Objective To explore the molecular mechanism of chronic osteomyelitis and to clarify the role of MAPK signal pathway in the pathogenesis of chronic osteomyelitis,by collecting and analyzing the transcriptional information of bone tissue in patients with chronic osteomyelitis.Methods Four cases of traumatic osteomyelitis in limbs from June 2019 to June 2020 were selected,and the samples of necrotic osteonecrosis from chronic osteomyelitis(necrotic group),and normal bone tissue(control group)were collected.Transcriptome information was collected by Illumina Hiseq Xten high throughput sequencing platform,and the gene expression in bone tissue was calculated by FPKM.The differentially expressed genes were screened by comparing the transcripts of the Necrotic group and control group.Genes were enriched by GO and KEGG.MAP3K7 and NFATC1 were selected as differential targets in the verification experiments,by using rat osteomyelitis animal model and im-munohistochemical analysis.Results A total of 5548 differentially expressed genes were obtained by high throughput sequenc-ing by comparing the necrotic group and control group,including 2701 up-regulated and 2847 down-regulated genes.The genes enriched in MAPK pathway and osteoclast differentiation pathway were screened,the common genes expressed in both MAPK and osteoclast differentiation pathway were(inhibitor of nuclear factor κ subunit Beta,IκBKβ),(mitogen-activated protein ki-nase 7,MAP3K7),(nuclear factor of activated t cells 1,NFATC1)and(nuclear factor Kappa B subunit 2,NFκB2).In rat os-teomyelitis model,MAP3K7 and NFATC1 were highly expressed in bone marrow and injured bone tissue.Conclusion Based on the transcriptome analysis,the MAPK signaling and osteoclast differentiation pathways were closely related to chronic os-teomyelitis,and the key genes IκBKβ,MAP3K7,NFATC1,NFκB2 might be new targets for clinical diagnosis and therapy of chronic osteomyelitis.

DNA polymerase theta (Polθ), also known as DNA polymerase θ, is the member of the DNA polymerase A family and plays a crucial role in the repair of DNA double-strand breaks (DSB). Polθ has 3 distinct structural domains: the N-terminal helicase-like domain with a conserved sequence, the C-terminal polymerase domain, and the central domain, which is a disordered sequence connecting these two regions. Notably, Polθ is the only known polymerase in eukaryotes that possesses helicase activity. However, it is also an error-prone polymerase. When DNA DSBs occur, a specialized network consisting of at least 4 pathways, including classical-non homologous end joining (C-NHEJ), homologous recombination (HR), single-strand annealing (SSA), and alternative-end joining (Alt-EJ), is responsible for repairing DNA damage caused by DSBs. In the absence of major DNA repair pathways like HR, cells rely on Alt-EJ pathway mediated by Polθ to repair damaged DNA and maintain genomic stability. Nevertheless, due to the low fidelity of Polθ, Alt-EJ repair often leads to errors. Depletion of Polθ has shown to increases DSB formation and compromise genomic stability. Conversely, overexpression of Polθ has been associated with increases DNA damage markers and impairs cell cycle progression. As a result, the impact of Polθ on genome stability remains controversial. Furthermore, overexpression of Polθ is frequently observed in cancer and is associated with a characteristic mutational signature and poor prognosis. Depleting Polθ in an HR-deficient background has been shown to impair cell viability, suggesting a synthetic lethal (SL) relationship between Polθ and HR factors. In recent years, targeted chemotherapy drugs that inhibit tumor growth have gained significant attention. However, off-target effects and drug resistance pose challenges for clinical application, particularly with poly-ADP-ribose polymerase inhibitor (PARPi). Blocking Polθ activity in HR-deficient tumor cells has been found to reverse PARPi resistance, making Polθ a very promising therapeutic target in cancer treatment. The availability of crystal structures for both helicase and polymerase domain has facilitated the design of potent inhibitors of Polθ. Currently, several highly specific and effective small molecule inhibitors targeting Polθ, such as Novobiocin, RP-6685, and ART558, have been reported to effectively block various cancers with HR deficiency. The initial success of these inhibitors points to new directions for treating BRCA1/2-mutated tumors. Additionally, reducing the Alt-EJ repair pathway mediated by Polθ can improve HR repair efficiency and increase the chance of exogenous gene target integration (TI), suggesting potential new applications for Polθ inhibitors. This article reviews the recent research progress on the molecular function of Polθ and its involvement in the Alt-EJ pathway modification mechanism, providing insights for a deeper understanding of this field.

Objective To observe the clinical efficacy of"triple-posture positive bone-setting"chiropractic manipulation combined with Tongluo Huoxue Formula for the treatment of lumbar spinal stenosis(LSS)with qi deficiency and blood stasis syndrome.Methods Sixty patients with LSS of qi deficiency and blood stasis type were randomly divided into trial group and control group,with 30 cases in each group.The trial group was treated with"triple-posture positive bone-setting"chiropractic manipulation(a chiropractic manipulation performed under the positive cooperation of the patients at three postures)combined with Tongluo Huoxue Formula,while the control group was treated with"triple-posture positive bone-setting"chiropractic manipulation combined with conventional western medicine.The course of treatment for the two groups covered 4 weeks.Before and after treatment,the patients of the two groups were observed in the changes of pain visual analogue scale(VAS)score,Japanese Orthopedic Association(JOA)score of lumbar function,Oswestry Disability Index(ODI)score,straight-leg raising test results and serum interleukin 6(IL-6)and C-reactive protein(CRP)levels.After treatment,the clinical efficacy and safety of the two groups were evaluated.Results(1)After 4 weeks of treatment,the total effective rate of the trial group was 96.67％(29/30)and that of the control group was 63.33％(19/30).The intergroup comparison(tested by Fisher's exact test)showed that the clinical efficacy of the trial group was significantly superior to that of the control group(P＜0.05).(2)After treatment,the lumbar function indicators of pain VAS scores and ODI scores in the trial group were significantly lower(P＜0.05),and the JOA scores were significantly higher than those before treatment(P＜0.05),while in the control group,only the ODI scores were significantly lower than those before treatment(P＜0.05).The intergroup comparison showed that the decrease of VAS and ODI scores and the increase of JOA scores in the trial group were significantly superior to those in the control group(P＜0.05 or P＜0.01).(3)After treatment,the Laseque s sign of the trial group was significantly improved compared with that before treatment(P＜0.05),while no significant improvement was presented in the control group(P＞0.05).The intergroup comparison showed that the improvement of Laseque's sign in the trial group was significantly superior to that in the control group(P＜0.01).(4)After treatment,the levels of serum inflammatory factors of IL-6 and CRP in the two groups were lower than those before treatment(P＜0.05),and the decrease of serum IL-6 level in the trial group was significantly superior to that in the control group(P＜0.05),but CRP level in the two groups after treatment did not differ from that before treatment,no statistically significant difference was shown between the two groups after treatment,either(P＞0.05).(5)The incidence of adverse reactions in the trial group was 6.67％(2/30)and that in the control group was 13.33％(4/30),and the intergroup comparison(by Fisher's exact test)showed that there was no significant difference between the two groups(P＞0.05).Conclusion The therapeutic effect of"triple-posture positive bone-setting"chiropractic manipulation combined with Tongluo Huoxue Formula exert certain effect for the treatment of LSS patients with qi deficiency and blood stasis syndrome,and it has more obvious advantages in improving the lumbar function,promoting the rehabilitation of the patients,and lowering the level of serum inflammatory factors than"triple-posture positive bone-setting"chiropractic manipulation combined with conventional western medication.

Aim To investigate the effect of discoidin domain receptor 1(DDR1)on high glucose induced endothelial cell dysfunction and the underlying mecha-nism.Methods Human umbilical vein endothelial cells(HUVECs)were cultured in vitro and divided in-to the control group and high glucose induction group(HG).HUVECs were treated with 33 mmol·L-1 D-glucose for 48 hours to construct endothelial dysfunc-tion.Pyroptosis was detected using propidium iodide staining(PI);lactate dehydrogenase(LDH)and IL-1β,IL-18 levels were determined using enzyme linked immunosorbent assay(ELISA);the expression of DDR1 and NF-κB/NLRP3 signaling pathway proteins and pyroptosis related proteinses were detected using Western blot.Subsequently,the experiment was divid-ed into the control group,HG group,HG+DDR1 NC group,and HG+DDR1 siRNA group.The effect of high glucose on the proliferation and migration of HU-VECs was observed after transfection with DDR1 siR-NA for 24 hours;ELISA was used to detect the endo-thelial nitric oxide synthase(eNOS),vascular cell ad-hesion molecule-1(VCAM-1),intercellular adhesion molecule-1(ICAM-1),as well as LDH,IL-1β,IL-18 levels;PI was employed to detect pyroptosis;Western blot was applied to detect DDR1 and NF-κB/NLRP3 signaling pathway proteins and pyroptosis related pro-teins.Results Compared with the control group,HG group decreased eNOS content,increased VCAM-1 and ICAM-1 contents,decreased cell viability and migration ability,and significantly increased the expressions of DDR1,p-NF-κB,NLRP3 and pyroptosis related pro-teins.The levels of LDH,IL-1β,IL-18 and the rate of pyroptosis significantly increased(P＜0.05).Com-pared with HG group,DDR1 siRNA could promote the secretion of eNOS,decrease the levels of VCAM-1,ICAM-1,LDH,IL-1β and IL-1 8,increase cell viability and migration ability,reduce the expression of p-NF-κB,NLRP3 and pyroptosis related proteins,and inhibit high glucose-induced pyroptosis of HUVECs(P＜0.05).Conclusions Gene silencing DDR1 can im-prove vascular endothelial cell dysfunction induced by high glucose,and the mechanism is related to the inhi-bition of NF-κB/NLRP3 signaling pathway mediated pyroptosis.

Objective To study the efficiency of 3D-STI technology on trastuzumab (TRA) treatment related early myocardial toxicity.Methods In a retrospective study,120 breast cancer postoperative patients receiving TRA treatment and maintenance therapy in this hospital from January 2020 to December 2022 were selected and conducted the routine ultrasound and 3D-STI technological examinations before chemotherapy,in 2,4,6 cycles of chemotherapy.Follow-up continued until October 2023.The patients were divided into the my-ocardial toxicity group and non-myocardial toxicity group according to whether or not developing myocardial toxicity.By combining with the baseline data,the univariate and multivariate logistic regression were em-ployed to analyze and determine the influencing factors of myocardial toxicity.The predictive value of 3D-STI parameters at different time points for myocardial toxicity was evaluated by using the receiver operating char-acteristic (ROC) curve.Results There was no statistically significant difference in 3D-STI technical parame-ters such as GLS,GAS,GCS and GRS before chemotherapy and in 2 cycles of chemotherapy between the myo-cardial toxicity group and the non-myocardial toxicity group (P>0.05);GLS,GAS and GRS after 4,6 cycles of chemotherapy in the myocardial toxicity group were lower than those in the non-myocardial toxicity group (P<0.05).The logistic regression analysis results showed that GLS (OR=0.542,95％CI:0.424-0.694),GAS (OR=0.580,95％CI:0.360-0.936) and GCS (OR=1.699,95％CI:1.035-2.790) after 4 cycles of chemotherapy,and GLS (OR=0.534,95％CI:0.440-0.648),GAS (OR=0.559,95％CI:0.347-0.901) and GCS (OR=1.613,95％CI:1.131-2.300) after 6 cycles of chemotherapy were the influencing factors of myocardial toxicity in TRA treatment after breast cancer surgery (P<0.05).The results of the ROC curve showed that after 4 cycles of chemotherapy,the diagnostic critical value of GLS was-17.23％ and the area under the curve (AUC) was 0.645 (95％CI:0.541-0.749);the diagnostic critical value of GCS was-19.22％ and AUC was 0.556 (95％CI:0.444-0.668).The GLS diagnostic critical value after 6 cycles of chemotherapy was-17.82％,and AUC was 0.856 (95％CI:0.786-0.927);the GAS diagnostic critical value was-27.17％,and AUC was 0.994 (95％CI:0.983-<1.000);the diagnostic critical value of GCS was-18.38％,and AUC was 0.842 (95％CI:0.771-0.913).Conclusion The 3D-STI parameters in 4,6 cycles of chemotherapy could predict the myocardial toxicity after TRA treatment after breast cancer surgery.

Objective To evaluate the bioequivalence of a single oral dose of ritonavir in fasted and fed conditions in healthy Chinese adult subjects with the test and reference formulations.Methods A single-center,open-label,randomized,single-dose,two-periods,two-sequence crossover design was used,and 64 subjects were enrolled in both the fasted and fed groups.The subjects received 100 mg of the test preparation or reference preparation orally per cycle,and the drug concentration of ritonavir in plasma was detected using the high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS)method.Pharmacokinetic parameters were estimated by a non-compartment model,and SAS 9.4 software was used for statistical analysis.Results Arithmetic mean values of the main pharmacokinetic parameters of the subject formulation of ritonavir tablets and the reference formulation in the fasting group:Cmax were(791.90±400.20)and(809.60±449.14)ng·mL-1;AUC0_t were(6 072.61±2 631.98)and(6 296.30±3 388.95)ng·h·mL-1;AUC0-∞ were(6 129.59±2 655.57)and(6 347.26±3 434.12)ng·h·mL-1,respectively.Arithmetic mean values of the main pharmacokinetic parameters of the subject formulation of ritonavir tablets and the reference formulation in the fed group:Cmax were(512.37±233.60)and(521.74±223.87)ng·mL-1;AUC0_t were(4 203.43±2 221.33)and(4 200.13±1 993.50)ng·h·mL-1;AUC0_∞ were(4 259.21±2 266.88)and(4 259.63±2 044.12)ng·h·mL-1.The 90％confidence intervals for the geometric mean ratios of Cmax,AUC0_t and AUC0_∞ of the prototype drug ritonavir in plasma after oral administration of 100 mg of the test and reference formulations of ritonavir tablets under fasting and fed conditions fell within the 80.00％to 125.00％equivalence interval.Conclusion The test and reference formulations of ritonavir tablets were bioequivalent under fasting and postprandial conditions.

Background/Aims: Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1–3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. Methods: We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. Results: The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. Conclusions Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

Background/Aims: Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. Methods: We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Results: Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients. Conclusions Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.

Background/Aims: Steatotic liver disease (SLD) is a common manifestation in chronic hepatitis C (CHC). Metabolic alterations in CHC are associated with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to elucidate whether hepatitis C virus (HCV) eradication mitigates MASLD occurrence or resolution. Methods: We enrolled 5,840 CHC patients whose HCV was eradicated by direct-acting antivirals in a nationwide HCV registry. MASLD and the associated cardiometabolic risk factors (CMRFs) were evaluated at baseline and 6 months after HCV cure. Results: There were 2,147 (36.8%) patients with SLD, and 1,986 (34.0%) of them met the MASLD criteria before treatment. After treatment, HbA1c (6.0% vs. 5.9%, p<0.001) and BMI (24.8 kg/m2 vs. 24.7 kg/m2, p<0.001) decreased, whereas HDL-C (49.1 mg/dL vs. 51.9 mg/dL, p<0.001) and triglycerides (102.8 mg/dL vs. 111.9 mg/dL, p<0.001) increased significantly. The proportion of patients with SLD was 37.5% after HCV eradication, which did not change significantly compared with the pretreatment status. The percentage of the patients who had post-treatment MASLD was 34.8%, which did not differ significantly from the pretreatment status (p=0.17). Body mass index (BMI) (odds ratio [OR] 0.89; 95% confidence intervals [CI] 0.85–0.92; p<0.001) was the only factor associated with MASLD resolution. In contrast, unfavorable CMRFs, including BMI (OR 1.10; 95% CI 1.06–1.14; p<0.001) and HbA1c (OR 1.19; 95% CI 1.04–1.35; p=0.01), were independently associated with MASLD development after HCV cure. Conclusions HCV eradication mitigates MASLD in CHC patients. CMRF surveillance is mandatory for CHC patients with metabolic alterations, which are altered after HCV eradication and predict the evolution of MASLD.

Ulcerative colitis (UC) is a chronic inflammation of the gastrointestinal tract and is characterized by alternating periods of inflammation and remission. Although UC incidence is lower in Taiwan than in Western countries, its impact remains considerable, demanding updated guidelines for addressing local healthcare challenges and patient needs. The revised guidelines employ international standards and recent research, emphasizing practical implementation within the Taiwanese healthcare system. Since the inception of the guidelines in 2017, the Taiwan Society of Inflammatory Bowel Disease has acknowledged the need for ongoing revisions to incorporate emerging therapeutic options and evolving disease management practices. This updated guideline aims to align UC management with local contexts, ensuring comprehensive and context-specific recommendations, thereby raising the standard of care for UC patients in Taiwan. By adapting and optimizing international protocols for local relevance, these efforts seek to enhance health outcomes for patients with UC.