OBJECTIVE To explore the effects of CD20 coding gene （MS4A1） polymorphism on the blood concentration and efficacy of rituximab in patients with non-Hodgkin’s lymphoma. METHODS A prospective observational study was conducted on 160 newly diagnosed non-Hodgkin’s lymphoma patients who received the R-CHOP regimen at the Sun Yat Sen University Cancer Center from January 2016 to December 2020， with a minimum follow-up period of approximately 5 years. The blood concentration of rituximab was detected by enzyme-linked immunosorbent assay. MS4A1 tagSNPs were selected by Haploview4.2 software， including rs1051461， rs17155034， rs4939364， and rs10501385. The genotype of MS4A1 was detected by Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Univariate linear regression analysis was employed to examine the correlation between various factors（demographic， clinical， and genotypic variables） in patients and the steady-state trough concentration of rituximab during the first course of treatment， followed by multivariate linear regression analysis. Kaplan-Meier curves were drawn to evaluate progression-free survival （PFS） and overall survival （OS）. Using MS4A1 genotype and tumor stage as independent variables， Cox regression model was employed to evaluate the factors influencing patient prognosis. RESULTS The blood concentration of rituximab in MS4A1 rs10501385 CC carriers was 15.20 μg/mL，which was significantly lower than 21.95 μg/mL in AA+AC carriers （P＜0.05）. The multivariate linear regression model incorporating tumor stage and MS4A1 rs10501385 polymorphism explained 7.3% of the interindividual variability in rituximab concentrations. Compared with MS4A1 rs1051461 CC carriers， CT+TT carriers had significantly prolonged PFS and OS （P＜0.05）. The Cox proportional hazards regression model showed that the MS4A1 rs1051461 CC genotype （HR＝4.406， 95%CI：1.743-11.137， P＜0.05） and tumor Ⅲ&Ⅳ （HR＝3.233， 95%CI： 1.413-7.399， P＜0.05） were independent risk factors for PFS. CONCLUSIONS The tumor staging and MS4A1 rs10501385 polymorphism are key influencing factors for blood concentration of rituximab， and MS4A1 rs1051461 polymorphism significantly affects PFS in non-Hodgkin’s lymphoma patients.

The innate immune sensor NLRP3 inflammasome overactivation is involved in the pathogenesis of ulcerative colitis. PGAM5 is a mitochondrial phosphatase involved in NLRP3 inflammasome activation in macrophages. However, the role of PGAM5 in ulcerative colitis and the mechanisms underlying PGAM5 regulating NLRP3 activity remain unknown. Here, we show that PGAM5 deficiency ameliorates dextran sodium sulfate (DSS)-induced colitis in mice via suppressing NLRP3 inflammasome activation. By combining APEX2-based proximity labeling focused on PGAM5 with quantitative proteomics, we identify NEK7 as the new binding partner of PGAM5 to promote NLRP3 inflammasome assembly and activation in a PGAM5 phosphatase activity-independent manner upon inflammasome induction. Interfering with PGAM5-NEK7 interaction by punicalagin inhibits the activation of the NLRP3 inflammasome in macrophages and ameliorates DSS-induced colitis in mice. Altogether, our data demonstrate the PGAM5-NEK7 interaction in macrophages for NLRP3 inflammasome activation and further provide a promising therapeutic strategy for ulcerative colitis by blocking the PGAM5-NEK7 interaction.

Radiochemotherapy-induced oral mucositis (OM) is a common oral complication in patients with tumors following head and neck radiotherapy or chemotherapy. Erosion and ulcers are the main features of OM that seriously affect the quality of life of patients and even the progress of tumor treatment. To date, differences in clinical prevention and treatment plans for OM have been noted among doctors of various specialties, which has increased the uncertainty of treatment effects. On the basis of current research evidence, this expert consensus outlines risk factors, clinical manifestations, clinical grading, ancillary examinations, diagnostic basis, prevention and treatment strategies and efficacy indicators for OM. In addition to strategies such as basic oral care, anti-inflammatory and analgesic agents, anti-infective agents, pro-healing agents, and photobiotherapy recommended in previous guidelines, we also emphasize the role of traditional Chinese medicine in OM prevention and treatment. This expert consensus aims to provide references and guidance for dental physicians and oncologists in formulating strategies for OM prevention, diagnosis, and treatment, standardizing clinical practice, reducing OM occurrence, promoting healing, and improving the quality of life of patients.
Humans ; Chemoradiotherapy/adverse effects* ; Consensus ; Risk Factors ; Stomatitis/etiology*

Inflammation plays a pivotal role in the etiology and progression of various diseases. In traditional Chinese medicine, the whole plants of Thesium chinense Turcz. and its preparations (e.g. Bairui Granules) have been employed to manage inflammatory conditions. While flavonoids were previously considered the primary anti-inflammatory components, other potentially active constituents have been largely overlooked and not thoroughly investigated. This study presents a novel finding that the total alkaloids of T. chinense (BC-Alk) are potent active substances underlying the traditional and clinical applications of T. chinense and Bairui Granules as anti-inflammatory agents. UPLC-MS/MS analysis identified the composition of BC-Alk as quinolizidine alkaloids. The anti-inflammatory efficacy of BC-Alk was evaluated using a lipopolysaccharide (LPS)-induced lung inflammation model in mice. Results demonstrated that BC-Alk significantly mitigated LPS-induced lung inflammation, attenuated the overproduction of IL-1β and the overproduction of inflammatory factors (TNF-α), and ameliorated lung tissue hyperplasia in mice in vivo. Mechanistic studies in vitro revealed that BC-Alk upregulated the expression of Nrf2 and its downstream proteins NQO1 and glutamate-cystine ligase and modifier subunit (GCLM), inhibited NF-κB phosphorylation, and suppressed NLRP3 activation. Collectively, these findings indicate that BC-Alk exerts potent inhibitory effects against lung inflammation by modulating Nrf2, NF-κB, and NLRP3 pathways. This study provides new insights into the anti-inflammatory constituents of T. chinense and Bairui Granules.
Animals ; Lipopolysaccharides/adverse effects* ; Alkaloids/pharmacology* ; NF-kappa B/metabolism* ; NF-E2-Related Factor 2/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Mice ; Signal Transduction/drug effects* ; Anti-Inflammatory Agents/pharmacology* ; Male ; Mice, Inbred C57BL ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; Pneumonia/genetics*

Objective To compare the hemodynamic effects of anesthesia induction with remimazolam tosylate and etomidate in elderly frail patients.Methods This study was a single-center,prospective,randomized,single-blind trial.From January to April 2024,96 elderly frail patients undergoing elective surgery in Fuyang People's Hospital were recruited.After excluding 6 cases(3 refused to participate,1 had tracheal intubation time＞30 s,and 2 had missing data),90 patients were finally included.They were randomly divided into remimazolam tosylate group(intravenous injection of 0.2 mg/kg remimazolam tosylate for anesthesia induction,n=45)and etomidate group(intravenous injection of 0.3 mg/kg etomidate for anesthesia induction,n=45)by the random number table method.The area under the curve for mean arterial pressure(MAP)below or above baseline values(AUCMAP-and AUCMAP+),the heart rate(HR)below or above baseline values by 10％(AUCHR-and AUCHR+)within 10 minutes of anesthesia induction,the time to loss of consciousness,the time from the start of anesthesia induction to a bispectral index(BIS)＜60,the incidence of drug-related adverse reactions,the incidence of cardiovascular adverse events,and the usage of vasoactive drug administrations were compared between the two groups.Results Compared with the etomidate group,the AUCMAP-(145.10±35.75 vs.178.52±39.78)and AUCHR-[43.20(26.58,56.35)vs.54.99(43.01,65.85)]in remimazolam tosylate group were significantly reduced(P＜0.001,P=0.001).The time to loss of consciousness and the time from the start of anesthesia induction to BIS＜60 were prolonged(P＜0.001).The incidence of drug-related adverse reactions was significantly decreased(P＜0.05),and the number of norepinephrine administrations was significantly reduced(P＜0.05)in remimazolam tosylate group.However,there were no statistically significant differences in AUCMAP+,AUCHR+,the incidence of cardiovascular adverse events,and the usages of atropine,urapidil,and esmolol between the two groups(P＞0.05).Conclusion The use of remimazolam tosylate during anesthesia induction in elderly frail patients can provide more stable hemodynamic parameters and results in fewer adverse reactions than etomidate.

Objective : To explore the utility of a nomogram integrating contrast-enhanced CT radiomics with clinical features in the preoperative prediction of WHO/ISUP grade for clear cell renal cell carcinoma(ccRCC). Methods: A total of 214 patients with pathologically proven ccRCC who underwent enhanced CT scan before surgery were retrospectively included. According to the WHO/ISUP grade system, the cases were classified into low-grade(grades Ⅰ-Ⅱ) and high-grade(grades Ⅲ-Ⅳ), and then randomly divided into training and test set with a ratio of 4 ∶1. Regions of interest were segmented from both unenhanced and three-phase enhanced images, and radiomic features were extracted. Feature selection and dimensionality reduction were performed using Spearman rank correlation coefficients and LASSO regression, followed by the construction of the radiomic model with the KNN algorithm. Clinical and semantic imaging features were selected through univariate and multivariate analyses, and a clinical model was developed using the KNN algorithm. The clinical and radiomics signatures were used to construct a combined model and a nomogram was developed. The ROC curve and delong test were used to evaluate the diagnostic performance of the model, while calibration and decision curve analyses assessed its accuracy and clinical applicability. Results: 8 clinical features and 11 radiomic features were selected. The combined model, integrating these clinical and radiomics signatures, exhibited robust predictive performance with AUC values of 0.887 in the training set and 0.800 in the test set. The calibration curve demonstrated good consistency between the nomogram model and actual outcomes, while decision curve analysis indicated a favorable net benefit for the nomogram. Conclusion The nomogram constructed by combining radiomics and clinical signatures can provide evidence for preoperative prediction of ccRCC grade and guide clinical decision-making.

Objective To investigate renal expression level of STING in mice with renal ischemia-reperfusion injury(IRI)and its regulatory role in IRI.Methods C57BL/6 mice were divided into sham operation group,IRI(induced by clamping the renal artery)model group,IRI+DMSO treatment group,and IRI+SN-011 treatment group.Serum creatinine and blood urea nitrogen of the mice were analyzed,and pathological changes in the renal tissue were assessed with PAS staining.RT-qPCR,ELISA,Western blotting,and immunohistochemistry were used to detect the expression levels of STING,KIM-1,Bcl-2,Bax,caspase-3,TLR4,P65,NLRP3,caspase-1,CD68,MPO,IL-1β,IL-6,and TNF-α in the renal tissues.In the cell experiment,HK-2 cells exposed to hypoxia-reoxygenation(H/R)were treated with DMSO or SN-011,and cellular STING expression levels and cell apoptosis were analyzed using RT-qPCR,Western blotting or flow cytometry.Results In C57BL/6 mice,renal IRI induced obvious renal tissue damage,elevation of serum creatinine and blood urea nitrogen levels and renal expression levels of KIM-1,STING,TLR4,P65,NLRP3,caspase-1,caspase-3,Bax,CD68,MPO,IL-1β,IL-6,and TNF-α,and reduction of Bcl-2 expression level.Treatment of the mouse models with SN-011 for inhibiting STING expression significantly alleviated these changes.In HK-2 cells,H/R exposure caused significant elevation of cellular STING expression and obviously increased cell apoptosis rate,which was significantly lowered by treatment with SN-011.Conclusion Renal STING expression is elevated in mice with renal IRI to exacerbate renal injury by regulating the TLR4/NF-κB/NLRP3 pathway and promoting inflammation and apoptosis in the renal tissues.

[Objective] To investigate the functional differences and potential effects of chromatin spatial structure in patients with normal karyotype and complex karyotype multiple myeloma. [Methods] High-throughput chromosome conformational capture (Hi-C) analysis was performed on plasma cells of 1 case with 1q21 complex karyotype and 1 case with normal karyotype multiple myeloma, and the differences in three-dimensional genome structure between the two patients were analyzed, and the transcriptome characteristics of plasma cells were combined to investigate the differential features through gene functional enrichment. [Results] A/B switch occurred in 36% of the chromatin compartments in two cases, and 1 041 genes in patient with complex karyotype had B/A switch. About 3 500 topological association domains (TADs) were identified in each sample, and there was no significant difference. The number of loops identified in complex karyotype sample was 1 069, which was 1/6 of the normal sample, and there were significant differences in the number of three different types of loops, which to some extent reflected the loss of genome stability. Transcriptome analysis showed significant differences in expression profiles between the two patients, and a total of 6 150 differentially expressed genes (3 303 up-regulated genes and 2 847 down-regulated genes) were identified. [Conclusion] Compared with patient with normal karyotype, patient with 1q21 complex karyotype multiple myeloma exhibit significant changes in the spatial structure of plasma cell chromatin at different levels, which leads to changes in gene expression and activation of pathways related to cancer progression.

Objective:To investigate the causal association between testosterone and nonalcoholic fatty liver disease(NAFLD) in men and women using a two-sample Mendelian randomization(MR) approach.Methods:Genetic variation in testosterone(total testosterone, bioavailable testosterone) and sex hormone-binding globulin(SHBG) in females and males was used as an instrumental variable using the genome-wide association study(GWAS) pooled data, and the inverse variance weighting method was applied. Inverse variance weighted(IVW) was used as the main analytical method, along with six univariate MR methods based on other modeling assumptions to assess the causal relationship between testosterone(total testosterone, bioavailable testosterone) as well as SHBG and NAFLD in women and men. In addition, NAFLD data from Finnish Biobank(FinnGen) were applied to validate the results of the exploratory analysis. Further, sensitivity analyses were performed to assess the level of heterogeneity, genetic pleiotropy, and stability of the instrumental variables using Cochran′ s Q test, MR-Egger regression, and leave-one-out methods. Results:The results of exploratory analysis of IVW model showed that bioavailable testosterone and SHBG were causally associated with NAFLD in women, for each unit increase in bioavailable testosterone levels, the risk of developing non-alcoholic fatty liver disease(NAFLD) rose by 24%( OR=1.24, 95% CI 1.07-1.43, P=0.004); and with each unit decrease in women′s SHBG, the NAFLD risk increased by 31%( OR=0.69, 95% CI 0.57-0.83, P<0.001). However, testosterone(total testosterone, bioavailable testosterone) as well as SHBG in men and female total testosterone did not show a causal relationship with NAFLD. The results of the other six MR methods were generally consistent with the IVW method. The results of the external validation data provided further evidence of a causal relationship between female bioavailable testosterone and SHBG and NAFLD. Conclusion:Elevated levels of bioavailable testosterone along lower levels of SHBG may increase the risk of developing NAFLD in women.

Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.