were enrolled. In contrast to the usual care without risk assessment-based statin treatment strategy, Strategy 1 using the WHO non-laboratory-based risk charts could prevent 3 482 [95% uncertainty interval (UI): 2 110-4 661] cardiovascular events, Strategy 2 using the WHO laboratory-based risk charts could prevent 3 685 (95%UI: 2 255-4 912) events, and Strategy 3 using the China-PAR model could prevent 3 895 (95%UI: 2 396-5 181) events. NNTs with statin per cardiovascular event prevented were 22 (95%UI: 14-54), 21 (95%UI: 14-52), and 27 (95%UI: 17-67), respectively. Strategy 3 could prevent more cardiovascular events, while Strategies 1 and 2 required fewer numbers need to treat with statin per cardiovascular event prevented. The results were consistent in the sensitivity analyses.@*CONCLUSION@#The statin treatment strategies based on risk assessment for the primary prevention of cardiovascular diseases recommended by the Western guidelines could achieve substantive health benefits in adults from developed areas of China. Using the China-PAR model for cardiovascular risk assessment could prevent more cardiovascular diseases while using the WHO risk charts seems more efficient.

Rapamycin enhances the anti-tumor activity of cabozantinib in cMet inhibitor-resistant hepatocellular carcinoma / 医学前沿

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.

Agkistrodon halys venom antitumor component-I inhibits vasculogenic mimicry in triple-negative breast cancer cells in vitro by down-regulating MMP2 / 南方医科大学学报

OBJECTIVE@#To investigate the inhibitory effect of agkistrodon halys venom antitumor component-I (AHVAC-I) on vasculogenic mimicry (VM) formation in triple-negative breast cancer MDA-MB-231 cells and explore its possible mechanism.@*METHODS@#CCK8 assay was used to determine the optimal concentration of AHVAC-I for cell treatment based on its halfinhibitory concentration (IC50). MDA-MB-231 cells were treated with different concentrations of AHVAC-I or 5-Fu, and the changes in vasomimetic capacity of the cells were examined using Matrigel assay. The expression levels of matrix metalloproteinase-2 (MMP2) and MMP9 in the treated cells were detected using quantitative PCR and Western blotting.@*RESULTS@#Compared with the control treatment with culture medium, treatment with 5, 10 and 20 μg/mL AHVAC-I significantly reduced vasomimetic ability of MDA-MB-231 cells in a dose-dependent manner (P < 0.01). MMP2 supplementation obviously restored the vasomimetic ability of the cells inhibited by AHVAC-I.@*CONCLUSION@#AHVAC-I inhibits VM formation in triplenegative breast cancer cells in vitro by down-regulating MMP2 production.

Effect of the rolC gene on biosynthesis of tropane alkaloids in Atropa belladonna / 药学学报

Hair roots induced by Agrobacterium rhizogene produce higher levels of secondary metabolites than non-induced plants, and the enhanced metabolic capacity is driven by the rol gene. We hypothesized that rol genes can be utilized to improve the biosynthesis of tropane alkaloids (TAs) in Atropa belladonna. In this study, the rolC gene from Agrobacterium rhizogene pRiA4 plasmid, driven by a CaMV35S promoter, was overexpressed in A. belladonna. The phenotypes, TAs content and transcriptional expression of key genes in TAs biosynthesis were analyzed in transgenic A. belladonna plants. Results show that transgenic A. belladonna exhibited a well-developed root system, male sterility, higher stamen column length than pistil, early flowering, internode shortening, smaller but more flowers, increased axillary buds and lateral buds, decreased apical dominance, and long and narrow leaves as compared to wild-type plants. Transgenic A. belladonna produced more TAs than wild-type plants, with the content of hyoscyamine, anisodamine and scopolamine reaching 2.58, 3.59 and 15.77-fold that of the control group, respectively. The gene expression of putrescine N-methyltransferase (PMT), tropinone reductase I (TRⅠ) and hyoscyamine 6-β-hydroxylase (H6H), key enzymes in TAs biosynthesis, were up-regulated compared with the control group. The above results indicate that the rolC gene enhances TAs biosynthesis in A. belladonna by up-regulating the expression of key enzymes in the TAs biosynthesis pathway, laying a foundation for genetic manipulation of A. belladonna to increase TAs content by increasing rolC gene expression.

Effect of acupotomy intervention on the morphology and ultrastructure of rectus femoris muscle in rabbits with knee osteoarthritis / 中国骨伤

OBJECTIVE@#To observe the effect of acupotomy on the morphology and ultrastructure of rectus femoris muscle in rabbits with knee osteoarthritis and to reveal the possible therapeutic mechanism involved in the effect of acupotomology on the treatment of knee osteoarthritis(KOA).@*METHODS@#Twenty-four male New Zealand rabbits aged 6 months and weighed (2.0±0.5) kg were randomly divided into blank group, model group and acupotomy group, 8 rabbits in each group. KOA model was established by modified Videman method with left hind limb extended plaster immobility for 6 weeks. In acupotomy group, the transfascial focal points of quadriceps femoris muscle were released by acupotomy under the guidance of Jingjin theory for 4 times and once a week, and the treatment points include Hedingci, Binwaixia, Binneixia. Blank group and model group were fed normally without intervention. One week after the end of the intervention, the pennation angle(PA), muscle thickness(MT), cross-sectional area(CSA) and strain ratio(SR) of rectus femoris were measured by ultrasound. HE staining was used to observe the changes of the tissue morphology, the number of muscle fibers and the average area of muscle fibers. The myofibril of rectus femoris, sarcomere and myofilament were observed by transmission electron microscope.@*RESULTS@#The PA of rectus femoris muscle in the blank group was (9.05±0.21)°. The MT was(1.09±0.09) cm and the CSA was(1.30±0.01) cm2. The PA of rectus femoris muscle in the model group was (3.06±0.15)°. The MT was (0.71±0.02) cm and the CSA was(0.77±0.02) cm2. The PA of rectus femoris muscle in the acupotomy group was (6.94±0.28)°. The MT was (0.80±0.05) cm and the CSA was(0.94±0.03) cm2. The muscle PA, MT and CSA of rectus femoris in the model group were significantly smaller than those in the blank group (P<0.05). Those in acupotomy group were significantly increased compared with those in model group (P<0.05). The SR of rectus femoris muscle was 1.19±0.02 in the blank group, 3.50±0.05 in the model group and 1.99±0.07 in the acupotomy group. The elastic SR of the model group was significantly higher than that of the blank group (P<0.05). These in acupotomy group was significantly lower than that in model group(P<0.05). The results of HE staining showed:in blank group, the fascicles of rectus femoris were arranged neatly, the number of beam of muscle fibers within the fixed visual field was 94.38±3.50 and the average CSA was(0.75±0.22) mm2. In model group, the fascicles of rectus femoris with different sizes were disorganized with a small amount of inflammatory cell infiltration, the number of beam of muscle fibers within the fixed visual field was 196.63±2.62 and the average CSA was(0.26±0.03) mm2. Compared to the blank group, a significant increase in the number of muscle fibers in the fixed field in the model group (P<0.05) and the average CSA decreased significantly(P<0.05). In acupotomy group, the rectus femoris fascicles in the acupotomy group tended to be arranged in a more orderly manner, with the inflammatory cells decreased, the number of beam of muscle fibers within the fixed visual field was 132.88±4.61 and the average CSA was(0.70±0.07) mm2. Compared to the model group, a significant decrease in the number of muscle fibers in the fixed field in the model group(P<0.05) and the average CSA increased significantly(P<0.05). The results of transmission electron microscope showed:compared with the blank group, the overall arrangement of the myofibrils of the rectus femoris in the model group was less structured. There was fracture between the muscle fibers and the sarcomere, the myofilaments were disordered, and the fracture of the Z line was discontinuous. Compared with the model group, the myofibrillar texture of rectus femoris in acupotomy group was clearer, and the Z line was more continuous.@*CONCLUSION@#Based on the jingjin theory, the release of quadriceps femoris by acupotomy can effectively improve the morphology and structure of rectus femoris, and promote the repair and reconstruction of chronic skeletal muscle injury in rabbits with KOA, which may be one of the mechanisms of acupotomy in the treatment of KOA.

The Advance in Research into Immunotherapy for Neuroendocrine Carcinoma of Digestive System / 罕见病研究

Gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) is a rare heterogeneous tumor. The heterogeneity in pathology, differentiation, grade and clinical stages results in different prognosis and treatment strategy. Patients with recurrent or metastatic NEN have limited treatment options and poor prognosis.Programmed cell death 1(PD-1) blockade has played indispensable roles in management of cancers recently.Immunotherapy is being explored in NENs in the world with emerging clinical trials. The results of the trials provide evidence and guidance in the application of NEC.The article analizes and summarizes of the findings of major investigations in this field.

Analysis on the promotion effect of the national multi-disciplinary team diagnosis and treatment pilot project of digestive system tumors / 中华医院管理杂志

Objective:To analyze the progress and promotion effect of the national multidisciplinary team(MDT) pilot project of digestive system tumor diagnosis and treatment, for the reference in promoting the popularition of tumor MDT model.Methods:The data of MDT project evaluation forms of 231 digestive system tumor MDT pilot hospitals in 2018(July 2017 to June 2018), 2019(July 2018 to June 2019)and 2020(July 2018 to June 2019)were obtained. The MDT of digestive system tumors, the development of outpatient and inpatient MDT, the distribution of cases, and the management, charging and regional radiation of MDT in the pilot hospital were analyzed. Descriptive analysis and frequency analysis were used for all the data.Results:With pilot hospitals of missing data excluded, the number of pilot hospitals included in the analysis from 2018 to 2020 was 227, 224 and 224, respectively.The number of pilot hospitals carrying out digestive system tumor MDT increased from 174 in 2018 to 222 in 2020, the number of outpatient and inpatient MDT cases increased from 48 332 and 61 823 to 72 493 and 106 899 respectively, and the proportion of pilot hospitals implementing the MDT management system increased from 159 to 214. In 2020, the average expenses of outpatient and inpatient MDT were mainly 200-500 yuan, and 135(60.3%) pilot hospitals became the leading MDT hospitals in the region.Conclusions:The MDT pilot project of digestive system tumors in China has achieved remarkable results.For example, the number of pilot hospitals carrying out MDT keeps increasing year by year, and the pilot hospitals have played a leading role in the region. In order to accelerate the coverage of the tumor MDT model, the authors suggested that the hospitals should optimize MDT in terms of patient accessibility, optimize management mode, promote the medical insurance reimbursement, and strengthen regional influence.