Objective:To investigate the effect of metformin(MET)on endoplasmic reticulum stress-induced apoptosis and its role and molecular mechanisms in preeclamptic(PE)rats.Methods:Thirty SD rats were ran-domly assigned into control,PE and MET groups,10 in each group.From days 14 to 18 of gestation,rats in the PE and MET groups were subcutaneously injected with L-nitro-arginine methyl ester(L-NAME)at a dose of 200 mg/(kg·d),while the control group was administered subcutaneous injections containing a 0.9％solution of sodium chloride at the same dose.Additionally,the MET group was administered MET by gavage at a dose of 200 mg/(kg·d)from days 13 to 18 of gestation.On days0,6,12,15,17,and 19 of pregnancy,blood pressure of rats was measured.On days 12 and 19 of pregnancy,24-hour urinary protein content was assessed.On day 20 of pregnan-cy,rats were anesthetized and underwent cesarean section to measure pup weight,crown-rump length,placental weight,and diameter.We used reverse transcription quantitative polymerase chain reaction(qRT-PCR),Western blotting,and immunohistochemistry(IHC)to detected mRNA and protein expression of apoptosis-related genes in rat placental tissue,and enzyme-linked immunosorbent assay(ELISA)to assess the expression of apopto-sis-related genes in rat serum.Results:Compared with the control group,systolic blood pressure on days 15,17 and 19 of gestation and 24h proteinuria level on day 19 of gestation were significantly higher,and body mass and top rump length of littermates were lower in the PE group,and the differences were statistically significant(P＜0.05);Compared with the PE group,systolic blood pressure on days 15,17 and 19 of gestation and 24h proteinuri-a level on day 19 of gestation were significantly decreased,and body mass and top rump length of littermates were increased in the MET group,and the differences were all statistically significant(P＜0.05).Pairwise com-parisons of placental weight,placental diameter,and the number of pups born among the three groups showed no statistically significant differences(P＞0.05).Compared to the control group,the PE group exhibited significantly increased expression of B-cell lymphoma-2(Bcl-2)associated X protein(Bax),bcl-2 antagonist/killer 1(Bak),and apoptosis-inducing factor(AIF)mRNA and protein in placental tissues,decreased expression of Bcl-2 mRNA and protein,as well as elevated levels of Bax,Bak,and AIF in serum,while Bcl-2 expression levels were de-creased.These differences were statistically significant(P＜0.05).Compared to the PE group,the MET group exhibited decreased expression of Bax,Bak,and AIF mRNA and protein in placental tissue,along with increased expression of Bcl-2 mRNA and protein.Serum levels of Bax,Bak,and AIF were decreased,while Bcl-2 expression levels were increased.All differences were statistically significant(P＜0.05).Conclusions:L-NAME significantly induced elevated levels of apoptosis in rat placental tissues,whereas MET was able to effectively inhibit L-NAME-induced apoptosis induced by endoplasmic reticulum stress,which has the potential to be a new therapeu-tic intervention point for PE.

Objective To analyze the reasons for the failure of subject screening in clinical trials of antineoplastic drugs and the impact of natriuretic criteria on the entry of subjects into clinical trials,to explore the strategies to improve the suc-cessful enrolment of screened subjects,and to provide reference bases for research institutes and sponsors in the formulation of na-triuretic criteria.Methods This study selected data from 40 drug clinical trials conducted at the Drug Clinical Trial Research Center of the Cancer Hospital of the Chinese Academy of Medical Sciences from January 1,2016,to June 30,2022.It statistically described the collected data on the frequency and percentage composition of screening failures among participants and the inclu-sion and exclusion criteria in the protocols.Results A total of 425 subjects were screened out of 40 clinical trial programmers covering 8 tumor types,with the majority being＜65 years of age(333,78.4％),of which the most important reasons included vol-untary withdrawal(71,16.7％),tumor metastasis(52,12.2％),failure to recover from treatment of pre-existing disease(38,8.9％),failure of bone marrow function(19,4.5％),and non-compliant liver function(15,3.5％).Among the nadir indicators,the age of the subjects(100％),ECOG score(97.5％),bone marrow function(ANC:95.0％,PLT:97.5％,HB:97.5％),liver function(T-BiL:95.0％,ALT:87.5％,AST:95.0％),renal function(CR:80.0％),and viral screening(HIV:80.0％,HBV:70.0％,HCV:62.5％)were relatively stringent.Conclusion The main reasons for subject screening failure in clinical trials in oncology in our hospital are voluntary withdrawal,brain metastasis,and failure of their biochemical test standards,which are close-ly related to the setting of clinical trial nadir criteria.Therefore,an in-depth understanding of subjects'characteristics,accurate set-ting of appropriate nadir criteria,continuous improvement of trial design,and strengthening of communication with subjects to pro-vide more relevant information will help to improve the screening success rate of clinical trials.

Objective:To investigate the effect of metformin(MET)on endoplasmic reticulum stress-induced apoptosis and its role and molecular mechanisms in preeclamptic(PE)rats.Methods:Thirty SD rats were ran-domly assigned into control,PE and MET groups,10 in each group.From days 14 to 18 of gestation,rats in the PE and MET groups were subcutaneously injected with L-nitro-arginine methyl ester(L-NAME)at a dose of 200 mg/(kg·d),while the control group was administered subcutaneous injections containing a 0.9％solution of sodium chloride at the same dose.Additionally,the MET group was administered MET by gavage at a dose of 200 mg/(kg·d)from days 13 to 18 of gestation.On days0,6,12,15,17,and 19 of pregnancy,blood pressure of rats was measured.On days 12 and 19 of pregnancy,24-hour urinary protein content was assessed.On day 20 of pregnan-cy,rats were anesthetized and underwent cesarean section to measure pup weight,crown-rump length,placental weight,and diameter.We used reverse transcription quantitative polymerase chain reaction(qRT-PCR),Western blotting,and immunohistochemistry(IHC)to detected mRNA and protein expression of apoptosis-related genes in rat placental tissue,and enzyme-linked immunosorbent assay(ELISA)to assess the expression of apopto-sis-related genes in rat serum.Results:Compared with the control group,systolic blood pressure on days 15,17 and 19 of gestation and 24h proteinuria level on day 19 of gestation were significantly higher,and body mass and top rump length of littermates were lower in the PE group,and the differences were statistically significant(P＜0.05);Compared with the PE group,systolic blood pressure on days 15,17 and 19 of gestation and 24h proteinuri-a level on day 19 of gestation were significantly decreased,and body mass and top rump length of littermates were increased in the MET group,and the differences were all statistically significant(P＜0.05).Pairwise com-parisons of placental weight,placental diameter,and the number of pups born among the three groups showed no statistically significant differences(P＞0.05).Compared to the control group,the PE group exhibited significantly increased expression of B-cell lymphoma-2(Bcl-2)associated X protein(Bax),bcl-2 antagonist/killer 1(Bak),and apoptosis-inducing factor(AIF)mRNA and protein in placental tissues,decreased expression of Bcl-2 mRNA and protein,as well as elevated levels of Bax,Bak,and AIF in serum,while Bcl-2 expression levels were de-creased.These differences were statistically significant(P＜0.05).Compared to the PE group,the MET group exhibited decreased expression of Bax,Bak,and AIF mRNA and protein in placental tissue,along with increased expression of Bcl-2 mRNA and protein.Serum levels of Bax,Bak,and AIF were decreased,while Bcl-2 expression levels were increased.All differences were statistically significant(P＜0.05).Conclusions:L-NAME significantly induced elevated levels of apoptosis in rat placental tissues,whereas MET was able to effectively inhibit L-NAME-induced apoptosis induced by endoplasmic reticulum stress,which has the potential to be a new therapeu-tic intervention point for PE.

Objective To analyze the reasons for the failure of subject screening in clinical trials of antineoplastic drugs and the impact of natriuretic criteria on the entry of subjects into clinical trials,to explore the strategies to improve the suc-cessful enrolment of screened subjects,and to provide reference bases for research institutes and sponsors in the formulation of na-triuretic criteria.Methods This study selected data from 40 drug clinical trials conducted at the Drug Clinical Trial Research Center of the Cancer Hospital of the Chinese Academy of Medical Sciences from January 1,2016,to June 30,2022.It statistically described the collected data on the frequency and percentage composition of screening failures among participants and the inclu-sion and exclusion criteria in the protocols.Results A total of 425 subjects were screened out of 40 clinical trial programmers covering 8 tumor types,with the majority being＜65 years of age(333,78.4％),of which the most important reasons included vol-untary withdrawal(71,16.7％),tumor metastasis(52,12.2％),failure to recover from treatment of pre-existing disease(38,8.9％),failure of bone marrow function(19,4.5％),and non-compliant liver function(15,3.5％).Among the nadir indicators,the age of the subjects(100％),ECOG score(97.5％),bone marrow function(ANC:95.0％,PLT:97.5％,HB:97.5％),liver function(T-BiL:95.0％,ALT:87.5％,AST:95.0％),renal function(CR:80.0％),and viral screening(HIV:80.0％,HBV:70.0％,HCV:62.5％)were relatively stringent.Conclusion The main reasons for subject screening failure in clinical trials in oncology in our hospital are voluntary withdrawal,brain metastasis,and failure of their biochemical test standards,which are close-ly related to the setting of clinical trial nadir criteria.Therefore,an in-depth understanding of subjects'characteristics,accurate set-ting of appropriate nadir criteria,continuous improvement of trial design,and strengthening of communication with subjects to pro-vide more relevant information will help to improve the screening success rate of clinical trials.

Renal fibrosis is the main pathological foundation of chronic kidney diseases progressing to end-stage renal diseases. With complex pathogenic factors and prolonged disease course， it threatens the quality of life of patients and brings about heavy financial burden to medical care. In the instance of intestinal flora disturbance， the internal homeostasis is broken， resulting in various "imbalances". The "combination of state and target" endows the syndrome differentiation-based treatment of renal fibrosis with new connotation from the perspective of intestinal flora reconstruction and microbial diversity restoration. In addition， traditional Chinese medicine （TCM）-targeted intervention of intestinal microecology has unique advantages under the principle of "treating different diseases with the same method"， which can guide the diagnosis and treatment of renal fibrosis. To be specific， TCM emphasizes macroscopic regulation of state and microscopic targeting. In view of the inflammatory response， accumulation of endotoxin， and excessive deposition of extracellular matrix （ECM） in the process of renal fibrosis， the strategies for treating this disease have been developed， such as alleviating dampness，removing turbid toxin， and relieving deficiency and stasis. Famous prescriptions in ancient books or compound Chinese medicine prescriptions， classical formulas， Chinese medicine monomers， or active components of Chinese medicine target intestinal microecology. Therefore， from the perspective of common pathogenic factors of renal diseases （renal fibrosis） or pathological product-intestinal microecological imbalance， this article combines TCM basic theory with modern medical pathogenesis， and summarizes the research on TCM intervention of renal fibrosis by regulating intestinal microecology and the scientific connotation of renal fibrosis， which is expected to provide ideas and methods for the product development and related preparations and in-depth molecular biological research.

Objective:To establish a predictive model of moderate to severe pain in patients with hepatocellular carcinoma (HCC) undergoing transcatheter arterial chemoembolization (TACE).Methods:264 patients with HCC who underwent TACE operation in Southern Medical University from January 2017 to April 2018 were selected as the modeling set. The pain was assessed by numeric rating scales. The patients were divided into pain group ( n=96) and non-pain group ( n=168) according to whether moderate to severe pain occurred within 24 hours after the operation. Binary Logistic regression analysis were performed for variables that were statistically significant in the univariate analyses. The predictive nomogram was constructed and the internal validation was performed. In addition, 87 patients with HCC who underwent TACE operation from January 2020 to June 2020 were selected as the validation set for external validation. Results:In the modeling set, 96 patients (36.36%) had moderate to severe pain within 24 hours after TACE operation in 264 patients with HCC, and the dosage of morphine intramuscularly injected within 24 hours was 1015 mg, with an average of 10.57 mg per patient. Multivariate Logistic regression analysis showed that preoperative pain, the distance between the tumor and capsule ≤2 cm, high prothrombin activity, dosage of lipiodol>10 ml, and several thromboembolic tumors were independent risk factors for moderate to severe pain after TACE ( P<0.05). Age>50 was the protective factor of moderate to severe pain after TACE ( P<0.05). The area under ROC curve was 0.799 (95% CI: 0.745-0.853) in the modeling set. The area under Roc curve for internal validation and external validation were 0.780 and 0.788, respectively. The calibration curves showed satisfactory agreements between the model predicted probability and the actually observed probability. Conclusion:The predictive model of moderate to severe pain after TACE was established in this study has good differentiation and accuracy, it has certain guiding significance for predicting the high-risk group of moderate to severe pain after TACE operation and formulating the targeted prevention strategy.

CaMKII is essential for long-term potentiation (LTP), a process in which synaptic strength is increased following the acquisition of information. Among the four CaMKII isoforms, γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons (LTP_E→I). However, the molecular mechanism underlying how γCaMKII mediates LTP_E→I remains unclear. Here, we show that γCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10-30 Hz range. Following stimulation, γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95. Knocking down γCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors (AMPARs) in putative inhibitory interneurons, which are restored by overexpression of γCaMKII but not its kinase-dead form. Taken together, these data suggest that γCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.
Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism* ; Hippocampus/metabolism* ; Interneurons/physiology* ; Long-Term Potentiation/physiology* ; N-Methylaspartate/metabolism* ; Receptors, AMPA/physiology* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Synapses/physiology*

OBJECTIVE: To evaluate the diagnostic ability of toxicity pathology in patho-toxicological testing institutions in China. METHODS: The institutions participated in the 2018 Interlaboratory Comparison Activity of Toxicity Pathology Testing(hereinafter referred to as reference unit) were selected as the research subjects. The heart, spleen, skin, soft tissue, liver and mammary gland of SD rats of different groups in the 2-year carcinogenesis test were selected. The femur, knee joint and nose of Beagle dogs in the 4-week toxicity test and a total of 10 pathological tissues were selected as the comparison samples. The pathological diagnosis was carried out by the pathological diagnostic personnel of the reference unit, and the diagnostic results were reported. The expert appointed by the Toxicology and Pathology Committee of Chinese Toxicology Association compared the diagnostic results with the appointed value. RESULTS: A total of 167 pathological diagnostic personnel from 75 reference units in 24 provinces and municipalities participated in the comparison activity. The reference units were mainly distributed in East China, South China and North China, accounting for 77.3%(58/75). Totally 75 reference units fed back 750 effective diagnostic results. The qualified rates of diagnosis on heart, spleen, skin, soft tissue and breast samples were higher than 60.0%. The qualified rates of diagnosis on femur and knee joint, and nose samples were low(30.7% and 6.7%, respectively). There were 1(1.3%), 46(61.4%) and 28(37.3%) reference units rated as unqualified, qualified and excellent, respectively. CONCLUSION: Most of the testing institutions in China have a high level of patho-toxicological diagnostic ability, that can provide reliable diagnostic results for toxicology safety evaluation tests.

OBJECTIVE: To investigate the chronic toxicity and carcinogenicity of kresoxim-methyl in rats. METHODS: Specific pathogen free SD rats were randomly divided into control group and low-, medium-and high-dose groups according to the body weight of rats, 120 rats in each group with half male and half female rats. The chronic toxicity and carcinogenesis was induced in rats for 104 weeks by oral feeding. The dose of kresoxim-methyl in feed of male and female rats was 0, 75, 300 and 1 200 mg/kg. During the process of experiment, the body weight of rats was weighed. The blood biochemistry, organ coefficient and histopathology were examined at the end of the exposure, and the tumor incidence was calculated. RESULTS: There was no significant difference in mortality of the female or male rats in the four groups(P>0.05). At the 32 nd, 48 th and 56 th week after exposure, the body mass of female rats in the high dose group was lower than that in control group(P<0.05); at the 8 th, 16 th, 24 th and 32 nd week, the body mass of male rats in the high dose group was lower than that in the control group(P<0.05). The organ coefficients of heart and adrenal gland of female rats in the high dose group were higher than those in the control group and the low dose group(P<0.05). The organ coefficient of liver of male rats in the high dose group was lower than that in the control group(P<0.05). The alkaline phosphatase of male rats in the three dose groups was lower than that in the control group(P<0.05). The blood glucose of male rats in the high dose group was higher than that in the control group(P<0.05). The aspartate aminotransferase of male rats in the high dose group was lower than that in the control group(P<0.05). There was no significant difference among the three indexes in female rats(P>0.05). The tumor incidence of the control group and the low, medium and high dose groups were 68.3%, 75.0%, 75.0% and 78.8%, respectively, with no significant difference(P>0.05). The tumor incidence of the female rats was higher than that of the male rats(87.0% vs 61.5%,P<0.01).The tumor multiplicity of the above four groups were 38.3%, 35.8%, 35.0%, 39.8%, respectively, with no significant difference(P>0.05). The tumor multiplicity in female rats was higher than that in male rats(56.9% vs 17.6%,P<0.01). CONCLUSION: The no observed adverse effect level of kresoxim-methyl to female and male SD rats was 24.726 and 20.002 mg/(kg·d), respectively. No carcinogenicity of kresoxim-methyl to SD rats was observed.

Objective: To evaluate the current status and related factors of influenza vaccination among health care workers (HCWs) in tertiary hospitals of Xining city after the implementation of the free influenza vaccination policy. Methods: In August 2018, the cluster sampling method was used to select four medical institutions in Xining that had previously conducted investigations and interventions. All HCWs(excluding logistic staff) in each medical institution were included in the study. A total of 3 260 valid respondents were included. Questionnaires were used to collect the demographic characteristics, influenza and influenza vaccination awareness, implementation of free policy in the influenza epidemic season from 2017 to 2018, influenza vaccination status, awareness of influenza vaccination schedule and free policy. The multivariate logistic regression model was used to analyze related factors of influenza vaccination. Results: The age of respondents was (31.41±5.00) years. The influenza vaccination rate was 6.80% (226/3 260) in 2017-2018 influenza epidemic season. After controlling for related factors, the awareness of the influenza vaccination schedule (OR=17.05, 95%CI: 5.86-49.59), vaccination frequency (OR=8.22, 95%CI: 2.98-22.61) and the free policy (OR=3.15, 95%CI: 1.49-6.67) had higher vaccination rate. Conclusion The influenza vaccination rate of HCWs in tertiary hospitals of Xining city was low. Increasing the awareness of the vaccination schedule, frequency and free policy may promote the influenza vaccination rate of HCWs.