ObjectiveTo investigate the effect and mechanism of Qingre Sanzhuo decoction in treating gouty arthritis （GA） combined with hyperuricaemia （HUA）. MethodsSixty male SD rats were randomized into normal， model， colchicine （0.5 mg·kg^-1）， and low-， medium-， and high-dose （17， 34， 68 g·kg^-1， respectively） Qingre Sanzhuo decoction groups （n=10）. The rats in other groups except the normal group were treated with the modified method for the modeling of GA combined with HUA. The drug intervention groups were administrated with corresponding drugs by gavage in the afternoon every day and the normal group and the model group were administrated with an equal volume of sterile normal saline by gavage. The level of uric acid （SUA） in the serum was measured 2 h after the last administration. The degree of ankle joint swelling was calculated 0.5， 12， 24， 48 h after modeling， and joint inflammation was scored. The pathological changes of ankle joints were observed by hematoxylin-eosin staining， and the serum levels of tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， C reactive protein （CRP）， and interleukin-18 （IL-18） were measured by enzyme-linked immunosorbent assay. Real-time PCR was performed to determine the mRNA levels of NOD-like receptor protein 3 （NLRP3）， apoptosis-associated speck-like protein containing CARD （ASC）， cysteinyl aspartate-specific protease-1 （Caspase-1）， gasdermin D （GSDMD）， and nuclear factor-kappa B （NF-κB） in the synovial tissue of ankle joints. Western blot was employed to determine the protein levels of NLRP3， ASC， and Caspase-1 in ankle joints. The immunohistochemical method was used to detect the expression of GSDMD and NF-κB in the synovial tissue of ankle joints. ResultsCompared with the normal group， the model group showed increased SUA in the serum （P<0.05）， ankle joint swelling and joint inflammation （P<0.05）， increased number of blood vessels in the synovium， inflammatory cell foci in the synovial bursa， elevated serum levels of TNF-α， IL-1β， CRP， and IL-18 （P<0.05）， and up-regulated mRNA and protein levels of NLRP3， ASC， Caspase-1， GSDMD， and NF-κB in the synovial tissue of ankle joints （P<0.05）. Compared with the model group， the medium- and high-dose Qingre Sanzhuo decoction groups showed reduced SUA in the serum （P<0.05）， alleviated ankle joint swelling and joint inflammation （P<0.05）， lowered serum levels of TNF-α， IL-1β， CRP， and IL-18 （P<0.05）， and down-regulated mRNA and protein levels of NLRP3， ASC， Caspase-1， GSDMD， and NF-κB in the synovial tissue of ankle joints （P<0.05）. However， in terms of ameliorating the pathological changes of ankle joints， only the high-dose Qingre Sanzhuo decoction group showed normal morphology of the synovial membrane of ankle joints and no obvious lesion in the articular cartilage. ConclusionQingre Sanzhuo decoction may play a role in preventing and controlling GA combined with HUA by down-regulating the activity of NLRP3/ASC/Caspase-1 pathway and inhibiting the expression of inflammatory cytokines， such as TNF-α， IL-1β， CRP， and IL-18.

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

Liver fibrosis is a vital cause of morbidity in patients with liver diseases and developing novel anti-fibrotic drugs is imperative. Isovalerylspiramycin I (ISP I) as a major component of carrimycin applied to upper respiratory infections, was first found to possess anti-fibrotic potential. The present study aims to evaluate the functions and mechanisms of ISP I in protecting against liver fibrosis. According to our results, ISP I not only reduced the expressions of fibrogenic markers in LX-2 cells but also appeared great protective effects on liver injury and liver fibrosis in bile duct ligation (BDL) rats and carbon tetrachloride (CCl₄) mice. We proved that nucleotide-binding protein 2 (NUBP2) was the direct target of ISP I. ISP I through targeting NUBP2, increased the amount of vascular non-inflammatory molecule-1 (VNN1) on the cell membrane, which will inhibit oxidative stress and fibrosis. Simultaneously, the original carrimycin's protective effect on liver damage and fibrosis was verified. Therefore, our study provides potential agents for patients with liver fibrosis-related diseases, and the clear mechanism supports wide application in the clinic.

Objective:To analyze the cellular composition characteristics of the nasal tissue immune microenvironment in patients with control, chronic rhinosinusitis without nasal polyps (CRSsNP), non-eosinophilic chronic rhinosinusitis with nasal polyps (neCRSwNP), and eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) using mass cytometry flow technology.Methods:Thirteen CRS patients who underwent endoscopic nasal surgery at the Department of Otorhinolaryngology Head and Neck Surgery of Peking Union Medical College Hospital from March to December 2022 were recruited, including 8 males and 5 females, aged 22.3 to 58.3 years. Three control mucosae were obtained from normal ethmoid or sphenoid sinuses of patients with benign tumors of the temporal fossa or non-functional pituitary adenomas who underwent endoscopic surgery, excluding allergic rhinitis and sinusitis. Sixteen clinical tissue samples (3 of control, 3 of CRSsNP, 4 of neCRSwNP, and 6 of eCRSwNP) were prepared into single-cell suspensions. Mass cytometry flow detection was performed using a combination of 42 molecular markers to analyze the differences in cell subpopulations among the groups. Data were analyzed using GraphPad Prism 9.Results:Based on the mass cytometry flow results, cells from control, CRSsNP, neCRSwNP, and eCRSwNP were divided into seven main cell subgroups, with detailed subgrouping of T/NK cells and myeloid cells. In T/NK cells, compared with the control group, the number of NK CD56bright cells increased in the CRSsNP group, while NK CD56dim cells decreased; compared with the CRSsNP group, the eCRSwNP group showed a decrease in NKT cells and CD4 +Tem cells; compared with the CRSsNP group, the eCRSwNP group showed a significant increase in CD25 expression within Treg cells; compared with the CRSsNP group, the eCRSwNP group showed a significant decrease in Tbet expression in CD8 +Teff cells and CD8 +TRM cells; in eCRSwNP, the expression of CD103 in CD8 +TRM cells was significantly lower than in CRSsNP. In myeloid cells, compared with the other three groups, the eCRSwNP group showed a significant increase in macrophages and a significant decrease in cDC1 and monocytes; compared with the control group and CRSsNP, the eCRSwNP group also showed a significant decrease in resting state macrophages; compared with the CRSsNP group, the eCRSwNP group showed a significant decrease in the level of CX3CR1 within cDC2 and monocytes; the expression levels of NLRP3 in cDC2 and macrophages in the eCRSwNP group were significantly higher than in the other three groups; compared with the control group, the expression levels of Gata3 in cDC2 and macrophages in the eCRSwNP group were also significantly increased; additionally, the expression of CCR2 within monocytes in the eCRSwNP group was lower than in the CRSsNP group. In ILC, compared with the control group, the expression of CCR6 decreased in the eCRSwNP group. Conclusions:Compared with the control group, CRSsNP, and neCRSwNP, eCRSwNP shows an increase in macrophage number, a decrease in cDC1 and resting state macrophages, and depletion of protective cells CD103 +CD8 +TRM. Additionally, the expression levels of CCR2 and CX3CR1 in monocytes of eCRSwNP are decreased.

Objective To explore the effects of image registration using various regions of interest(ROI)on the setup error for nasopharyngeal carcinoma(NPC)patients who were immobilized individually.Methods Forty-three NPC patients who required radiotherapy were enrolled.The patients were immobilized with customized plastic foam and thermoplastic mask,and CBCT verification was performed once a week.In CBCT images,ROI was divided into the whole ROI(ROIPTV)and 7 local ROI containing different cervical structures(ROIsphenoid sinus,ROIatlantoaxial,ROIneck3,ROIneck4,ROIneck5,ROIneck6,and ROIneck7),which were then used for registrations with localized CT image.The setup errors in superior-inferior(SI),left-right(LR),anterior-posterior(AP),Pitch,Roll,and Yaw directions were recorded.Results In SI direction,the setup errors within 0.3 cm accounted for 89.74%for ROIneck7,and more than 90%for the other ROI.The proportion of setup errors within 0.3 cm gradually increased with the neck upward in LR direction,and they were 76.78%,81.70%,85.26%,and above 90%for ROIneck7,ROIneck6,ROIneck5,and the other ROI,respectively.In AP direction,the proportions of setup errors within 0.3 cm were less than 90%,except for ROIatlantoaxial and ROIneck3.The setup errors of ROIsphenoid sinus,ROIatlantoaxial,ROIneck3,and ROIneck4 were significantly positively correlated with ROIPTV in SI direction,and the correlation coefficients(R)were 0.94,0.95,0.90,and 0.83,respectively.In LR direction,there were positive correlations between the setup errors of ROIatlantoaxial and ROIsphenoid sinus(R=0.95),ROIneck3 and ROIsphenoid sinus(R=0.91),ROIPTV and ROIneck3(R=0.91).The setup errors of ROIPTV in AP direction were positively correlated with ROIatlantoaxial vertebrae and ROIneck3(R=0.88,0.90).The margins of all ROIs ranged from 0.38 cm to 1.01 cm.The extension of ROIneck6 and ROIneck7 in AP direction exceeded 0.9 cm,and the extension of ROIneck7 reached 0.95 cm in SI direction.Conclusion ROIPTV and ROIsphenoid sinus,ROIatlantoaxial,ROIneck3 are significantly correlated in SI,LR,and AP directions.The setup error of nasopharyngeal carcinoma patients gradually increases with the neck down.The nasopharyngeal and cervical regions need to be expanded in segments when patients are immobilized individually.

Objective To study the splenic injuries caused by high-altitude falling and underwater explosion and the 2-dimensional ultrasound and contrast-enhanced ultrasound(CEUS)characteristics.Methods Twenty-three healthy Beagle dogs were divided into high-altitude falling group(n=13)and underwater explosion group(n=10).Free-fall high-platform device and gram-grade trinitrotoluene were used to simulate high-altitude falling injury and underwater explosion injury in Beagle dogs,respectively.Ultrasound examination of the spleen was performed immediately after injury,with follow-up examinations every hour.CEUS examination was performed in surviving dogs.Spleen specimens were taken from deceased dogs after injury to observe gross injuries.Pathological changes in tissue morphology and cell apoptosis were observed by hematoxylin-eosin(H-E)staining.Results In the high-altitude falling model,6,2,1,and 1 dogs died in the 6 m,7 m,8 m,and 9 m groups,respectively;in the underwater explosion model,1 and 4 dogs died in the buoyancy and frogman groups,respectively.Two-dimensional ultrasound examination of the high-altitude falling model showed spleen rupture(disruption of splenic parenchymal structure),perisplenic fluid accumulation,subcapsular hematoma,intrasplenic hematoma,increased splenic vein echo,and uneven splenic parenchymal echo.Two-dimensional ultrasound examination of the underwater explosion model showed increased splenic vein echo and uneven splenic parenchymal echo,which were less serious compared with the high-altitude falling model.CEUS results indicated 4 major contrast patterns in both models.The Beagle dogs with type Ⅰ(large focal contrast defect),type Ⅱ(diffuse contrast defect),or type Ⅲ(no contrast agent entry into the splenic vein)contrast patterns all had splenic rupture after injury.H-E staining results showed true splenic rupture,diffuse intrasplenic hemorrhage,splenic hematoma/ecchymosis,subcapsular hematoma/ecchymosis,and venous congestion after spleen injury,which were consistent with the 2-dimensional ultrasound findings.Conclusion High-altitude falling causes more serious spleen injuries in Beagle dogs compared with underwater explosions.Routine ultrasound performs well in diagnosing typical splenic injuries,while CEUS has advantages in evaluating atypical splenic injuries and has good predictive ability for delayed splenic rupture.

Objective:To verify and calibrate the CT modeling curves of three CT devices in RayStation proton treatment planning system (TPS).Methods:CT-mass density (CT-MD) curves were established by CT Hounsfield units of different tissue substitute materials obtained by scanning the model with CT equipment. CT-stopping power (CT-SP) curves were established by calculation based on the chemical composition of various human tissues. The equivalent water thickness of tissue substitute modules was calculated with different CT modeling curves in TPS. The actual equivalent water thickness of various modules was measured by a Bragg peak detector, and compared with the calculated values of TPS to verify the accuracy of different CT models.Results:The differences of CT modeling curves were significantly different under different tube voltage scanning protocols. Compared with CT-MD curves, CT-SP curves based on the stoichiometric calibration were more suitable for proton dose calculation. However, the values of stopping power corresponding to high CT values still needed to be optimized, and the calculation error after calibration was less than 3%.Conclusion:The method of verifying and calibrating CT unit curves of proton TPS is described, proving that the CT-SP curves after stoichiometric calculation are more suitable for proton dose calculation.

Objective:To investigate the efficacy and safety of oral semaglutide in Chinese patients with type 2 diabetes mellitus(T2DM) inadequately controlled by diet and exercise only.Methods:In the randomized, double-blind, multicenter, multinational PIONEER-11 trial, Chinese patients were prospectively randomly assigned to receive oral semaglutide 3, 7, or 14 mg, or placebo. The primary endpoint was the change from baseline in glycated hemoglobin(HbA 1C) at week 26. This is a pre-defined subset analysis to assess the efficacy and safety in Chinese patients. Results:Totally 390 Chinese T2DM patients were enrolled(mean age 51 years), with a T2DM duration of 1.8 years, HbA 1C of 7.9%, and BMI of 26.5 kg/m 2 at baseline. Overall, changes at week 26 from baseline in HbA 1C were -1.1%, -1.6%, -1.6%, and 0.0%, and in bodyweight were -0.7, -1.9, -2.6, and -0.7 kg in oral semaglutide(3, 7, or 14 mg) and placebo groups, respectively. Compared to the placebo group, estimated treatment differences(ETDs) in HbA 1C for the 3, 7, and 14 mg groups were -1.2%(95% CI -1.4, -0.9), -1.7%(95% CI -1.9, -1.4), and -1.6%(95% CI -1.9, -1.4)(all P<0.001), respectively, and in weight loss for the 7 mg and 14 mg groups were -1.2 kg(95% CI -2.1, -0.4; P=0.006) and -1.9 kg(95% CI -2.8, -1.0; P<0.001), respectively. The most frequent gastrointestinal adverse events were diarrhea(oral semaglutide: 3.1%-12.5% vs placebo: 2.0%) and nausea(3.1%-6.3% vs 2.0%), mostly mild in severity and transient. Conclusion:In Chinese patients with T2DM who had insufficient glycemic control with diet and exercise only, oral semaglutide showed better glycemic control at doses of 3, 7, and 14 mg and more weight loss at doses of 7 and 14 mg compared to placebo, with a safety profile consistent with that observed in the global trial population.

In order to understand the difference and expression of genes in CEK cells before and af-ter baicalin interferes with IBV,further reveal and analyze the mechanism of baicalin interfering IBV replication in CEK cells in vitro.After IBV infected CEK cells for 2 h,9.75 mg/L baicalin liq-uid was added to interfere with CEK cells,which was recorded as the baicalin(H-IBV)group,and three replicate wells were set in the control group and the IBV(IBV)infection group.After 36 h culture,cell samples were collected and subject to transcriptome for sequencing.The results showed that there were 102 differentially expressed genes in H-IBV group compared with IBV in-fection group,among which 48 genes weresignificantly up-regulated and 54 genes were significantly down-regulated.Through functional annotation in GO and KEGG databases,it was found that dif-ferentially expressed genes were mainly annotated in biological processes such as cellular proces-ses,biological regulation,metabolism,and secondary pathways such as viral infectious diseases,signal transduction and interaction.Retinol metabolism pathway,phospholipid transfer to mem-brane,IL-27 mediated signaling pathway,MDA5/RIG-I and Toll-like receptor signaling pathway were significantly enriched in CEK cells,and the production of type Ⅰ interferon and interferon al-pha and the process of antiviral infection were also positively regulated.There were more differen-tial genes enriched in nucleic acid catalysis,immune system,and reaction,and interbiological reac-tion.Through the STRING network interaction map,it was found that most immune-related genes could form a 36-node interaction network centered on IRF7,TLR3 and STAT1.Therefore,com-pared with IBV group,the differentially expressed genes after baicalin treatment were mainly an-notated and enriched in the biological process,and the immune system and response were en-hanced,mainly through the positive regulation of IRF7 in the MDA5/RIG-I receptor signaling pathway and the inhibition of TLR3 signal transduction in the Toll-like receptor signaling path-way.Positive regulation of IL-27 mediated pathway and regulation of JAK-STAT signaling path-way were supplemented by activation of the expression of IRF7,TLR3,STAT1 and other related genes,and interaction with corresponding downstream proteins to promote the expression of IFN-α and regulatory cytokines,coupled with negative regulation of viral(defense)response and viral processes.Thus,baicalin interferes with IBV replication in CEK cells.

Ankylosing spondylitis(AS)is a typical spinal arthritis characterised by inflammatory back pain,which seriously affects the health and quality of life of patients.The clinical efficacy of Chinese medicine in the treatment of ankylosing spondylitis is clear,but the mechanism is not clear,and the existing animal models cannot be well applied to the evaluation of Chinese medicine in the treatment of ankylosing spondylitis.Therefore,this paper summarizes the existing animal models based on Chinese and Western medicine clinical diagnosis,disease characteristics,etiology and Chinese medicine evidence,and finds that among the existing animal models,the proteoglycan-induced arthritis mouse model has a higher Chinese and Western medicine clinical fit than the other models,but lacks the corresponding Chinese medicine evidence model evaluation.The other animal models had a higher Western clinical match,but lacked the characteristics of the Traditional Chinee Medicine(TCM)syndrome.As ankylosing spondylitis is a chronic inflammatory autoimmune disease with complex pathogenic factors,the existing animal models cannot better simulate the clinical symptoms.Therefore,the establishment of animal models of ankylosing spondylitis with the characteristics of Chinese and Western clinical evidence is a future research priority for AS TCM.