ObjectiveTo address the challenges of unstructured classical Chinese expressions， nested entity relationships， and limited annotated data in famous traditional Chinese medicine（TCM） case records， this study proposes a joint relation extraction framework that integrates data augmentation and entity mapping， aiming to support the construction of TCM diagnostic knowledge graphs and clinical pattern mining. MethodsWe developed an annotation structure for entities and their relationships in TCM case texts and applied a data augmentation strategy by incorporating multiple ancient texts to expand the relation extraction dataset. A cascade binary tagging framework for relation triple extraction（CasRel） model for TCM semantics was designed， integrating a pre-trained bidirectional encoder representations from transformers（BERT） layer for classical TCM texts to enhance semantic representation， and using a head entity-relation-tail entity mapping mechanism to address entity nesting and relation overlapping issues. ResultsExperimental results showed that the CasRel model， combining data augmentation and entity mapping， outperformed the pipeline-based Bert-Radical-Lexicon（BRL）-bidirectional long short-term memory（BiLSTM）-Attention model. The overall precision， recall， and F₁-score across 12 relation types reached 65.73%， 64.03%， and 64.87%， which represent improvements of 14.26%， 7.98%， and 11.21% compared to the BRL-BiLSTM-Attention model， respectively. Notably， the F₁-score for tongue syndrome relations increased by 22.68%（69.32%）， and the prescription-syndrome relations performed the best with the F₁-score of 70.10%. ConclusionThe proposed framework significantly improves the semantic representation and complex dependencies in TCM texts， offering a reusable technical framework for structured mining of TCM case records. The constructed knowledge graph can support clinical syndrome differentiation， prescription optimization， and drug compatibility， providing a methodological reference for TCM artificial intelligence research.

Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.

OBJECTIVE To form an expert consensus on the clinical application of parenteral direct thrombin inhibitors （DTIs） in patients during the perioperative period. METHODS Led by Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital （the Affiliated Hospital of UESTC）， a multidisciplinary working group was established. Through literature review and the Delphi method， clinical questions related to the rational perioperative use of parenteral DTIs were identified. A structured design was adopted using the “Population-Intervention-Comparison-Outcome” framework； systematic searches were conducted in CNKI， Medline， Embase and other databases. Relevant evidence from randomized controlled trials and cohort studies was included and synthesized. Evidence quality was assessed using the Grades of Recommendations Assessment，Development and Evaluation （GRADE） approach， and recommendations were formulated through multiple rounds of Delphi surveys and expert consensus meetings. RESULTS &CONCLUSIONS Seven recommendations （each with an expert consensus rate exceeding 90%） on the use of parenteral DTIs in perioperative patients were developed. These recommendations specify drug selection， dosing ranges， key monitoring points， and safety management strategies for parenteral DTIs in various scenarios， including the perioperative period of ventricular assist device implantation， the perioperative period of cardiac surgery， perioperative patients with lower-extremity atherosclerotic disease， the perioperative period of percutaneous coronary intervention in patients with acute coronary syndrome， the perioperative period of carotid artery stenting in patients with carotid stenosis， the perioperative period of patients with right heart thrombosis， and patients who develop related thrombosis and dysfunction after a central venous catheter insertion. In addition， warning and management pathways for perioperative bleeding and thrombotic events were proposed. This expert consensus， which is formulated based on the best available evidence， provides evidence-based guidance for standardized and individualized use of parenteral DTIs in perioperative period.

ObjectiveTo investigate whether Huanglian Jiedutang （HLJD） and its major active constituents （geniposide， baicalin， and berberine） can inhibit the inflammatory response of BV2 cells under lipopolysaccharide （LPS） stimulation via the high-mobility group protein B1 （HMGB1）/Toll-like receptor 4 （TLR4）/nuclear factor-κB （NF-κB） signaling pathway， and to explore differences in therapeutic efficacy among the three monomers， their combined formula， and HLJD under equal content ratios. MethodsBV2 microglial cells were used as the primary experimental model. Cell viability was assessed using the cell counting kit-8 （CCK-8） method to examine the effects of different concentrations of dimethyl sulfoxide （DMSO， 0.8%， 0.4%， 0.2%， 0.1%， and 0.05%） on cell viability. IncuCyte was employed to monitor the growth of cells under different concentrations of HLJD （200， 100， 50， 25， 12.5， 6.25 mg·L^-1）. Nitric oxide （NO） assay was used to screen the optimal HLJD concentration. High-performance liquid chromatography （HPLC） determined the content of geniposide， baicalin， and berberine in HLJD， and experimental groups were subsequently established according to the relative proportions of these constituents. CCK-8 assay evaluated cell viability under different treatments. Enzyme-linked immunosorbent assay （ELISA） measured levels of inflammatory factors （TNF-α， IL-1β， IL-6， IL-10） in the supernatant. Flow cytometry assessed the effects of treatments on M1-type polarization of BV2 cells. Western blot determined the expression levels of HMGB1， TLR4， and NF-κB-related proteins. ResultsCompared with the blank group， DMSO at concentrations ≤0.2% did not affect cell viability within 48 h. BV2 cell growth plateaued at 24 h after treatment with 200 mg·L^-1 HLJD. Under stimulation with 2 mg·L^-1 LPS， this concentration of HLJD effectively reduced NO release， and 6 h pre-treatment had a stronger inhibitory effect on NO than direct administration. HPLC results showed that 1 mg of HLJD freeze-dried powder contained approximately 24 μg of geniposide， 15 μg of baicalin， and 30 μg of berberine. Based on these ratios， experimental groups were blank， LPS （2 mg·L^-1）， HLJD （200 mg·L^-1）， monomer combination， geniposide （4.8 mg·L^-1）， baicalin （3 mg·L^-1）， and berberine （6 mg·L^-1）. The monomer combination group consisted of all three active constituents dissolved together. LPS and HLJD or its active constituents did not affect cell viability compared with the blank group. LPS significantly increased TNF-α， IL-1β， IL-6， and IL-10 in the supernatant （P<0.01）. HLJD and its active constituents significantly reduced pro-inflammatory factors TNF-α， IL-1β， and IL-6 （P<0.05， P<0.01） while upregulating anti-inflammatory IL-10 （P<0.01）， with the monomer combination showing the strongest effect （P<0.05， P<0.01）. Compared with the blank group， LPS significantly increased the proportion of CD80⁺CD86⁺ （M1-type） BV2 cells （P<0.01）. HLJD and its constituents partially inhibited M1 polarization （P<0.05， P<0.01）， with the monomer combination exhibiting the most pronounced effect （P<0.05， P<0.01）. Compared with the blank group， LPS upregulated HMGB1， TLR4， and NF-κB-related proteins （P<0.01）， whereas HLJD and its active constituents significantly reduced their expression （P<0.05， P<0.01）， with the monomer combination having the strongest regulatory effect （P<0.05， P<0.01）. ConclusionHLJD and its major active constituents （geniposide， baicalin， berberine） can inhibit LPS-induced inflammatory responses in BV2 cells. The combination of the three active constituents demonstrates the most potent anti-inflammatory effect， significantly attenuating M1-type polarization of BV2 cells via the HMGB1/TLR4/NF-κB signaling pathway.

ObjectiveTo explore the possible mechanism of Qishao Tongbi Capsule （芪芍通痹胶囊， QTC） in the treatment of intervertebral disc degeneration （IDD）. MethodsSeventy-five rats were randomly divided into control group， model group， low-dose QTC group， high-dose QTC group， high-dose QTC +agonist group， with 15 rats in each group. Except for the control group， all other groups were subjected to a fibrous ring puncture to prepare an IDD model. After modeling， rats in low-dose QTC group and high-dose QTC group were given QTC at doses of 0.2 and 0.8 g/（kg·d） by gavage， respectively. Rats in high-dose QTC+ agonist group was given QTC at 0.8 g/（kg·d） and SKL2001 solution at 10 mg/（kg·d） by gavage. The control group and model group were given 10 ml/（kg·d） distilled water by gavage. All treatments were given once a day for 4 consecutive weeks. After treatment， X-ray and magnetic resonance imaging （MRI） were used to detect IDD degree. Hematoxylin-eosin （HE） staining and Safranin O-Fast Green staining were used to observe the morphological changes of the intervertebral disc tissue. Immunohistochemical staining was performed to examine the levels of proteoglycan， type Ⅱ collagen （COL Ⅱ）， and matrix metalloproteinase-3 （MMP-3） in the intervertebral disc tissue. Western blotting was used to detect the extracellular matrix （ECM）-related proteins （proteoglycan， COL Ⅱ， MMP-3， MMP-9， MMP-13）， aging-related proteins （P53， P21， P16）， apoptosis related proteins， including B-cell lymphoma/leukemia 2 （BCL-2）， BCL-2 related X protein （BAX）， Cleaved Caspase-3， and Wnt/β-catenin pathway related proteins such as Wnt3a， glycogen synthase kinase-3β （GSK-3β） and β-catenin in the intervertebral disc nucleus pulposus （NP） tissue. Reverse Transcription Quantitative Polymerase Chain Reaction （RT-qPCR） was used to assess the mRNA expression of Wnt3a， GSK-3β， and β-catenin in intervertebral disc tissue. ResultsCompared with the model group， rats in the low-dose QTC group and high-dose QTC group exhibited improved DHI， decreased Pfirmann grading， and alleviated IDD. The structural integrity of the NP and annulus fibrosus increased， and the number of the NP increased. The levels of proteoglycan， COL Ⅱ， BCL-2 and GSK-3β increased， while the levels of MMP-3， MMP-9， MMP-13， P53， P21， P16， BAX， Cleaved Caspase-3， Wnt3a and β-catenin protein decreased. The mRNA expression of Wnt3a and β-catenin mRNA decreased， while GSK-3β mRNA expression increased （P＜0.05）. Compared with the low-dose QTC group， the high-dose QTC group showed further improvements in DHI， decrease in Pfirrmann grading （P＜0.05）， and greater alleviation of IDD. The structural integrity of NP and annulus fibrosus was further enhanced， and the number of NP cells further increased. The levels of proteoglycan， COL Ⅱ， BCL-2 and GSK-3β were higher， while the levels of MMP-3， MMP-9， MMP-13， P53， P21， P16， BAX， Cleaved Caspase-3， Wnt3a and β-catenin were lower. The mRNA expression of Wnt3a and β-catenin decreased， while GSK-3β mRNA expression increased （P＜0.05）. Compared with the high-dose QTC group， the high-dose QTC +agonist group showed a decrease of DHI， an increase of Pfirmann grading （P＜0.05）， significant aggravation of IDD， reduction in structural integrity of the NP and annulus fibrosus， a decrease of NP cell count， lower levels of proteoglycan， COL Ⅱ， BCL-2 and GSK-3β， and higher levels of MMP-3， MMP-9， MMP-13， P53， P21， P16， BAX and Cleaved Caspase-3. Additionally， GSK-3β mRNA expression decreased （P＜0.05）. ConclusionQTC can inhibit NP cell aging， apoptosis， and ECM degradation in IDD rats， and its therapeutic effect may be mediated through the inhibition of the Wnt/β-catenin pathway.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

BACKGROUND:The mechanism of programmed death receptor-1(PD-1)effect on osteogenic differentiation of bone marrow mesenchymal stem cells in high glucose environment remains unclear. OBJECTIVE:To explore the effect of PD-1 on osteogenic differentiation of rat bone marrow mesenchymal stem cells in high glucose environment and its regulatory mechanism. METHODS:Rat bone marrow mesenchymal stem cells were randomly divided into normal glucose group(5.6 mmol/L),high glucose group(30 mmol/L),PD-1 overexpression group,PD-1 overexpression no-load group,PD-1 knockdown group,PD-1 knockdown no-load group,and PI3K/AKT pathway inhibitor group(PD-1 knockdown+5 μmol/L LY294002).Rat bone marrow mesenchymal stem cells were cultured in high glucose to simulate the diabetic environment in vitro.The mRNA expression of PD-1 and ligand PD-L1 and the mRNA expression of osteogenic markers Runx2 and OSX in rat bone marrow mesenchymal stem cells were detected by qRT-PCR.The osteogenic differentiation ability was observed by alkaline phosphatase staining and alizarin red staining.Cell proliferation was detected by CCK-8 assay.The protein expressions of PD-1,PD-L1,p-PI3K,and p-AKT were detected by western blot assay. RESULTS AND CONCLUSION:(1)The levels of PD-1 and PD-L1 were significantly increased in the high glucose environment in vitro,and the osteogenic differentiation ability of bone marrow mesenchymal stem cells was inhibited in the high glucose environment.(2)Knockdown of PD-1 expression could promote osteogenic differentiation of bone marrow mesenchymal stem cells,increase cell proliferation activity,and activate the PI3K/AKT pathway.(3)After addition of PI3K/AKT pathway inhibitor LY294002,the ability of bone marrow mesenchymal stem cells to differentiate into osteoblasts decreased.The results show that PD-1 is dependent on the PI3K/AKT signaling pathway to inhibit osteogenic differentiation of rat bone marrow mesenchymal stem cells under high glucose environment.

The concept of holism is the core idea of traditional Chinese medicine （TCM）. Various organs and tissues coordinate with each other to maintain the body's life activities， with a close and mutual influence between the spleen， stomach， and the central nervous system （brain）. The gut-brain axis plays an important bridging role between the digestive system and the central nervous system， achieving bidirectional information exchange between the brain and the gastrointestinal tract through complex neuroendocrine and immune mechanisms. The theory of cross-organ interaction involves the mutual influence， coordination， and integration between different organs and systems； multimodality， on the other hand， utilizes multiple sensory modalities， such as vision， hearing， and touch， to convey information. By combining TCM theory with the gut-brain axis theory， a cross-organ multimodal characterization system is established to explore its mechanism and application value in refractory diseases such as functional gastrointestinal disorders， precancerous gastrointestinal diseases， Alzheimer's disease， Parkinson's syndrome， type 2 diabetes， and depression.

ObjectiveTo investigate the effect and potential mechanism of caffeic acid （CA） on severe acute pancreatitis （SAP） induced by caerulein combined with lipopolysaccharide （LPS）， and to provide a basis for the research on novel drugs for the treatment of SAP. MethodsC57BL/6J mice， aged 6 weeks， were divided into control group， model group， CA group， and octreotide acetate （OA） group， with 6 mice in each group. The mice in the control group were given injection of normal saline， and those in the other groups were given intraperitoneal injection of caerulein combined with LPS to establish a mouse model of SAP. At 1 hour after the first injection of caerulein， the mice in the CA group and the OA group were given intraperitoneal injection of CA or subcutaneous injection of OA at an interval of 8 hours. The general status of the mice was observed after 24 hours of modeling， and serum， pancreas， lung， and colon samples were collected. HE staining was used to observe the histopathological changes of the pancreas and lungs， and the serum levels of α-amylase， lipase， tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， alanine aminotransferase， aspartate aminotransferase， and creatinine were measured. RT-PCR was used to measure the expression of proinflammatory factors in the pancreas and lungs； myeloperoxidase （MPO） immunohistochemistry was used to observe the degree of neutrophil infiltration； Western blot was used to measure the activation of nuclear factor-kappa B （NF-κB） and the level of citrullinated histone H3 （CitH3）， a marker for the formation of neutrophil extracellular traps （NETs）， in the pancreas and lungs， as well as the expression level of ZO-1 in colon tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the Dunnett’s t-test was used for further comparison between two groups. ResultsCompared with the control group， the model group had severe injury in the pancreas and lungs and significant increases in the activity of serum α- amylase and lipase and the levels of the proinflammatory cytokines IL-6， interleukin-1β （IL-1β）， and TNF-α in serum and lung tissue （all P<0.05）， as well as significant increases in NF-κB activation， neutrophil infiltration， and the formation of NETs in the pancreas and lungs （all P<0.05）. Compared with the model group， the CA group had alleviated pathological injury of the pancreas and lungs and significant reductions in the activity of serum α-amylase and the levels of the proinflammatory cytokines IL-6， IL-1β， and TNF-α in serum and lung tissue （all P<0.05）， as well as significant reductions in NF-κB activation， neutrophil infiltration， and the formation of NETs in the pancreas and lungs （all P<0.05）. ConclusionCA can alleviate SAP induced by caerulein combined with LPS in mice， possibly by inhibiting neutrophil recruitment and the formation of NETs.

OBJECTIVE To explore the effects of Polygala tenuifolia compatibility on toxicity， anti-inflammatory and analgesic efficacy of sand-ironing Strychnos nux-vomica （SS）. METHODS The preparation of SS single decoction， SS-P. tenuifolia core-removed （PC） （1∶2.5） or （1∶5） combined decoction， and SS-PC （1∶5） mixture were carried out to investigate their median lethal dose （LD50）. Using aspirin as positive control， the number of writhing movements， analgesic rate， pain latency， ear swelling degree and inflammation inhibition rate induced by the above-mentioned medicinal liquids in mice were compared. The contents of the active and toxic components， strychnine and brucine， in the above-mentioned medicinal liquids were also determined. RESULTS The LD50 values of SS single decoction， SS-PC （1∶2.5） combined decoction， SS-PC （1∶5） combined decoction and SS- PC （1∶5） mixture were 302.00， 614.47， 1 445.44 and 1 778.28 mg/kg， respectively. Compared with control group， the number of writhing movements and ear swelling degree in the mice of the above-mentioned medicinal liquid groups were reduced or decreased significantly （P＜0.05 or P＜0.01）； pain latency [at 90 and 120 minutes in the SS single decoction group， at 60 and 90 minutes in the SS-PC （1∶2.5） combined decoction group， and at 60，90， 120 minutes in the SS-PC （1∶5） combined decoction group and SS-PC （1∶5） mixture group] was significantly prolonged （P＜0.05 or P＜0.01）； analgesic rates of the respective medicinal liquids were 39.30%， 70.87%， 80.00% and 82.46%， and inflammation inhibition rates were 38.08%，TD 57.89%， 76.47% and 50.46%； analgesic and anti-inflammatory effects of combined decoction and mixture were generally better than those of the single decoction （P＜0.05 or P＜0.01）. In the above-mentioned four medicinal liquids， the total contents of strychnine were 0.71%， 0.42%， 0.47% and 0.64%， and the total contents of brucine were 0.88%， 0.63%， 0.57% and 0.88%， respectively. CONCLUSIONS The combination of P. tenuifolia can reduce the toxicity of SS and enhance its anti-inflammatory and analgesic effects. Moreover， there is a tendency for the toxicity-reducing and efficacy-enhancing effects to increase with the increasing dosage of P. tenuifolia. Additionally， the combined decoction of SS and P. tenuifolia can reduce the contents of the active and toxic components， strychnine and brucine， in SS.