OBJECTIVE: Circadian rhythm disruption (CRD) is a risk factor that correlates with poor prognosis across multiple tumor types, including hepatocellular carcinoma (HCC). However, its mechanism remains unclear. This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity. METHODS: To quantify CRD, the HCC CRD score (HCCcrds) was developed. Using machine learning algorithms, we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort (n = 369), and the robustness of this method was validated. Furthermore, we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes. RESULTS: We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis. The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis, higher pathological grade, and advanced clinical stages, while the CRD-related subtype with low HCCcrds had better clinical outcomes. We also identified novel biomarkers for each subtype, such as nicotinamide n-methyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1. CONCLUSION We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers. Within these groups greater HCCcrds was associated with worse prognosis. This approach has the potential to improve prediction of an individual's prognosis, guide precision treatments, and assist clinical decision making for HCC patients. Please cite this article as: Li XJ, Chang L, Mi Y, Zhang G, Zhu SS, Zhang YX, et al. Integrated-omics analysis defines subtypes of hepatocellular carcinoma based on circadian rhythm. J Integr Med. 2025; 23(4): 445-456.
Humans ; Carcinoma, Hepatocellular/pathology* ; Liver Neoplasms/pathology* ; Circadian Rhythm/genetics* ; Prognosis ; Male ; Female ; Biomarkers, Tumor/genetics* ; Middle Aged ; Machine Learning ; Computational Biology

OBJECTIVE: Hepatocellular carcinoma (HCC) is sensitive to ferroptosis, a new form of programmed cell death that occurs in most tumor types. However, the mechanism through which ferroptosis modulates HCC remains unclear. This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy. METHODS: Using clinicopathological parameters and bioinformatic techniques, we comprehensively examined the expression of FANCD2 macroscopically and microcosmically. We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death. RESULTS: FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration. As an independent risk factor for HCC, a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade. Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism. CONCLUSION To the best of our knowledge, this is the first study to comprehensively elucidate the oncogenic role of FANCD2. FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC; hence, it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.
Humans ; Carcinoma, Hepatocellular/diagnosis* ; Liver Neoplasms/diagnosis* ; Immunotherapy ; Fanconi Anemia Complementation Group D2 Protein/metabolism* ; Prognosis ; Male ; Female ; Middle Aged ; Biomarkers, Tumor/metabolism*

This research investigated the contamination level,distribution of drug-resistant strains,and molecular epidemiologi-cal characteristics of Campylobacter,and further explored transmission pathways and prevention strategies.Cecum,chicken carcass,chicken product,and environmental samples,as well as swabs from workers'hands,were collected from a slaughterhouse in a large broiler group in the Jiaodong area between August 2023 and July 2024.Quantitative contamination assessment of Campylobacter in chicken carcasses and chicken products was performed.After microbial mass spectrometry identification,the representative strains of different links were selected for drug resistance testing and whole genome sequencing(WGS).On the basis of the sequencing results,the resistance genes,virulence genes,multilocus sequence typing(MLST),and phylogenetic characteristics of representative strains were analyzed.Homology comparisons were performed between isolates and strains from patients with diarrhea in the NCBI database.A total of 297 Campylobacter strains were isolated from 806 samples,and the overall detection rate was 36.85%.The detection rate of Campylobacter was highest in the evisceration process(47.33%),followed by the cutting process(35.64%).Overall,the Campylo-bacter detection rate first increased,then decreased,and subsequently increased.Drug sensitivity testing revealed that 90 isolates were resistant to nalidixic acid and ciprofloxacin,and 94.97%of isolates were resistant to tetracycline.WGS showed that both Campylo-bacter jejuni(C.jejuni)and Campylobacter coli(C.coli)carried many drug resistance and virulence genes.ST-14176 of C.jejuni was isolated for the first time herein.The predominant ST-8261 strain of C.jejuni and ST-860,ST-829,and ST-1586 strains of C.coli are known to cause human diarrhea.LOS expression genes associated with Guillain-Barré syndrome(GBS)were detected in both C.jejuni isolates from the slaughter chain and patients with GBS.Some strains exhibited close genetic relatedness to human-derived Campylo-bacter strains from the NCBI database.The detection rate of Campylobacter in the slaughterhouse first increased,then decreased,and subsequently increased,and the quantitative contamination level of each link was similar to the detection rate.Quantitative analysis of chicken carcasses/products revealed that the average bacterial load was highest in eviscerated carcasses(102.80 cfu/g),and the high-est amount of Campylobacter in chicken products reached 451.80 cfu/g.Abundant drug resistance genes and virulence genes were iden-tified,and the drug resistance genes were highly correlated with the drug resistance rate.Therefore,surveillance intensity and control measures for Campylobacter in slaughter processes should be strengthened.

Objective To observe the effects of four different modeling method on the hypothalamus-pituitary-adrenal(HPA)axis,blood rheology,platelet aggregation rate,and myocardial ischemia in rats,and to provide new ideas for the establishment of a rat model of"double heart"disease in line with clinical diagnosis and treatment characteristics.Methods Sixty-nine male Sprague-Dawley rats were divided randomly into a Control group(unstimulated),chronic unpredictable mild stimulation(CUMS)group,isoproterenol(ISO)group(intraperitoneal injection of ISO),high-fat diet(HFD)group(fed high-fat chow),and composite model(CUMS+ISO+HFD)group(n=12 rats in the Control and HFD groups;n=15 rats in the other three groups,respectively).Modeling procedures were carried out for a total of 8 weeks,with ISO injection started from week 6 of the experiment for a total of 3 weeks.At the end of modeling,rats in each group were subjected to absent-field and sugar-water preference behavioral tests.Electrocardiography(ECG)was performed to observe changes in ECG lead Ⅱ in each group.Serum levels of adrenocorticotropic hormone(ACTH),cortisol(Cor),corticosterone(CORT),endothelin-1(ET-1),and soluble intercellular adhesion molecule-1(sICAM-1)were detected by enzyme-linked immunosorbent assay.Myocardial histopathological changes were detected by hematoxylin/eosin(HE)staining.Serum total cholesterol(TC),triglycerides(TG),low-density lipoprotein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C)were measured using an enzyme labeling instrument.Whole-blood high-cut viscosity(200 V/S),whole-blood low-cut viscosity(10 I/S),plasma viscosity,and fibrinogen were assessed using an automatic blood rheology analyzer.The maximum platelet aggregation rate(MAR)and average platelet aggregation rate(AAR)induced by arachidonic acid and adenosine diphosphate were detected using a whole-blood platelet aggregometer.Results Compared with the Control group,all four model groups had significantly lower absenteeism distance and number of entries into the central region in the absent-field test,and a lower sugar-water preference ratio(P＜0.01).ECG revealed ST-segment elevation in the ISO and CUMS+ISO+HFD groups,tachycardia in the CUMS group,and mild ST-segment elevation in the HFD.Serum ACTH,Cor,CORT,ET-1,and sICAM-1 were all significantly elevated in the four model groups(P＜0.01).HE staining showed that myocardial tissue was severely damaged in rats in the ISO and CUMS+ISO+HFD groups,with pathological changes such as localized fibrosis and inflammatory infiltration of the myocardium,while mild cardiomyocyte disarrangement and fracture was seen in the CUMS and HFD groups.Rats in the HFD group had increased serum TC and LDL(P＜0.01)and decreased HDL contents(P＜0.01).Compared with the Control group,whole-blood high-cut viscosity(200 V/S),whole-blood low-cut viscosity(10 I/S),plasma viscosity,and fibrinogen were all increased in the CUMS,HFD,and CUMS+ISO+HFD groups(P＜0.01,P＜0.05),while whole blood high-cut viscosity(200 V/S),whole blood low-cut viscosity(10 I/S),plasma viscosity,and fibrinogen levels were decreased in rats in the ISO group(P＜0.01,P＜0.05).MAR and AAR were significantly higher in rats in the CUMS,HFD,and CUMS+ISO+HFD groups(P＜0.01),while the platelet aggregation rate was decreased in the ISO group compared with the Control group(P＜0.01,P＜0.05).Conclusions These result showed that the rat CUMS+ISO+HFD model better reflected the complexity of clinical double heart disease than the other three models.

OBJECTIVE To explore the clinical distribution and drug resistance of common species of pathogens iso-lated from a three-A hospital of Guangzhou from Jan.2017 to 2023 Dec.so as to provide bases for clinical diagno-sis and reasonable use of antibiotics.METHODS A total of 10,086 strains of aerobic bacteria were clinically isola-ted from the patients who were hospitalized in a three-A hospital of Guangzhou from 2017 to 2023.The constituent ratios of the common species of pathogens,specimen sources,distribution of departments and drug resistance rates to commonly used antibiotics were retrospectively analyzed.RESULTS Totally 10,086 strains of pathogens were isolated from the specimens of the hospitalized patients from 2017 to 2023.Klebsiella pneumoniae,Pseudo-monas aeruginosa,Escherichia coli,Acinetobacter baumannii and Staphylococcus aureus ranked the top 5 species of pathogens.The sputum,midstream urine and whole blood were the major specimen sources.The hospital-asso-ciated infection was highly prevalent in critical care medicine department,neurology department,geriatrics depart-ment,neurosurgery department and urology department.The result of drug resistance showed that the drug re-sistance rates of the K.pneumoniae and P.aeruginosa strains to various types of antibiotics showed upward trends(P＜0.05);the drug resistance rate of the A.baumannii strains to imipenem was decreased,while the drug resist-ance rates to most of the antibiotics were more than 45％.No gram-positive cocci strains that were resistant to vancomycin,teicoplanin or linezolid were found.CONCLUSIONS The common clinical isolates of pathogens are generally resistant to antibiotics.It is necessary for clinicians to attach great importance to the culture of pathogens and drug susceptibility testing and reasonably use antibiotics based on the result of drug susceptibility testing so as to reduce the occurrence and spread of drug-resistant strains.The hospital should strengthen the surveillance of drug resistance of bacteria so as to boost the clinical curative effect,standardize the management and use of antibi-otics and take effective measures to control of the hospital-associated infection.

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

OBJECTIVE: To investigate the effects of low-dose irradiated autologous peripheral blood reinfusion (LDIAPBR) on a rat model of radiation-induced leukopenia. METHODS: The rats were randomly divided into four groups. In the LDIAPBR group, LDIAPBR was performed 1 day before modeling (10% of the total circulating blood volume was withdrawn, irradiated with 100 mGy ex vivo, and completely reinfused). Meanwhile, the normal group and model group only underwent blood withdrawal and reinfusion of the same proportion without blood irradiation. Except for the normal group, all groups were subjected to 1 Gy X-ray whole-body irradiation to establish a radiation-induced leukopenia rat model. The positive drug group received subcutaneous injection of rhG-CSF after modeling. It was monitored that the general condition of the rats, peripheral blood cell counts, immune organ indices, bone marrow nucleated cell counts and viability, and the pathological analysis of bone marrow sections was conducted. RESULTS: The LDIAPBR group exhibited significant improvements in overall condition compared to the model group. Notably, compared with the model group, peripheral blood leukocyte and lymphocyte counts were markedly higher in the LDIAPBR group. Furthermore, there was a significant increase in both the number and viability of nucleated cells in the bone marrow. Pathological examination of bone marrow sections revealed increased nucleated cell density and reduced cavity area in the LDIAPBR group. CONCLUSION LDIAPBR can effectively improve hematological parameters and bone marrow hematopoietic function in a rat model of radiation-induced leukopenia, providing a new approach for the prevention and treatment of radiation-related injuries.
Animals ; Leukopenia/prevention & control* ; Rats ; Blood Transfusion, Autologous ; Whole-Body Irradiation ; Radiation Injuries, Experimental/therapy*

Objective:To investigate the predictive value of A2DS2 score combined with neutrophil percentage/albumin ratio(NPAR)and D-dimer for the occurrence of stroke-associated pneumonia(SAP)in acute ischemic stroke(AIS)patients.Methods:Retrospective analysis of the clinical data of 265 AIS patients admitted to the Southern Theater Command Air Force Hospital from November 2017 to November 2023.AIS patients were divided into SAP group and non-SAP group according to whether occurrence of SAP within one week of onset.Collect clinical data from two groups of patients,calculate A2DS2 score,NPAR,detected the D-dimer levels of two groups.Spearman correlation analysis on the relationship between A2DS2 score and NPAR,D-dimer levels.Multiple factor logistic regression analysis were used to identify independent risk factors.The predictive values were analyzed by receiver operating characteristic(ROC)curve,Constructing a modifed A2DS2(mA2DS2)score based on the optimal cutoff values of A2DS2 score,NPAR and D-dimer,the predictive values of the mA2DS2 score was analyzed by ROC curve.Results:A total of 265 AIS patients were included in this study,of which 78 patients with AIS developed SAP within one week of onset,and the incidence rate of SAP was 29.43％.There were statistically difference in comparison of age,national institute of health stroke scale(NIHSS)score at admission,swallowing difficulties,atrial fibrillation,history of stroke,A2DS2 score,D-dimer,fibrinogen levels,systemic immune-inflammation index(SII),neutrophil to lymphocyte ratio(NLR),platelet to lymphocyte ratio(PLR),NPAR between SAP group and non-SAP group(P＜0.05).A2DS2 score was positively correlated with NPAR and D-dimer(P＜0.05).The results of the multifactor logistic regression model analysis showed that,elevated NPAR,elevated D-dimer and elevated A2DS2 score were risk factors for the occurrence of SAP in AIS patients(P＜0.05).The area under curve(AUC)predicted by A2DS2 score for the occurrence of SAP in AIS patients was 0.866,the AUC predicted by NPAR for the occurrence of SAP in AIS patients was 0.815,and the AUC predicted by D-dimer for the occurrence of SAP in AIS patients was 0.705.The ROC curve analysis results show that,the AUC predicted by mA2DS2 score for the occurrence of SAP in AIS patients was 0.898,which was greater than the AUC predicted by A2DS2 score alone.Conclusions:The significant increase in A2DS2 score,NPAR and D-dimer levels is associated with the occurrence of SAP in AIS patients,and the A2DS2 score combined with NPAR and D-dimer detection has a high predictive efficiency for the occurrence of SAP in AIS patients.

Purpose Based on the WHO(5th edition)classification of cervical adenocarcinoma and Silva infiltra-tion pattern classification,this study explores the value of etiological classification and Silva classification in the clinical treatment and prognosis prediction of cervical adenocarcinoma.Methods The clinical and pathological features of 112 cases of cervical invasive adenocarcinoma were reviewed.Through HE morphological classification,immunohistochemi-cal detection,and Silva classification of infiltration pattern,the related factors and prognosis of patients were statistical-ly analyzed.Results The median age of 112 patients was 46.5 years(30-80 years),with a maximum tumor diame-ter of 0.35-9.0 cm and an average diameter of 3.2 cm.Most patients showed vaginal bleeding after sexual inter-course.89 cases were HPV-associated adenocarcinoma(HPVAs),18 cases were non HPV-associated adenocarcinoma(NHPVAs).There were 5 cases of other types of adenocarcinomas of the uterine cervix,including 4 cases of endome-trial adenocarcinoma and 1 case of serous adenocarcinoma.There were 5 cases(4.5％)of Silva A pattern,30 cases(26.8％)of Silva B pattern,and 77 cases(68.7％)of Silva C pattern.112 cases were followed up for a median time of 34 months(15-78 months),with 16 deaths and 20 metastases.The progression-free survival(PFS)(P＜0.001)and overall survival(OS)(P=0.001)in the NHPVA group were significantly lower than those in the HPVA group.All cases with Silva A and Silva B pattern had a favorable prognosis and survived without tumor.Of the cases with Silva C pattern,16 died after recurrence.The PFS and OS of patients with Silva C type were lower than those of Silva A type and B type(P＜0.05).Conclusion The fifth edition of WHO classification of cervical adenocarcinoma revealed the correlation between etiology and morphology.Silva classification is of great significance for accurately predicting progno-sis and guiding treatment.