OBJECTIVE: To retrospectively analyze the clinical characteristics, co-mutated genes in newly diagnosed acute myeloid leukemia (AML) patients with NRAS and KRAS gene mutations, and the impact of NRAS and KRAS mutations on prognosis. METHODS: The clinical data and next-generation sequencing results of 80 newly diagnosed AML patients treated at our hospital from December 2018 to December 2023 were collected. The clinical characteristics, co-mutated genes of NRAS and KRAS , and the impact of NRAS and KRAS mutations on prognosis in newly diagnosed AML patients were analyzed. RESULTS: Among 80 newly diagnosed AML patients, NRAS mutations were detected in 20 cases(25.0%), and KRAS mutations were detected in 9 cases(11.3%). NRAS mutations predominantly occurred at codons 12 and 13 of exon 2, as well as codon 61 of exon 3, while KRAS mutations were most commonly occurred at codons 12 and 13 of exon 2, all of which were missense mutations. There were no statistically significant differences observed in terms of age, sex, white blood cell count(WBC), hemoglobin(Hb), platelet count(PLT), bone marrow blasts, first induction chemotherapy regimen, CR1/CRi1 rates, chromosome karyotype, 2022 ELN risk classification and allogeneic hematopoietic stem cell transplantation(allo-HSCT) among the NRAS mutation group, KRAS mutation group and NRAS/KRAS wild-type group (P >0.05). KRAS mutations were significantly correlated with PTPN11 mutations (r =0.344), whereas no genes significantly associated with NRAS mutations were found. Survival analysis showed that compared to the NRAS/KRAS wild-type group, patients with NRAS mutation had a relatively higher 5-year overall survival (OS) rate and relapse-free survival (RFS) rate, though the differences were not statistically significant (P =0.097, P =0.249). Compared to the NRAS/KRAS wild-type group, patients with KRAS mutation had a lower 5-year OS rate and RFS rate, with no significant differences observed (P =0.275, P =0.442). There was no significant difference in the 5-year RFS rate between the KRAS mutation group and NRAS mutation group (P =0.157), but the 5-year OS rate of patients with KRAS mutation was significantly lower than that of patients with NRAS mutation (P =0.037). CONCLUSION In newly diagnosed AML patients, KRAS mutation was significantly correlated with PTPN11 mutation. Compared to patients with NRAS/KRAS wild-type, those with NRAS mutation showed a more favorable prognosis, while patients with KRAS mutation showed a poorer prognosis; however, these differences did not reach statistical significance. Notably, the prognosis of AML patients with KRAS mutation was significantly inferior compared to those with NRAS mutation.
Humans ; Leukemia, Myeloid, Acute/diagnosis* ; Mutation ; Prognosis ; Proto-Oncogene Proteins p21(ras)/genetics* ; GTP Phosphohydrolases/genetics* ; Retrospective Studies ; Membrane Proteins/genetics* ; Female ; Male ; Middle Aged ; Adult ; Aged

BACKGROUND: Prior studies have shown that drivers with type 2 diabetes are more likely to be involved in motor vehicle collisions (MVCs) compared to the general population. Certain meteorological factors have been increasingly recognized as contributors to MVC risk. This study aims to examine the association of MVCs with temperature, rainfall, wind speed, and sunshine duration among drivers with type 2 diabetes. METHODS: Using Taiwan's National Health Insurance data (2019-2021), we identified individuals diagnosed with type 2 diabetes and linked their records to the Police-Reported Traffic Accident Registry to obtain daily MVC counts. Meteorological data were sourced from the Central Weather Administration. Associations between daily weather conditions and MVCs were assessed using a Distributed Lag Non-Linear Model. RESULTS: Over the 1,096-day study period, 170,468 MVC events involving drivers with type 2 diabetes were recorded. A U-shaped association was observed between same-day temperature and MVC rates. Compared with the reference temperature of 17.5 °C, both lower temperatures (≤15 °C; rate ratio [RR] = 1.014-1.053) and higher temperatures (≥30 °C; RR = 1.062) were associated with increased MVC risk. Rainfall showed an inverse relationship with MVCs. Compared with 70 mm of rainfall, the lowest MVC rate occurred at 129 mm (RR = 0.873), while the highest was on rain-free days (0 mm; RR = 1.068). Stronger effects were observed when lag periods up to 14 days were considered. Wind speed and sunshine duration were not significantly associated with MVC risk. CONCLUSIONS These findings suggest that drivers with type 2 diabetes should exercise greater caution on days with extreme temperatures or in days with lesser rainfall, as these conditions may elevate MVC risk.
Humans ; Diabetes Mellitus, Type 2/epidemiology* ; Taiwan/epidemiology* ; Accidents, Traffic/statistics & numerical data* ; Male ; Middle Aged ; Female ; Weather ; Aged ; Adult ; Temperature ; Risk Factors

OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets

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: 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*

Purpose::Shaping and assembling contemporary external fixators rapidly for the severe mandibular fractures remains a challenge, especially in emergency circumstance. We designed a novel external fixator that incorporates universal joints to provide the stabilization for mandibular comminuted fractures. This study aims to confirm the efficacy of this novel external fixator through biomechanical tests in vitro and animal experiments. Methods::In vitro biomechanical tests were conducted using 6 fresh canine with mandibular defect to simulate critical comminuted fractures. Three mandibles were stabilized by the novel external fixator and other mandibles were fixed by 2.5 mm reconstruction plates. All fixed mandibles were subjected to loads of 350 N on the anterior regions of teeth and 550 N on the first molar of the unaffected side. The stability was evaluated based on the maximum displacement and the slope of the load-displacement curve. In animal experiments, 9 beagles with comminuted mandibular fractures were divided into 3 groups, which were treated with the novel external fixation, reconstruction plate, and dental arch bar, respectively. The general observation, the changes in animals’ weight, and the surgical duration were recorded and compared among 3 groups. The CT scans were performed at various intervals of 0 day (immediately after the surgery), 3 days, 7 days, 14 days, 21 days, and 28 days to analyze the displacement of feature points on the canine mandible and situation of fracture healing at 28 days. The statistical significance was assessed by the two-way analysis of variance test followed by the Bonferroni test, enabling multiple comparisons for all tests using GraphPad Prism10.1.0 (GraphPad Inc, USA). Results::The outcomes of the biomechanical tests indicated that no statistically significant differences were found in terms of the maximum displacement ( p = 0.496, 0.079) and the slope of load displacement curves ( p = 0.374, 0.349) under 2 load modes between the external and internal fixation groups. The animal experiment data showed that there were minor displacements of feature points between the external and internal fixation groups without statistic difference, while the arch bar group demonstrated inferior stability. The CT analysis revealed that the best fracture healing happened in the internal fixation group, followed by the external fixation and arch baring at 28 days after fixation. The external fixation group had the shortest fixation duration (25.67 ± 3.79) min compared to internal fixation ((70.67 ± 4.51) min, p < 0.001) and arch baring ((42.00 ± 3.00) min, p = 0.046). Conclusion::The conclusion of this study highlighted the efficacy and reliability of this novel external fixator in managing mandibular fractures rapidly, offering a viable option for the initial stabilization of comminuted mandibular fractures in the setting of emergency rescue.

Objective To explore the acupoint selection rules of opposing needling in the treatment of post-stroke hemiplegia by using data mining technology.Methods CNKI,VIP,Wanfang,SinoMed,PubMed and Web of Science were searched for relevant literature on the treatment of post-stroke hemiplegia by opposing needling from the establishment of the database to September 2023.Microsoft Excel 2019 was used to establish a database and perform descriptive analysis of acupoints.SPSS Modeler 18.0 was used to analyze the association rules and draw the co-occurrence network diagram of high-frequency acupoints.SPSS Statistics 26.0 was used to perform hierarchical cluster analysis on acupoints and draw a tree diagram.Results ①A total of 104 articles were included,and 136 acupuncture prescriptions were extracted,involving 107 acupoints,with a total frequency of 1 267 times.②The top 10 acupoints were Hegu(LI4),Quchi(LI11),Zusanli(ST36),Jianyu(LI15),Waiguan(SJ5),Yanglingquan(GB34),Sanyinjiao(SP6),Shousanli(LI10),Taichong(LR3),Xuanzhong(GB39).③ The selected meridians were mainly hand,foot yangming meridian and foot shaoyang meridian.④ The acupoints were mostly selected in the upper and lower limbs and head and neck.⑤ In terms of acupoint compatibility,Hegu(LI4)-Quchi(LI11)has the highest support.⑥ The top 25 high-frequency acupoints can be divided into four effective clustering groups.⑦ Opposing needling often combined with scalp acupuncture,rehabilitation training,ordinary acupuncture and other methods to treat hemiplegia after stroke.Conclusion Modern opposing needling attaches importance to the use of yang meridians in the treatment of post-stroke hemiplegia.At the same time,it also selects yin meridians and acupoints to harmonize yin and yang,unblock meridians and collateral,attach importance to the near-treatment effect of acupoints,and follow the holistic view of Chinese medicine treatment.

Objective To investigate the value of acute pancreatitis severity bedside index(BISAP)score,monocyte to lymphocyte ratio(MLR),and neutrophil to albumin ratio(NAR)in the severity and prognosis of acute pancreatitis(AP).Methods The clinical data of 208 patients with acute pancreatitis admitted to the Affiliated Hospital of Southwest Medical University from January 2022 to December 2023 were retrospectively collected and divided into mild(MAP,n=131 cases)and severe(SAP,n=77 cases)groups according to the severity of the disease.Spearman correlation test was used to analyze the relationship between BISAP score,MLR,NAR and severity of disease and hospitalization days,and subject operating curve(ROC curve)analyzes the clinical significance of the above indicators in the prognosis of AP patients.Results The number of hospitalization days,BISAP score,MLR,NAR,WBC,PCT,FPG,TC,and Ca+were greater in the SAP group than in the MAP group,differences were statistically significant(P＜0.05);while the differences in Comorbidities,etiology,history of smoking,history of alcohol consumption,TC、TG、Ceea、GFR were not statistically significant(P＞0.05).By correlation analysis,the BISAP score,MLR and NAR were positively correlated with the severity of the disease(r=0.474、0.542、0.519)and the number of hospitalization days(r=0.401、0.370、0.396),differences were statistically significant(P＜0.05).Binary Loginstic regression showed that BISAP score,MLR,NAR,and FPG were all risk factors affecting patient prognosis.ROC curve analysis of BISAP score,MLR,and NAR were predictive of poor prognosis in AP patients(AUC=0.766、0.825、0.808),the combined predictive effect of the three was greater than that of a single index(AUC=0.863).Conclusion The number of hospitalization days,BISAP score,MLR,NAR,WBC,PCT,FPG,TC,and Ca+were greater in the SAP group than in the MAP group,differences were statistically significant(P＜0.05);while the differences in Comorbidities,etiology,history of smoking,history of alcohol consumption,TC、TG、Ceea、GFR were not statistically significant(P＞0.05).By correlation analysis,the BISAP score,MLR and NAR were positively correlated with the severity of the disease(r=0.474、0.542、0.519)and the number of hospitalization days(r=0.401、0.370、0.396),differences were statistically significant(P＜0.05).Binary Loginstic regression showed that BISAP score,MLR,NAR,and FPG were all risk factors affecting patient prognosis.ROC curve analysis of BISAP score,MLR,and NAR were predictive of poor prognosis in AP patients(AUC=0.766、0.825、0.808),the combined predictive effect of the three was greater than that of a single index(AUC=0.863).

Objective This study was aimed to investigate the impact of probiotics on regulating the ROS/JNK signaling pathway their underlying mechanism of action in the treatment of metabolic associated fatty liver disease.Methods Male C57BL/6 mice were randomly divided into three groups:control,probiotics,and model groups.Serum levels of ALT,AST,TC,and TG were detected.Moreover,the pathological changes of the liver and ileum tissues were observed by hematoxylin and eosin(H&E)staining,and the content of reactive oxygen species(ROS)in liver tissues was determined.In addition,the levels of D-lactic acid and serum and small intestine diamine oxidase were measured to evaluate the effects of probiotics on the intestinal tract of MAFLD mice.Results Mice in the probiotic group were treated with probiotic intervention,compared with model group,mice hepatic lobule structure was complete,hepatic steatosis in cells and inflammatory cells infiltration were relieved.After C57BL/6 mice were fed the MCD diet,the body weight of the model group was significantly lower than that of the control group,showing poor mental state.After 4 weeks of probiotics treatment,the body weight of mice in the probiotics group was higher than that in the model group,and their mental state was better than that in the model group.Biochemical analysis showed that the levels of ALT,AST,TC,TG,D-lac,serum and small intestinal DAO and ROS in liver in the model group were considerably higher than those in the control group.After 4 weeks of probiotics intervention,serum ALT,AST,TC,TG,D-lac,DAO and ROS levels decreased compared with the model group(P＜0.05).Western blot analysis showed that the expression levels of p-JNk,Caspase-3,Bax in the model group were up-regulated,and the expression level of intestinal tight junction protein ZO-1 was down-regulated compared with the control group.After 4 weeks of probiotics intervention,the expression levels of p-JNK,caspase-3,Bax in the probiotics group were down-regulated compared with that in the model group,while the expression level of intestinal tight junction protein ZO-1 was up-regulated compared with that in the model group(P＜0.05).PCR analysis showed that the expression levels of Bax and Caspase-3 in the model group were significantly increased,while the expression levels of Bax and Caspase-3 in the probiotic group were significantly decreased compared with those in the model group(P＜0.05).Immunohistochemistry analysis showed that the expression levels of P-JNk,Caspase-3 and Bax in the liver of mice in the probiotic group were lower than those in the model group(P＜0.05).The pathological results in our investigation showed that the ileum mucosa in the control group was intact,and the intestinal villi were complete and neatly arranged,without any infiltration of inflammatory cells.However,in the model group the ileum mucosal structure was seriously damaged,with loose and disorderly villi arrangement.Importantly,the ileum mucosa in the probiotic group had fewer injuries and the villi were arranged more neatly.Besides,the ileum tissue of the control group had the lowest Chiu's score range(0-1),whereas that of the model group was 3-4,and the one of the probiotic group was 1-2.Conclusion The increased expression of P-JNk,ROS,Caspase-3 and Bax in MAFLD indicates that it is associated with the onset of MAFLD.The use of probiotics can improve the histological and serological indicators of MAFLD.Western blot,PCR and immunohistochemical results confirmed that probiotics can regulate the expression of factors related to ROS/JNK signaling pathway,reduce oxidative stress and inhibit cell apoptosis to achieve the goal of treating MAFLD.