Background/Aims: Liver transplantation (LT) following total hepatectomy is a life-saving treatment for hepatocellular carcinoma (HCC). The HCC recurrence after LT hinders the effectiveness of the procedure. The objective of this study is to develop a pre-operative risk stratification model based on a liquid biopsy. Methods: We conducted a comprehensive multi-omics study of 260 HCC patients from three centers, including clinical data, low-coverage whole-genome sequencing of cell-free DNA (cfDNA) from plasma, as well as whole-exome, single-nucleus RNA, and spatial transcriptomics from matched tumor and non-tumor tissues. Results: We identified cfDNA-derived copy number alteration (CNA) signatures associated with post-transplant recurrence. By integrating cfDNA-derived CNA profiles with single-cell transcriptomic data, we traced recurrence-associated cfDNA to a distinct subpopulation of malignant cells within the primary tumor. These cells were embedded in a pro-metastatic microenvironment of specialized endothelial subtypes and cancer-associated fibroblasts. Notably, most recurrence-associated lesions were detectable in cfDNA prior to liver transplantation (LT). Building on these insights, we developed the ZJU Criteria based on CNA fragments and tumor markers, a pre-LT risk prediction tool that integrates conventional clinical factors with cfDNA-derived CNA signatures, and validated it using internal and independent external cohorts. Conclusion Our findings suggest that post-transplant recurrence commonly originates from advanced subclones that emerge late during tumor evolution. The ZJU Criteria provides an accurate, non-invasive strategy that significantly improves pre-LT risk stratification and clinical decision-making for patients with HCC.

The circadian clock is a highly conserved timekeeping system in organisms, which maintains physiological homeostasis by precisely regulating periodic fluctuations in gene expression. Substantial clinical and experimental evidence has established a close association between circadian rhythm disruption and the development of various malignancies. Research has revealed characteristic alterations in the circadian gene expression profiles in tumor tissues, primarily manifested as a dysfunction of core clock components (particularly circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1)) and the widespread dysregulation of their downstream target genes. Notably, CLOCK demonstrates non-canonical oncogenic functions, including epigenetic regulation via histone acetyltransferase activity and the circadian-independent modulation of cancer pathways. This review systematically elaborates on the oncogenic mechanisms mediated by CLOCK/BMAL1, encompassing multidimensional effects such as cell cycle control, DNA damage response, metabolic reprogramming, and tumor microenvironment (TME) remodeling. Regarding the therapeutic strategies, we focus on cutting-edge approaches such as chrononutritional interventions, chronopharmacological modulation, and treatment regimen optimization, along with a discussion of future perspectives. The research breakthroughs highlighted in this work not only deepen our understanding of the crucial role of circadian regulation in cancer biology but also provide novel insights for the development of chronotherapeutic oncology, particularly through targeting the non-canonical functions of circadian proteins to develop innovative anti-cancer strategies.
Humans ; ARNTL Transcription Factors/physiology* ; Neoplasms/therapy* ; CLOCK Proteins/physiology* ; Circadian Clocks/genetics* ; Animals ; Circadian Rhythm/genetics* ; Tumor Microenvironment ; Epigenesis, Genetic ; Gene Expression Regulation, Neoplastic

Early correction of childhood malocclusion is timely managing morphological, structural, and functional abnormalities at different dentomaxillofacial developmental stages. The selection of appropriate imaging examination and comprehensive radiological diagnosis and analysis play an important role in early correction of childhood malocclusion. This expert consensus is a collaborative effort by multidisciplinary experts in dentistry across the nation based on the current clinical evidence, aiming to provide general guidance on appropriate imaging examination selection, comprehensive and accurate imaging assessment for early orthodontic treatment patients.
Humans ; Malocclusion/diagnostic imaging* ; Child ; Consensus

Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

OBJECTIVE: To screen factors affecting the prognosis of chronic myeloid leukemia (CML) patients, and construct a nomogram model for event-free survival (EFS). METHODS: To screen out meaningful variables by univariate and multivariate Cox regression analysis in CML patients, and construct a nomogram model using R software. The nomogram was validated using consistency index (C-index), receiver operating characteristic (ROC) curve, area under the ROC curve (AUC), calibration curve, decision curve analysis (DCA), and risk stratification analysis. RESULTS: This study analyzed data from 116 CML patients. Univariate and multivariate Cox regression analysis demonstrated that age, peripheral blood basophil percentage, BCR-ABL1 ^IS at 3 months, and red blood cell distribution width (RDW) were independent prognostic factors of EFS. Subsequently, a nomogram was constructed based on the above predictors. The C-index of the nomogram was 0.733(95%CI : 0.676-0.790). The AUC values for predicting 1-, 3-, and 5-year EFS rate were 0.765, 0.855, and 0.827, respectively. The results of the calibration curve and DCA curve showed that the predictive model had good consistency, as well as strong clinical utility. The patients were stratified into high-risk group and low-risk group based on the total score of the model, there was a significant difference in EFS between the two groups (P < 0.001). CONCLUSION Age, peripheral blood basophil percentage, BCR-ABL1 ^IS at 3 months, and RDW were associated with the prognosis of CML patients. The nomogram model constructed in this study can accurately predict the prognostic status of CML patients, but its widespread application still requires external and prospective validation.
Nomograms ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality* ; Proportional Hazards Models ; Erythrocyte Indices ; Risk Assessment/methods* ; Fusion Proteins, bcr-abl/genetics* ; Basophils ; Leukocyte Count ; Humans

BACKGROUND: Lung cancer is one of the malignant cancers with the highest incidence rate, and it is important to identify the factors contributing to lung cancer carcinogenesis for prevention. Lifestyle and genetic factors play important roles in cancer development, however the impact of dietary factors, such as soy product intake, on lung cancer risk remains inadequately understood. This study aims to explore the associations between soy product intake, genetic risk, and lung cancer incidence, and validate the consistent effects of soy product intake in European populations, thereby providing new insights for lung cancer prevention. METHODS: Utilizing the Shanghai Suburban Adult Cohort and Biobank (SSACB) (n=66,311), Cox proportional hazards model was adopted to assess the association between soy product intake and lung cancer incidents, followed by subgroup analyses stratified by gender, smoking status, and pathological types of lung cancer. The UK Biobank (UKB) was used for validation of the effect of soy product intake on lung cancer. To investigate the association between genetic factors and lung cancer, in addition to previously reported loci, we incorporated newly identified loci from two independent studies in Southeast China: a nested case-control population from the SSACB cohort (433 cases/650 controls) and a case-control study from the Shanghai Cancer Center-Taizhou cohort (1359 cases/1359 controls). Meta-analysis and Linkage disequilibrium clumping (LD clumping) of the association results identified 23 loci for polygenic risk score (PRS) construction. Subsequently, conditional Logistic regression model was used to assess the association between genetic risk and lung cancer. RESULTS: In SSACB cohort, after adjusting for age, gender, smoking, chronic bronchitis, body mass index (BMI), vegetable intake and red meat intake, sufficient soy product intake was significantly associated with a reduced risk of lung cancer [hazard ratio (HR)=0.60, 95%CI: 0.47-0.77, Padj=6.69E-05], an effect that was consistent in males and females, smokers and non-smokers. In UKB, although the association did not reach statistical significance, a protective trend against lung cancer was also observed (HR=0.76, 95%CI: 0.55-1.06, Padj=0.10). In the nested case-control population within SSACB, a PRS score generated in the Chinese population was significantly correlated with lung cancer risk. After adjustment of age, gender, smoking, chronic bronchitis, and soy product intake, the high-PRS group had a 1.88 times higher risk of lung cancer compared to the low-PRS group (Padj=1.84E-03). CONCLUSIONS The prospective cohort study found that adequate intake of soy products was significantly associated with a reduced risk of lung cancer, while a high PRS is a risk factor for lung cancer development. Integrating soy product intake and PRS into traditional epidemiological risk factor prediction will guide personalized lung cancer prevention and high-risk population stratification.
Humans ; Lung Neoplasms/etiology* ; Male ; Female ; China/epidemiology* ; Middle Aged ; Adult ; Aged ; Prospective Studies ; Biological Specimen Banks ; Risk Factors ; Case-Control Studies ; Cohort Studies

Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.

Objective To investigate the risk factor for adverse events(AEs)after non-sedated esophagogastroduodenoscopy(EGD).Methods The data on clinical manifestations,adverse events after non-sedated EGD and common risk factors were collected and retrospectively analyzed with statistical methods in patients who underwent non-sedated EGD from May 2018 to June 2019.These patients were divided into AEs group and non-AEs group.Results Of 2 384 patients,57.67%(1 375/2 384)presented with nausea,12.79%(305/2 384)vomiting,and 5.79%(138/2 384)presented with pharyngalgia.Multivariate Logistic regression analysis was performed.Advanced age(≥65 years old)(OR=0.683,95%CI:0.506-0.921)was protective factors for nausea after non-sedated EGD.Hypertension(OR=1.361,95%CI:1.026-1.806),overweight(OR=1.399,95%CI:1.154-1.695),obesity(OR=2.594,95%CI:1.760-3.823)and inspection duration>15 min(OR=3.107,95%CI:2.296-4.206)were independent risk factors for nausea after non-sedated EGD.Advanced age(OR=0.393,95%CI:0.221-0.699)and imported equipment(OR=0.697,95%CI:0.546-0.890)were protective factors for vomiting after non-sedated EGD.Moreover,inspection duration>15 min(OR=1.641,95%CI:1.008-2.699)was independent risk factors for vomiting after non-sedated EGD.There was no difference in success rate of non-sedated EGD between two groups(P<0.05).Conclusion Hypertension,overweight and obesity were independent risk factors for nausea after non-sedated EGD.The advanced age and imported equipment were protective factors for vomiting after non-sedated EGD.In addition,inspection duration over 15 min is a risk factor for AEs such as nausea and vomiting after nonsedative EGD.Whether AEs occurred or not is non-related to success rate of non-sedated EGD.