Pulmonary fibrosis（PF） is a progressive and life-threatening disease with limited therapeutic options， highlighting the urgent need for innovative drug discovery strategies. To address this challenge， the authors propose the formula-originated rational intelligent screening&translation（FIRST）， a systematic framework for developing anti-fibrotic monomers derived from classical traditional Chinese medicine（TCM）. The strategy integrates three key dimensions， including tissue-oriented intelligent screening of active compounds， structural optimization based on drug-target spatial interactions and plant biosynthetic pathways， and cross-scale validation of drug. We further highlight its applications in discovering tissue-oriented novel drugs from clinically validated TCM， the development and mechanistic elucidation of anti-fibrotic therapeutics， as well as the clinical translation and secondary development of candidate drugs. This strategy paves the way for first-in-class， formula-derived monomeric drugs with defined structures， clarified mechanisms， and proven safety， offering a transformative avenue to meet the urgent therapeutic needs of PF and setting a new paradigm for TCM-based drug innovation.

Pulmonary fibrosis（PF） is a progressive and life-threatening disease with limited therapeutic options， highlighting the urgent need for innovative drug discovery strategies. To address this challenge， the authors propose the formula-originated rational intelligent screening&translation（FIRST）， a systematic framework for developing anti-fibrotic monomers derived from classical traditional Chinese medicine（TCM）. The strategy integrates three key dimensions， including tissue-oriented intelligent screening of active compounds， structural optimization based on drug-target spatial interactions and plant biosynthetic pathways， and cross-scale validation of drug. We further highlight its applications in discovering tissue-oriented novel drugs from clinically validated TCM， the development and mechanistic elucidation of anti-fibrotic therapeutics， as well as the clinical translation and secondary development of candidate drugs. This strategy paves the way for first-in-class， formula-derived monomeric drugs with defined structures， clarified mechanisms， and proven safety， offering a transformative avenue to meet the urgent therapeutic needs of PF and setting a new paradigm for TCM-based drug innovation.

Objective To explore the value of CT signs and quantitative parameters of artificial intelligence (AI) in predicting the efficacy of neoadjuvant chemotherapy for colorectal cancer. Methods A total of 349 colorectal cancer patients who received neoadjuvant chemotherapy at Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine in Hebei Province from January 2022 to January 2025 were selected and and divided into the effective group (n = 267) and the ineffective group (n = 82) according to the evaluation criteria for the efficacy of solid tumors. Conduct a CT examination and extract AI quantitative parameters from the CT images based on the lesion. The data were analyzed using SPSS21.0 software, Logistic regression was used to screen the influencing factors of ineffective neoadjuvant chemotherapy in patients with colorectal cancer, and separate and combined models of CT signs and AI quantitative parameters were established. The predictive effect of the model was verified by using the ROC curve, calibration curve and decision curve. Results Compared with the effective group, the proportion of regular tumor morphology and the proportion of non-enlarged lymph nodesin the ineffective group were smaller. The tumor volume, peak value and entropy value were larger (P < 0.05). Multivariable analysis showed that irregular shape (OR= 4.216), presence of lymph node enlargement (OR = 8.998), larger tumor volume (OR = 1.109), higher average CT value (OR = 1.120), elevated peak value (OR = 2.528), and increased entropy value (OR = 1.390) were independent risk factors for ineffective neoadjuvant chemotherapy in colorectal cancer (P < 0.05). The areas under the ROC curves of the individual and combined models of CT signs and AI quantitative parameters were 0.777, 0.818, and 0.877, respectively(P < 0.05). The calibration curve showed a Brier score of 0.091. The decision curve showed that the threshold was between 0.10 and 0.85, and the combined model achieved a relatively high net clinical benefit. Conclusion CT signs combined with AI quantitative parameters has a predictive value for the efficacy of neoadjuvant chemotherapy in colorectal cancer. To provide evidence-based basis for clinical screening of the population benefiting from chemotherapy and optimization of treatment strategies.

Microwave thermochemotherapy (MTC) has been applied to treat lip squamous cell carcinoma (LSCC), but a deeper understanding of its therapeutic mechanisms and molecular biology is needed. To address this, we used single-cell transcriptomics (scRNA-seq) and spatial transcriptomics (ST) to highlight the pivotal role of tumor-associated neutrophils (TANs) among tumor-infiltrating immune cells and their therapeutic response to MTC. MNDA⁺ TANs with anti-tumor activity (N1-phenotype) are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion, and these TANs are characterized by enhanced cytotoxicity, ameliorated hypoxia, and upregulated IL1B, activating T&NK cells and fibroblasts via IL1B-IL1R. In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC, fibroblasts accumulated in the tumor front (TF) can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs (pro-tumor phenotype) via CXCL12-CXCR4, which results in the aggregation of N1-TANs and extracellular matrix (ECM) deposition. In addition, we construct an N1-TANs marker, MX2, which positively correlates with better prognosis in LSCC patients, and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin (H&E)-stained images so as to conveniently guide decision making in clinical practice. Collectively, our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.
Humans ; Neutrophils/metabolism* ; Single-Cell Analysis ; Lip Neoplasms/genetics* ; Hyperthermia, Induced/methods* ; Microwaves/therapeutic use* ; Transcriptome ; Carcinoma, Squamous Cell/immunology* ; Tumor Microenvironment

Background: Microsporum canis is a zoonotic disease that can cause dermatophytosis in animals and humans. Objectives: In clinical practice, ketoconazole (KTZ) and other imidazole drugs are commonly used to treat M. canis infection, but its molecular mechanism is not completely understood.The antifungal mechanism of KTZ needs to be studied in detail. Methods: In this study, one strain of fungi was isolated from a canine suffering with clinical dermatosis and confirmed as M. canis by morphological observation and sequencing analysis.The clinically isolated M. canis was treated with KTZ and transcriptome sequencing was performed to identify differentially expressed genes in M. canis exposed to KTZ compared with those unexposed thereto. Results: At half-inhibitory concentration (½MIC), compared with the control group, 453 genes were significantly up-regulated and 326 genes were significantly down-regulated (p < 0.05). Quantitative reverse transcription polymerase chain reaction analysis verified the transcriptome results of RNA sequencing. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that the 3 pathways of RNA polymerase, steroid biosynthesis, and ribosome biogenesis in eukaryotes are closely related to the antifungal mechanism of KTZ. Conclusions The results indicated that KTZ may change cell membrane permeability, destroy the cell wall, and inhibit mitosis and transcriptional regulation through CYP51, SQL, ERG6, ATM, ABCB1, SC, KER33, RPA1, and RNP genes in the 3 pathways. This study provides a new theoretical basis for the effective control of M. canis infection and the effect of KTZ on fungi.

Objective:To analyze the risk factors of hepatocellular carcinoma microvascular invasion (MVI) and to construct a preoperative prediction clinical scoring system.Methods:A retrospective analysis was made on 113 patients with hepatocellular carcinoma undergoing hepatectomy at Zhongshan Hospital from March 2018 to Jun 2019.Postoperative pathology confirmed 35 cases with microvascular invasion.Results:The multivariate logistic regression model showed that the maximum tumor diameter( OR: 1.028, 95% CI: 1.001-1.005), the smoothness of the capsule edge( OR: 0.208, 95% CI: 0.062-0.699), the positive circulating tumor cells (CTC)( OR: 3.728, 95% CI: 1.029-13.501) and abnormal prothrombin(PIVKA-Ⅱ)( OR: 1.001, 95% CI: 1.000-1.002) were risk factors for MVI. The area, sensitivity and specificity of the clinical score constructed by assigning 1 point to each risk factor were 0.906, 74.29% and 92.31%, respectively. Clinical scores of 0, 1, 2, 3, and 4 predict MVI positive rates of 0 (0/26), 9.09% (3/33), 28.57% (6/21), 77.78% (14/ 18), 85.71% (12/14). Conclusions:Tumor maximum diameter>62 mm, PIVKA-Ⅱ>115 mAU/ml, unsmooth tumor capsule and CTC in peripheral blood are independent high risk factors in patients with MVI.

Objective:To explore the application value of detecting circulating tumor cells (CTC) before liver transplantation for predicting the recurrence and survival of hepatocellular carcinoma (HCC).Methods:From October 2015 to October 2019, 62 HCC patients at Affiliated Zhongshan Hospital were collected and analyzed by Cyttel method before liver transplantation. CTC was determined by X-tile software and Kaplan-Meier method for determining the optimal cutoff value of CTC before liver transplantation and the relationship between CTC and clinical factors was analyzed. Univariate and multivariate COX regression analyses were performed for determining the independent risk factors affecting the prognosis. Kaplan Meier method was employed for describing the survival curve of tumor-free survival and overall survival after transplantation.Results:The optimal preoperative critical value of CTC was 3.2 ml. CTC ≥3/3.2 mL was set as CTC positive group while CTC <3/3.2 mL CTC negative group. The positive/negative CTC before transplantation was significantly correlated with preoperative Alpha-fetoprotein(AFP) level, maximal tumor diameter, lymph node metastasis, liver transplantation criteria and degree of differentiation ( P<0.05). Univariate and multivariate COX regression models indicated that the number of preoperative CTC (HR: 1.262, 95%CI: 1.069-1.489, P=0.006) and microvascular invasion (HR: 2.657, 95%CI: 1.120-6.305, P=0.027) were independent risk factors for tumor-free survival after transplantation while microvascular invasion (HR: 3.738, 95%CI: 1.219-11.459, P=0.027) was the sole independent risk factor affecting the overall survival of HCC after transplantation. Statistically significant difference existed between preoperative CTC positive/negative and tumor recurrence or metastasis (no recurrence, intrahepatic recurrence, and distant metastasis)( χ2=7.790, P=0.020). The disease-free survival rates of 1/2/3-year CTC-negative/positive patients were 82.90%, 68.70%, 58.90% and 49.00%, 29.40%, 22.10%; the 1/2/3-year overall survival rates of preoperative CTC-negative/positive patients were 85.50%, 77.10%, 69.79% and 64.90%, 47.20%, 40.50% respectively. The disease-free survival curve of CTC-negative patients was significantly higher than that of CTC-positive counterparts ( P<0.001) and the overall survival curve of CTC-negative patients was significantly higher than that of CTC-positive counterparts ( P<0.005). Conclusions:Preoperative CTC detection has certain application value in evaluating the prognosis of liver cancer after liver transplantation, which has important clinical significance and application prospects.

Objective:To investigate the correlation between preoperative circulating tumor cells (CTC) and microvascular invasion (MVI) in patients with hepatocellular carcinoma.Methods:The data of 227 patients who underwent hepatocellular carcinoma resection in Zhongshan Hospital Affiliated to Sun Yat-sen University from January 2018 to March 2020 were retrospectively analyzed. The peripheral blood CTC was detected by Cyttel detection before operation. The relationship between preoperative peripheral blood CTC and clinical characteristics of patients was analyzed; the multivariate logistic regression model was used to analyze the independent risk factors for MVI; the receiver operating characteristic (ROC) curve was used to compare the efficacy of each independent risk factor in predicting the occurrence of MVI, and the relationship between CTC and MVI was clarified.Results:According to the ROC curve, the cut-off values for predicting MVI of CTC, alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist Ⅱ (PIVKA-Ⅱ), and tumor long-axis diameter were 3 CTC/3.2 ml, 158 μg/L, 178 AU/L and 59 mm. CTC-positive group had ≥3 CTC/3.2 ml in peripheral blood, and CTC-negative group had <3 CTC/3.2 ml, and there were 117 and 110 cases in the two groups. The median AFP levels of preoperative CTC-positive group and CTC-negative group were 123.0 μg/L (0-20 000.0 μg/L) and 9.6 μg/L (0-18 676.0 μg/L), and the median tumor long-axis diameter was 50.0 mm (5.0-200.0 mm) and 36.0 mm (2.0-150.0 mm), the differences between the two groups were statistically significant (both P < 0.05). Before operation, AFP≥158 μg/L ( OR = 3.551, 95% CI 1.426-8.843, P = 0.006), PIVKA-Ⅱ≥178 AU/L ( OR = 12.250, 95% CI 4.384-34.231, P < 0.01), peripheral blood CTC ≥ 3 CTC/3.2 ml ( OR = 8.913, 95% CI 3.561-22.306, P < 0.01) and tumor long-axis diameter ≥59 mm ( OR = 3.250, 95% CI 1.339-7.885, P = 0.009) were independent risk factors for the occurrence of MVI; the area under the ROC curve (AUC) of these factors for predicting MVI was 0.752, 0.777, 0.857 and 0.743. CTC was more effective in predicting MVI than AFP and tumor long-axis diameter, and the differences were statistically significant (both P < 0.05). The efficacy of CTC in predicting MVI was slightly better than that of PIVKA-Ⅱ, but the difference was not statistically significant ( P > 0.05). Conclusion:CTC may be one of the important indicators of hepatocellular carcinoma MVI in clinical practice.

Objective:To study the independent risk factors of tumor recurrence after radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC), and to establish a preoperative prediction score.Methods:A retrospective study was conducted on 168 HCC patients treated with RFA at Zhongshan Hospital affiliated to Sun Yat-sen University from June 2016 to September 2019. The X-tile software was used to determine the optimal cut-off value of preoperative circulating tumor cells (CTC) which was then used to analyze the relationship between different CTCs values with various clinical factors. The Cox regression model was used to analyze independent risk factors of recurrence after RFA, and each independent risk factor was assigned a score of 1 to compose the prediction score. The patients were divided into the low-risk group (0-2 scores), intermediate-risk group (3 scores) and high-risk group (4-5 scores). The Kaplan-Meier method was used to draw cumulative recurrence curves in calculating the cumulative recurrence rates of the 3 different groups.Results:Of 168 patients, there were 151 males and 17 females. Their age (Mean±SD) was 58.33±9.53 years. CTC≥1/3.2 ml was detected in 131 patients (77.98%) (range 0-20/3.2 ml). The X-tile software determined the preoperative CTC cut-off value of HCC patients to be 2/3.2ml which separated a CTC-negative group with 93 patients, and a positive group of 75 patients. On analyses, the relationship between preoperative CTC and various preoperative clinical parameters were related to number of tumor nodules, tumor maximum diameter and alpha-fetoprotein (AFP) levels ( P<0.05). Multivariate analysis showed that CTC positivity[ HR(95% CI): 1.990(1.332-2.974)], AFP>20 ng/ml[ HR(95% CI): 1.659(1.111-2.477)], PIVKA-II>40 mAU/ml[ HR(95% CI): 1.580 (1.022-2.443)], number of tumor nodules ≥2[ HR(95% CI): 1.568 (1.057-2.326)], and tumor diameter>30 mm[ HR (95% CI): 1.544 (1.007-2.369)] were independent risk factors of recurrence ( P<0.05) after RFA in HCC patients. The cumulative recurrence rates of patients at 6 months, 12 months, and 18 months were 14.9%, 35.6%, and 56.4% in the low-risk group, 38.9%, 70.5%, and 85.0% in the intermediate-risk group, and 64.5%, 84.5% and 100% in the high-risk group. The differences were significant ( P<0.05). Conclusion:Preoperative CTC positivity, AFP>20 ng/ml, PIVKA-II>40 mAU/ml, tumor nodules ≥2, and tumor diameter>30 mm were independent risk factors of recurrence after RFA in HCC patients. This preoperative predictive score could be used to guide clinical treatment strategies.

Objective:To explore the effect of family doctor system on the risk stratification of community hypertensive population by application of Markov modelMethods:Retrospective investigation was conducted on hypertensive patients under continuing management from 13 community health service centers in Shanghai Xuhui District from January 2014 to December 2016. Among 98 996 subjects, 50 920 (51.45%) were contracted to family doctors (contracted group) and 48 046 (48.55%) did not contracted to family doctors (non-contracted group). According to the risk stratification of hypertension, the four-state Markov model (low-risk, medium-risk, high-risk, and extremely high-risk) was established. The prediction effect of the model was validated, and the changes in the risk stratification status of hypertension in the study subjects from 2017 to 2020 was predicted by using the Markov model.Results:Among all subjects the number of medium-risk and extremely high-risk accounted for the majority(>80%). Compared with 2014, in 2016 the number of low-risk patients with hypertension was decreased from 9 042 cases (17.76%) to 6 851 cases (13.45%) in contracted group; and from 9 971 cases (20.75%) to 7 906 cases (16.46%) in non-contracted group; the number of people at extremely high risk of hypertension was increased from 15 609 cases (30.65%) to 17 639 cases (34.64%) in the contracted group; from 13 847 cases (28.82%) to 15 641 cases (32.55%) in the non-contracted group. According to the Markov model one year after the risk stratification, the risk status of most subjects remained in the original one. There was not transform from extremely high-risk to low-risk state (0%), but there was transform from low-risk to extremely high-risk state in some extend, and the degree of transform in non-contracted group [2.06%(205/9 971)] was higher than the contracted group [1.85%(167/9 042)]. Predicted by the Markov model, between 2017 and 2020 the number and proportion of the medium-risk>extremely high-risk>low-risk>high-risk in both contracted group and non-contracted group. With the extension of time, low-risk proportion is gradually reduces, and the rate of reduction of the contracted group was lower than that of the non-contracted group, while proportion of medium-risk, high-risk and extremely high-risk is gradually increased.Conclusions:The constructed Markov model is accruable and stable, which can be used in the study of hypertension prognosis. The study indicates that the contracted services of family doctor have positive effects on the management of community hypertensive patients.