Objective Our previous study has shown that porcine antigen-primed and CD4 + T cells activated macrophages are capable of the ecognition and rejection of porcine xenografts but not mouse allografts, and therefore suggested the involvement of signaling between the graft and macrophages in this specific graft recognition and destruction. Methods NOD-SCID mice were transplanted with fetal pig pancreatic fragment (FPP) before adoptive transfer with exogenous macrophages isolated from rejecting FPP xenografts of BALB/c recipient mice. The exogenous macrophages were tracked by Ly5.1 surface antigen or via CSFE staining. Gene expression of CCR2 and CCR5 and their chemokines in transplanted FPP xenografts was evaluated by real-time PCR. Results After the adoptive transfer, recently transplanted but not established FPP xenografts were rejected by exogenous activated macrophages. In the meantime, greater level of chemokine gene expression was detected in recently-transplanted compared with the established xenografts. Furthermore, expression of both CCR2 and CCR5 genes was enhanced significantly in activated macrophages when compared with non-activated macrophages. Conclusion Upregulated chemokines were associated with macrophage recruitment and destruction of islet xenografts.

Objectives: To compare regional cerebral tissue oxygen saturation (rScO2) changes during cardiac surgery in children with ventricular septal defect (VSD) and tetralogy of Fallot (TOF). Methods: A total of 60 children aged 3~36 months were enrolled (28 in VSD group 32 in TOF group). rScO2was monitored by Fore-Sight near-infrared spectroscopy device. rScO2, pulse oxygen saturation (SpO2), systolic pressure, diastolic pressure, heart rate, stroke volume index, cardiac index, systemic vascular reststance index the maximal slope of systolic upstroke (dp/dt max) were obtained at following time points: after anesthesia induction (t0), pericardium opening (t1), 5 min after cardiopulmonary bypass (CPB) initiation (t2), 5 min before separation from CPB (t3), separation from CPB (t4), post-modified ultrafiltration (t5), end of surgery (t6). Results: (1) The lowest rScO2value was observed at separation from CPB (t4), and which was significantly lower than that at t0(P<0.05) for both groups; rScO2, stoke volume index, cardiac index, and dp/dt max at t5were significantly higher than at t4(all P<0.001) for both groups. (2) rScO2and SpO2were significantly higher at t5and t6than at t0(both P<0.05) in TOF group. rScO2at t0-t2was significantly lower in TOF group than in VSD group (both P<0.05). rScO2increased more significantly after modified ultrafiltration and rScO2was positively correlated with SpO2at t0and t1(r=0.35, P<0.05 and r=0.64,P<0.01) in TOF group. (3) In the total cohort, rScO2was positively correlated with age, weight at t0, t1, t3, t4, t5, t6(all P<0.01). After modified ultrafiltration, the increase in cardiac index was positively correlated with increase in rScO2(r=0.41, P<0.05), and the amount of cardiac index and rScO2increases were negatively correlated with age (r=-0.30;r=-0.34, both P<0.05). Conclusions: rScO2is closely related with age and weight. Cerebral oxygen delivery before biventricular surgical correction is lower in TOF group than in VSD group, and the cerebral oxygenation improves significantly after surgical repair. Modified ultrafiltration could significantly improve systemic hemodynamics and rScO2, and TOF children and younger children benefit more from modified ultrafiltration. Pre- and post-separation from CPB period is vulnerable to cerebral desaturation, it is therefore of importance to maintain the cerebral oxygen delivery-consumption balance at these periods for children with TOF and VSD undergoing surgical repair.

Objective:To analyze the changes in the disease burden of prostate,testis,kidney and bladder cancers among uri-nary and reproductive system tumors in Chinese men from 1990 to 2019 with a prediction of the future trend.Methods:We re-trieved the data on the incidence,mortality and disease burden of prostate,testis,kidney and bladder cancers in Chinese men between 1990 and 2019 from the database of Global Burden of Disease Study 2019.Using the Joinpoint regression model,we analyzed the trend of changes in the disease burden,and predicted the prevalence of the tumors with the ARIMA model.Results:From 1990 to 2019,the standardized incidence and prevalence of prostate,testis,kidney and bladder cancers were on the rise in Chinese men,and those of testis cancer increased most significantly,by 326.79% and 1070.93% respectively.The disease burden of PCa was the highest,with standardized incidence,prevalence and mortality ratios of 17.34/100 000,117.65/100 000 and 7.79/100 000 respectively in 2019.The standardized mortality and disability-adjusted life years(DALY)of kidney cancer were increased by 103.59% and 103.17% respectively.The highest incidence,mortality and DALY of prostate,kidney and bladder cancers in 2019 were found in 90-94 years old males,the highest prevalence rates of prostate,kidney and bladder cancers in the 70-89-year-olds,and the highest prevalence of testis cancer in the25-49-year-olds.ARIMA model prediction showed that the standardized incidence rates of prostate,testis,kidney and bladder cancers in Chinese men kept rising from 2020 to 2029.Conclusion:The disease burden of prostate,tes-tis,kidney and bladder cancers in Chinese men is on the rise,and their standardized incidence rates will be even higher by 2029,with a significant increase in the disease burden in young men,which suggests the need of more attention to the prevention and treatment of genitourinary system tumors in young males.

OBJECTIVETo investigate the effect of ischemia/reperfusion (I/R) on tumor metastasis in a experimental mouse model of hematogenous metastasis after I/R and to quantify expression of vascular cell adhesion molecule-1 (VCAM-1) during I/R.

METHODSAn experimental mouse model of metastasis after partial hepatic I/R was designed to determine the effects of I/R on tumor metastasis to liver. Tumor loads were valued 14 days after operation. In addition, the expressions of alanine transaminase (ALT), aspartate transaminase (AST), and VCAM-1 were detected.

RESULTSTwo hours after hepatic reperfusion, ALT and AST levels in ischemia 45-minute group and ischemia 30-minute group were significantly higher than in the sham group (all P < 0.05). Also, the changes of ALT and AST were more obvious in the ischemia 45-minute group than in ischemia 30-minute group (all P < 0.05). In the sham group, both ALT and AST slightly and transiently increased. ALT and AST in the ischemia 45-minute group and ischemia 30-minute group at 8 hours were both significantly higher than those at 2 hours reperfusion (P<0.05). The tumor load (valued by hepatic replacement area) and the expression of VCAM-1 in ischemic lobe were significantly larger in the ischemia 45-minute group than in the ischemia 30-minute group and sham group (P = 0.013, P = 0.007). However, there was no statistical difference on tumor load between the right lobe of sham operated mice and the right lobe (nonischemic lobes) of mice subjected to I/R (P = 0.089). Mouse survivals were significantly longer in the sham group than in the ischemia 30-minute group (P = 0.041) but were not significantly different between the ischemia 45-minute group and ischemia 30-minute group (P = 0.055). VCAM-1 expression in ischemia 45-minute group was significantly higher than in ischemia 30-minute group and sham group(P = 0.003, P < 0.001), and it was positively correlated with the hepatic replacement area (r = 0.491, P = 0.045).

CONCLUSIONHepatic I/R promotes liver hematogenic metastasis of hepatocellular carcinoma in mice and at least in part, through the induction of VCAM-1 expression.

Animals ; Liver ; blood supply ; Liver Neoplasms ; pathology ; Male ; Mice ; Mice, Inbred BALB C ; Neoplasm Metastasis ; Reperfusion Injury ; complications ; Vascular Cell Adhesion Molecule-1 ; physiology

Background/Aims: Finite nucleos(t)ide analog (NA) therapy has been proposed as an alternative treatment strategy for chronic hepatitis B (CHB), but biomarkers for post-treatment monitoring are limited. We investigated whether measuring hepatitis B core-related antigen (HBcrAg) after NA cessation may stratify the risk of subsequent clinical relapse (CR). Methods: This retrospective multicenter analysis enrolled adults with CHB who were prospectively monitored after discontinuing entecavir or tenofovir with negative HBeAg and undetectable HBV DNA at the end of treatment (EOT). Patients with cirrhosis or malignancy were excluded. CR was defined as serum alanine aminotransferase > two times the upper limit of normal with recurrent viremia. We applied time-dependent Cox proportional hazard models to clarify the association between HBcrAg levels and subsequent CR. Results: The cohort included 203 patients (median age, 49.8 years; 76.8% male; 60.6% entecavir) who had been treated for a median of 36.9 months (interquartile range [IQR], 36.5–40.1). During a median post-treatment follow-up of 31.7 months (IQR, 16.7–67.1), CR occurred in 104 patients with a 5-year cumulative incidence of 54.8% (95% confidence interval [CI], 47.1–62.4%). Time-varying HBcrAg level was a significant risk factor for subsequent CR (adjusted hazard ratio [aHR], 1.53 per log U/mL; 95% CI, 1.12–2.08) with adjustment for EOT HBsAg, EOT anti-HBe, EOT HBcrAg and time-varying HBsAg. During follow-up, HBcrAg <1,000 U/mL predicted a lower risk of CR (aHR, 0.41; 95% CI, 0.21–0.81). Conclusions Dynamic measurement of HBcrAg after NA cessation is predictive of subsequent CR and may be useful to guide post-treatment monitoring.

Objective: To investigate the current status of antithrombotic strategy for elderly patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) after stent implantation in Beijing area and to study the safety and efficacy of different therapeutic strategy. Methods: A total of 467 relevant patients were enrolled by re-travelling electronic medical records from 12 hospitals in Beijing area. The patients' mean age was (78.70±3.32) years and they were divided into 2 groups by antithrombotic therapy condition: Triple therapy group, n=17 (3.64％), Double therapy group, n=450 (96.36％). The incidence of major adverse cardiac and cerebral events (MACCE) including all-caused death, non-fatal myocardial infarction, stent thrombosis, target vessel revascularization (TVR), stoke and bleeding was compared between Triple therapy group and Double therapy group.Results: The medication in Double therapy group included aspirin+ticagrelor, aspirin+clopidogrel, clopidogrel+warfarin and cilostazol+clopidogrel; in Triple therapy group was aspirin+clopidogrel+warfarin. Patient with HAS-BLED score≥3 was defined as high risk of bleeding and they were all treated by double therapy; HAS-BLED<3 was defined as low risk of bleeding, only 5.03％ patients were treated by triple therapy. 3 patients in Triple therapy group and 33 in Double therapy group suffered from gastrointestinal bleeding, P=0.338; 6 patients in Triple therapy group and 128 in Double therapy group had MACCE, P=0.589; 3 and 80 patients died in Triple therapy group and Double therapy group, P=0.766. Conclusion: Triple therapy was rarely used in elderly AF and ACS patients after stent implantation, double therapy was the main strategy; the incidence of MACCE and mortality were similar between triple and double therapies; patients with triple therapy had the higher incidence of gastrointestinal bleeding.

Objective Coronavirus disease 2019 (COVID-19) and tuberculosis (TB) are major public health and social issues worldwide. The long-term follow-up of COVID-19 with pulmonary TB (PTB) survivors after discharge is unclear. This study aimed to comprehensively describe clinical outcomes, including sequela and recurrence at 3, 12, and 24 months after discharge, among COVID-19 with PTB survivors. Methods From January 22, 2020 to May 6, 2022, with a follow-up by August 26, 2022, a prospective, multicenter follow-up study was conducted on COVID-19 with PTB survivors after discharge in 13hospitals from four provinces in China. Clinical outcomes, including sequela, recurrence of COVID-19, and PTB survivors, were collected via telephone and face-to-face interviews at 3, 12, and 24 months after discharge. Results Thirty-two COVID-19 with PTB survivors were included. The median age was 52 (45, 59) years, and 23 (71.9％) were men. Among them, nearly two-thirds (62.5％) of the survivors were moderate, three (9.4％) were severe, and more than half (59.4％) had at least one comorbidity (PTB excluded). The proportion of COVID-19 survivors with at least one sequela symptom decreased from 40.6％ at 3 months to 15.8％ at 24 months, with anxiety having a higher proportion over a follow-up. Cough and amnesia recovered at the 12-month follow-up, while anxiety, fatigue, and trouble sleeping remained after 24 months. Additionally, one (3.1％) case presented two recurrences of PTB and no re-positive COVID-19 during the follow-up period. Conclusion The proportion of long symptoms in COVID-19 with PTB survivors decreased over time, while nearly one in six still experience persistent symptoms with a higher proportion of anxiety. The recurrence of PTB and the psychological support of COVID-19 with PTB after discharge require more attention.

ObjectiveTo assess the value of apparent diffusion coefficient （ADC） in the treatment of uterine fibroid using magnetic resonance guided focused ultrasound surgery （MRgFUS）. MethodsThe MRI and clinical data of 56 patients with uterine fibroid before， at 3 and 6 months after MRgFUS treatment， at Foshan Hospital of Traditional Chinese Medicine from December 2018 to October 2022， were retrospectively analyzed. The correlation between the ADC value and lesion volume， symptoms severity score （SSS） and uterine fibroid symptoms quality of life questionnaire （UFS-QOL） were analyzed. ANOVA was used to compare the differences in related parameters before and after treatment， and Pearson’s method was performed to analyze data correlation. ResultsThere were significant differences in ADC value ［（1.11±0.13）， （1.84±0.09）， （2.12±0.24），×10^-3/（mm²/s）］， lesion volume （102±35.30， 56.70±18.88， 46.93±18.99，cm³）， SSS （36.73±11.74， 21.77±10.21， 17.66±9.30） and UFS-QOL score （59.05±17.48， 76.54±16.50， 82.46±12.37） between before treatment and each time point after treatment （F value was 557.837， 73.589， 53.976 and 37.606， respectively， all P<0.05）. The ADC values were negatively correlated with lesion volume and SSS， and positively correlated with UFS-QOL score， with correlation coefficients of -0.586， -0.630 and 0.592， respectively （all P<0.05）. ConclusionThe ADC value has clinical significance for the treatment of uterine fibroid using MRgFUS.

Compound reserpine and triamterene tablets (CRTT), a compound antihypertensive drug developed by Chinese scientists, is still widely used in clinical practice. However, the mechanisms by which CRTT treats hypertension remain to be fully understood. This study used network pharmacology to analyze CRTT's antihypertensive mechanisms with in vitro experiments. The targets of the four chemical components of CRTT were collected from the Swiss Target Prediction database; 1 828 protein targets related to hypertension were collected from the Therapeutic Target Database (TTD) and Online Mendelian Inheritance in Man (OMIM) database. The CRTT-hypertension network model was constructed using a search tool for recurring instances of neighbouring genes (STRING). Gene ontology (GO) and pathway enrichment analysis of targets of interest was conducted with the Metascape database. In the in vitro study, human umbilical vein endothelial cells (HUVEC) and vascular smooth muscle cells (VSMC) were treated with 1 μmol·L^-1 angiotensin Ⅱ (AngⅡ) and CRTT was administered at concentrations of 0.01, 0.1, and 1 μmol·L^-1. Changes in the phosphatidylinositol-3-kinase/protein serine threonine kinase/endothelial nitric oxide synthase (PI3K/Akt/eNOS) pathway in HUVEC and the cyclic guanosine monophosphate/cGMP-dependent protein kinase (cGMP/PKG) pathway in VSMC were determined by Western blot. Network pharmacological analysis revealed that the antihypertensive effect of CRTT is closely associated with biological pathways such as vascular tone regulation, adrenergic receptor activation, protein kinase activity and signaling pathways such as the cGMP/PKG signaling pathway, vascular smooth muscle contraction, neuroactive ligand-receptor interaction, adrenergic signaling in cardiomyocytes and calcium signaling pathways. The in vitro study confirmed that CRTT increased the levels of phosphorylated phosphatidylinositol-3-kinase (p-PI3K), phosphorylated protein serine threonine kinase (p-Akt), phosphorylated endothelial nitric oxide synthase (p-eNOS) in HUVEC and the levels of eNOS, phosphorylated vasodilator-stimulated phosphoprotein (p-VASP), and PKG in VSMC through multiple targets and pathways. These results suggest that the activation of PI3K/Akt/eNOS pathway and endothelial-dependent NO/cGMP signaling may be involved in the CRTT-mediated hypotensive effect.

Epigenetic therapies that cause genome-wide epigenetic alterations, could trigger local interplay between different histone marks, leading to a switch of transcriptional outcome and therapeutic responses of epigenetic treatment. However, in human cancers with diverse oncogenic activation, how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood. We herein discover that the hedgehog (Hh) pathway reprograms the histone methylation landscape in breast cancer, especially in triple-negative breast cancer (TNBC). This facilitates the histone acetylation caused by histone deacetylase (HDAC) inhibitors and gives rise to new therapeutic vulnerability of combination therapies. Specifically, overexpression of zinc finger protein of the cerebellum 1 (ZIC1) in breast cancer promotes Hh activation, facilitating the switch of H3K27 methylation (H3K27me) to acetylation (H3K27ac). The mutually exclusive relationship of H3K27me and H3K27ac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes. Using multiple in vivo breast cancer models including patient-derived TNBC xenograft, we show that Hh signaling-orchestrated H3K27me and H3K27ac interplay tailors combination epigenetic drugs in treating breast cancer. Together, this study reveals the new role of Hh signaling-regulated histone modifications interplay in responding to HDAC inhibitors and suggests new epigenetically-targeted therapeutic solutions for treating TNBC.