AIM:To analyze the reasons for screening failure and explore the influencing fac-tors in clinical trial in healthy volunteers,guidance was provided to improve the success rate of screen-ing in the future.clarify the reasons for the failure in healthy subjects(HS)screening,and to provide guidance for screening in phase Ⅰ clinical trials.METHODS:We performed a retrospective study that described the process of HS screening in phase Ⅰ clinical trials carried out in department of clinical pharmacology lab,Nanjing First Hospital be-tween 2019 and 2022.We analyzed the reasons for screening failure and their impact on the failure rate.A retrospective analysis was conducted on the data of subjects who participated in drug clinical trial screening 2019 to 2022.The reasons for screening failure were analyzed,and statistical methods were used to explore the independent factors that led to screening failure.RESULTS:A to-tal of 11 clinical trials were included in this study,and 502 out of 1 582 participants(31.7％)passed the screening.The analysis of the remaining 1 080 subjects showed that the items that did not pass the screening were laboratory examinations(631 cases,58.4％),abnormal vital signs results(228 cas-es,21.1％),intolerance to blood drawn(86 cases,8.0％),sufficient subjects(62 cases,5.7％),with-drawal at the screening(54 cases,5.0％),demogra-phy(54 cases,5.0％),urinary cotinine examination(42 cases,3.9％),imaging examination(31 cases,2.9％),electrocardiogram(24 cases,2.2％),inquiry(medical inquiry 19 cases,1.8％,smoking inquiry 2 cases,0.2％,alcohol inquiry 2 cases,0.2％)and identity verification(17 cases,1.8％).In the popula-tion with a body mass index(BMI)of 19.0 to 26.0,an increase in BMI is an independent factor signifi-cantly associated with screening failure(P＜0.000 1,OR=0.890 4,95％CI 0.841 9-0.941 3).The impact of different examination items on the screening fail-ure rate varies.CONCLUSION:In clinical trials of healthy subjects,laboratory tests,vital signs and in-tolerance to blood drawn are the main reasons for screening failure.Lowering the upper limit of BMI when recruiting subjects may increase the success rate of screening.Laboratory examinations,vital signs,intolerance to blood drawn are the most im-portant three reasons for screening failure,and im-provements can be made to reduce the screening failure rate of phase Ⅰ clinical trials in response to the main screening failure reasons.

AIM:To analyze the reasons for screening failure and explore the influencing fac-tors in clinical trial in healthy volunteers,guidance was provided to improve the success rate of screen-ing in the future.clarify the reasons for the failure in healthy subjects(HS)screening,and to provide guidance for screening in phase Ⅰ clinical trials.METHODS:We performed a retrospective study that described the process of HS screening in phase Ⅰ clinical trials carried out in department of clinical pharmacology lab,Nanjing First Hospital be-tween 2019 and 2022.We analyzed the reasons for screening failure and their impact on the failure rate.A retrospective analysis was conducted on the data of subjects who participated in drug clinical trial screening 2019 to 2022.The reasons for screening failure were analyzed,and statistical methods were used to explore the independent factors that led to screening failure.RESULTS:A to-tal of 11 clinical trials were included in this study,and 502 out of 1 582 participants(31.7％)passed the screening.The analysis of the remaining 1 080 subjects showed that the items that did not pass the screening were laboratory examinations(631 cases,58.4％),abnormal vital signs results(228 cas-es,21.1％),intolerance to blood drawn(86 cases,8.0％),sufficient subjects(62 cases,5.7％),with-drawal at the screening(54 cases,5.0％),demogra-phy(54 cases,5.0％),urinary cotinine examination(42 cases,3.9％),imaging examination(31 cases,2.9％),electrocardiogram(24 cases,2.2％),inquiry(medical inquiry 19 cases,1.8％,smoking inquiry 2 cases,0.2％,alcohol inquiry 2 cases,0.2％)and identity verification(17 cases,1.8％).In the popula-tion with a body mass index(BMI)of 19.0 to 26.0,an increase in BMI is an independent factor signifi-cantly associated with screening failure(P＜0.000 1,OR=0.890 4,95％CI 0.841 9-0.941 3).The impact of different examination items on the screening fail-ure rate varies.CONCLUSION:In clinical trials of healthy subjects,laboratory tests,vital signs and in-tolerance to blood drawn are the main reasons for screening failure.Lowering the upper limit of BMI when recruiting subjects may increase the success rate of screening.Laboratory examinations,vital signs,intolerance to blood drawn are the most im-portant three reasons for screening failure,and im-provements can be made to reduce the screening failure rate of phase Ⅰ clinical trials in response to the main screening failure reasons.

Objective: To investigate factors influencing adolescent idiopathic scoliosis (AIS), and to provide a scientific basis for effective prevention and treatment programs. Methods: A questionnaire survey was conducted among 6 757 students who participated in the scoliosis screening program for primary and middle school students in Zhongshan City, China from April 2019 to March 2020. Visual examination and Adams flexion test were used to measure the rotation angle of trunk. For each student, individual and family demographics, family history of scoliosis, daily postural habits, school bag carrying habits, vision, health, school environment, and physical activity were collected by questionnaire. Factors influencing AIS were analyzed using Chi square test and multivariate Logistic regression. Results: The positive screening rate for AIS was 2.0%(135 cases). Multivariate Logistic regression analysis revealed that female gender, no family history of AIS, standing with lumbar spine tilted forward, habit of leaning to the left when seated, and a monthly family income of >10 000 yuan were related to the occurrence of AIS in adolescents ( OR =3.01, 0.38, 2.29, 1.74, 0.44, P <0.05). Conclusion Female students aged 10-16 years with a family history of scoliosis in Zhongshan are identified as a high risk group for scoliosis screening. Developing proper standing and sitting habits helps to reduce the risk of AIS in adolescents.

Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin (DOX) massively amplified ICD via substantial generation of reactive oxygen species (ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways: (1) ROS elevated endoplasmic reticulum (ER) stress, leading to surface exposure of calreticulin; (2) ROS promoted release of various mitochondria-associated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback, we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.

Myostatin (Mstn) is a member of the transforming growth factor-beta superfamily that functions as a negative regulator of skeletal muscle growth and differentiation in mammals. The transcriptional regulation of Mstn is controlled by multiple genes including MEF2, which raise the importance of identifying the binding sites of MEF2 on myostatin promoter region and mechanisms underlying. In this study, we investigated the transcriptional regulation of MEF2 on porcine Mstn promoter activity in C2C12 cells. Sequence analysis of the 1 969 bp porcine Mstn promoter region revealed that it contained three potential MEF2 motifs. Using a serial deletion strategy, we tested the activity of several promoter fragments by luciferase assay. Overexpression of MEF2C, but not MEF2A increased Mstn promoter activity in all the promoter fragments with MEF2 motifs by two to six folds, in both C2C12 myoblasts and myotubes. When we transfected exogenous MEF2C, Mstn mRNA level was also upregulated in C2C12 cells, but the protein level was only significantly increased in myotubes. Thus, we propose that MEF2C could modulate and restrain myogenesis by Mstn activation and Mstn-dependent gene processing in porcine. Our research also provided potential targets and an effective molecule to regulate Mstn expression and gave a new way to explore the functional performance of Mstn.
Animals ; Cells, Cultured ; Gene Expression Regulation ; MEF2 Transcription Factors ; Mice ; Muscle, Skeletal ; metabolism ; Myoblasts ; cytology ; Myogenic Regulatory Factors ; genetics ; physiology ; Myostatin ; genetics ; physiology ; Promoter Regions, Genetic ; Swine

AIM:To establish a microthrombus model by carrageenan (Ca)/ lipopolysaccharides (LPS) intraperitoneal injection in rats with hyperhomocysteinemia (HHcy) and endothelial dysfunction induced by L-methionine intake. METHODS: ① Male Sprague Dawley rats were randomly divided into 2 groups: control and endothelial dysfunction (HHcy) groups. L-methionine was administered by gavage in HHcy group for total 4 weeks. Purified water was administered by gavage in control rats. Plasma Hcy, NO and vWF were examined and the thoracic aorta were excised after 4 weeks of L-methionine treatment to evaluate endothelial function. ② Male Sprague Dawley rats were randomly divided into 3 groups to establish a microthrombus formation model with Ca/ LPS: control, microthrombus formation (Ca/LPS) and endothelial dysfunction plus mitoarothrombus formation (HHcy+Ca/LPS) groups. Control rats were injected with normal saline (NS). Ca/LPS rats were intraperitoneally injected with carrageenan (Ca) and followed by lipopolysaccharides (LPS) 16 h later. HHcy+Ca/LPS rats were intragastric gavaged by L-methionine for total 4 weeks, and then were injected with Ca/LPS in the same way as Ca/LPS group. Cruor parameters and platelet count were detected at 20 h after LPS or NS injection and the mesentery microcirculation was monitored. Plasma NO and vWF were also detected at 24 h after LPS or NS injection. RESULTS: ① Plasma Hcy concentrations and vWF level were significantly increased in HHcy group, while plasma NO content was significantly decreased compared with that in control group. Endothelial dependent relaxation (EDR) of aortic rings was significantly decreased in HHcy group, suggesting endothelial damage/dysfunction was induced by HHcy. ② Mesentery capillary was obviously blocked by microthrombus in Ca/LPS rats and was blocked more seriously in HHcy+Ca/LPS rats. Cruor parameter results suggested that Ca/LPS rats were in hypercoagulable phase and HHcy+Ca/LPS rats were in hypocoagulable phase at 20 h after LPS injection. Platelet count and plasma NO content in HHcy+Ca/LPS group were significantly decreased, while plasma vWF level was significantly increased compared with Ca/LPS group. CONCLUSION: L-methionine intake induces severe HHcy and causes endothelial dysfunction in rats. Microcirculation dysfunction and microthrombosis can be caused by Ca/LPS intraperitoneal injection and may be aggravated by endothelial dysfunction.