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.

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.

Background Neonicotinoid insecticides (NEOs) are emerging synthetic insecticides that have been used in various pest management regimens worldwide as alternatives to conventional insecticides. Recently, several studies have indicated that humans are widely exposed to NEOs, but limited is known about the levels and associated health risks of NEOs exposure among children. Objective To estimate exposure levels of four kinds of NEOs in urine samples among 5-year-old children from Laizhou Wan, Shandong Province, and to evaluate health risks of single and cumulative exposure to NEOs among children in this area. Methods A total of 205 children who participated in the 5-year-old follow-up in Laizhou Wan Birth Cohort (LWBC) were included. Urinary concentrations of four NEOs [imidacloprid (IMI), acetamiprid (ACE), clothianidin (CLO), and thiamethoxam (THM)] were measured by high-performance liquid chromatography coupled with triple quadrupole mass spectrometry. Based on the detected NEOs concentrations, estimated daily intake (EDI) was calculated, and the health risk of exposure to single NEO was assessed using hazard quotient (HQ, risk threshold=1). A relative potency factor (RPF) approach was used to standardize the concentrations of the four NEOs by IMI to calculate their cumulative concentrations. Then, the health risk of cumulative exposure to the four NEOs was further evaluated based on the HQ method. Results The detection rates of the four NEOs in the 5-year-old children were all above 90%, and their median creatinine-adjusted urinary concentrations were in the order from high to low as follows: CLO (1.373 μg·g⁻¹) > THM (0.628 μg·g⁻¹) > IMI (0.310 μg·g⁻¹) > ACE (0.073 μg·g⁻¹). Of the four NEOs, the median EDI of IMI was 0.035 µg·kg⁻¹·d⁻¹, higher than those of CLO (0.032 µg·kg⁻¹·d⁻¹), THM (0.012 µg·kg⁻¹·d⁻¹), and ACE (0.002 µg·kg⁻¹·d⁻¹). The maximum HQ values of IMI, CLO, THM, and ACE were 0.168, 0.152, 0.055, and 0.022, respectively, which were all far lower than the risk threshold of 1. The median concentration of cumulative exposure to the four NEOs standardized by IMI was 21.241 μg·g⁻¹, and its median EDI was 2.370 µg·kg⁻¹·d⁻¹. The maximum HQ of cumulative exposure to the four NEOs was only 0.694, which also did not exceed the risk threshold of 1. Conclusion NEOs exposure is common among the 5-year-old children in Laizhou Wan, Shandong. Although there is no obvious health risk associated with single and cumulative exposure to NEOs in the children in this area, their exposure levels of NEOs are higher than those in some foreign areas. The adverse health effects of long-term exposure to low dose of NEOs deserve our extensive attention.

Objective To investigate the value of peripheral blood diamine oxidase(DAO)in evaluating the severity of ulcerative colitis(UC).Methods A total of 76 UC patients admitted to Daxing Hospital,Capital Medical University from June 2020 to June 2022 were included in UC group,and were divided into severe ulcerative colitis(SUC)group and non-SUC group according to the severity of the disease.A total of 76 healthy subjects were included as control group.The general data and serum DAO of all subjects were collected for statistical analysis.Results The serum DAO level in UC group was significantly higher than that in control group(P<0.05).The serum DAO level in SUC group was significantly higher than that in non-SUC group(P<0.05).Receiver operating characteristic curve analysis showed that DAO predicted area under the curve(AUC)of UC was 0.751(95%CI:0.672-0.829,P<0.001),and DAO predicted AUC of SUC was 0.866(95%CI:0.807-0.925,P<0.001).Conclusion Serum DAO is an effective test index for evaluating the severity of UC,which is worthy of clinical promotion.

Artificial Intelligence ; Humans ; Neonatology

Numerous studies have demonstrated that estrogens may exert multifaceted effects on the cardiovascular system via activating the classical nuclear receptors ERα or ERβ and the novel G protein coupled estrogen receptor (Gper). However, some studies have reported inconsistent cardiovascular phenotypes in Gper-deficient mice. The current study was aimed to reveal the effects of genetic deletion of Gper on the arterial blood pressure (ABP) and heart rate in rats. Gper-deficient Sprague-Dawley rats were generated by utilizing the CRISPR-Cas9 gene-editing technique. ABP of 10-week old male (n = 6) and 12-week old female (n = 6) Gper-deficient rats and age-matched wild type (WT) rats (6 females and 6 males) were measured under awake and restrained conditions through the non-invasive tail-cuff method daily for 8 (females) or 9 days (males). In the male WT rats, ABP and heart rate were slightly higher in day 1 to 4 than those in day 5 to 9, indicative of stress-related sympathoexcitation in the first few days and gradual adaptation to the restrained stress in later days. Gper-deficient rats had significantly higher ABP initially (male: day 1 to day 5; female: day 1 to day 3) and similar ABP in later days of measurement compared with the WT rats. The heart rate of male Gper-deficient rats was consistently higher than that of the male WT rats from day 1 to day 8. Both male and female Gper-deficient rats appeared to show slower body weight gain than the WT counterparts during the study period. Under anesthesia, ABP of Gper-deficient rats was not significantly different from their WT counterparts. These results indicate that Gper-deficient rats may be more sensitive to stress-induced sympathoexcitation and highlight the importance of Gper in the regulation of the cardiovascular function in stressful conditions.

Purpose To evaluate the diagnostic value of contrast-enhanced ultrasound (CEUS) in papillary thyroid carcinomas (PTC) by exploring the relationship between quantitative parameters of time-intensity curve (TIC) of CEUS for PTC and tumor size and metastasis of cervical lymph nodes.Materials and Methods 124 patients with PTC confirmed by surgery and pathology in the Affiliated Hospital of Qingdao University were retrospectively analyzed.According to maximum diameter of lesions (D),the lesions were divided into three groups with D＜1.0 cm,1.0 cm ≤ D ≤ 2.0 cm and D＞2.0 cm.The lesions were also divided into LN(+) group with lymph node metastasis and LN(-) group without lymph node metastasis based on pathology of cervical lymph nodes.The features of CEUS and quantitative parameters of TIC of the above groups were analyzed.Results ① The CEUS showed that the PTC nodules were mainly concentric and heterogeneous enhancement.Thyroid carcinoma with D＜1.0 cm and 1.0 cm≤D≤2.0 cm showed low enhancement (45/57,31/42),while thyroid carcinomas with D＞2.0 cm exhibited high enhancement (14/25),and the difference was significant (P＜0.05).① With the increase of the diameter of PTC,the peak intensity [(12.75 ± 3.77)％,(15.53 ± 3.62)％,(18.11 ± 4.28)％],the area under the curve [(820.52±289.19)％.s,(873.84± 156.19)％· s,(1118.8± 152.48)％ ·s] and the ratio of the perfusion defects (24.56％,52.38％,72.00％) were increased,and the differences were statistically significant (P＜0.05).③ The cervical lymph node metastasis rate of PTCs with isoenhancement or hyperenhancement patterns showed by CEUS was significantly higher than that with hypoenhancement (P＜0.05).The peak intensity and the area under the curve of LN (+) group were higher than that of LN (-) group,and the differences were statistically significant (P＜0.05).Conclusion There were significant differences in imaging features of CEUS between the PTC nodules with different size and lymph node metastasis,which can provide valuable information for clinical diagnosis.