1.Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity.
Yongshun ZHANG ; Lan YANG ; Yangsen OU ; Rui HU ; Guangsheng DU ; Shuang LUO ; Fuhua WU ; Hairui WANG ; Zhiqiang XIE ; Yu ZHANG ; Chunting HE ; Cheng MA ; Tao GONG ; Ling ZHANG ; Zhirong ZHANG ; Xun SUN
Acta Pharmaceutica Sinica B 2024;14(1):350-364
Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.
2.Relationship between serum MBL,HRG,IL-23/IL-17 inflammatory axis and cerebral vasospasm and prognosis in patients with aneurysmal subarachnoid hemorrhage after interventional embolization
Chen SHEN ; Wei SHI ; Yuanjie ZHANG ; Zhirong YANG ; Huayi CHENG
International Journal of Laboratory Medicine 2024;45(2):134-140
Objective To investigate the relationship between serum mannan binding lectin(MBL),histi-dine rich glycoprotein(HRG),interleukin(IL)-23/IL-17 inflammatory axis and cerebral vasospasm(CVS)and prognosis in patients with aneurysmal subarachnoid hemorrhage(aSAH)after interventional emboliza-tion.Methods A total of 195 patients with aSAH who underwent interventional embolization treatment in the hospital from March 2019 to February 2022 were selected and were divided into no CVS group(126 cases),mild CVS group(18 cases),moderate CVS group(39 cases),and severe CVS group(12 cases)according to the occurrence and severity of CVS detected by digital subtraction angiography at the 4th postoperative day.The levels of serum MBL,HRG,IL-23 and IL-17 among the four groups before and 3 d after surgery were compared.The patients were followed up for 6 months and divided into good prognosis group(137 cases)and poor prognosis group(58 cases)according to their prognosis.Factors influencing poor prognosis in aSAH pa-tients were analyzed by multivariate Logistic regression model.The predictive value of serum MBL,HRG,IL-23,IL-17 levels and their combined application models for poor prognosis in patients with aSAH was analyzed by receiver operating characteristic(ROC)curve.Results The incidence rate of CVS after interventional em-bolization was 35.38%in 195 patients with aSAH.3 d after surgery,the serum levels of MBL,IL-23 and IL-17 in the mild,moderate,and severe CVS groups were higher than those in the no CVS group,those in the severe CVS group were higher than those in the moderate CVS group,those in the moderate CVS group were higher than those in the mild CVS group(P<0.05).The serum HRG levels in the mild,moderate,and severe CVS groups were lower than those in the non CVS group,those in the severe CVS group were lower than those in the moderate CVS group,those in the moderate CVS group were lower than those in the mild CVS group(P<0.05).3 d after surgery,the levels of serum MBL,IL-23 and IL-17 in the four groups were higher than that before surgery,while the levels of serum HRG were lower than that before surgery(P<0.05).The pro-portions of patients with aneurysm diameter≥6 mm,number of aneurysms>1,surgery time>24 h,Hunt-Hess grade Ⅲ/Ⅳ and postoperative CVS,and serum levels of MBL,IL-23,and IL-17 on the 3rd day after sur-gery in the good prognosis group were lower than those in the poor prognosis group,and serum HRG levels at 3 d after surgery in the good prognosis group were higher than that in the poor prognosis group(P<0.05).Multivariate Logistic regression analysis showed that aneurysm diameter≥6 mm,Hunt-Hess grade Ⅲ/Ⅳ and postoperative CVS,elevated serum levels of MBL,IL-23,and IL-17 and decreased HRG level at 3 d after sur-gery were independent risk factors for poor prognosis in aSAH patients(P<0.05).ROC results showed that serum levels of MBL,HRG,IL-23,and IL-17 at 3 d after surgery had certain predictive power for poor progno-sis in patients with aSAH.The predictive model with the combined application of four indicators had relatively high efficiency(the area under the curve was 0.853).Conclusion Elevated levels of MBL,IL-23,IL-17,and decreased HRG levels in aSAH patients after interventional embolization could increase the risk of CVS and are associated with poor prognosis in aSAH patients after interventional embolization.The above indicators have a certain predictive power for poor prognosis in aSAH patients.
3.The predictive value of serum sTWEAK,Netrin-1 combined with APACHE Ⅱ score for poor prognosis in patients with severe craniocerebral injury after surgery
Chen SHEN ; Wei SHI ; Yuanjie ZHANG ; Zhirong YANG ; Huayi CHENG
International Journal of Laboratory Medicine 2024;45(4):404-409,415
Objective To investigate the predictive value of serum soluble tumor necrosis factor-like weak inducer of apoptosis(sTWEAK)and Netrin-1 combined with acute physiology and chronic health evaluationⅡ(APACHE Ⅱ)score for poor prognosis in patients with severe craniocerebral injury after surgery.Methods Totally 120 patients with severe craniocerebral injury admitted to a hospital from June 2020 to June 2022 were divided into good prognosis group and poor prognosis group according to the prognosis 30 days af-ter surgery.The serum levels of sTWEAK,Netrin-1 and APACHE Ⅱ score were compared between the two groups.Univariate and multivariate Logistic regression were used to analyze the influencing factors of poor prognosis in patients with severe craniocerebral injury,and the prediction model of serum sTWEAK,Netrin-1 and APACHE Ⅱ score combined was constructed.The predictive value of serum sTWEAK,Netrin-1 level and APACHE Ⅱ score in patients with severe craniocerebral injury after surgery was analyzed by receiver operat-ing characteristic(ROC)curve.Results The duration of intensive care unit stay in the poor prognosis group was longer than that in the good prognosis group,and the albumin level,Glasgow Coma scale and serum Ne-trin-1 level at admission were lower than those in the good prognosis group.The proportion of multiple brain contusion and laceration,the proportion of mechanical ventilation,APACHE Ⅱ score at admission and the lev-els of serum sTWEAK,blood creatinine and blood urea nitrogen were higher than those in the group with good prognosis,and the differences were statistically significant(P<0.05).Multivariate Logistic regression analysis showed that multiple brain contusion and laceration,decreased Netrin-1 level,increased APACHE Ⅱscore and increased sTWEAK level at admission were risk factors for poor prognosis in patients with severe craniocerebral injury(P<0.05).ROC curve analysis showed that the area under the curve and 95%CI of ser-um sTWEAK,Netrin-1 and APACHE Ⅱ scores were 0.742(0.552-0.925),0.731(0.488-0.963),0.714(0.502-0.911)and 0.882(0.795-0.947)respectively when the three indexes were used alone and in com-bination.Conclusion Serum sTWEAK and Netrin-1 combined with APACHE Ⅱ score have good predictive value for the poor prognosis of patients with severe craniocerebral injury after surgery,and can provide refer-ence for the formulation of clinical treatment.
4.Prediction of premature mortality of major chronic and non-communicable diseases and exploration of influencing factors in Anhui Province
Qin HE ; Yan ZHANG ; Xiuya XING ; Dan DAI ; Qianyao CHENG ; Wei XU ; Zhenqiu ZHA ; Rui LI ; Yeji CHEN ; Huadong WANG ; Zhirong LIU
Chinese Journal of Epidemiology 2024;45(5):700-707
Objective:To analyze and predict the future trend of the premature mortality of major chronic and non-communicable diseases in Anhui Province, evaluate the implementation of the "Healthy China 2030" Plan, and explore its influencing factors.Methods:Using data from death-cause surveillance and statistical yearbooks in Anhui, the trend prediction and analysis on influencing factors were conducted by using methods such as time series accumulation and logarithmic linear Joinpoint regression, principal component regression.Results:In Anhui, 28.10% of the deaths were premature ones, of which 84.40% were attributed to chronic and non-communicable diseases. In premature deaths attributed to chronic and non-communicable diseases, the deaths caused by malignant tumor and cardiovascular disease accounted for 45.88% and 41.65% respectively. The prediction results showed that the premature mortality of major chronic and non-communicable diseases would decrease in Anhui in the future, and by 2030, the goal in the "Healthy China 2030" Plan would be reached only in rural area. To reduce premature death, it is necessary to pay attention to the prevention and control of malignant tumor and cardiovascular disease. Men in urban area are the key population. Factors that reflect urban infrastructure had a significant impact on premature mortality of major chronic non-communicable diseases, such as garden and green space area per capita. Factors such as concentration of PM 2.5 had a negative impact on premature mortality of chronic non-communicable diseases, while factors such as garden and green space area per capita had a positive impact. Conclusions:Disease burden caused by chronic and non-communicable diseases, such as malignant tumor, exits in Anhui. Men in urban area are key population in the prevention and control of chronic and non-communicable diseases in the future.
5.Association between serum uric acid and metabolic syndrome among adult residents in Anhui province
Wei XU ; Huadong WANG ; Xiuya XING ; Jingqiao XU ; Dan CAO ; Qianyao CHENG ; Yili LYU ; Zhirong LIU
Chinese Journal of Endocrinology and Metabolism 2023;39(10):865-869
Objective:To investigate the prevalence of metabolic syndrome(MS) among adult residents with different characteristics and the relationship between serum uric acid(SUA) level and MS using the data of Chinese Adult Chronic Diseases and Nutrition Surveillance(2018) program in Anhui.Methods:Multi-stage stratified cluster random sampling was used to select participants aged 18 and over for questionnaires, physical measurements, and laboratory tests. The complex weighted method was used to estimate the prevalence of MS among residents with different characteristics. Logistic regression model based on complex sampling data was used to analyze the relationship between SUA and MS. Receiver operating characteristic(ROC) curve was used to evaluate the reliability of SUA in diagnosing MS and determine the optimal cutoff point.Results:A total of 7 182 participants were included and the prevalence of MS among adult residents was 29.46%. The prevalence of MS was higher in females(33.76%) than that in males(25.28%), and the difference was statistically significant( P<0.05). After adjusting for other factors, for every 10 μmol/L increase in SUA, the risk of MS increased by 4% in males( OR=1.040, 95% CI 1.019-1.061) and 7% in females( OR=1.070, 95% CI 1.059-1.082). The area under the curve(AUC) for SUA in diagnosing MS was 0.816(95% CI 0.806-0.826), with a sensitivity of 0.761 and specificity of 0.727. The optimal cutoff point for SUA was 450 μmol/L. Conclusion:The prevalence of MS among adult residents in Anhui Province is 29.46%. SUA is a risk factor for MS, and increasing SUA level indicated a higher risk of MS. The optimal cutoff value of SUA may be helpful in diagnosing MS.
6.Temporal trend of probability of premature death caused by four major non-communicable diseases in Anhui province, 2014 to 2018, and the potential of achieving healthy goals
Xiuya XING ; Qin HE ; Qianyao CHENG ; Rui LI ; Yeji CHEN ; Zhirong LIU
Chinese Journal of Epidemiology 2021;42(3):531-537
Objective:To investigate the current status and temporal trend of probability of premature death, caused by four major non-communicable diseases (NCDs) in Anhui province, from 2014 to 2018, and to explore the possibility of achieving the goal of "Healthy China 2030".Methods:Data of death were collected from the "Information System for Death Cause Register and Management". The mortality, standardized mortality, premature mortality rate and annual percentage change (APC) were calculated. Based on the reduction target of "Healthy China 2030"(-30%) and "Healthy Anhui 2030"(-25%) for premature death probability of four major NCDs, the possibility of achieving the target was evaluated.Results:From 2014 to 2018, the proportion of four major NCDs deaths to total deaths increased from 82.76% to 84.77%, showing an upward trend(APC=0.50%). The standardized mortality rate of four major NCDs in the population aged 30-69 years was decreasing annually (APC=-1.78%). The premature death probability of four major NCDs decreased from 15.53% to 14.43% with a downward trend. The decline rate of men (APC=-1.80%) was slightly lower than that of women (APC =-2.00%). The decline rate of urban (APC=-1.57%) and rural (APC=-1.99%), Northern Anhui (APC=-2.32%) and Central Anhui (APC=-1.81%) areas were all showed a downward trend. The premature death probability in the same year was higher in men, rural areas and northern Anhui areas. The decrease of chronic respiratory diseases was the greatest (APC=-9.19%), followed by cancer (APC=-1.77%), but increased in diabetes for men (APC=-2.90%). According to the average growth rate of premature death probability from 2014 to 2018, it was predicted that the goal of healthy Anhui would be achieved by 2030. However, to achieve the goal of healthy China, the rate of decline needs to be increased by 26.40% on the existing basis. Comparing to the proportion, the descent speed needs to be increased between different genders, urban and rural areas and regions. Conclusions:The premature death probability of four major NCDs in Anhui province has a continuous downward trend. Men, rural residents and residents in northern Anhui province are the key population. We should carry out intervention against the main risk factors of NCDs, reduce the premature mortality rate of NCDs, and strive to achieve the goal of "Healthy China 2030".
7.Current situation, problems and suggestions of environmental health standardization
Bo SUN ; Yibin CHENG ; Xiaoyuan YAO ; Kangfeng ZHAO ; Zhirong ZHOU ; Xiaoming SHI
Chinese Journal of Preventive Medicine 2021;55(3):424-427
In this paper, the history and current situation of environmental health standardization in China are reviewed, and the experience and shortcomings in the process of environmental health standardization in China are analyzed, suggestions for the next step of environmental health standards are also put forward.
8.Current situation, problems and suggestions of environmental health standardization
Bo SUN ; Yibin CHENG ; Xiaoyuan YAO ; Kangfeng ZHAO ; Zhirong ZHOU ; Xiaoming SHI
Chinese Journal of Preventive Medicine 2021;55(3):424-427
In this paper, the history and current situation of environmental health standardization in China are reviewed, and the experience and shortcomings in the process of environmental health standardization in China are analyzed, suggestions for the next step of environmental health standards are also put forward.
9.Dosimetry test of domestically-made accelerator intensity-modulated radiation therapy and volumetric-modulated arc therapy
Dazhen JIANG ; Hui LIU ; Xiaoyong WANG ; Dajiang WANG ; Jiuling SHEN ; Ji CHEN ; Cheng CHEN ; Hongli ZHAO ; Zhirong BAO ; Jun ZHANG
Chinese Journal of Radiation Oncology 2020;29(7):551-553
Objective:To create AAPM TG 119 test plans for intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) in order to evaluate the accuracy of the United Imaging Healthcare′s URT treatment planning system (URT-TPS). The plans were delivered to the phantom using the United Imaging Healthcare′s URT-Linac 506C.Methods:The overall accuracy of IMRT and VMAT planning, measurement, and analysis were evaluated for four test geometries provided by American Association of Physicists in Medicine (AAPM) Task Group Report 119(TG-119) on multi-target, prostate, head and neck and C-shape (easy). The dose distributions were measured in the coronal plane. The point measurements were measured by a Farmer type ion chamber and fluence measurements were completed with film and Delta4 phantom, respectively. Measured planar dose distributions were analyzed using gamma index with criteria 3%/3 mm.Results:For IMRT and VMAT plans, the planning results matched the TG-119 planning results. Measured point doses of IMRT and VMAT were within 2.62% and 3.90% of the planned doses, respectively. Measured film dosimetry gamma values of IMRT and VMAT were> 97.50% and> 93.27%, respectively.Conclusion:Based on these analyses which were performed in line with the TG119 recommendations, it is evident that the URT treatment planning system and URT-Linac 506C have commissioned IMRT and VMAT techniques with adequate accuracy.
10.Efficacy and safety of 0.03% tacrolimus ointment in the long-term intermittent maintenance treatment of atopic dermatitis in children: a multicenter randomized controlled clinical trial
Yuan LIANG ; Lingling LIU ; Shan WANG ; Zuotao ZHAO ; Lin MA ; Xin XIANG ; Heng GU ; Kun CHEN ; Hua WANG ; Hong YI ; Jinping CHEN ; Jintao ZHANG ; Zhirong YAO ; Yifeng GUO ; Ji CHEN ; Ying CHENG ; Xuejun ZHU
Chinese Journal of Dermatology 2019;52(8):519-524
Objective To compare the efficacy and safety of the long-term intermittent maintenance treatment with tacrolimus 0.03% ointment versus traditional treatment in reducing relapses and prolonging the recurrence interval in children with moderate to severe atopic dermatitis (AD).Methods A two-phase randomized,open-labelled,controlled clinical trial was conducted from September 2012 to November 2013.In the first phase,a total of 171 children aged 2-15 years with moderate to severe AD were enrolled from 7 hospitals in China,and received conventional treatment with tacrolimus 0.03% ointment twice a day for 2-6 weeks.At the end of the treatment,the patients who achieved an investigator's global assessment (IGA) score ≤ 2 (n =125) were randomly classified into 2 groups to receive the second-phase treatment:test group (n =62) receiving intermittent maintenance treatment with tacrolimus 0.03% ointment twice a week (Monday and Thursday),and control group (n =63) receiving no treatment.If the patients in the 2 groups experienced relapse,they received conventional treatment with tacrolimus 0.03% ointment twice a day.The overall observation period was 6 months.The primary endpoint was the time to the first relapse,which was defined as the number of days from the end of the first-phase treatment to the first relapse.The secondary endpoints included the number of relapses at the second-phase trial,the disease severity at the time of relapse,the duration of relapse,the pruritus score at the time of relapse,the total amount of tacrolimus ointment used,the total response rate at the second-phase trial,and the incidence of adverse events.Results A total of 125 children with AD were enrolled into the second-phase trial,and 121 of them completed the follow-up.Among the 121 patients,the recurrence rate was significantly lower in the test group (25/60,41.7%) than in the control group (46/61,75.4%;x2 =14.20,P < 0.001).The time to the first relapse was significantly longer in the test group (46.9 ± 37.7 d) than in the control group (28.8 ± 32.3 d;Z =1 093.50,P =0.020).The total number of recurrence was 31 and 86 in the test group and control group respectively,and the mean number of recurrence in each patient was significantly lower in the test group (0.52 ± 0.68) than in the control group (1.41 ± 1.23,t =4.96,P < 0.001).There were no significant differences between the two groups regarding disease severity during relapse (eczema area and severity index:Z =971.50,P =0.39),duration of relapse (Z =747.00,P =0.07),and pruritus score during relapse (Z =894.00,P =0.95).The therapeutic drug was tolerated well in all the children,and no tacrolimus-related serious adverse events occurred.Conclusion The intermittent maintenance treatment with tacrolimus 0.03% ointment twice a week for 6 months can effectively and safely prevent and reduce relapses,and prolong the recurrence interval in children with moderate to severe AD.

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