Objective: To explore the potential application of PAK4-PROTAC targeted degradation drug (PpD) in renal cancer immunotherapy. Methods: TIMER 2.0 and TISIDB databases were used to analyze the relationship among PAK4 expression, tumor purity and abundance of immune cell infiltration in renal tumor microenvironment (TEM).Renal cancer cell lines OS-RC-2, 786-O and ACHN were treated with 0, 125 and 250 nmol/L PpD, and the effects of Jurkat cell co-culture on the results were investigated.The cell apoptosis was detected with flow cytometry, and the expression of programmed cell death 1 ligand 1 (PD-L1) in renal cancer cells was detected with immunoblotting. Results: The high expression of PAK4 was positively related to immune purity, and inhibited the abundance of immune killer cells in TEM, such as CD8 T cells, CD4 T cells, natural killer cells and dendritic cells.With 250 nmol/L PpD treatment, there were 21.02% apoptotic cells in OS-RC-2, 29.67% apoptotic cells in 786-O, and 15.39% apoptotic cells in ACHN, respectively.However, with the same concentration of 250 nmol/L PpD treatment, cell apoptotic rate was sharply increased to 70.13% in OS-RC-2/Jurkat, 70.68% in 780-O/Jurkat, and 60.27% in ACHN/Jurkat co-culture models, respectively. Conclusion: PpD can promote apoptosis of renal cancer cells by reducing the expression of PAK4 protein, and enhance the killing effects of immune cells on tumor cells.

BACKGROUND: Congenital heart disease (CHD) is a leading cause of birth defect-related mortality. However, more recent CHD mortality data for China are lacking. Additionally, limited studies have evaluated sex, rural-urban, and region-specific disparities of CHD mortality in China. METHODS: We designed a population-based study using data from the Dataset of National Mortality Surveillance in China between 2008 and 2021. We calculated age-adjusted CHD mortality using the sixth census data of China in 2010 as the standard population. We assessed the temporal trends in CHD mortality by age, sex, area, and region from 2008 to 2021 using the joinpoint regression model. RESULTS: From 2008 to 2021, 33,534 deaths were attributed to CHD. The period witnessed a two-fold decrease in the age-adjusted CHD mortality from 1.61 to 0.76 per 100,000 persons (average annual percent change [AAPC] = -5.90%). Females tended to have lower age-adjusted CHD mortality than males, but with a similar decline rate from 2008 to 2021 (females: AAPC = -6.15%; males: AAPC = -5.84%). Similar AAPC values were observed among people living in urban (AAPC = -6.64%) and rural (AAPC = -6.12%) areas. Eastern regions experienced a more pronounced decrease in the age-adjusted CHD mortality (AAPC = -7.86%) than central (AAPC = -5.83%) and western regions (AAPC = -3.71%) between 2008 and 2021. Approximately half of the deaths (46.19%) due to CHD occurred during infancy. The CHD mortality rates in 2021 were lower than those in 2008 for people aged 0-39 years, with the largest decrease observed among children aged 1-4 years (AAPC = -8.26%), followed by infants (AAPC = -7.01%). CONCLUSIONS CHD mortality in China has dramatically decreased from 2008 to 2021. The slower decrease in CHD mortality in the central and western regions than in the eastern regions suggested that public health policymakers should pay more attention to health resources and health education for central and western regions.
Humans ; Heart Defects, Congenital/mortality* ; Male ; Female ; China/epidemiology* ; Infant ; Child, Preschool ; Adult ; Child ; Adolescent ; Infant, Newborn ; Middle Aged ; Young Adult ; Aged ; Rural Population

Intentional tooth replantation (ITR) is an advanced treatment modality and the procedure of last resort for preserving teeth with inaccessible endodontic or resorptive lesions. ITR is defined as the deliberate extraction of a tooth; evaluation of the root surface, endodontic manipulation, and repair; and placement of the tooth back into its original socket. Case reports, case series, cohort studies, and randomized controlled trials have demonstrated the efficacy of ITR in the retention of natural teeth that are untreatable or difficult to manage with root canal treatment or endodontic microsurgery. However, variations in clinical protocols for ITR exist due to the empirical nature of the original protocols and rapid advancements in the field of oral biology and dental materials. This heterogeneity in protocols may cause confusion among dental practitioners; therefore, guidelines and considerations for ITR should be explicated. This expert consensus discusses the biological foundation of ITR, the available clinical protocols and current status of ITR in treating teeth with refractory apical periodontitis or anatomical aberration, and the main complications of this treatment, aiming to refine the clinical management of ITR in accordance with the progress of basic research and clinical studies; the findings suggest that ITR may become a more consistent evidence-based option in dental treatment.
Humans ; Tooth Replantation/methods* ; Consensus ; Periapical Periodontitis/surgery*

Objective To study the expression levels of serum complement C1q/tumor necrosis factor-related protein 6(CTRP6)in women in early pregnancy and to explore its relationship with gestational diabetes mellitus(GDM).Methods Women at the Second Affiliated Hospital of Zhengzhou University from March 2021 to March 2022 were prospectively and consecutively selected from 10 to 13 weeks gestation for outpatient obstetric check-ups.The age,height,weight,and time of last menstruation of pregnant women were collected,and the levels of total cholesterol(TC),triglyceride(TG),high density lipoprotein(HDL),low density lipoprotein(LDL),fasting plasma glucose(FPG),glycosylated hemoglobin(HbA1c),fasting insulin(FINS)and CTRP6 were measured in early pregnancy,and the pre-pregnancy body mass index(BMI),baseline BMI,prenatal BMI,and homeostatic model assessment of insulin resistance(HOMA-IR)were calculated.All pregnant women underwent a 75g oral glucose tolerance test at 24-28 weeks of gestation and were divided into GDM group and normal glucose tolerance(NGT)group according to the test results.The clinical data and laboratory indexes of the two groups in early pregnancy were compared,and the correlation between serum CTRP6 and various indexes in early pregnancy and its relationship with GDM were analyzed.Results A total of 213 maternal cases were enrolled,and 203 cases were completed for follow-up.Among them,52 mothers were diagnosed with GDM,with a GDM prevalence rate of 25.62%.Serum CTRP6,age,pre-pregnancy BMI,baseline BMI,antenatal BMI,TC,LDL,FPG,HbA1c,FINS,and HOMA-IR were higher in GDM group compared to NGT group,with a statistically significant difference(P<0.05).CTRP6 in early pregnancy was positively correlated with age,pre-pregnancy BMI,baseline BMI,prenatal BMI,TG,LDL,FPG,HbA1c,FINS,HOMA-IR,and negatively correlated with HDL(P<0.05).After correcting for age,BMI,glycolipid metabolism index and HOMA-IR,CTRP6 in early pregnancy remained an independent factor in the development of GDM.Conclusion Elevated serum CTRP6 in early pregnancy is associated with GDM and is an independent risk factor for GDM.

Objective:To investigate the effect of total saponins of Panax japonicus(TSPJ) on ferroptosis of myocardial cells in diabetic cardiomyopathy(DCM) rats and underlying mechanism.Methods:Experiment 1: SD rats were divided into control group, DCM group, low-dose TSPJ group, high-dose TSPJ group, and metformin(Met) group, with 10 rats in each group. Experiment 2: SD rats were divided into control group, DCM group, TSPJ group, adenosine monophosphate-activated protein kinase(AMPK) inhibitor Compound C group, and TSPJ+ AMPK agonist AICAR group, with 10 rats in each group. Except for the control group, all rats were intraperitoneally injected with streptozotocin to construct a DCM model. After 8 weeks of corresponding drug intervention, the body weight as well as glucose and lipid metabolism of rats in each experimental group were assessed, and the cardiac function indicators were detected with echocardiography. The levels of serum lactate dehydrogenase(LDH), cardiac troponin I(cTnI) and creatine kinase isoenzyme MB(CK-MB) were detected by ELISA technique. The pathological changes of myocardial tissue were observed using hematoxylin-eosin(HE) staining. The levels of dismutase(SOD), glutathione(GSH), malondialdehyde(MDA), reactive oxygen species(ROS) and Fe 2+ in myocardial tissue were detected. Western blot was used to detect ferroptosis, ferritinophagy, and the AMPK/mammalian target of rapamycin/UNC-51-like kinase 1(mTOR/ULK1) signaling pathway related proteins expression in myocardial tissue. Results:Compared with control group, left ventricular ejection fraction(EF), left ventricular short axis shortening rate(FS), peak blood velocity ratio(E/A) between early and late diastolic periods were significantly decreased in DCM group, left ventricular inner diameter(LVEDd) was increased, and the serum LDH, cTnI, CK-MB were increased, the levels of SOD, GSH were decreased, MDA, ROS, Fe 2+ were increased in myocardial tissue, the expressions of TFR1, NCOA4 LC3-II/LC3-I, Beclin-1, phosphorylated AMPK and phosphorylated ULK1 were increased, the expressions of GPX4, SLC7A11 and phosphorylated mTOR were decreased. Compared with DCM group, the above indicators of rats were significantly improved in each treatment group. Compared with the TSPJ group, the AMPK agonist AICAR reversed the effects of TSPJ on ferroptosis and ferritinophagy mediated by the AMPK/mTOR/ULK1 pathway in DCM rat cardiomyocytes. Conclusion:TSPJ can inhibit ferroptosis in DCM rat cardiomyocytes and improve myocardial injury by regulating AMPK/mTOR/ULK1 mediated ferritinophagy.

Objective:To analyze the mutation characteristics of rpoB gene in rifampicin-resistant Brucella strains. Methods:DNA of 4 rifampicin-resistant Brucella strains (JSY-26, G-9, WSY-13 and AW-3) isolated from Xinjiang Uygur Autonomous Region was selected, rifampicin rpoB gene was amplified by PCR and its nucleotide sequence was sequenced. The rpoB gene sequences of rifampicin-resistant Brucella standard strain (RB51) and sensitive strain (ALT-8) were used as reference, the mutation sites and types of the rpoB gene inside and outside the rifampicin resistance determination region (RRDR) of the 4 rifampicin-resistant Brucella strains were analyzed by Mega 7.0 software. Results:Through sequence alignment, both JSY-26 and WSY-13 strains underwent a single base point mutation at the RRDR 1 576 bp of the rpoB gene, with the base changing from guanine (G) to adenine (A). The G-9 strain underwent a single base point mutation at the RRDR 1 606 bp of the rpoB gene, with the base changing from cytosine (C) to A. The AW-3 strain showed 5 mutations of 3 types outside rpoB gene RRDR at 2 536, 2 537, 2 626, 2 636 and 2 654 bp, namely 3 insertion mutations [thymine (T) insertion once and C insertion twice], 1 deletion mutation (C deletion), and 1 single base point mutation (from G to C mutation).Conclusion:The RRDR mutations in the rpoB gene of the rifampicin-resistant Brucella strains are mainly characterized by single base point mutations, while multiple insertion and deletion mutations occur outside the RRDR.

OBJECTIVE To explore the predictive factors of cefoperazone/sulbactam-induced thrombocytopenia in adult inpatients， and to establish and validate the nomogram prediction model. METHODS Data of adult inpatients treated with cefoperazone/sulbactam in Xi’an Central Hospital from Jun. 30th， 2021 to Jun. 30th， 2023 were retrospectively collected. The training set and internal validation set were randomly constructed in a 7∶3 ratio. Singler factor and multifactor Logistic regression analysis were used to screen the independent predictors of cefoperazone/sulbactam-induced thrombocytopenia. The nomogram was drawn by using “RMS” of R 4.0.3 software， and the predictive performance of the model was evaluated by the receiver operating characteristic curve and C-index curve. Hosmer-Lemeshow goodness-of-fit test was used to evaluate the calibration degree of the model. Using the same standard， the clinical data of hospitalized patients receiving cefoperazone/sulbactam in Xi’an First Hospital in the same period were collected for external validation of the nomogram prediction model. RESULTS A total of 1 045 patients in Xi’an Central Hospital were included in this study， among which 67 patients suffered from cefoperazone/sulbactam-induced thrombocytopenia， with an incidence of 6.41%. After the false positive patients were excluded， 473 patients were included finally， including 331 in the training set and 142 in theinternal validation set. Multifactor Logistic regression analysis showed that age [OR＝1.043， 95%CI （1.017， 1.070）]， estimated glomerular filtration rate （eGFR） [OR＝0.988，95%CI（0.977， 0.998）]， baseline platelet （PLT） [OR＝0.989， 95%CI（0.982， 0.996）]， nutritional risk [OR＝3.863， 95%CI（1.884， 7.921）] and cumulative defined daily doses （DDDs） [OR＝1.082， 95%CI（1.020， 1.147）] were independent predictors for cefoperazone/sulbactam-induced thrombocytopenia （P＜0.05）. The C-index values of the training set and the internal validation set were 0.824 [95%CI （0.759， 0.890）] and 0.828 [95%CI （0.749， 0.933）]， respectively. The results of the Hosmer-Lemeshow test showed that χ 2 values were 0.441 （P＝0.802） and 1.804 （P＝0.406）. In the external validation set， the C-index value was 0.808 [95%CI （0.672， 0.945）]， the χ 2 value of the Hosmer-Lemeshow test was 0.899 （P＝0.638）. CONCLUSIONS The independent predictors of cefoperazone/sulbactam-induced thrombocytopenia include age， baseline PLT， eGFR， nutritional risk and cumulative DDDs. The model has good predictive efficacy and extrapolation ability， which can help clinic identify the potential risk of cefoperazone/sulbactam-induced thrombocytopenia quickly and accurately.

Objective To investigate the relationship between serum levels of E-cadherin and β-catenin and calcium phosphorus metabolism and carotid artery calcification in patients with diabetic nephropathy.Methods A total of 112 patients with diabetic nephropathy admitted to the hospital from May 2019 to No-vember 2022 were selected as the study group,and were divided into a carotid artery calcification group(n=44)and a non-carotid artery calcification group(n=68)according to the results of bilateral carotid artery col-or Doppler ultrasound.In addition,90 healthy people who underwent physical examination in the hospital dur-ing the same period were selected as the control group.Serum E-cadherin,β-catenin,calcium phosphorus me-tabolism levels were detected and compared.Pearson correlation analysis was used to explore the relationship between serum E-cadherin,β-catenin and calcium phosphorus metabolism in patients with diabetic nephropa-thy.Receiver operating characteristic(ROC)curve was used to evaluate the predictive value of serum E-cad-herin and β-catenin for carotid artery calcification in patients with diabetic nephropathy.Multivariate Logistic regression analysis was used to explore the influencing factors of carotid artery calcification in patients with di-abetic nephropathy.Results The levels of glycosylated hemoglobin,serum phosphorus,calcium-phosphorus product,parathyroid hormone(iPTH),creatinine,alkaline phosphatase and β-catenin in the study group were higher than those in the control group,and the level of E-cadherin was lower than that in the control group(P＜0.05).The levels of serum phosphorus,serum calcium,calcium phosphorus product,iPTH,creatinine,al-kaline phosphatase and β-catenin in the carotid artery calcification group were higher than those in the non-ca-rotid artery calcification group,and the level of E-cadherin was lower than that in the non-carotid artery calci-fication group(P＜0.05).Pearson correlation analysis showed that serum E-cadherin level in patients with di-abetic nephropathy was negatively correlated with serum phosphorus,serum calcium,calcium phosphorus product,iPTH,creatinine and alkaline phosphatase(r=-0.453,-0.654,-0.365,-0.490,-0.411,-0.377,all P＜0.001).The level of serum β-catenin was positively correlated with serum phosphorus,serum calcium,calcium phosphorus product,iPTH,creatinine,and alkaline phosphatase(r=0.444,0.345,0.421,0.398,0.651,0.622,all P＜0.001).ROC curve analysis showed that the area under the curve of serum E-cad-herin,β-catenin and their combination for predicting carotid artery calcification in diabetic nephropathy were 0.844(95％CI 0.795-0.894),0.853(95％CI 0.801-0.901)and 0.901(95％CI 0.801-0.901),respec-tively.Multivariate Logistic regression analysis showed that serum E-cadherin(OR=3.789,95％CI 2.055-6.983),β-catenin(OR=4.104,95％CI 1.795-9.385),calcium phosphorus product(OR=2.998,95％CI 1.895-4.743)and iPTH(OR=2.713,95％CI 1.787-4.118)were the influencing factors of carotid artery calcification in patients with diabetic nephropathy(P＜0.05).Conclusion The level of β-catenin is increased and the level of E-cadherin is decreased in patients with diabetic nephropathy.β-catenin and E-cadherin are closely related to calcium phosphorus metabolism and carotid artery calcification,which could be used as effec-tive indicators to evaluate carotid artery calcification in patients with diabetic nephropathy.The combination ofβ-catenin and E-cadherin has a higher predictive value for carotid artery calcification.

Objective To investigate the relationship between serum levels of growth differentiation factor-11(GDF-11)and S100 calcium binding protein A4(S100A4)and the severity and disease outcome in diabetic nephropathy(DN)patients.Methods A total of 95 DN patients admitted to the hospital from May 2021 to January 2023 were selected as the study group,and 110 healthy people were selected as the healthy group.The DN patients were divided into mild group(n=66)and severe group(n=29)according to the severity of the disease.The patients were followed up for half a year after discharge,and were divided into good prognosis group(n=64)and poor prognosis group(n=31)according to the prognosis.Serum GDF-11 and S100A4 lev-els were detected by enzyme-linked immunosorbent assay.Spearman rank correlation analysis was used to ex-plore the relationship between serum GDF-11,S100A4 levels and the severity of the disease.Receiver operat-ing characteristic(ROC)curve was used to evaluate the predictive value of serum GDF-11 and S100A4 for dis-ease outcome in DN patients,and multivariate Logistic regression was used to analyze the influencing factors of disease outcome in DN patients.Results The levels of serum GDF-11 and S100A4 in mild group and severe group were higher than those in healthy group,and those in severe group were higher than those in mild group(P＜0.05).Serum GDF-11 and S100A4 levels were positively correlated with the severity of DN patients(P＜0.05).The good prognosis group had significantly lower serum levels of GDF-11 and S100A4 than the poor prognosis group(P＜0.05).The area under the curve(AUC)of serum GDF-11 and S100A4 in predicting the outcome of DN patients was 0.785 and 0.839,respectively,and the AUC of combined prediction was 0.902.The proportion of type 2 diabetes(T2DM)duration,glomerular grade Ⅲ-Ⅳ,interstitial inflammation score 2,interstitial fibrosis and tubular atrophy(IFTA)score 2-3 points,estimate glomerular filtration rate＜60 mL/(min·1.73 m2)and the levels of total cholesterol,triglyceride,low-density lipoprotein choles-terol,24 h urinary protein,glycosylated hemoglobin,C-peptide,hematocrit,and erythrocyte sedimentation rate in the good prognosis group were higher than those in the good prognosis group(P＜0.05).Multivariate Lo-gistic regression analysis showed that the duration of T2DM ≥12.0 years,IFTA score ≥2 points,GDF-11≥700.82 ng/mL,S100A4 ≥ 211.53 ng/L were risk factors for poor prognosis in DN patients(P＜0.05).Conclusion The levels of serum S100A4 and GDF-11 are highly expressed in patients with diabetes mellitus,and are related to the severity and outcome of the disease,which are expected to be potential markers for eval-uating the condition and prognosis of diabetes mellitus.