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

Endotoxins are common exogenous pyrogens. Excessive endotoxins in medical devices and injections can lead to serious consequences such as sepsis, septic shock, and even death. Therefore, endotoxin detection plays a crucial role in medical, pharmaceutical, and food sectors. The wide application of Limulus amebocyte lysate (LAL) has led to a sharp decline in the number of horseshoe crabs. Moreover, the LAL assay has limitations such as interbatch variations and difficulty in quantification. The recombinant factor C (rFC) assay is stable between batches, highly sensitive, and capable of quantitation, and thus it can be used as an alternative for the LAL assay. However, the high cost and complex procedures involved in producing recombinant factor C have limited the widespread application of this method. In order to simplify the preparation and reduce the production cost of recombinant factor C, this study focuses on the production of recombinant factor C based on the baculovirus expression system. Multiple measures such as a high-yield and anti-apoptotic vector qBac-IIIG, the optimal signal peptide, and the optimized codon were used to reach the goal of endotoxin detection with cell supernatant. This method simplifies the steps of protein purification. The sensitivity of the supernatant reached 0.05 EU/mL in a 1-L fermentation system, and 500 000 detecting reactions can be supported per liter of fermentation broth. This study increases the yield and activity of recombinant factor C, simplifies the procedures of protein purification, and reduces the cost, laying a foundation for the promotion and application of recombinant factor C in endotoxin detection.
Animals ; Recombinant Proteins/genetics* ; Horseshoe Crabs/chemistry* ; Baculoviridae/metabolism* ; Endotoxins/analysis* ; Protein C/biosynthesis* ; Genetic Vectors/genetics* ; Arthropod Proteins/genetics* ; Enzyme Precursors ; Serine Endopeptidases

The application of mechanics in clinical wound healing has a long history;however,the systematic underlying mechanisms remain unclear.With recent advancements in biomechanics and mechanobiology,the principles regarding how mechanical factors influence the formation,progression,and healing of wounds have gradually been elucidated.Herein,based on progress in theories,technologies,and clinical practices concerning the interplay between mechanics and wound healing,this study introduces the concept of wound-repairing mechanomedicine.Relevant research is systematically reviewed from the perspectives of biomechanics,mechanobiology,and mechanotherapy.Additionally,potential future development directions are prospectively analyzed to provide novel insights into wound care and strategies for preventing scar formation.

Objective:To investigate the risk factors of amputation in patients with diabetic foot ulcer (DFU) in order to improve the prognosis and reduce the amputation rate.Methods:The clinical data of 359 DFU patients admitted to the People′s Hospital of Xinjiang Uygur Autonomous Region from January 2017 to August 2021 were retrospectively analyzed, and they were divided into amputation group (161 cases) and non-amputation group (198 cases) according to whether amputation surgery was performed. Demographic characteristics, Wagner grading and other data of the two groups were collected. Forward step logistic regression analysis was used to identify independent risk factors for amputation, and receiver operating characteristic (ROC) curves were used to evaluate the predictive value of each risk factor for amputation in DFU patients.Results:There were significant differences between the amputation and non-amputation groups in terms of previous amputation history, peripheral vascular diseases (PVD), diabetic foot secondary osteomyelitis, diabetic nephropathy (DN), history of angioplasty, Wanger grade, K +, age, white blood cell count, C-reactive protein, high density lipoprotein cholesterol (HDL-C), estimated glomerular filtration rate, cardiac troponin T, and cardiac troponin I, lactic acid (all P<0.05). Previous amputation history ( OR=2.329, 95% CI: 1.092-4.970, P=0.029), DN ( OR=4.091, 95% CI: 2.222-7.532, P<0.001), PVD ( OR=2.556, 95% CI: 1.487-4.395, P=0.001), diabetic foot secondary osteomyelitis ( OR=6.332, 95% CI: 3.595-11.153, P<0.001), Wagner grade were independent risk factors for amputation in DFU patients, HDL-C ( OR=0.392, 95% CI: 0.182-0.842, P=0.016) were protective factors for amputation in DFU patients. Moreover, the combined accuracy of the above factors in predicting amputation in DFU patients was high, and the area under ROC curve was 0.839 (95% CI: 0.798-0.880), sensitivity was 83%, and specificity was 73% ( OR=0.05). Conclusions:Previous amputation history, DN, PVD, diabetic foot secondary osteomyelitis and Wagner grade are independent risk factors for amputation in DFU patients, while HDL-C is a protective factor for amputation in DFU patients. Further investigation will help to establish a stratified system for predicting the risk of diabetic foot, so as to achieve better individualized treatment.

Objective:To investigate the risk factors of amputation in patients with diabetic foot ulcer (DFU) in order to improve the prognosis and reduce the amputation rate.Methods:The clinical data of 359 DFU patients admitted to the People′s Hospital of Xinjiang Uygur Autonomous Region from January 2017 to August 2021 were retrospectively analyzed, and they were divided into amputation group (161 cases) and non-amputation group (198 cases) according to whether amputation surgery was performed. Demographic characteristics, Wagner grading and other data of the two groups were collected. Forward step logistic regression analysis was used to identify independent risk factors for amputation, and receiver operating characteristic (ROC) curves were used to evaluate the predictive value of each risk factor for amputation in DFU patients.Results:There were significant differences between the amputation and non-amputation groups in terms of previous amputation history, peripheral vascular diseases (PVD), diabetic foot secondary osteomyelitis, diabetic nephropathy (DN), history of angioplasty, Wanger grade, K +, age, white blood cell count, C-reactive protein, high density lipoprotein cholesterol (HDL-C), estimated glomerular filtration rate, cardiac troponin T, and cardiac troponin I, lactic acid (all P<0.05). Previous amputation history ( OR=2.329, 95% CI: 1.092-4.970, P=0.029), DN ( OR=4.091, 95% CI: 2.222-7.532, P<0.001), PVD ( OR=2.556, 95% CI: 1.487-4.395, P=0.001), diabetic foot secondary osteomyelitis ( OR=6.332, 95% CI: 3.595-11.153, P<0.001), Wagner grade were independent risk factors for amputation in DFU patients, HDL-C ( OR=0.392, 95% CI: 0.182-0.842, P=0.016) were protective factors for amputation in DFU patients. Moreover, the combined accuracy of the above factors in predicting amputation in DFU patients was high, and the area under ROC curve was 0.839 (95% CI: 0.798-0.880), sensitivity was 83%, and specificity was 73% ( OR=0.05). Conclusions:Previous amputation history, DN, PVD, diabetic foot secondary osteomyelitis and Wagner grade are independent risk factors for amputation in DFU patients, while HDL-C is a protective factor for amputation in DFU patients. Further investigation will help to establish a stratified system for predicting the risk of diabetic foot, so as to achieve better individualized treatment.

The application of mechanics in clinical wound healing has a long history;however,the systematic underlying mechanisms remain unclear.With recent advancements in biomechanics and mechanobiology,the principles regarding how mechanical factors influence the formation,progression,and healing of wounds have gradually been elucidated.Herein,based on progress in theories,technologies,and clinical practices concerning the interplay between mechanics and wound healing,this study introduces the concept of wound-repairing mechanomedicine.Relevant research is systematically reviewed from the perspectives of biomechanics,mechanobiology,and mechanotherapy.Additionally,potential future development directions are prospectively analyzed to provide novel insights into wound care and strategies for preventing scar formation.

Objective To investigate the role of miR-125b on hepatic angiogenesis,with the hope of providing new targets for the prevention and treatment of liver fibrosis.Methods The human hepatic sinusoidal endothelial cells were transfected with miR-125b mimics and inhibitors,and the mRNA and protein expression of vascular endotheli-al growth factor(VEGF),cluster of differentiation antigens 31(CD31),von Willebrand factor(vWF),collagenⅣ,and laminin(LN)were detected by qRT-PCR and ELISA,and the expression of nitric oxide(NO)was detec-ted by fluorescent probe,scanning electron microscopy detected the alteration of the window holes on the surface of human hepatic sinusoidal endothelial cells,angiogenesis assay was performed to observe the neovascularization of each group,and dual luciferase reporter gene assay was performed to validate the targeting relationship between miR-125b and VEGF.Results qRT-PCR and ELISA showed that compared with the negative control group,the mRNA and protein expressions of VEGF,CD31,vWF,Collagen Ⅳ,and LN significantly decreased after miR-125b mimic transfection(P＜0.05),while the mRNA and protein expressions of VEGF,CD31,vWF,CollagenⅣ,and LN were significantly increased after transfection with miR-125 b mimics(P＜0.05);fluorescent probe detection showed that compared with the negative control group,the average fluorescence of intensity expression NO decreased significantly(P＜0.05),while the average fluorescence intensity expression of NO increased significant-ly after miR-125b inhibitor transfection(P＜0.05);the number of fenestrations on the surface of human liver sinu-soidal endothelial cells significantly increased after miR-125b mimic transfection(P＜0.05),while the number of fenestrations on the surface of human liver sinusoidal endothelial cells decreased significantly after miR-125 b inhibi-tor transfection(P＜0.05);angiogenesis assay showed that compared with the negative control group,the number of angiogenesis significantly decreased after miR-125b mimic transfection(P＜0.05),while the number of angio-genesis significantly increased after miR-125b inhibitor transfection(P＜0.05);dual luciferase reporter gene assay showed that compared with negative control group,the expression of relative fluorescence intensity after transfection of miR-125b mimics in VEGF wild-typ significantly decreased(P＜0.05),while the expression of relative fluores-cence intensity after transfection of miR-125b mimics in VEGF mutant significantly decreased(P＞0.05).Con-clusion miR-125b can inhibit liver angiogenesis and thus play an anti-fibrosis role,which can provide a new ref-erence for the prevention and treatment of chronic liver disease and the development of new drugs.

Objective:To assess the risk of noise-induced hearing loss in workers from a petrochemical plant.Methods:In October 2020, 488 male workers exposed to noise in a petrochemical plant in Guangdong Province were selected by cluster sampling. Acoustics-Estimation of Noise-Induced Hearing Loss (ISO 1999: 2013) was used to assess the risk of noise-induced hearing loss of workers, and individual fit testing was used to evaluate the sound attenuation obtained by the workers. The risk assessment results and fitness test results of workers with different hearing levels were compared.Results:The average noise exposure equivalent sound level of the workers in the petrochemical plant was 86.7 dB (A) . The median of PARs (personal attenuation ratings) was 16 (4, 23) dB. There were statistically significant differences in age and service years among workers with different hearing results ( P<0.05) , but no statistically significant differences in noise intensity and PARs ( P>0.05) . According to risk assessment results of ISO 1999: 2013, the current risk of high-frequency hearing loss in 488 workers were negligible risk and acceptable risk. The risk of noise-induced deafness weredivided into three levels: negligible risk in 452 workers (92.7%) , medium risk in 27 workers (5.5%) and high risk in 9 workers (1.8%) . The risk of high-frequency hearing loss in next 5 to 15 years for workers with noise exposure level of >94 to 97 dB and >97 dB or above would be medium risk or above. The risk of noise-induced deafness in next 5 to 15 years for workers exposed to noise withlevel of 91 to 94 dB would be medium risk or above. Conclusion:The risk of noise-induced hearing loss in workers from the petrochemical plant is high in next 5 to 15 years, and noise prevention and control measures need to be strengthened. ISO1999: 2013 assessment method may underestimate the risk of hearing loss among workers.

Objective:To assess the risk of noise-induced hearing loss in workers from a petrochemical plant.Methods:In October 2020, 488 male workers exposed to noise in a petrochemical plant in Guangdong Province were selected by cluster sampling. Acoustics-Estimation of Noise-Induced Hearing Loss (ISO 1999: 2013) was used to assess the risk of noise-induced hearing loss of workers, and individual fit testing was used to evaluate the sound attenuation obtained by the workers. The risk assessment results and fitness test results of workers with different hearing levels were compared.Results:The average noise exposure equivalent sound level of the workers in the petrochemical plant was 86.7 dB (A) . The median of PARs (personal attenuation ratings) was 16 (4, 23) dB. There were statistically significant differences in age and service years among workers with different hearing results ( P<0.05) , but no statistically significant differences in noise intensity and PARs ( P>0.05) . According to risk assessment results of ISO 1999: 2013, the current risk of high-frequency hearing loss in 488 workers were negligible risk and acceptable risk. The risk of noise-induced deafness weredivided into three levels: negligible risk in 452 workers (92.7%) , medium risk in 27 workers (5.5%) and high risk in 9 workers (1.8%) . The risk of high-frequency hearing loss in next 5 to 15 years for workers with noise exposure level of >94 to 97 dB and >97 dB or above would be medium risk or above. The risk of noise-induced deafness in next 5 to 15 years for workers exposed to noise withlevel of 91 to 94 dB would be medium risk or above. Conclusion:The risk of noise-induced hearing loss in workers from the petrochemical plant is high in next 5 to 15 years, and noise prevention and control measures need to be strengthened. ISO1999: 2013 assessment method may underestimate the risk of hearing loss among workers.

Objective To understand the current status of synthetic drug use and associated factors among men who have sex with men (MSM) at high risk of HIV infection.Methods A crosssectional study was conducted in Guangzhou,Wuxi and Shenzhen through January to August 2017.MSM at high risk of HIV infection were recruited from attendants at the health clinics,through internet advertisement and snowball sampling method.Eligible MSM were the ones who had met the following criteria:≥ 18 years old,having either 2 male sex partners,or condomless anal sex with a casual male sex partner,or a STD historg during the past 6 months.Data regarding demographic,sexual behavior,HIV/STD testing history and previous drug use were collected by sely-administered questionnaires.Blood was also drawn for HIV testing.Results Of the 603 MSM at high risk of HIV,25.5％ (154/603,95％CI:22.0％-29.0％) of them had used drugs in the past 6 months,including 29.1％ (88/302,95％CI:24.0％-34.3％) in Guangzhou,26.3％ (40/152,95％CI:19.2％-33.4％)in Shenzhen,and 17.4％ (26/149,95％CI:11.3％-23.6％) in Wuxi.'Rush'(85.1％,131/154) was the most commonly used drug.Results from the multivariable logistic regression revealed that drug use was associated with the following factors:having multiple casual sexual partners (aOR=3.24,95％CI:1.29-7.43) and alcohol use (aOR=1.78,95％CI:1.12-2.80) in the past 6 months after adjusting for age,education and monthly income.Conclusions Drug use seemed common among MSM population at high risk of HIV infection and was associated with higher risk behavior that leading to HIV infection.Synthetic drug use among MSM deserved more attention.