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 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.

OBJECTIVE To study the extraction technology of Sophora flavescens-Phellodendron chinense drug pair and provide a reference for the development of new drugs for the treatment of anorectal diseases. METHODS Using the contents of total alkaloids of S. flavescens （matrine+oxymatrine）， berberine hydrochloride and total flavonoid， and extract yield as evaluation indicators， analytic hierarchy process-entropy weight method was used to calculate the weight coefficient of each indicator， and was combined with Box-Behnken design-response surface method to study the extraction technology of S. flavescens-P. chinense drug pair and verify it. RESULTS The optimal extraction technology of S. flavescens-P. chinense drug pair was immersed in 12-fold amount of 58% ethanol for 30 minutes and extracted twice， each time for 120 minutes. The relative error between the verification experimental results and the predicted value was 1.88%. CONCLUSIONS The obtained extraction technology is stable and feasible and can provide reference for the application of S. flavescens-P. chinense drug pair and development of new drugs.

Objective: To assess the association of adverse experiences and subsequent incidence of depressive symptoms among middle school students in Liangshan, so as to provide a basis for preventing the occurrence of depression symptoms among middle school students. Methods: In October 2021, a convenient sampling combined with cluster random sampling method was employed to select 888 students from three high schools (junior first year and second year, senior first year) in Liangshan for a questionnaire survey. In March 2023, a followup survey was conducted to collect data on adverse experiences (such as school bullying, domestic violence, and lack of parental understanding). Depressive symptoms were assessed using the Chinese version of the Center for Epidemiologic Studies Depression Scale (CES-D). Logistic regression model analysis was used to examine the relationship between the number of adverse experiences at baseline and the incidence of depressive symptoms during the followup period. Results: The detection rate of depressive symptoms among middle school students was 9.4% at followup. School bullying (OR=2.26, 95%CI=1.37-3.73), domestic violence (OR=2.56, 95%CI=1.55-4.21), and lack of parental understanding (OR=1.91, 95%CI=1.15-3.16) at baseline were positively associated with the incidence of depressive symptoms at followup (P<0.05). Compared with participants with no adverse experiences at both baseline and followup, those with adverse experiences at both baseline and followup were more likely to exhibit depressive symptoms at followup, regardless of the type of adverse experiences (P<0.01). The incidence of depressive symptoms increased with the increase of baseline adverse experiences (P<0.01). Compared to the participants with no adverse experiences at both baseline and followup, those with adverse experiences at baseline but not at followup did not show a statistically significant difference in the likelihood of developing depressive symptoms at followup (OR=0.78, 95%CI=0.13-4.80, P>0.05). Conclusions Adverse experiences increase the risk of developing depressive symptoms among middle school students. Participants who have reversed adverse experiences show no increased risk of depressive symptoms compared to those with no adverse experiences. Measures should be taken to prevent the occurrence of depression symptoms among middle school students based on their adverse experiences during their middle school years.

BACKGROUND:The repair and clinical outcome of bone defects remains a hot and difficult area of clinical research,which is a common problem that plagues clinicians.Constructing suitable,reproducible and infinitely close to clinical animal experimental models and their scientific evaluation are essential for further clinical treatment of related diseases. OBJECTIVE:To retrospectively analyze the preparation methods and characteristics of common animal models of femoral bone defects and to assess their strengths and weaknesses,thereby providing some reference for relevant researchers to select appropriate animal models of femoral bone defects. METHODS:PubMed,Web of Science,Medline,and CNKI were retrieved for relevant literature published from January 1,2000 to August 1,2022.The keywords were"bone defect,bone,bones,defect,defects,defective,animal model,animal,model,laboratory,laboratory animal,animal laboratory"in English and"bone defect,animal model,experiment"in Chinese. RESULTS AND CONCLUSION:Twenty-seven randomized controlled animal experiments involving rats,mice,New Zealand rabbits,and sheep were included,analyzed and assessed.The most common types of bone defects were cylindrical bone defects and segmental osteotomy bone defects,generally found in the middle and distal femur.These models are mostly used to evaluate the effects of bone repair materials,drugs,drug-loaded active substances and physical therapy on bone defect repair and explore defect healing mechanisms,particularly the weight-bearing bone defect repair mechanism.Different defect kinds and femoral bone defect ranges have been found in different animal experiments.Researchers can select the suitable animal model and bone defect type based on the goal of the experiment and then set an acceptable bone defect value.Current studies have shown that cylindrical and segmental osteotomy-induced bone defects,mainly in the distal and middle femur,are mostly used in the animal models of femoral bone defects and that the surgical methods and postoperative management are more mature and operable to provide mature experimental animal models.In terms of cylindrical bone defects,rats and New Zealand rabbits are more suitable,whereas segmental osteotomy has no special requirements and all types of animals can meet the experimental requirements.