ObjectiveTo explore effect of Xianlian Jiedu prescription on the recurrence of colorectal cancer （CRC） and investigate the related mechanisms. MethodsA postoperative recurrence model was established in 25 Balb/c mice by injecting CT26 cells subcutaneously into the armpit， followed by surgical removal of 99% of the subcutaneous tumor. The mice were randomly divided into model group， low-dose Xianlian Jiedu prescription （XLJDP-L） group （6.45 g·kg^-1·d^-1）， medium-dose Xianlian Jiedu prescription （XLJDP-M） group （12.9 g·kg^-1·d^-1）， high-dose Xianlian Jiedu prescription （XLJDP-H） group （25.8 g·kg^-1·d^-1）， and 5-fluorouracil （5-FU） group （1×10^-3 g·kg^-1·d^-1）. The mice were euthanized after 14 days of continuous intervention， and recurrent tumor tissue was harvested. Hematoxylin and eosin （HE） staining was used to observe pathological and morphological changes in the recurrent tumor tissue. Immunohistochemistry （IHC） was employed to assess the expression of proliferating cell nuclear antigen （Ki67）， vascular endothelial growth factor （VEGF）， and platelet-endothelial cell adhesion molecule （CD31） in recurrent tumor tissue. The Western blot was used to detect the protein expression levels of angiopoietin-2 （ANG-2）， VEGF， phosphorylated-protein kinase B （p-Akt）， protein kinase B （Akt）， phosphorylated-phosphatidylinositol 3-kinase （p-PI3K）， and phosphatidylinositol 3-kinase （PI3K） in recurrent tumor tissue. ResultsBefore treatment， there were no statistical differences in tumor volume， tumor weight， and body mass among the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group compared to the model group， indicating model stability. After treatment， compared with those in the model group， the tumor volume and tumor weight in the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group were significantly reduced （P<0.01）， showing dose dependency. Meanwhile， there were no significant differences in body weight among the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group compared to the model group. HE staining showed that compared with that in the model group， tumor tissue in the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group had loosely arranged cells， increased intercellular spaces， small and shriveled nuclei， light staining， fewer mitotic figures and atypical nuclei， and increased necrotic areas. IHC showed that compared with those of the model group， the positive rates of Ki67， VEGF， and CD31 in the recurrent tumor tissue of the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group were significantly reduced （P<0.01） in a dose-dependent manner. Western blot results showed that compared with those of the model group， the protein expression levels of ANG-2 and VEGF in the recurrent tumor tissue of the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group were significantly downregulated （P<0.05， P<0.01）， and the p-Akt/Akt and p-PI3K/PI3K ratios were significantly decreased in a dose-dependent manner （P<0.05， P<0.01）. ConclusionXianlian Jiedu prescription significantly inhibits the recurrence of CRC in mice after subcutaneous tumor surgery. The mechanism may involve regulating the PI3K/Akt pathway and downregulating key angiogenic proteins such as ANG-2， VEGF， and CD31.

Investigator initiated trial （IIT） represents a primary format for clinical research in traditional Chinese medicine （TCM）. As key implementation sites for TCM-based IIT targeting malignant tumors， western medicine institutions often face unique challenges in conducting such studies， which limit their feasibility and standardization. This paper reviews the registration status of TCM-based IIT for malignancies conducted in western medical institutions and analyzes key difficulties， including complex project initiation and management processes， limited TCM knowledge and skills among western medicine physicians， and relatively low patient acceptance of TCM. From a practical perspective， the study proposes several optimization strategies. These include improving the review and management mechanisms of TCM-related IIT within western medical institutions， establishing multidisciplinary clinical research teams that integrate TCM and western medicine， and enhancing investigators' training in TCM theory and clinical skills. Additionally， the study suggests standardizing IIT operational procedures， objectifying the collection of TCM diagnostic information， refining subject recruitment methods， and increasing TCM involvement in patient follow-up and management. These investigator-oriented， TCM-featured， and operable strategies aim to promote the high-quality development of TCM-based IIT in western medicine institutions and enhance the clinical application of TCM.

Abstract Modern western medicine typically focuses on treating specific symptoms or diseases, and traditional Chinese medicine (TCM) emphasizes the interconnections of the body’s various systems under external environment and takes a holistic approach to preventing and treating diseases. Phenomics was initially introduced to the field of TCM in 2008 as a new discipline that studies the laws of integrated and dynamic changes of human clinical phenomes under the scope of the theories and practices of TCM based on phenomics. While TCM Phenomics 1.0 has initially established a clinical phenomic system centered on Zhenghou (a TCM definition of clinical phenome), bottlenecks remain in data standardization, mechanistic interpretation, and precision intervention. Here, we systematically elaborates on the theoretical foundations, technical pathways, and future challenges of integrating digital medicine with TCM phenomics under the framework of “TCM phenomics 2.0”, which is supported by digital medicine technologies such as artificial intelligence, wearable devices, medical digital twins, and multi-omics integration. This framework aims to construct a closed-loop system of “Zhenghou–Phenome–Mechanism–Intervention” and to enable the digitization, standardization, and precision of disease diagnosis and treatment. The integration of digital medicine and TCM phenomics not only promotes the modernization and scientific transformation of TCM theory and practice but also offers new paradigms for precision medicine. In practice, digital tools facilitate multi-source clinical data acquisition and standardization, while AI and big data algorithms help reveal the correlations between clinical Zhenghou phenomes and molecular mechanisms, thereby improving scientific rigor in diagnosis, efficacy evaluation, and personalized intervention. Nevertheless, challenges persist, including data quality and standardization issues, shortage of interdisciplinary talents, and insufficiency of ethical and legal regulations. Future development requires establishing national data-sharing platforms, strengthening international collaboration, fostering interdisciplinary professionals, and improving ethical and legal frameworks. Ultimately, this approach seeks to build a new disease identification and classification system centered on phenomes and to achieve the inheritance, innovation, and modernization of TCM diagnostic and therapeutic patterns.

ObjectiveTo observe and analyze the plasma metabolite differences among colorectal cancer patients with spleen-qi deficiency， damp-heat stasis-toxin syndrome（SRYD）， non-spleen-qi deficiency， damp-heat stasis-toxin syndrome（non-SRYD）， and normal human beings（Normal）， aiming to identify unique metabolites specific to SRYD colorectal cancer patients and their potential biomarkers. MethodsBased on the diagnostic criteria of SRYD and non-SRYD colorectal cancer， 30 patients were included， including 10 patients with SRYD colorectal cancer and 20 patients with non-SRYD colorectal cancer， while 10 individuals were recruited for the Normal group. Metabolome sequencing of plasma from the three groups was performed by ultra-performance liquid chromatography-quadrupole-electrostatic field orbitrap mass spectrometry（UPLC-Q-Exactive-Orbitrap-MS）. Multivariate statistical analysis were performed by principal component analysis（PCA） and partial least squares-discriminant analysis（PLS-DA）， and the intergroup differential metabolites were identified based on variable importance in the projection（VIP） value>1 and t-test P<0.05. And pathway enrichment analysis based on Kyoto Encyclopedia of Genes and Genomes（KEGG） was performed to explore the metabolites and metabolic pathways specific to SRYD colorectal cancer patients. ResultsMetabolome sequencing results showed some differences in metabolic profiles between the groups. A total of 111 plasma differential metabolites were found in the SRYD group and the Normal group， of which 31 were up-regulated and 80 were down-regulated， mainly including stearoyl lysophosphatidylcholine， indole-3-acrylic acid， and dehydroepiandrosterone sulfate（P<0.05）. The non-SRYD group exhibited 97 differentially expressed metabolites compared to the Normal group， with 36 up-regulated and 61 down-regulated， mainly including stearoyl lysophosphatidylcholine， sphingosine， and palmitoyl lysophosphatidylcholine（P<0.05）. And the SRYD group exhibited 19 differentially expressed metabolites compared to the non-SRYD group， of which 5 were up-regulated and 14 were down-regulated， mainly including dihydrosphingosine， palmitic acid， and linoleoylethanolamide（P<0.05）. The significant differential metabolites were subjected to KEGG analysis to obtain significantly enriched metabolic pathways in each group， and the results showed that 11 metabolic pathways such as primary bile acid synthesis， cholesterol metabolism and bile secretion were differential signaling pathways specific to SRYD colorectal cancer. Further retrieval of the above key signaling pathways showed that bile acids were up-regulated in both bile secretion and primary bile acid synthesis pathways， and there was a trend of up-regulation of glycochenodeoxycholic acid， taurochenodeoxycholic acid， and chenodeoxycholic acid. ConclusionPrimary bile acid synthesis， cholesterol metabolism， and bile secretion-related pathways may be differential signaling pathways specific to SRYD colorectal cancer， and bile acid is a core molecule in the metabolic pathway， which can serve as potential biomarkers closely related to the development and progression of SRYD colorectal cancer.

ObjectiveTo observe and analyze the plasma metabolite differences among colorectal cancer patients with spleen-qi deficiency， damp-heat stasis-toxin syndrome（SRYD）， non-spleen-qi deficiency， damp-heat stasis-toxin syndrome（non-SRYD）， and normal human beings（Normal）， aiming to identify unique metabolites specific to SRYD colorectal cancer patients and their potential biomarkers. MethodsBased on the diagnostic criteria of SRYD and non-SRYD colorectal cancer， 30 patients were included， including 10 patients with SRYD colorectal cancer and 20 patients with non-SRYD colorectal cancer， while 10 individuals were recruited for the Normal group. Metabolome sequencing of plasma from the three groups was performed by ultra-performance liquid chromatography-quadrupole-electrostatic field orbitrap mass spectrometry（UPLC-Q-Exactive-Orbitrap-MS）. Multivariate statistical analysis were performed by principal component analysis（PCA） and partial least squares-discriminant analysis（PLS-DA）， and the intergroup differential metabolites were identified based on variable importance in the projection（VIP） value>1 and t-test P<0.05. And pathway enrichment analysis based on Kyoto Encyclopedia of Genes and Genomes（KEGG） was performed to explore the metabolites and metabolic pathways specific to SRYD colorectal cancer patients. ResultsMetabolome sequencing results showed some differences in metabolic profiles between the groups. A total of 111 plasma differential metabolites were found in the SRYD group and the Normal group， of which 31 were up-regulated and 80 were down-regulated， mainly including stearoyl lysophosphatidylcholine， indole-3-acrylic acid， and dehydroepiandrosterone sulfate（P<0.05）. The non-SRYD group exhibited 97 differentially expressed metabolites compared to the Normal group， with 36 up-regulated and 61 down-regulated， mainly including stearoyl lysophosphatidylcholine， sphingosine， and palmitoyl lysophosphatidylcholine（P<0.05）. And the SRYD group exhibited 19 differentially expressed metabolites compared to the non-SRYD group， of which 5 were up-regulated and 14 were down-regulated， mainly including dihydrosphingosine， palmitic acid， and linoleoylethanolamide（P<0.05）. The significant differential metabolites were subjected to KEGG analysis to obtain significantly enriched metabolic pathways in each group， and the results showed that 11 metabolic pathways such as primary bile acid synthesis， cholesterol metabolism and bile secretion were differential signaling pathways specific to SRYD colorectal cancer. Further retrieval of the above key signaling pathways showed that bile acids were up-regulated in both bile secretion and primary bile acid synthesis pathways， and there was a trend of up-regulation of glycochenodeoxycholic acid， taurochenodeoxycholic acid， and chenodeoxycholic acid. ConclusionPrimary bile acid synthesis， cholesterol metabolism， and bile secretion-related pathways may be differential signaling pathways specific to SRYD colorectal cancer， and bile acid is a core molecule in the metabolic pathway， which can serve as potential biomarkers closely related to the development and progression of SRYD colorectal cancer.

Hearing loss is the most prevalent disabling disease. Cochlear implantation（CI） serves as the primary intervention for severe to profound hearing loss. This consensus systematically explores the value of genetic diagnosis in the pre-operative assessment and efficacy prognosis for CI. Drawing upon domestic and international research and clinical experience, it proposes an evidence-based medicine three-tiered prognostic classification system（Favorable, Marginal, Poor）. The consensus focuses on common hereditary non-syndromic hearing loss（such as that caused by mutations in genes like GJB2, SLC26A4, OTOF, LOXHD1） and syndromic hereditary hearing loss（such as Jervell & Lange-Nielsen syndrome and Waardenburg syndrome）, which are closely associated with congenital hearing loss, analyzing the impact of their pathological mechanisms on CI outcomes. The consensus provides recommendations based on multiple round of expert discussion and voting. It emphasizes that genetic diagnosis can optimize patient selection, predict prognosis, guide post-operative rehabilitation, offer stratified management strategies for patients with different genotypes, and advance the application of precision medicine in the field of CI.
Humans ; Cochlear Implantation ; Prognosis ; Hearing Loss/surgery* ; Consensus ; Connexin 26 ; Mutation ; Sulfate Transporters ; Connexins/genetics*

Colorectal tumorigenesis generally progresses from adenoma to adenocarcinoma, accompanied by dynamic changes in the tumor microenvironment (TME). A randomized controlled trial has confirmed the efficacy and safety of Shen-Bai-Jie-Du decoction (SBJDD) in preventing colorectal tumorigenesis. However, the mechanism remains unclear. In this study, we employed single-cell RNA sequencing (scRNA-seq) to investigate the dynamic evolution of the TME and validated cell infiltration with multiplex immunohistochemistry and flow cytometry. Bulk RNA sequencing was utilized to assess the underlying mechanisms. Our results constructed the mutually verifiable single-cell transcriptomic atlases in Apc ^Min/+ mice and clinical patients. There was a marked accumulation of CCL22⁺ dendritic cells (DCs) and an enhanced immunosuppressive action, which SBJDD and berberine reversed. Combined treatment with cholesterol and lipopolysaccharide induced characteristic gene expression of CCL22⁺ DCs, which may represent "exhausted DCs". Intraperitoneal injection of these DCs after SBJDD treatment eliminated its therapeutic effects. TMEM131 derived CCL22⁺ DCs generation by TNF signaling pathway and may be a potential target of berberine in retarding colorectal tumorigenesis. These findings emphasize the role of exhausted DCs and the regulatory mechanisms of SBJDD and berberine in colorectal cancer (CRC), suggesting that the multi-component properties of SBJDD may help restore TME homeostasis and offer novel cancer therapy.

OBJECTIVE To identify the chemical components of Shenbai Jiedu Decoction(SBJDD),a traditional Chinese medi-cine(TCM)prescription clinically used for the treatment of colorectal adenoma(CRA),and explore the potential mechanism of SBJDD preventing and treating CRA carcinogenesis.METHODS An ultra-high performance liquid chromatography-time of flight-mass spectrometry(UPLC-Q-TOF-MS)method was established to detect the chemical components in the decoction of SBJDD and the plas-ma samples of rats after administration with SBJDD.Based on the network pharmacological method,SBJDD was screened for the poten-tial active ingredients at different stages of CRA carcinogenesis,and the mechanism of the anti-cancer effect of SBJDD was explored.In vitro experiments were also carried out to verify the mechanism of anti-colorectal cancer(CRC)action of SBJDD.RE-SULTS The detection data of UPLC-Q-TOF-MS showed that 152 components were found from SBJDD water extraction.41 chemical compounds were identified in plasma samples from rats administrated with SBJDD.Network pharmacology analysis indicated that during the CREI stage,the potential active ingredients in SBJDD,including epiberberine,and kushenol H,might affect target proteins such as PIK3CA,MAPK3 and PIK3CB.This,in turn,can influence signaling pathways like PI3K-AKT and Ras signaling pathways,and regulate biological processes like protein phosphorylation,and signal transduction.During the CRA stage,the potential active ingredi-ents from SBJDD,such as 3,7-dihydroxycoumarin,palmatine,and kushenol A,might affect target proteins such as AKT and EGFR.This can regulate the negative regulation of apoptotic process,and positive regulation of cell proliferation,and modify HIF-1,and Rap1 signaling pathways.During the progression of CRA carcinogenesis,potential active ingredients such as 3,7-dihydroxycouma-rin may interact with TP53,and impact the PI3K-AKT,and Thyroid hormone signaling pathways to regulate biological processes,in-cluding positive regulation of transcription from RNA polymerase Ⅱ promoter,and negative regulation of apoptotic process.In the CRC stage,core ingredients like p-coumaric acid may bind with proteins such as PRKCB.This binding may impact the signaling pathways that negatively affect EGFR tyrosine kinase inhibitor resistance,and PI3K-AKT signaling pathways.Additionally,it may regulate bio-logical processes,including negative regulation of apoptotic process,signal transduction,and protein phosphorylation.In vitro experi-ment results indicated that SBJDD inhibited the proliferation of HT29 cells and suppressed the expression of EGFR and PKC proteins.CONCLUSION The UPLC-Q-TOF-MS method is established to effectively separate the chemical constituents in SBJDD,which are mainly composed of alkaloids,organic acids and flavonoids components.Components from SBJDD dock with different targets during the carcinogenesis process of CRA and regulate cancer-related signaling pathways to exert therapeutic effects.

Objective:To investigate the prognosis and the factors that influence it in patients with non-gastric gastrointestinal stromal tumors (GISTs) who are at low risk of recurrence.Methods:This was a retrospective cohort study. Clinicopathologic and prognostic data from patients with non-gastric GISTs and at low risk of recurrence (i.e., very low-risk or low-risk according to the 2008 version of the Modified NIH Risk Classification), who attended 18 medical centers in China between January 2000 and June 2023, were collected. We excluded patients with a history of prior malignancy, concurrent primary malignancy, multiple GISTs, and those who had received preoperative imatinib. The study cohort comprised 1,571 patients with GISTs, 370 (23.6%) of whom were at very low-risk and 1,201 (76.4%) at low-risk of recurrence. The cohort included 799 (50.9%) men and 772 (49.1%) women of median age 57 (16–93) years. Patients were followed up to July 2024. The prognosis and its influencing factors were analyzed. Receiver operating characteristic curves for tumor diameter and Ki67 were established, and the sensitivity, specificity, area under the curve (AUC) and optimal cut-off value with 95% confidence intervals were calculated. Propensity score matching was implemented using the 1:1 nearest neighbor matching method with a matching tolerance of 0.02.Results:With a median follow-up of 63 (12–267) months, the 5- and 10-year overall survival (OS) rates of the 1,571 patients were 99.5% and 98.0%, respectively, and the 5- and 10-year disease-free survival (DFS) rates were 96.3% and 94.4%, respectively. During postoperative follow-up, 3.8% (60/1,571) patients had disease recurrence or metastasis, comprising 0.8% (3/370) in the very low-risk group and 4.7% (57/1,201) in the low-risk group. In the low-risk group, recurrence or metastasis occurred in 5.5% (25/457) of patients with duodenal GISTs, 3.9% (25/645) of those with small intestinal GISTs, 9.2% (6/65) of those with rectal GISTs, and 10.0% (1/10) of those with colonic GISTs. Among the 60 patients with metastases, 56.7% (34/60) of the metastases were located in the abdominal cavity, 53.3% (32/60) in the liver, and 3.3% (2/60) in bone. During the follow-up period, 13 patients (0.8%) died of disease. Receiver operating characteristic curves were plotted for tumor diameter and Ki67 and assessed using the Jordon index. This showed that the difference in DFS between the two groups was statistically significant when the cutoff value for tumor diameter was 3.5 cm (AUC 0.731, 95% CI: 0.670–0.793, sensitivity 77.7%, specificity 64.1%). Furthermore, the difference in DFS between the two groups was statistically significant when the cutoff value for Ki67 was 5% (AUC 0.693, 95% CI: 0.624–0.762, sensitivity 60.7%, specificity 65.3%). Multifactorial analysis revealed that tumor diameter ≥3.5 cm, Ki67 ≥5%, and R1 resection were independent risk factors for DFS in patients with non-gastric GISTs at low risk of recurrence (all P<0.05). Furthermore, age >57 years, Ki67 ≥5%, and R1 resection were also independent risk factors for OS in patients with non-gastric GISTs at low risk of recurrence (all P<0.05). We also grouped the patients according to whether they had received postoperative adjuvant treatment with imatinib for 1 or 3 years. This yielded 137 patients in the less than 1-year group, 139 in the 1-year plus group; and 44 in both the less than 3 years and 3-years plus group. After propensity score matching for age, tumor diameter, Ki67, and resection status, the differences in survival between the two groups were not statistically significant (all P>0.05). The 10-year DFS and OS were 87.5% and 95.5%, respectively, in the group treated with imatinib for less than 1 year and 88.5% and 97.8%, respectively, in the group treated for more than 1 year. The 10-year DFS and OS were 89.6% and 92.6%, respectively, in the group treated with imatinib for less than 3 years and 88.0% and 100.0%, respectively, in the group treated with imatinib for more than 3 years. Conclusion:The overall prognosis of primary, non-gastric, low recurrence risk GISTs is relatively favorable; however, recurrences and metastases do occur. Age, tumor diameter, Ki67, and R1 resection may affect the prognosis. For some patients with low risk GISTs, administration of adjuvant therapy with imatinib for an appropriate duration may help prevent recurrence and improve survival.

Background::A phase II trial on recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA) has previously shown its preliminary efficacy in ST elevation myocardial infarction (STEMI) patients. This study was designed as a pivotal postmarketing trial to compare its efficacy and safety with rrecombinant human tissue-type plasminogen activator alteplase (rt-PA) in Chinese patients with STEMI.Methods::In this multicenter, randomized, open-label, non-inferiority trial, patients with acute STEMI were randomly assigned (1:1) to receive an intravenous bolus of 16 mg rhTNK-tPA or an intravenous bolus of 8 mg rt-PA followed by an infusion of 42 mg in 90 min. The primary endpoint was recanalization defined by thrombolysis in myocardial infarction (TIMI) flow grade 2 or 3. The secondary endpoint was clinically justified recanalization. Other endpoints included 30-day major adverse cardiovascular and cerebrovascular events (MACCEs) and safety endpoints.Results::From July 2016 to September 2019, 767 eligible patients were randomly assigned to receive rhTNK-tPA ( n = 384) or rt-PA ( n = 383). Among them, 369 patients had coronary angiography data on TIMI flow, and 711 patients had data on clinically justified recanalization. Both used a –15% difference as the non-inferiority efficacy margin. In comparison to rt-PA, both the proportion of patients with TIMI grade 2 or 3 flow (78.3% [148/189] vs. 81.7% [147/180]; differences: –3.4%; 95% confidence interval [CI]: –11.5%, 4.8%) and clinically justified recanalization (85.4% [305/357] vs. 85.9% [304/354]; difference: –0.5%; 95% CI: –5.6%, 4.7%) in the rhTNK-tPA group were non-inferior. The occurrence of 30-day MACCEs (10.2% [39/384] vs. 11.0% [42/383]; hazard ratio: 0.96; 95% CI: 0.61, 1.50) did not differ significantly between groups. No safety outcomes significantly differed between groups. Conclusion::rhTNK-tPA was non-inferior to rt-PA in the effect of improving recanalization of the infarct-related artery, a validated surrogate of clinical outcomes, among Chinese patients with acute STEMI.Trial registration::www.ClinicalTrials.gov (No. NCT02835534).