Background/Aims: Biliary tract cancer (BTC) frequently harbors KRAS mutations, which are associated with resistance to traditional treatment and a poor prognosis. Synthetic lethality (SL) strategy may provide other targets of KRAS. Therefore, we aim to identify and validate potential therapeutic targets of KRAS for the treatment of BTC via SL. Methods: The dependency (DepMap) projects were used to predict the synthetic lethal gene of KRAS. FDA-approved anticancer drug library was applied to screen potential drugs effective against KRAS-mutant BTC. Furthermore, the synthetic lethal effects or corresponding mechanisms of potential genes and drugs on BTC were investigated using KRAS-mutant and KRAS-wild type BTC cell lines, patient-derived xenografts (PDX), and KRAS oncogene-driven tumor models, as well as other KRAS-mutant cancer cell lines. Results: Initially, we discovered that the loss of GATA2 reduced the viability of KRAS-mutant but not KRAS-wild-type BTC. Subsequently, the drug library screened out disulfiram, which primarily exerts a synthetic lethal effect by inhibiting interleukin-1β (IL-1β) in KRAS-mutant BTC. Mechanistically, GATA2 specifically enhanced the transcription of IL-1β to promote NF-κB signaling in KRAS-mutant BTC. IL-1β inhibition phenocopied GATA2 deficiency, leading to reduced KRAS-mutant BTC viability. These synthetically lethal effects were confirmed using PDX, a KRAS oncogene-driven tumor model, as well as in other KRAS-mutant cancer cell lines. Conclusions In summary, these results indicate that inhibiting GATA2/IL1β could be a therapeutic strategy in KRAS-mutant BTC and potentially other cancers.

Objective:We aimed to develop a nomogram in corporating multidetector computed tomography(MDCT)imaging features and clinicopathological indicators for the preoperative prediction of axillary lymph node metastasis(ALNM)in patients with triple-negative breast cancer(TNBC).Methods:We retrospectively analyzed data from 265 female patients with pathologically confirmed TNBC treated at Harbin Medical University Cancer Hospital between November 2020 and October 2024.Patients were randomly assigned into a training cohort(n=161)and a validation cohort(n=104)in a 6:4 ratio.Feature selection was performed using least absolute shrinkage and selection operator(LASSO)regression with 10-fold cross-validation.Independent predictors of ALNM were identified by multivariate Logistic regression analysis,and a nomogram was constructed accordingly.Model performance was assessed using receiver operating characteristic(ROC)curves,calib-ration plots,and decision curve analysis(DCA).Results:Three independent predictors of ALNM were identified:clinical N-stage(odds ratio[OR]=6.789;95%confidence interval[CI]:2.203-22.20;P=0.001),short-axis diameter of lymph nodes on CT(OR=1.686;95%CI:1.349-2.257;P<0.001),and cortical thickness(OR=6.296;95%CI:2.170-19.310;P=0.001).The nomogram showed strong discrimination,with areas under the ROC curve(AUC)of 0.918(95%CI:0.860-0.977)in the training cohort and 0.885(95%CI:0.809-0.962)in the validation cohort.Calibration was confirmed by Hosmer-Lemeshow tests(P=0.609 and P=0.694 for training and validation cohorts,respectively).DCA demon-strated clinical utility across probability thresholds of 0.02-0.96 and 0.03-0.87 in the training and validation cohorts,respectively.Conclu-sions:This nomogram,integrating MDCT imaging features and clinical indicators,provides a practical tool for individualized preoperative risk assessment and may aid clinical decision-making in patients with TNBC.

The construction of a new cultural system for high-quality development in public hospitals serves as a crucial pillar for achieving their high-quality advancement.During this developmental processe stablishing a cultural framework that aligns with the new development model holds particular significance.Through content analysis methodology,it identifies 18 core elements of the new cultural system for high-quality development in public hospitals.Furthermore it synthesizes seven implementation pathways across three dimensions-organizational patientand employee perspectives:digital leadership organizational reform capability talent innovation capability resource integration capability normative constraint force value co-creation capability and employee support capability.These findings provide both theoretical and practical references for cultivating new cultural constructs that facilitate high-quality development in public hospitals.

BACKGROUND: Double-stranded RNA-specific adenosine deaminase 1 (ADAR1) binds to double-stranded RNA and catalyzes the deamination of adenosine (A) to inosine (I). The functional mechanism of ADAR1 in non-small cell lung cancer (NSCLC) remains incompletely understood. This study aimed to investigate the prognostic significance of ADAR1 in NSCLC and to elucidate its potential role in regulating tumor cell proliferation and migration. METHODS: Data from The Cancer Genome Atlas (TCGA) and cBioPortal were analyzed to assess the correlation between high ADAR1 expression and clinicopathological features as well as prognosis in lung cancer. We performed Western blot (WB), cell proliferation assays, Transwell invasion/migration assays, and nude mouse xenograft modeling to examine the phenotypic changes and molecular mechanisms induced by ADAR1 knockdown. Furthermore, the ADAR1 p150 overexpression model was utilized to validate the proposed mechanism. RESULTS: ADAR1 expression was significantly elevated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tissues compared with adjacent non-tumor tissues (LUAD: P=3.70×10-15, LUSC: P=0.016). High ADAR1 expression was associated with poor prognosis (LUAD: P=2.03×10-2, LUSC: P=2.81×10-2) and distant metastasis (P=0.003). Gene Set Enrichment Analysis (GSEA) indicated that elevated ADAR1 was associated with mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway activation, matrix metalloproteinase-9 (MMP-9) expression, and cell adhesion. ADAR1 and MMP-9 levels showed a strongly positive correlation (P=6.45×10-34) in 10 lung cancer cell lines, highest in H1581. Knockdown of ADAR1 in H1581 cells induced a rounded cellular morphology with reduced pseudopodia. Concomitantly, it suppressed cell proliferation, invasion, migration, and in vivo tumorigenesis. It also suppressed ERK phosphorylation and downregulated cellular Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog (c-FOS), MMP-9, N-cadherin, and Vimentin. Conversely, ADAR1 p150 overexpression in PC9 cells enhanced ERK phosphorylation and increased c-FOS and MMP-9 expression. CONCLUSIONS High ADAR1 expression is closely associated with poor prognosis and distant metastasis in NSCLC patients. Mechanistically, ADAR1 may promote proliferation, invasion, migration, and tumorigenesis in lung cancer cells via the ERK/c-FOS/MMP-9 axis.
Humans ; Lung Neoplasms/physiopathology* ; Adenosine Deaminase/genetics* ; Matrix Metalloproteinase 9/genetics* ; Cell Proliferation ; Carcinoma, Non-Small-Cell Lung/physiopathology* ; Cell Movement ; Animals ; Mice ; RNA-Binding Proteins/genetics* ; Female ; Male ; Cell Line, Tumor ; Proto-Oncogene Proteins c-fos/genetics* ; Middle Aged ; MAP Kinase Signaling System ; Gene Expression Regulation, Neoplastic ; Mice, Nude ; Extracellular Signal-Regulated MAP Kinases/genetics*

Objective To explore the relationship between hemorheology and Carotid Atherosclerosis.Methods The clinical data of 153 patients who underwent both hemorheological testing and carotid artery ultrasound were divided into a CAS group(n=96)and a non-CAS group(n=57)based on ultrasound findings.Clinical data and laboratory indicators were compared between two groups.Multivariate logistic regression analysis was used to explore the influencing factors of CAS.The ROC curves graph were drawn to observe the role of hemorheological indicators in predicting CAS and select the optimal cutoff value based on the maximum Youden index.Results The CAS group demonstrated higher levels in age,BMI,RBC aggregation index,low&high shear reduced viscosity of whole blood,plasma viscosity and fibrinogen compared to the non-CAS group(P<0.05).The multivariate logistic regression analysis showed that plasma viscosity(OR=38.270,95%CI:1.206～1214.508),age(OR=1.119,95%CI:1.065～1.176)were risk factors for the occurrence of CAS(P<0.05).The ROC curves showed that the area under the curve(AUC)of plasma viscosity and age were 0.623、0.728.Conclusion CAS patients have high levels of plasma viscosity and advanged age compared to the patient without CAS.Elevated plasma viscosity and age is a risk factor for CAS,with plasma viscosity≥1.46 mPa·s,over the age of 56.5 as a significant value for predicting CAS.

BACKGROUND: Spicy food consumption has been reported to be inversely associated with mortality from multiple diseases. However, the effect of spicy food intake on the incidence of vascular diseases in the Chinese population remains unclear. This study was conducted to explore this association. METHODS: This study was performed using the large-scale China Kadoorie Biobank (CKB) prospective cohort of 486,335 participants. The primary outcomes were vascular disease, ischemic heart disease (IHD), major coronary events (MCEs), cerebrovascular disease, stroke, and non-stroke cerebrovascular disease. A Cox proportional hazards regression model was used to assess the association between spicy food consumption and incident vascular diseases. Subgroup analysis was also performed to evaluate the heterogeneity of the association between spicy food consumption and the risk of vascular disease stratified by several basic characteristics. In addition, the joint effects of spicy food consumption and the healthy lifestyle score on the risk of vascular disease were also evaluated, and sensitivity analyses were performed to assess the reliability of the association results. RESULTS: During a median follow-up time of 12.1 years, a total of 136,125 patients with vascular disease, 46,689 patients with IHD, 10,097 patients with MCEs, 80,114 patients with cerebrovascular disease, 56,726 patients with stroke, and 40,098 patients with non-stroke cerebrovascular disease were identified. Participants who consumed spicy food 1-2 days/week (hazard ratio [HR] = 0.95, 95% confidence interval [95% CI] = [0.93, 0.97], P <0.001), 3-5 days/week (HR = 0.96, 95% CI = [0.94, 0.99], P = 0.003), and 6-7 days/week (HR = 0.97, 95% CI = [0.95, 0.99], P = 0.002) had a significantly lower risk of vascular disease than those who consumed spicy food less than once a week ( Ptrend <0.001), especially in those who were younger and living in rural areas. Notably, the disease-based subgroup analysis indicated that the inverse associations remained in IHD ( Ptrend = 0.011) and MCEs ( Ptrend = 0.002) risk. Intriguingly, there was an interaction effect between spicy food consumption and the healthy lifestyle score on the risk of IHD ( Pinteraction = 0.037). CONCLUSIONS Our findings support an inverse association between spicy food consumption and vascular disease in the Chinese population, which may provide additional dietary guidance for the prevention of vascular diseases.
Humans ; Male ; Female ; Prospective Studies ; Middle Aged ; Aged ; Vascular Diseases/etiology* ; Risk Factors ; China/epidemiology* ; Adult ; Proportional Hazards Models ; Cerebrovascular Disorders/epidemiology* ; East Asian People

Objective:To explore the optimal age cutoff for diagnosis and the prognosis of early-onset gastric cancer in young patients.Methods:Clinicopathological data of patients with gastric adenocarcinoma aged ≤45 years who had undergone radical gastrectomy in the Department of Gastric Surgery, Fudan University Shanghai Cancer Center from January 2013 to December 2018 were retrospectively collected. Patients with distant metastases, other malignant tumors, combined organ resection, gastric stump cancer, positive margin, and incomplete clinical or follow-up data were excluded. X-tile software analysis of the actual overall survival of the collected cases yielded an optimal cut-off of 32 years. Accordingly, the enrolled cases were divided into an early-onset young group (age ≤32 years) and young adult group (age >32 years). Clinicopathological characteristics, long-term survival, and postoperative recurrence were compared between the two groups. Univariate and multivariate analyses were performed using the Cox proportional hazards model to identify the factors affecting the prognosis of young patients with gastric cancer.Results:The study cohort comprised 462 patients, including 256 (55.4%) women, 419 (90.7%) with middle and lower gastric cancers, and 343 (74.2%) with poorly differentiated tumors. There were 101 patients in the early-onset young group and 361 in the young adult group. These groups did not differ significantly in terms of sex, body mass index, tumor location, tumor size, surgical procedure, neurovascular invasion, or tumor stage (all P>0.05). The proportion of patients with poorly differentiated tumors in the early-onset young group was significantly higher than that in the young adult group (89.1%[90/101] vs. 70.1%[253/361], χ 2=15.26, P<0.001). All study patients completed 5 years of follow-up, the median duration of which was 101 months (61-133 months). Death or tumor recurrence occurred in 151 patients (32.7%), in 118 of whom the sites of recurrence and metastasis could be identified, 38 in the early-onset young group and 80 in the young adult group. Fifty-five (46.6%) patients developed peritoneal metastases and 40 (33.9%) hematogenous metastases. In the early-onset young group, 20 patients developed peritoneal metastases, 11 hematogenous metastases, five distant lymph node metastases, and two local recurrence. In the young adult group, 35 patients developed peritoneal metastases, 29 hematogenous metastases, six local recurrences, and 10 distant lymph node metastases. The 5-year overall survival and disease-free survival rates were significantly higher in the young adult group than in the early-onset young group (73.7% vs. 57.4%, P=0.002 and 70.6% vs. 55.4%, P=0.004, respectively). Cox multivariate analysis showed that age >32 years (HR=0.63, 95%CI: 0.43-0.90, P=0.012) was an independent protective factor for overall survival, whereas later N stage (HR=1.67, 95%CI:1.09-2.57, P=0.018) was an independent risk factor for overall survival after surgery ( P<0.05). Age >32 years (HR=0.60, 95%CI: 0.41-0.86, P=0.006) was also an independent protective factor for disease-free survival, whereas later N stage was an independent risk factor (HR=1.69, 95%CI: 1.08-2.64, P=0.021). Conclusion:Young patients with early-onset gastric cancer aged ≤32 years have worse tumor differentiation and prognosis.

Objective:To investigate the impact of bedside ultrasound-guided hyperthermic intraperitoneal chemotherapy (HIPEC) after laparoscopic gastric cancer surgery on the prognosis of patients with only positive peritoneal lavage cytology (CY+) and no other distant metastases.Methods:The clinicopathological data of 49 patients with only positive peritoneal lavage cytology who underwent laparoscopic gastrectomy and D2 lymph node dissection from December 2017 to December 2022 were retrospectively analyzed. The patients were divided into the HIPEC group (27 cases) and the non-HIPEC group (22 cases) based on whether they received postoperative bedside ultrasound-guided HIPEC. The patterns of postoperative recurrence and metastasis and the 3-year survival rates were compared between the two groups. Univariate and multivariate analyses using the Cox proportional hazards model were conducted to determine the prognostic factors.Results:There was no statistically significant difference in all baseline clinicopathological data between the two groups ( P>0.05); the median follow-up time for all patients was 31 months (ranging from 13 to 73 months), and the overall recurrence rate for all patients was 55.1% (27/49). Among them, 12 cases (24.5%) had peritoneal metastasis, 7 cases (14.3%) had hematogenous recurrence, 5 cases (10.2%) had distant lymph node metastasis, and 3 cases (6.1%) had local recurrence. The overall recurrence rates of patients in the HIPEC group and the non-HIPEC group were 51.8% (14/27) and 59.1% (13/22), respectively. There was no statistically significant difference (χ 2=0.26, P=0.612). The peritoneal metastasis rate of patients in the HIPEC group was 18.5% (5/27), which was lower than that of the non-HIPEC group at 31.8% (7/22). However, there was no statistically significant difference (χ 2=1.16, P=0.282). The proportions of local recurrence, hematogenous metastasis, and distant lymph node metastasis were comparable between the two groups (all P>0.05). The cumulative 3-year recurrence rates of the two groups were similar (70.7% vs. 71.3%, P=0.266). In the HIPEC group, the 3-year overall survival rate was 61.1%, which was significantly higher than that of the non-HIPEC group (31.5%). The difference was statistically significant ( P=0.014). The disease-free progression survival rates of the two groups were 29.3% and 28.7% respectively, and there was no statistically significant difference between them ( P=0.266). Cox multivariate analysis showed that no postoperative HIPEC (HR=5.21, 95%CI:1.90-14.31, P=0.001), poor tumor differentiation (HR=3.78, 95%CI:1.07-13.26, P=0.038), and later N stage (HR=6.18, 95%CI:1.39-7.59, P=0.017) were independent risk factors for the overall survival rate after surgery ( P<0.05). Later N stage (HR=3.67, 95%CI:1.07-12.55, P=0.038) was an independent risk factor for the disease-free progression survival rate after surgery ( P<0.05). Conclusion:Bedside ultrasound-guided HIPEC after laparoscopic gastrectomy and D2 lymph node dissection can improve the overall survival of CY+ gastric cancer patients.

Protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in liver cancer, yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined. Here, we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8⁺ T-cell-mediated antitumor immunity both in vivo and in vitro. Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule, fibrinogen-like protein 1 (FGL1). Mechanistically, PRMT5 catalyzed symmetric dimethylation of transcription factor 12 (TCF12) at arginine 554 (R554), prompting the binding of TCF12 to FGL1 promoter region, which transcriptionally activated FGL1 in tumor cells. Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression, which promoted CD8⁺ T-cell-mediated antitumor immunity. Notably, combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice. Collectively, our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.

Cells and exosomes derived from them are extensively used as biological carrier systems. Cells demonstrate superior targeting specificity and prolonged circulation facilitated by their rich array of surface proteins, while exosomes, due to their small size, cross barriers and penetrate tumors efficiently. However, challenges remain, cells' large size restricts tissue penetration, and exosomes have limited targeting accuracy and short circulation times. To address these challenges, we developed a novel concept termed exosomal spheres. This approach involved incorporating platelet-derived exosomes shielded with phosphatidylserine (PS) and linked via pH-sensitive bonds for drug delivery applications. The study demonstrated that, compared with exosomes, the exosomal spheres improved blood circulation through the upregulation of CD47 expression and shielding of phosphatidylserine, thereby minimizing immune clearance. Moreover, the increased expression of P-selectin promoted adhesion to circulating tumor cells, thereby enhancing targeting efficiency. Upon reaching the tumor site, the hydrazone bonds of exosome spheres were protonated in the acidic tumor microenvironment, leading to disintegration into uniform-sized exosomes capable of deeper tumor penetration compared to platelets. These findings suggested that exosome spheres addressed the challenges and offered significant potential for efficient and precise drug delivery.