By tracing back to the classical literature of traditional Chinese medicine （TCM）， this paper proposes a TCM philosophy integrating "dao （道）-shen（神）-formula" as a unified whole. It systematically elaborates the formula-constructing thought that "the monarch drug follows dao， and the formula carries dao"， analyzes shen （spirit/ life vitality） from the perspectives of its substance， manifestation and function， and explains the pivotal role of shen in connecting dao and formula. Taking Treatise on Cold Damage and Miscellaneous Diseases （《伤寒杂病论》） as an example， the paper explores how the "dao-shen-formula" union is implemented in classics. Based on the Inner Canon of Yellow Emperor （《黄帝内经》）， the paper articulates a practical pathway for the "dao-shen-formula" union， namely "observing shen to differentiate the mechanism → restoring dao to regulate shen → achieving harmony of shen and restoration of dao"， thereby transforming abstract concepts into operable and verifiable practical approaches. It is hoped that this study will provide theoretical foundation and practical guidance for the shift from treating diseases to treating the person， and from correcting deviations to restoring dao in TCM.

By tracing back to the classical literature of traditional Chinese medicine （TCM）， this paper proposes a TCM philosophy integrating "dao （道）-shen（神）-formula" as a unified whole. It systematically elaborates the formula-constructing thought that "the monarch drug follows dao， and the formula carries dao"， analyzes shen （spirit/ life vitality） from the perspectives of its substance， manifestation and function， and explains the pivotal role of shen in connecting dao and formula. Taking Treatise on Cold Damage and Miscellaneous Diseases （《伤寒杂病论》） as an example， the paper explores how the "dao-shen-formula" union is implemented in classics. Based on the Inner Canon of Yellow Emperor （《黄帝内经》）， the paper articulates a practical pathway for the "dao-shen-formula" union， namely "observing shen to differentiate the mechanism → restoring dao to regulate shen → achieving harmony of shen and restoration of dao"， thereby transforming abstract concepts into operable and verifiable practical approaches. It is hoped that this study will provide theoretical foundation and practical guidance for the shift from treating diseases to treating the person， and from correcting deviations to restoring dao in TCM.

Objective To evaluate the impact of an integrated management mode of prenatal diagnosis-postnatal treatment for congenital heart disease (CHD) on perioperative and long-term outcomes of the arterial switch operation (ASO), and to analyze the efficacy of ASO in a single center. Methods This retrospective study analyzed the clinical data of 183 children who underwent ASO at Guangdong Provincial People’s Hospital from 2018 to 2024. The cohort included 106 (57.9%) patients of transposition of the great arteries with intact ventricular septum (TGA/IVS), 61 (33.3%) patients of transposition of the great arteries with ventricular septal defect (TGA/VSD), and 16 (8.7%) patients of Taussig-bing anomaly (TBA). Perioperative indicators were compared between 91 patients in the prenatal-postnatal integrated management group (an integrated group) and 92 patients in the traditional management group (a non-integrated group). Long-term survival and reoperation rates were analyzed using Kaplan-Meier curves. Results The overall perioperative mortality rate was 4.9% (9/183), showing a downward trend year by year. The primary cause of perioperative mortality was low cardiac output syndrome (LCOS), which occurred in 12 patients (6.6% incidence) with a mortality rate of 75.0%. The integrated group had a higher proportion of males (89.0% vs. 72.8%, P<0.05) and lower body weight [3.1 (2.7, 3.3) kg vs. 3.3 (3.0, 3.7) kg, P<0.05] compared to the non-integrated group. The age at surgery was significantly earlier in the integrated group [7 (3, 10) d vs. 14 (9, 48) d, P<0.05], and all children in the integrated group underwent ASO within the optimal surgical window (100.0% vs. 82.6%, P<0.05). Intraoperatively, cardiopulmonary bypass time [173 (150, 207) min vs. 186 (159, 237) min, P<0.05] and aortic cross-clamp time [100 (90, 117) min vs. 116 (97, 142) min, P<0.05] were significantly shorter in the integrated group. Although the integrated group had longer postoperative mechanical ventilation time [145 (98, 214) h vs. 116 (77, 147) h, P<0.05] and higher 48-hour maximum vasoactive inotropic score [15 (10, 21) points vs. 12 (8, 16) points, P<0.05], there was no statistically significant difference in the incidence of severe complications (LCOS, necrotizing enterocolitis, extracorporeal membrane oxygenation) or mortality rate (3.3% vs. 6.5%, P=0.51) between the two groups, despite earlier surgical intervention and a higher proportion of critically ill cases in the integrated group. The length of hospital stay in the emergency surgery group was significantly shorter than that in the elective surgery group [20 (15, 28) d vs. 25 (21, 30) d, P<0.05], suggesting that early surgery may be of potential benefit. A total of 163 patients were successfully followed up for a median of 4.7 years, with a 5-year survival rate of 95.1% and a freedom from reintervention survival rate of 95.1%. There were no late deaths, and the most common postoperative complication was pulmonary artery stenosis. Conclusion The integrated management model allowed critically ill children with lower body weights to safely undergo surgery, significantly optimizing the timing of surgery and shortening intraoperative times. The long-term risk of reoperation after ASO is primarily concentrated on pulmonary artery stenosis, necessitating long-term follow-up and monitoring.

Otitis media is an infection of the middle ear mainly caused by bacteria, and current treatments rely heavily on antibiotics. However, the emergence of antibiotic-resistant bacterial strains seriously affects their efficacy. In our study, we found that extracellular vesicles (EVs) derived from human natural killer cells (NKs) inhibit the proliferation of both standard and levofloxacin (LVX)-resistant strains of Staphylococcus aureus in a dose-dependent manner. Moreover, compared to LVX, EVs were more effective at reducing effusion and rescuing hearing thresholds in animal models. For LVX-sensitive strains, EVs were significantly more effective in terms of curative time but not curative rate. For LVX-resistant strains, EVs were significantly more effective in terms of both curative rate and curative time when applied alone or applied jointly with LVX. In summary, we found that NK EVs are highly effective in treating otitis media, providing an alternative approach for treating this common disease.
Killer Cells, Natural/metabolism* ; Exosomes/metabolism* ; Animals ; Humans ; Otitis Media/therapy* ; Staphylococcus aureus/drug effects* ; Disease Models, Animal ; Anti-Bacterial Agents/pharmacology* ; Levofloxacin/pharmacology*

Purpose This study aimed to evaluate the consistency of human epidermal growth factor receptor 2(HER2)status between primary breast cancer lesions and lung metastatic lesions and to establish a prognostic model for predicting the survival rate of HER2 low expression(HER2-low)breast cancer patients with lung metastasis.Methods Clinicopathological data from a cohort of 252 patients with breast cancer and lung metastasis were retrospec-tively analyzed.Results 50.00％of the patients had HER2-low expression in metastatic lesions,and HER2-low ex-pression was the most prevalent subgroup in both primary and metastatic lesions.A discordance in HER2 status be-tween primary and metastatic sites was observed in 28.07％of cases.The most frequent shift was from HER2-zero in the primary tumor to HER2-low expression in the metastasis(12.28％of all cases).Estrogen receptor(ER)status,menopausal status,and histological type were identified as independent prognostic factors for overall survival(OS)by univariate and multivariate Cox regression analyses.A prognostic model incorporating these factors was constructed to predict 3-year and 5-year survival.The model demonstrated area under the curve(AUC)values of 0.765 and 0.780 for 3-year and 5-year OS in the training cohort,and 0.667 and 0.706 in the validation cohort,respectively.Conclu-sion HER2-low expression is the most common subtype among breast cancer patients with lung metastasis.The ob-served shift from HER2-zero in primary lesions to HER2-low in metastases underscores the clinical necessity of re-biop-sy at metastatic sites.The developed prognostic model effectively predicts OS in this patient population.

Objective:Glioblastoma (GBM) is a primary malignant tumor in the central nervous system, whose tissue heterogeneity and invasive growth characteristics lead to a very poor prognosis for patients. Hub genes in GBM are screened by bioinformatics analysis; expressions of Hub genes in human GBM tissue, and their effects on GBM biological behaviors and Notch signaling pathway proteins are explored, and their regulatory roles in GBM proliferation in xenograft tumor model mice are evaluated.Methods:(1) The gene expression profiles of GBM tissue and normal brain tissue from the Gene Expression Omnibus (GEO) database were obtained; differentially expressed genes (DEGs) were screened, and gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses were conducted on DEGs. A co-expression network was constructed using weighted gene co-expression network analysis (WGCNA) to identify modules significantly related to GBM. Gene set enrichment analysis (GSEA) on the related module genes was performed; STRING database (version 12.0) was used to construct protein-protein interaction (PPI) network and screen the hub genes. (2) Normal brain tissue samples from 8 patients with epilepsy and GBM tissue samples from 10 patients with GBM who underwent surgical resection in Department of Neurosurgery, He'nan Provincial People's Hospital from January 1, 2022 to December 1, 2023 were collected; expressions of synaptosomal-associated protein 25 (SNAP25) and vesicle-associated membrane protein 2 (VAMP2) were detected by immunohistochemical staining and Western blotting. (3) LN229 and U87 cells were routinely cultured in vitro and divided into shRNA-SNAP25/shRNA-VAMP2 group and empty vector group, and then, cells in each group were transfected with shRNA-SNAP25/shRNA-VAMP2 lentivirus or empty vector lentivirus, respectively; 24 hours after transfection, SNAP25 and VAMP2 mRNA and protein expressions in the 2 groups were detected by real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and Western blotting. LN229 and U87 cells were routinely cultured in vitro and divided into shRNA-SNAP25 group, shRNA-VAMP2 group and empty vector group; cells in each group were transfected with shRNA-SNAP25 lentivirus, shRNA-VAMP2 lentivirus or empty vector lentivirus, respectively; 48 hours after transfection, proliferation was detected by clone formation assay, proliferating cell nuclear antigen Ki-67 expression was detected by immunofluorescent staining, invasion was detected by Transwell invasion assay, and Notch1, HEY1 and HES1 protein expressions in Notch signaling pathway of LN229 cells were detected by Western blotting. (4) LN229 cells transfected with shRNA-SNAP25 lentivirus, shRNA-VAMP2 lentivirus or empty vector lentivirus for 48 hours were subcutaneously injected into the right axilla of 4-week-old BALB/c nude mice, respectively, as shRNA-SNAP25 transplantation group, shRNA-VAMP2 transplantation group and empty vector transplantation group (5 mice in each group); on 28 th day of injection, immunohistochemical staining was used to detect the Ki-67 expression in the LN229 cell-transplanted tumor tissues. Results:(1) A total of 1,473 DEGs were screened, of which 880 were upregulated and 593 were downregulated. WGCNA indicated that DEGs were divided into 5 modules (greenish-blue, blue, black, brown and gray ones), among which the greenish-blue module was significantly negatively correlated with GBM ( r=-0.700, P<0.001); GSEA analysis showed that the greenish-blue module mainly involved Notch signaling pathway, and PPI network analysis identified SNAP25 and VAMP2 as hub genes. (2) Immunohistochemical staining results showed that expressions of SNAP25 and VAMP2 in GBM tissue were significantly lower than those in normal brain tissue ( P<0.05). (3) Compared with those in the empty vector group, the SNAP25 mRNA and protein expressions in LN229 and U87 cells of the shRNA-SNAP25 group were statistically decreased ( P<0.05). Compared with those in the empty vector group, the VAMP2 mRNA and protein expressions in LN229 and U87 cells of the shRNA-VAMP2 group were significantly decreased ( P<0.05). Compared with the empty vector group, the LN229 and U87 cells in the shRNA-SNAP25 group and shRNA-VAMP2 group had significantly increased colony formation number, Ki-67 expression and invasive cell number ( P<0.05). Compared with the empty vector group, LN229 cells in the shRNA-SNAP25 group and shRNA-VAMP2 group had statistically increased Notch1, HEY1, and HES1 protein expressions ( P<0.05). Immunohistochemical staining results showed that compared with that in the empty vector group (1.00±0.00), the Ki-67 expression in LN229 cell-transplanted tumor tissues of the shRNA-SNAP25 group and shRNA-VAMP2 group was statistically increased (1.41±0.05, 1.40±0.09, P<0.05). Conclusion:Hub genes SNAP25 and VAMP2 may negatively regulate the malignant biological behavior of GBM through Notch pathway, which might be the new candidate targets for GBM precise treatment.

Objective To investigate the regulatory effect and mechanism of Yiqi Jiedu Decoction(YQJD)on ionizing radiation-induced macrophage polarization and its correlation with the Toll-like receptor 4(TLR4)/myeloid differentiation primary response protein 88(MyD88)/nuclear factor kappa-B(NF-κB)signaling pathway.Methods Fifty-five specific-pathogen-free male Sprague-Dawley rats were randomly divided into blank(n=30),anduolin(n=10),and YQJD groups(n=15).They were respectively gavaged with deionized water,anduolin suspension(0.345 6 g/kg),and YQJD high-dose(20.88 g/kg)at a dose of 0.01 mL/g body weight once a day for seven consecutive days.2 hours after the last gavage,blood was collected from the abdominal aorta to prepare the control rat,andolin rat,and YQJD high-dose sera.Appropriate amounts of YQJD high-dose and control sera were mixed in a ratio of 1∶1 and 1∶3,respectively,to obtain YQJD medium-and low-dose rat serum.RAW264.7 cells were divided into blank(10%blank rat serum),model(10%blank rat serum),anduolin(10%anduolin rat serum),and YQJD-L,YQJD-M,YQJD-H groups(10%YQJD low-,medium-,and high-dose rat serum).Except for the blank group,the cells in other groups were irradiated with 12 Gy60 Co γ-rays once to establish the macrophage radiation injury model.At 24 h after irradiation,cell viability was detected using the CCK-8 method,and the cell migration rate was measured using the scratch test.Cell morphology was observed using phalloidin staining,tumor necrosis factor-alpha(TNF-α)and interleukin-10(IL-10)levels in the cell supernatant were quantified using enzyme-linked immunosorbent assay,and the proportion of M1 macrophages was detected using flow cytometry.TLR4,MyD88,and NF-κB protein expression were detected using Western blotting.Results Twenty-four hours after irradiation,compared with the blank group,the model group exhibited significantly reduced cell viability and migration rate(P<0.01),increased cell volume and pseudopodia formation,elevated TNF-α and IL-10 levels,an increased proportion of M1 macrophages,and upregulated TLR4,MyD88,and NF-κB protein expression(P<0.05,P<0.01).Compared with the model group,each drug-treated group showed improved cell viability and migration rate(P<0.05,P<0.01),decreased cell volume,more regular cell shape,reduced TNF-α levels,lower M1-type macrophage proportion,and downregulated TLR4,MyD88,and NF-κB protein expression(P<0.05,P<0.01).IL-10 level showed an upward trend.Conclusion YQJD can partially inhibit M1 macrophage polarization and suppress inflammatory responses,which may be related to the TLR4/MyD88/NF-κB signaling pathway.

Objective:To analyze the epidemiological information of oral leukoplakia and explore the relationship between clinical characteristics and different degrees of epithelial dysplasia.Methods:A total of 430 patients with oral leukoplakia confirmed by pathology in the Department of Oral Medicine, Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine from February 2013 to May 2021 were enrolled. Epidemiological information was recorded, and univariate and multivariate Logistic regression analysis were performed on age, gender, smoking, drinking, lesion size, lesion site and lesion type to evaluate the correlation between the risk factors and the degree of epithelial dysplasia in oral leukoplakia.Results:A total of 430 valid samples were included in this study, among which 23 patients were diagnosed with oral leukoplakia with concurrent cancer. The age of all patients was (52.9±12.9) years (22-85 years); 213 were male and 217 were female. One hundred and seventy-six cases (40.9%) had lesions on the lateral and ventral tongue, and 254 cases (59.1%) had lesions in other locations. Three hundred and two cases (70.2%) had homogeneous lesions, and 128 cases (29.8%) had heterogeneous lesions. The degrees of epithelial dysplasia included none [11.9% (51/430)], mild [51.9% (223/430)], moderate [24.4% (105/430)], severe [6.5% (28/430)], and concurrent cancer [5.3% (23/430)]. Smoking, drinking, and gender were correlated with the degree of epithelial dysplasia in some binary classification systems, while tongue (border and ventral) and non-homogeneous damage were significantly correlated with higher degrees of epithelial dysplasia in all binary classification systems ( P<0.05). Conclusions:Lesions on the lateral or ventral tongue and heterogeneous lesions are significantly associated with higher degrees of dysplasia, suggesting that clinicians should pay more attention to these types of oral leukoplakia during the follow-up monitoring process.

Transmission X-ray tubes are relatively new devices characterized by portability,suitability for miniaturization,and low requirements for shielding,making them ideal radiation sources for kilovoltage X-ray therapy.However,their application in radiotherapy remains underexplored.An electron target model of a transmission X-ray tube is developed using the Monte Carlo toolkit TOPAS 3.8.1.The study investigates the effect of tungsten target thickness on X-ray output efficiency,finding that a tube voltage of 50 kV and a tungsten thickness of 1.4 μm yields the highest emission efficiency.Based on the energy spectrum at this optimal efficiency,polynomial fitting approach is applied to determine the corresponding aluminum filter thickness for mean energies ranging from 20 keV to 35 keV,achieving a mean fitting error of 0.91%.Next,the study simulates dose deposition in a water phantom for spectra with different mean energies and various source-to-surface distances,and plots percent-depth-dose curves,relative normalized dose-depth curves,and relative normalized dose histograms under each treatment condition.Finally,the simulated results are compared with experimental data from the intraoperative radiotherapy system Intrabeam and the superficial X-ray therapy unit SRT-100,obtaining average relative errors of 3.71%and 4.38%,respectively.These findings provide a theoretical foundation for further optimization of transmission X-ray tubes in kilovoltage radiotherapy.

Objective:To investigate the clinical characteristics, postoperative complications, and risk factors for pouchitis in surgical patients with ulcerative colitis (UC).Methods:This was a retrospective observational study. The clinical data of 336 UC patients who had undergone surgical treatment at the Inflammatory Bowel Disease Center of the Department of General Surgery, Jinling Hospital Affiliated to Nanjing University Medical School from February 2014 to February 2024 were enrolled. The study patients were stratified into 2014-2019 ( n = 158) and 2020–2024 groups ( n = 178), these being the periods before and after biologics were covered for treatment of UC by national insurance in China in 2020. Clinical characteristics and surgical complications were analyzed and compared between the 2014-2019 and 2020-2024 groups. Multivariable logistic regression was performed to identify the risk factors associated with pouchitis in UC patients undergoing total proctocolectomy with ileal pouch-anal anastomosis (TPC-IPAA). Results:The study cohort comprised 336 UC patients, 193 (57.4%) of whom were men. The median preoperative disease course was 48.0 months and the mean age at colectomy was 46.4±15.4 years. TPC-IPAA had been performed on 275 patients (81.8%), 129 in the 2014-2019 group and 146 in the 2020-2024 group. Sixty-one patients had undergone total or subtotal colectomy, 29 in the 2014-2019 group and 32 in the 2020-2024 group. 262 (78.0%) UC patients underwent surgery due to medical refractory. Ninety-nine (29.5%) had used biopharmaceuticals within 2 months prior to surgery, 63 (18.8%) of them having received infliximab. A smaller proportion of patients had undergone surgery for UC that was refractory to medications in the 2020–2024 group than in the 2014–2019 group (73.0% [130/178] vs. 83.5% [132/158], χ 2=5.384, P=0.020), the patients were older at colectomy (48.0±15.4 years vs. 44.6±15.2 years, t=-2.008, P=0.045), the body mass index was higher (20.2±3.1 kg/m 2 vs. 19.4±3.2 kg/m 2, t=-2.201, P=0.028), the Mayo score prior to surgery was lower ( M[ Q1, Q3]: 11.0 [9.2, 12.0 points] vs. 12.0 [11.0, 12.0) points, Z=-4.242, P=0.001), the rate of Charlson Comorbidity Index ≥ 3 scores was higher (27.0% [48/178] vs. 17.1% [27/158], χ 2=5.384, P=0.020), a greater percentage of patients had received biologics prior to surgery (41.0% [73/178) vs. 16.5% [26/158], χ 2=24.285, P<0.001), and intraoperative blood loss was greater ( M[ Q1, Q3]: 100.0 [100.0, 150.0] ml vs. 50.0 [30.0, 100.0] ml, Z=-7.054, P<0.001) despite the operation time being shorter (253.8±74.6 minutes vs. 315.2±96.8 minutes, t=6.265, P<0.001). Among the 275 patients undergoing TPC-IPAA, 95 (34.6%) had early complications (within 30 days after surgery), 20 (7.3%) of which were Clavien-Dindo Grade III–IV complications. Among these patients, 50 (18.2%) had ileus or small bowel obstruction, 11 in the 2014-2019 group and 39 in the 2020-2024 group; this difference is statistically significant (χ 2=15.225, P<0.001). Ninety-one patients (33.1%) had late complications (more than 30 days after surgery), 75 (27.3%) being pouchitis (36 in the 2014-2019 group and 39 in the 2020-2024 group); this difference is not statistically significant (χ 2=0.049, P=0.824). Five patients (1.8%) had undergone pouch excision with permanent ileostomy. Among the 61 patients who had undergone total or subtotal colectomy, 26 (42.6%) developed early postoperative complications, including 10 (16.4%) Clavien-Dindo Grade III-IV complications and one death (1.6%), the last being attributable to multiorgan dysfunction. Three patients (4.9%) had late complications; the difference in incidence of postoperative complications between the 2014-2019 and 2020-2024 groups is not statistically significant (both P>0.05). Multivariable analysis identified intraoperative blood transfusion (OR: 2.12, 95% CI: 1.19–3.75, P=0.010) and interval to stoma closure > 120 days (OR: 2.05, 95%CI: 1.16-3.62, P = 0.013) as independent risk factors for development of pouchitis in UC patients undergoing TPC-IPAA. Conclusion:Surgical treatment of UC remains safe in the biologics era. Proactive strategies to reduce intraoperative blood transfusion and achieve timely stoma closure may reduce the risk of pouchitis in UC patients undergoing TPC-IPAA.