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PurposeThis study aimed to investigate the pharmacodynamic effects of indobufen and low-dose aspirin in patients with coronary atherosclerosis.MethodsIn the first phase, 218 patients with coronary atherosclerosis were randomly assigned to receive aspirin 100 mg once daily (standard dose); 100 mg once every 2 days; 100 mg once every 3 days; 50 mg twice daily; 75 mg once daily; 50 mg once daily; or indobufen 100 mg twice daily for 1 month. In the second phase, 20 healthy subjects were treated with indobufen 100 mg twice daily for 1 week followed after a 2-week washout by aspirin 100 mg once daily for 1 week. The primary outcome was arachidonic acid-induced platelet aggregation (PLAA), and the secondary outcomes included plasma thromboxane B2 (TXB2) and urinary 11-dehydro-TXB2 (11-dh-TXB2) levels at the end of each treatment. ResultsIn the first phase, compared with aspirin 100 mg once daily: all aspirin groups had similar suppression of PLAA whereas indobufen group had significantly less suppressed PLAA. Aspirin given every second or third day, and indobufen produced less suppression of plasma TXB2. All treatment regimens produced similar inhibition of 11-dh-TXB2. In the second phase, compared with aspirin, indobufen produced less suppression of plasma TXB2 at 8 h and 12 h after the last dose.ConclusionsAspirin 50 mg twice daily, 75 mg once daily, and aspirin 50 mg once daily produce antiplatelet effects that are similar to aspirin 100 mg once daily. Aspirin given less often than once daily and indobufen 100 mg twice daily do not suppress platelets as effectively as aspirin 100 mg once daily.

Background: Previous studies have suggested that proton pump inhibitors could impair the antiplatelet effect of clopidogrel. It is uncertain whether ilaprazole affects the antiplatelet effect of clopidogrel. This study aimed to determine the drug-drug interaction between ilaprazole and clopidogrel. Methods: A randomized crossover trial of 40 healthy subjects was performed. Clopidogrel was administered alone or in combination with ilaprazole for 7 days. The maximal platelet aggregation (MPA) to 5 μmol/L adenosine diphosphate was measured by light transmission aggregometry and the platelet reactivity index (PRI) was determined by vasodilator-stimulated phosphoprotein P2Y 12 assay. High on-treatment platelet reactivity (HOPR) was defined as a MPA of >40%. The inhibition of platelet aggregation (IPA) and PRI in the two phases were compared between two regimens after the last dosing. Results: IPA was comparable between the two regimens at 0, 10 and 24 h ( p > 0.05), but higher at 4 h in the clopidogrel alone regimen compared with that in the combined treatment regimen (75.66 ± 18.44% vs. 70.18 ± 17.67%, p = 0.031). The inhibition of PRI was comparable between the two regimens at 0 and 24 h. There were no significant differences in the area under the time-IPA% curve (AUC) or the incidence of HOPR at all time-points between the two regimens. Conclusion: In healthy subjects, ilaprazole has limited effect on the pharmacodynamics of clopidogrel and it may not be clinically relevant. Clinical Trial Registration : [ www.chictr.org.cn ], identifier [ChiCTR2000031482].

Objective This study was aimed to determine how platelet reactivity (PR) on dual antiplatelet therapy predicts ischemic and bleeding events in patients underwent percutaneous coronary intervention (PCI). Design A total of 2768 patients who had received coronary stent implantation and had taken aspirin 100 mg in combination with clopidogrel 75 mg daily for > 5 days were consecutively screened and 1885 were enrolled. The recruited patients were followed-up for 12 months. The primary end-point was the net adverse clinical events (NACE) of cardiovascular death, nonfatal myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST) and any bleeding. Result 1709 patients completed the clinical follow-up. By using the receiver operating characteristic (ROC) curve analysis, the optimal cut-off values were found to be 37.5 and 25.5% respectively in predicting ischemic and bleeding events. Patients were classified into 2 groups according to PR: inside the window group (IW) [adenosine diphosphate (ADP) induced platelet aggregation (PL ADP ) 25.5–37.4%)] and outside the window group (OW) (PL ADP  < 25.5% or ≥ 37.5%). The incidence of NACE was 16.8 and 23.1% respectively in the IW and OW group. The hazard ratio of NACE in IW group was significantly lower [0.69 (95% CI, 0.54–0.89, P  = 0.004)] than that in the OW group during 12-month follow-up. Conclusion An optimal therapeutic window of 25.5–37.4% for PL ADP predicts the lowest risk of NACE, which could be referred for tailored antiplatelet treatment while using LTA assay. Trial registration Trial registration number: ClinicalTrials.gov NCT01968499 . Registered 18 October 2013 - Retrospectively registered.

Liver fibrosis is a key pathological process shared by the progression of various chronic liver diseases. Treatment of liver fibrosis can effectively block the occurrence and development of hepatic cirrhosis or even carcinoma. Currently, there is no effective drug delivery vehicle for curing liver fibrosis. In this study, we designed matrine (MT)-loaded mannose 6-phosphate (M6P) modified human serum albumin (HSA) conjugated solid lipid nanoparticles (SLN), named M6P-HSA-MT-SLN for treatment of hepatic fibrosis. We demonstrated that M6P-HSA-MT-SLN exhibited controlled and sustained release properties and good stability over 7 days. The drug release experiments showed that M6P-HSA-MT-SLN exhibited slow and controlled drug release characteristics. In addition, M6P-HSA-MT-SLN showed a significant targeted ability to fibrotic liver. Importantly, in vivo studies indicated that M6P-HSA-MT-SLN could significantly improve histopathological morphology and inhibit the fibrotic phenotype. In addition, in vivo experiments demonstrate that M6P-HSA-MT-SLN could reduce the expression of fibrosis markers and alleviate the damage of liver structure. Hence, the M6P-HSA-MT-SLN provide a promising strategy to deliver therapeutic agents to fibrotic liver to prevent liver fibrosis.

Ozone pollution in densely populated urban regions poses a great threat to public health, due to the intensive anthropogenic emissions of ozone precursors and is further aggravated by global warming and the urban heat island phenomenon. Air quality models have been utilized to formulate and evaluate air pollution control strategies. This study presents a comprehensive modeling assessment of ozone mitigation strategies during an ozone pollution episode in Changzhou, an industrial city in the Yangtze River Delta region. Utilizing the Community Multiscale Air Quality Modeling System (CMAQ), we quantified the contribution of ozone from different emission sectors and counties within Changzhou using the integrated source apportionment method (ISAM). During the pollution period, local emissions within Changzhou account for an average of 41.5% of MDA8 ozone, with particularly notable contributions from Jingkai (11.2%), Wujin (9.5%), and Liyang (7.8%). Upon these findings, we evaluated three sets of emission reduction scenarios: uniform, sector-specific, and county-specific reductions. Results show that industry and transportation are responsible for over 20% of ozone concentrations, and targeted reductions in these sources yielded the most significant decreases in ozone levels. Notably, reducing industrial emissions alone decreased ozone concentrations by 3.2 μg m−3 during the pollution episode. County-specific reductions revealed the importance of targeted strategies, with certain counties showing more pronounced responses to emission controls. On a daily basis, emission reductions in Xinbei contributed to a maximum ozone decrease of 4.4 μg m−3. This study provides valuable insights into the efficacy of different mitigation measures in Changzhou and offers a practical and useful framework for policymakers to implement strategies while addressing the complexities of urban air quality management.

Cancer of the thyroid is a endocrine cancer. Although most patients achieve favorable outcomes with surgical resection, radioactive iodine (RAI) ablation, and thyroid-stimulating hormone (TSH) suppression therapy, a subset progresses to advanced or refractory disease. Immune checkpoint inhibitors (ICIs) blocking the PD-1/PD-L1 pathway reactivate T cells, enabling them to identify and eradicate malignant cells, thus reinstating immune surveillance against tumors. This review examines PD-L1 (Programmed Death-Ligand 1) expression in thyroid cancer, exploring its underlying regulatory mechanisms. It also discusses recent advances in PD-1/PD-L1 immune checkpoint inhibition (ICI) therapy. Furthermore, the review highlights regulatory pathways modulating PD-1/PD-L1 expression, including the mTOR pathway, androgen receptor (AR), and the CKS1B/STAT3 pathway. Notably, it summarizes recent clinical developments, such as combination regimens pairing PD-L1 blockade with mutation-targeted therapies, for which the median OS of the targeted combination therapy group was 14.7 months. This therapy has achieved the longest median OS for anaplastic thyroid carcinoma (ATC) patients so far. Additionally, the review examines innovative treatment modalities, offering a thorough synthesis of the existing state and emerging trends in PD-1/PD-L1 immunotherapies.

Tick-borne spotted fever group Rickettsia (SFGR) poses a significant threat to public health worldwide. The cofeeding behavior of ticks attaching host animals, such as hedgehogs, has been identified as a potential mechanism for transmitting SFGR between infected and uninfected ticks, potentially increasing the prevalence of SFGR. However, the overall positive rate of SFGR in free-living ticks remains relatively low, suggesting that the role of tick-cofeeding in amplifying SFGR prevalence may not be as substantial as previously believed. To explore the impact of tick-cofeeding hedgehogs on the natural transmission of SFGR, to clarify the underlying hypotheses, and to provide robust data to support targeted prevention and control strategies for spotted fever, this study developed a transmission model using tick-cofeeding hedgehogs that simulates the natural transmission process. Both Rickettsia -infected and uninfected tick populations were established and used for cofeeding on mice or hedgehogs. Among formerly uninfected nymphs that cofed on mice, 75.61% acquired Rickettsia after engorgement, but this infection rate dropped sharply to 9.68% after molting. In contrast, formerly uninfected adults that cofed on hedgehogs showed a 100% infection rate after engorgement. However, the infection rates declined significantly in their offspring, with only 11.12% of normal-hatching eggs and 3.12% of larvae testing positive. Additionally, we observed mortality in infected engorged adults and their eggs. Our results demonstrate that while tick-cofeeding on hedgehogs can lead to a high positive rate of Rickettsia in ticks, the infections acquired through cofeeding fail to sustain this high positivity rate due to several mechanisms. Firstly, rickettsiae obtained through cofeeding or blood meals do not consistently establish infections in all recipient ticks, resulting in a significant decline in positive rates as ticks progress to subsequent developmental stages. Secondly, adult ticks infected via cofeeding tend to reduce the infection rate in their offspring through various mechanisms, including tick mortality caused by rickettsiae, egg hatching failure, and a low transovarial transmission rate. Additionally, in natural settings, infections from other pathogens may similarly contribute to tick mortality and reduced egg hatching. This study elucidates why rickettsiae maintain a low prevalence in nature and evaluates the actual effects of tick-cofeeding on pathogen distribution among ticks. While tick-cofeeding on host animals have been considered important amplifiers of SFGR prevalence, our findings indicate that their impact is not as significant as previously assumed.

Metal–organic framework (UiO-66) derived nanoporous carbon/electrochemically reduced graphene oxide nanocomposite (UiO-66/NPC/ERGO) was developed to fabricate an electrochemical sensor for achieving efficient detection of methyl parathion (MP) residues in food. The carbonization derivative UiO-66/NPC was synthesized by one-step pyrolysis with only UiO-66 precursor. Based on the synergistic effect of enough active absorption sites and specific absorption of UiO-66/NPC for MP as well as the high conductivity of ERGO, the UiO-66/NPC/ERGO sensor exhibited excellent sensing performance. Under the optimal conditions, a linear determination range of 20–4000 ng/mL and low limit of detection (LOD) of 0.395 ng/mL for MP was obtained by direct electrochemical oxidation using SWV. Additionally, the sensor provided excellent stability and selectivity, as well as effective determination of real samples with satisfactory recoveries (98.5–104.0%), manifesting that the UiO-66/NPC/ERGO has great potential for organophosphorus pesticide detection. Graphical Abstract

Amino functionalized zirconium-based metal–organic framework (NH 2 -UiO-66) and zinc-based zeolitic imidazolate framework (ZIF-8) were integrated to develop a core–shell architectured hybrid material (NH 2 -UiO-66@ZIF-8, NU66@Z8). The morphology and structure evolutions of core–shell NU6@Z8 were investigated by FE-SEM, XRD, FTIR, and XPS. The NU66@Z8 combined with carboxylated multi-walled carbon nanotubes (CMWCNT) was deposited on a glassy carbon electrode (GCE) for fabricating an electrochemical platform towards detecting Pb 2+ and Cu 2+ . The NU66@Z8/CMWCNT/GCE revealed significantly improved electrochemical performance for determination of Pb 2+ and Cu 2+ compared with the individual components, which can be attributed to the strong adsorption capacity, unique core–shell structure, and large electrochemical active surface area of NU66@Z8/CMWCNT. Under the optimal conditions, the developed sensor exhibited excellent sensing capability with a low limit of detection (Pb 2+ ,1 nM; Cu 2+ , 10 nM) and a wide determination range (Pb 2+ ,0.003–70 μM; Cu 2+ , 0.03–50 μM). The sensor showed high selectivity towards common interfering ions and good repeatability. The real sample recoveries of proposed sensor were in the range 95.0–103% for Pb 2+ (RSD ≤ 5.3%) and 94.2–106% for Cu 2+ (RSD ≤ 5.9%), suggesting that the NU66@Z8/CMWCNT is suitable for examining trace heavy metals in natural environment. Graphical Abstract

Background The Syrian hamster ( Mesocricetus auratus ) has shown promise as a human diseases model, recapitulating features of different human diseases including COVID-19. However, the landscape of its genome and transcriptome has not been systematically dissected, restricting its potential applications. Results Here we provide a complete analysis of the genome and transcriptome of the Syrian hamster and found that its lineage diverged from that of the Chinese hamster ( Cricetulus griseus ) around 29.4 million years ago. 21,387 protein-coding genes were identified, with 90.03% of the 2.56G base pair sequence being anchored to 22 chromosomes. Further comparison of the transcriptomes from 15 tissues of the Syrian hamster revealed that the Syrian hamster shares a pattern of alternative splicing modes more similar to humans, compared to rats and mice. An integrated genomic-transcriptomic analysis revealed that the Syrian hamster also has genetic and biological advantages as a superior animal model for cardiovascular diseases. Strikingly, several genes involved in SARS-COV-2 infection, including ACE2, present a higher homology with humans compared to other rodents and show the same function as their human counterparts. Conclusion The detailed molecular characterisation of the Syrian hamster in the present study opens a wealth of fundamental resources from this small rodent for future research into human disease pathology and treatment.