BACKGROUND: Several studies have demonstrated the occurrence of secondary tumors as a rare but significant complication of chimeric antigen receptor T (CAR-T) cell therapy, underscoring the need for a detailed investigation. Given the limited variety of secondary tumor types reported to date, a comprehensive characterization of the various secondary tumors arising after CAR-T therapy is essential to understand the associated risks and to define the role of the immune microenvironment in malignant transformation. This study aims to characterize the immune microenvironment of a newly identified secondary tumor post-CAR-T therapy, to clarify its pathogenesis and potential therapeutic targets. METHODS: In this study, the bone marrow (BM) samples were collected by aspiration from the primary and secondary tumors before and after CD19 CAR-T treatment. The CD45 + BM cells were enriched with human CD45 microbeads. The CD45 + cells were then sent for 10× genomics single-cell RNA sequencing (scRNA-seq) to identify cell populations. The Cell Ranger pipeline and CellChat were used for detailed analysis. RESULTS: In this study, a rare type of secondary chronic myelomonocytic leukemia (CMML) were reported in a patient with diffuse large B-cell lymphoma (DLBCL) who had previously received CD19 CAR-T therapy. The scRNA-seq analysis revealed increased inflammatory cytokines, chemokines, and an immunosuppressive state of monocytes/macrophages, which may impair cytotoxic activity in both T and natural killer (NK) cells in secondary CMML before treatment. In contrast, their cytotoxicity was restored in secondary CMML after treatment. CONCLUSIONS This finding delineates a previously unrecognized type of secondary tumor, CMML, after CAR-T therapy and provide a framework for defining the immune microenvironment of secondary tumor occurrence after CAR-T therapy. In addition, the results provide a rationale for targeting macrophages to improve treatment strategies for CMML treatment.
Humans ; Lymphoma, Large B-Cell, Diffuse/therapy* ; Tumor Microenvironment/genetics* ; Antigens, CD19/metabolism* ; Leukemia, Myelomonocytic, Chronic/genetics* ; Immunotherapy, Adoptive/adverse effects* ; Male ; Single-Cell Analysis/methods* ; Female ; Sequence Analysis, RNA/methods* ; Receptors, Chimeric Antigen ; Middle Aged

BACKGROUND: China has made significant progress in medical accessibility and quality over the past decades, and quality improvements in gastroenterology and digestive endoscopy have been consistent. The study aimed to describe the status quo of gastroenterology and digestive endoscopy in the Chinese mainland based on the data from the National Clinical Improvement System (NCIS) and the Hospital Quality Monitoring System (HQMS). METHODS: Data were extracted from the NCIS and the HQMS. Data analysis included general information from the Department of Gastroenterology and Endoscopy centers, management of inpatients and outpatients, and annual volume and quality indicators of digestive endoscopy. Acute pancreatitis, gastrointestinal bleeding, inflammatory bowel disease, and cirrhosis were identified as priority diseases and were subjected to detailed analysis. RESULTS: Data from 4620 and 7074 hospitals were extracted from the NCIS and HQMS, respectively. In 2023, 9.6 gastroenterologists, 6.7 endoscopists, and 37.3 gastroenterology beds per hospital nationwide were observed, achieving 19,252.4 outpatient visits, 1615.2 hospitalizations (97.0 for acute pancreatitis, 146.1 for gastrointestinal bleeding, 40.2 for inflammatory bowel disease, and 111.4 for cirrhosis), and 9432.7 digestive endoscopic procedures per hospital. Overall, the quality of practice improved significantly. The proportion of early cancer among gastrointestinal cancers increased from 11.1% in 2015 to 23.4% in 2023, and the adenoma detection rate during colonoscopy increased from 19.3% in 2019 to 26.9% in 2023. Regarding priority diseases, hospitalizations increased, and 31-day unplanned readmission rates decreased between 2019 and 2023. The median hospitalization costs and median proportion of medication costs decreased for acute pancreatitis, gastrointestinal bleeding, and cirrhosis. However, it increased for inflammatory bowel disease. CONCLUSION This report evaluates the status quo and development of gastroenterology and digestive endoscopy in the Chinese mainland, providing guidance for future quality improvements.
Humans ; China ; Gastroenterology/statistics & numerical data* ; Gastrointestinal Hemorrhage ; Endoscopy, Gastrointestinal/statistics & numerical data* ; Endoscopy, Digestive System/statistics & numerical data*

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.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Protrusive facial deformities, characterized by the forward displacement of the teeth and/or jaws beyond the normal range, affect a considerable portion of the population. The manifestations and morphological mechanisms of protrusive facial deformities are complex and diverse, requiring orthodontists to possess a high level of theoretical knowledge and practical experience in the relevant orthodontic field. To further optimize the correction of protrusive facial deformities, this consensus proposes that the morphological mechanisms and diagnosis of protrusive facial deformities should be analyzed and judged from multiple dimensions and factors to accurately formulate treatment plans. It emphasizes the use of orthodontic strategies, including jaw growth modification, tooth extraction or non-extraction for anterior teeth retraction, and maxillofacial vertical control. These strategies aim to reduce anterior teeth and lip protrusion, increase chin prominence, harmonize nasolabial and chin-lip relationships, and improve the facial profile of patients with protrusive facial deformities. For severe skeletal protrusive facial deformities, orthodontic-orthognathic combined treatment may be suggested. This consensus summarizes the theoretical knowledge and clinical experience of numerous renowned oral experts nationwide, offering reference strategies for the correction of protrusive facial deformities.
Humans ; Orthodontics, Corrective/methods* ; Consensus ; Malocclusion/therapy* ; Patient Care Planning ; Cephalometry

The prevalence of Class III malocclusion varies among different countries and regions. The populations from Southeast Asian countries (Chinese and Malaysian) showed the highest prevalence rate of 15.8%, which can seriously affect oral function, facial appearance, and mental health. As anterior crossbite tends to worsen with growth, early orthodontic treatment can harness growth potential to normalize maxillofacial development or reduce skeletal malformation severity, thereby reducing the difficulty and shortening the treatment cycle of later-stage treatment. This is beneficial for the physical and mental growth of children. Therefore, early orthodontic treatment for Class III malocclusion is particularly important. Determining the optimal timing for early orthodontic treatment requires a comprehensive assessment of clinical manifestations, dental age, and skeletal age, and can lead to better results with less effort. Currently, standardized treatment guidelines for early orthodontic treatment of Class III malocclusion are lacking. This review provides a comprehensive summary of the etiology, clinical manifestations, classification, and early orthodontic techniques for Class III malocclusion, along with systematic discussions on selecting early treatment plans. The purpose of this expert consensus is to standardize clinical practices and improve the treatment outcomes of Class III malocclusion through early orthodontic treatment.
Humans ; Malocclusion, Angle Class III/classification* ; Orthodontics, Corrective/methods* ; Consensus ; Child

OBJECTIVE To explore the action mechanism of kushenol F （KSCF） in treating ulcerative colitis （UC） in mice. METHODS The potential targets of KSCF intervening in UC were predicted with network pharmacology and molecular docking. C57BL/6J mice were randomly divided by body weight into model group， positive control group （sulfasalazine， 703 mg/kg）， KSCF group （100 mg/kg）， and normal group， with 6 mice per group. The UC model of mice was induced by dextran sulfate sodium solution. During the modeling period， the mice were given relevant medicine intragastrically， once a day， for 7 consecutive days. After the last administration， the disease activity index （DAI） of the mice was scored； the length of the mice’s colon was measured； pathological changes in the colon tissue of mice were observed； the levels of lipopolysaccharide （LPS） in serum， myeloperoxidase （MPO）， nitric oxide （NO） and superoxide dismutase （SOD） in the colon were detected in mice； the expression levels of occludin and ZO-1 in colon tissue of mice were detected； the proportions of CD3+T， CD4+T， and CD8+T lymphocytes in the spleen and the ratio of CD4+/CD8+ were detected； changes in colonic microbiota were analyzed by 16S rDNA sequencing. RESULTS Results of network pharmacology indicated that KSCF may treat UC by regulating signaling pathways such as phosphatidylinositol-3 kinase/protein kinase B （PI3K/AKT） and nuclear factor kappa B （NF- κB）. Molecular docking results showed that KSCF bound most stably with NF-κB p65 protein. Animal experiment results demonstrated that， compared with the model group， the pathological characteristics of colon tissue in mice were improved in KSCF group. DAI scores， serum levels of LPS， the levels of MPO，NF-κB p65 phosphorylation and NLRP3 protein expression in the colon， and the proportion of CD8+T lymphocytes in the spleen were reduced significantly （P＜0.05）. Body weight， SOD levels， expression levels of occludin and ZO-1 in the colon， proportions of CD3+T and CD4+T lymphocytes， and the CD4+/CD8+ ratio in the spleen were significantly increased （P＜0.05）； the abundance of Firmicutes， Actinobacteria， Akkermansia， and Lactobacillus genera were increased， while Proteobacteria decreased； the microbial community structure tended towards that of the normal group. CONCLUSIONS KSCF alleviates UC by restoring intestinal microbial imbalance， enhancing immune response， and inhibiting colonic inflammatory responses， thereby improving intestinal barrier integrity.

OBJECTIVE To study the chemical composition and the function of solid excipients in relieving the "nourishing and spleen-impairing" effect of Zhangbang nine steaming nine sun-dying Rehmanniae Radix(RR) by using UPLC-Q-TOF-MS technique. METHODS UPLC-Q-TOF-MS was used to collect the data of Zhangbang nine steaming nine sun-dying RR, and UNIFI platform and self-built database were used for the rapid qualitative analysis and identification of the chemical components of Zhangbang nine steaming nine sun-dying RR. The effect of solid excipients on the function of RR "nourishing and spleen-impairing" was investigated by establishing a mouse model of low gastric motility and measuring its gastric residual rate and small intestine propulsion rate. RESULTS The UPLC-Q-TOF-MS and UNFI platforms identified 76 chemical components in nine steaming nine sun-dying RR, including 9 iridoid glycosides, 11 phenylethyl glycosides, 31 flavonoids, 6 saccharides and 19 other compounds; the results of gastric emptying and small intestinal propulsion experiments on mice showed that Zhangbang nine steaming nine sun-dying RR had gastric emptying and intestinal propulsion effects. CONCLUSION This method can be used for the rapid identification and analysis of nine steaming nine sun-dying RR, which has solid excipients Citri Reticulatae Pericarpium and Amomi Fructus to alleviate the "nourishing and spleen-impairing" function of RR. This study can provide a reference for quality control and elucidation of the material basis of the medicinal effects of specialty beverage of Zhangbang nine steaming nine sun-dying RR.