Objective To investigate the relationship between different interleukins (ILs) and gynecological tumors, including cervical cancer, endometrial cancer, and uterine leiomyoma using two-sample Mendelian randomization (MR) analysis. Methods IL and gynecological tumor data were obtained from European populations by using the IEU OpenGWAS open database. Two-sample MR analysis was applied, different interleukins were used as exposure factors, significant SNP in GWAS data were selected as instrumental variables, and the instrumental variables were independent of each other. The risk of three kinds of gynecological tumors was analyzed separately to explore the causal relationship between ILs predicted by genes and outcome indicators. The TwoSampleMR package in R language (4.3.1) software was used for statistical analysis. MR analysis was performed using inverse variance weighted, MR Egger regression, weighted median, simple mode, and weighted mode methods. Results IL-18 receptor 1 (P=0.039) and IL-24 (P=0.025) were negatively correlated with the risk of cervical cancer. IL-4 (P=0.040), IL-21 (P=0.026), and IL-37 (P=0.027) were positively correlated with the risk of endometrial cancer. IL-15 receptor subunit alpha (P=0.005) was negatively correlated with the risk of endometrial cancer. IL-17A (P=0.005) and IL-37 (P=0.018) were negatively correlated with the risk of uterine leiomyoma. IL-21 (P=0.035) was positively correlated with the risk of uterine leiomyoma. Conclusion Genetically predicted IL-4, IL-15Rα, IL-17A, IL-18R1, IL-21, IL-24, and IL-37 are causally associated with the risk of three gynecological tumors. Further exploration of the molecular mechanism of ILs in gynecological tumors may provide potential therapeutic targets for the treatment of gynecological tumors.

Objective:To understand the loss to follow-up of children born to pregnant women with HIV infection (HIV-exposed children) and analyze its influencing factors in China in 2019.Methods:The data were collected from the follow-up records of pregnant women with HIV infection and their children reported by the national "Management Information System for the Prevention of HIV, syphilis and Hepatitis B Mother-to-Child Transmission" in 2019. HIV-exposed children were defined as those who were not followed up after birth or who were not followed up at 18 months of age and who were not followed up at 21 months of age. The univariate and multivariate influencing factors of loss to follow-up of children born to HIV-infected pregnant women were analyzed by χ2 test and logistic regression model. SPSS 25.0 software was used for statistical analysis. Results:The number of HIV-infected pregnant women was 5 039, the number of live-born children was 5 035, the number of loss to follow-up children within 18 months of age was 283, and the loss to follow-up rate children was 5.62%(283/5 035). The results of multivariate logistic regression analysis showed that the rate of loss to follow-up of exposed children born to pregnant women who worked as farmers (animal husbandry and fishery) (a OR=0.34, 95% CI: 0.22-0.53), unmarried (a OR=0.47, 95% CI: 0.24-0.93), first marriage (a OR=0.38, 95% CI: 0.22-0.67), remarriage (a OR=0.36, 95% CI: 0.20-0.67) and cohabiting (a OR=0.47, 95% CI: 0.23-0.97), and knew they had HIV infection before this pregnancy (a OR=0.53, 95% CI: 0.40-0.70) was lower. Han nationality (a OR=1.52, 95% CI: 1.09-2.13), primary school (a OR=2.06, 95% CI: 1.10-3.89) and junior middle school (a OR=1.81, 95% CI: 1.03-3.17) educational level, non-use of antiviral drugs (a OR=6.21, 95% CI: 4.32-8.93) and delivery in township (street) level midwifery institutions (a OR=5.72, 95% CI: 1.61-20.27) had higher rates of loss to follow-up among infants born to HIV-infected pregnant women. Conclusions:HIV-exposed children still have a specific rate of loss to follow-up in China in 2019. In order to further reduce the rate of loss to follow-up, it is of great significance to improve the detection rate of HIV before pregnancy and the rate of antiviral drugs used in pregnant women with HIV infection, which is of great significance for the effective implementation of comprehensive intervention measures of prevention of mother-to-child transmission of HIV.

Breast cancer has become the malignant tumor with the highest incidence rate. Although the emergence of new drugs has prolonged the overall survival of breast cancer patients， it still possesses a high recurrence and metastasis rate due to tumor heterogeneity and drug resistance. Glucose is the main source of energy metabolism for breast cancer cells， and the glucose metabolism of breast cancer cells is significantly different from that of normal breast cells. The high energy demand and rapid growth of breast cancer cells make their demand for glucose much higher than that of normal cells. Moreover， even under aerobic conditions， the glycolytic effect of breast cancer cells will be significantly enhanced to meet the high energy metabolism demand of breast cancer cells. The main reason for the enhanced glycolytic effect of breast cancer cells is the enhanced activity of glycolysis-related enzymes and regulatory factors， including pyruvate kinase， hexokinase， phosphofructokinase， lactate dehydrogenase， and glucose transporter protein. The metabolism process of glycolysis in breast cancer cells can be regulated by interfering with the activity of these enzymes and regulatory factors， thus inhibiting the proliferation of breast cancer， promoting apoptosis， and reversing drug resistance， invasion， and metastasis. Traditional Chinese medicine （TCM） has a long history of treating breast cancer and has made significant achievements in the aspects of anti-recurrence， metastasis， and drug resistance. In recent years， more and more research related to the intervention of aerobic glycolysis in breast cancer by TCM monomers， single-flavored TCM， and compounds has been conducted and has made great achievements. In addition， a large number of in vivo and in vitro experiments have shown that aerobic glycolysis is an important potential target for the treatment of breast cancer by TCM， but there is a lack of a comprehensive review and summary. On this basis， this paper elaborated on the roles of key targets in aerobic glycolysis and breast cancer and summarized the relevant studies on the treatment of breast cancer by intervention of glycolysis with TCM， with a view to providing new ideas for further research.

Objective:To establish a Plaque-reduction Neutralization Test (PRNT) for the detection of neutralizing antibody titers of Human Respiratory Syncytial Virus (HRSV) and optimize the conditions for preliminary application.Methods:The CHO expression system was used to produce palivizumab monoclonal antibody (palivizumab) and the influencing factors such as cell type, cell culture duration, fixation and permeabilization protocols, and blocking agents. The reproducibility of the method was verified and its correlation was verified with conventional PRNT. Finally, the optimized PRNT assay was further used to determine neutralizing antibody titers against HRSV subtypes A and B in BALB/c mouse serum (immunized by intramuscular injection of HRSV fusion proteins).Results:Palivizumab was expressed at approximately 50 mg/L. The optimal working conditions for PRNT were as follows: culturing HEp-2 cells for 2 days, fixing with 4% (V/V) paraformaldehyde at room temperature for 15 min followed by 0.2% (V/V) Triton X-100 permeabilization for 15 minutes as the optimal fixation-permeabilization and removing the blocking step. The overall coefficient of variation (CV) for the reproducibility validation of this method was <15%, showing a good linear relationship with the conventional PRNT. The Spearman correlation coefficient r s was 0.983. This method was used to detect neutralizing antibody titers in mouse sera against HRSV subtype A strain long and subtype B strain 9320, and the fusion proteins combined with AlOH and CpG adjuvant induced the highest neutralizing antibody titers in mice. Conclusion:The HRSV neutralizing antibody assay established in this study is rapid, reproducible, high-throughput, and can be used to detect neutralizing antibodies to HRSV subtypes A and B.

Objective:To establish a Plaque-reduction Neutralization Test (PRNT) for the detection of neutralizing antibody titers of Human Respiratory Syncytial Virus (HRSV) and optimize the conditions for preliminary application.Methods:The CHO expression system was used to produce palivizumab monoclonal antibody (palivizumab) and the influencing factors such as cell type, cell culture duration, fixation and permeabilization protocols, and blocking agents. The reproducibility of the method was verified and its correlation was verified with conventional PRNT. Finally, the optimized PRNT assay was further used to determine neutralizing antibody titers against HRSV subtypes A and B in BALB/c mouse serum (immunized by intramuscular injection of HRSV fusion proteins).Results:Palivizumab was expressed at approximately 50 mg/L. The optimal working conditions for PRNT were as follows: culturing HEp-2 cells for 2 days, fixing with 4% (V/V) paraformaldehyde at room temperature for 15 min followed by 0.2% (V/V) Triton X-100 permeabilization for 15 minutes as the optimal fixation-permeabilization and removing the blocking step. The overall coefficient of variation (CV) for the reproducibility validation of this method was <15%, showing a good linear relationship with the conventional PRNT. The Spearman correlation coefficient r s was 0.983. This method was used to detect neutralizing antibody titers in mouse sera against HRSV subtype A strain long and subtype B strain 9320, and the fusion proteins combined with AlOH and CpG adjuvant induced the highest neutralizing antibody titers in mice. Conclusion:The HRSV neutralizing antibody assay established in this study is rapid, reproducible, high-throughput, and can be used to detect neutralizing antibodies to HRSV subtypes A and B.

Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation. In this study, we identify ubiquitin-specific protease 2 (USP2) as a novel deubiquitinating enzyme of KRAS in multiple myeloma (MM). Specifically, we demonstrate that gambogic acid (GA) forms a covalent bond with the cysteine 284 residue of USP2 through an allosteric pocket, inhibiting its deubiquitinating activity. Inactivation or knockdown of USP2 leads to the degradation of KRAS, resulting in the suppression of MM cell proliferation in vitro and in vivo. Conversely, overexpressing USP2 stabilizes KRAS and partially abrogates GA-induced apoptosis in MM cells. Furthermore, elevated USP2 levels may be associated with poorer prognoses in MM patients. These findings highlight the potential of the USP2/KRAS axis as a therapeutic target in MM, suggesting that strategically inducing KRAS degradation via USP2 inhibition could be a promising approach for treating cancers with KRAS mutations.

Immune Checkpoint Inhibitors ; Transcriptome ; Immunotherapy ; Biomarkers, Tumor

Objective:To investigate the risk factors and treatment of postpancreatico-duodenectomy hemorrhage(PPH).Methods:The retrospective case-control study was conducted. The clinical data of 712 patients who underwent pancreaticoduodenectomy in Peking University First Hospital from January 2012 to November 2021 were collected. There were 392 males and 320 females, aged from 16 to 89 years, with a median age of 62 years. Observation indicators: (1) diagnosis of PPH; (2) analysis of influencing factors for PPH; (3) treatment of PPH. Measurement data with skewed distribution were represented as M(range). Count data were described as absolute numbers or percentages. Univariate analysis was performed using the chi-square test or Fisher exact probability, and multivariate analysis was performed using the Logistic regression model. Results:(1) Diagnosis of PPH. Of the 712 patients, 72 cases had PPH and 7 cases died. The incidence of PPH was 10.11%(72/712), and PPH related mortality was 9.72%(7/72). There were 7 cases of early PPH and 65 cases of delayed PPH. There were 23 cases of mild PPH and 49 cases of severe PPH. (2) Analysis of influencing factors for PPH. Results of univariate analysis showed that preoperative serum total bilirubin (TBil), extended surgery, postoperative pancreatic fistula, postoperative biliary fistula, postoperative abdominal infection were related factors for delayed PPH ( χ2=13.17, 3.93, 87.89, 22.77, 36.13, P<0.05). Results of multivariate analysis showed that preoperative serum TBil ≥171 μmol/L, postoperative grade B or C pancreatic fistula, postoperative biliary fistula, postoperative abdominal infection were independent risk factors for delayed PPH ( odds ratio=1.91, 8.10, 2.11, 2.42, 95% confidence interval as 1.09-3.33, 4.62-14.20, 1.06-4.23,1.35-4.31, P<0.05). (3) Treatment of PPH. ① Treatment of early PPH. Of the 7 cases with early PPH, 4 cases had mild PPH and 3 cases had severe PPH. The 4 cases with mild PPH were stanched by conservative treatment. The bleeding location of the 3 cases with severe PPH were the posterior wall of pancreatoenteric anastomosis, the pancreatic uncinate stump and the unintentional puncture of the jejunostomy tube of the left upper abdominal wall vessels and the 3 cases were stanched by reoperation. All the 7 cases were discharged without other complications. ② Treatment of delayed PPH. Of the 65 cases with delayed PPH, 19 cases had mild PPH and 46 cases had severe PPH. Of the 19 cases with mild PPH, 18 cases were stanched by conservative treatment including 2 cases died of pancreatic fistula and abdominal infection, 1 case were stanched by endoscope therapy. Of the 46 cases with severe PPH, 18 cases with stable vital signs and slow bleeding were stanched by conservative treatment including 1 case died of infectious toxic shock and the other 28 cases underwent invasive treatment, including 2 cases undergoing gastroscopy, 20 cases undergoing interventional treatment and 6 cases under-going reoperation as the initial treatment. Of the 22 cases taking endoscope or interventional treatment as the initial treatment, 5 cases underwent rebleeding and 2 cases died, with the reblee-ding rate and mortality as 22.7%(5/22) and 9.1%(2/22), respectively. Of the 6 cases taking reopera-tion as the initial treatment, 3 cases underwent rebleeding and 2 cases died, with the rebleeding rate and mortality as 3/6 and 2/6, respectively. There was no significant difference in the rebleeding rate and mortality in patients taking endoscope or interventional treatment as the initial treatment and patients taking reoperation as the initial treatment ( P>0.05). Of the 28 cases undergoing invasive treatment, 10 cases underwent secondary surgical treatment, including 6 cases taking reoperation and 4 cases taking interventional treatment as the initial treatment for hemorrhage, and 4 cases died with the mortality as 4/10, and the other 18 cases who did not receive secondary surgical treatment survived. There was a significant difference in the mortality between patients with or without secondary surgical treatment ( P<0.05). Conclusions:Preoperative serum TBil ≥171 μmol/L, post-operative grade B or C pancreatic fistula, postoperative biliary fistula, postoperative abdominal infection are independent risk factors for delayed PPH. Surgical treatment should be performed decisively for early severe PPH. For delayed severe PPH patients who undergoing conservative treat-ment without effect, endoscope therapy and interventional treatment should be the first choice, and surgical treatment should be performed if those above procedures not working.

Objective:To explore the effect of CDIO (conceive, design, implement, operate) model workshop training on the training of new nurses in the operating room.Methods:Forty-two nurses with standardized training were selected as the research objects, and they were randomly divided into two groups: observation group ( n=21) and control group ( n=21). The control group used the traditional training method in the operating room, and the observation group used the workshop training based on the CDIO model. SPSS 17.0 was used to statistically analyze the operation skill scores and case scores after training. The measurement data is expressed by (mean±standard deviation), the independent sample t test is used for comparison between the two groups, and the chi-square test is used for the comparison of counting data. Results:After the training, the scores of operating room knowledge assessment of the two groups were (72.31±2.16) points and (73.61±2.18) points respectively, with statistical significance ( P<0.05); the operation skill scores of observation group were (7.42±0.13) points, which were higher than those of the control group (6.62±0.11) points, and the disposal scores of observation group after operation were (7.12±0.20) points, which were higher than those of the control group (6.27±0.16) points, with statistical significance ( P<0.05); the professional quality scores of observation group were (7.41±0.25) points, which were higher than those of the control group (6.55±0.22) points; the adaptability scores of observation group were (7.06±0.22), which were higher than those of control group (6.35±0.21) points, with statistical significance ( P<0.05). Conclusion:The workshop training based on the CDIO model is effective for the training of nurses in the operating room, and the combined application effect is better than the effect of the traditional teaching model, especially for the improvement of practical skills.

OBJECTIVES: Hypertrophic scar (HS) is the most common pathological scar in clinical practice. During its formation, angiogenesis-related factors show dynamic expression. Modern studies have found that Notch signaling pathway has an extremely important role in maintaining the construction and remodeling of vascular endothelial cells and vascular network. The correlation between Notch signaling pathway and angiogenesis in hypertrophic scar has been rarely reported. This study aims to investigate correlation between Notch signaling pathway and the expression of angiogenic factors in a proliferative scar model. METHODS: A total of 81 Sprague Dawley rats (SPF grade) were randomly assigned into a blank control group, a model group, and a blocker group. In the blocker group, a 2 cm diameter circular scald head was placed on the back of the rats for 10 s at 75 ℃ by using a constant temperature and pressure electrothermal scalding apparatus to form a rat deep II° burn model, and a hyperplastic scar model rat was obtained after natural healing of the wound skin (21 to 23 day epithelialization). A syringe was used to inject a needle from the normal skin around the scar at the 1st, 3rd, 5th, 7th, and 14th days after modeling. The γ-secretase inhibitor was injected locally at 2 mg/kg in a dilution of 0.1 mL at the base of the scar. The rats in the model group was injected with the same amount of saline after modeling; the rats in the blank control group was injected with the same amount of saline. Nine rats in each group was randomly killed by air embolization at the 21st, 28th, and 35th days, respectively. The protein expressions of collagen type I (COL-I) and collagen type III (COL-III) were detected by immunohistochemistry. The protein expressions of vascular endothelial growth factor (VEGF), angiopoietin 1 (Ang1), transforming growth factor-β1 (TGF-β1), and matrix metalloproteinase-2 (MMP-2) were detected by Western blotting. RESULTS: Immunohistochemical results showed that, at the 21st,28th, and 35th days, the protein expressions of COL-I and COL-III in the model group were up-regulated compared with the blank control group (all CONCLUSIONS In the Sprague Dawley rat proliferative scar model, inhibition of Notch signaling pathway could attenuate the expressions of COL-I and COL-III, reduce traumatic scar proliferation, down-regulate the expressions of VEGF, Ang1, TGF-β1, and MMP-2, and inhibit angiogenesis. The expressions of angiogenesis-related factors appeare to be up-regulated during the formation of proliferative scar. When the Notch signaling pathway is inhibited, the up-regulated angiogenic factors show a decreasing trend and the proliferative scar is alleviated, which suggests that Notch signaling pathway may affect the formation of hyperplastic scar by regulating the expression of angiogenic factors.
Animals ; Cicatrix, Hypertrophic/pathology* ; Endothelial Cells ; Matrix Metalloproteinase 2 ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Transforming Growth Factor beta1 ; Vascular Endothelial Growth Factor A