The inherent complexity of Alzheimer's disease (AD) and failed clinical trials have spiked the interest in multifunctional ligands that target at least two key disease-associated macromolecules in AD pathology. Here we present a focused series of pleiotropic N-carbamoylazole prodrugs with dual mechanism of action. Pseudo-irreversible inhibition of the first therapeutic target, human butyrylcholinesterase (hBChE), enhances cholinergic transmission, and thereby provides symptomatic treatment, same as the standard therapeutics in use for AD. Simultaneously, this step also functions as a metabolic activation that liberates a nanomolar selective α ₂-adrenergic antagonist atipamezole, which blocks pathological amyloid β (Aβ)-induced and noradrenaline-dependent activation of GSK3β that ultimately leads to hyperphosphorylation of tau, thus achieving a disease-modifying effect. Lead compound 8 demonstrated long-term pseudo-irreversible hBChE inhibition, metabolic activation in human plasma, blood-brain barrier permeability, and p.o. bioavailability in mice. Multi-day in vivo treatment with 8 in an Aβ-induced AD murine model revealed a significant alleviation of cognitive deficit that was comparable to rivastigmine, the current drug of choice for AD therapy. Furthermore, decreased GSK3β activation and lowered tau phosphorylation were observed in APP/PS1 mice. This surpasses the symptomatic-only treatment with cholinesterase inhibitors, as it directly blocks an essential pathological cascade in AD. Therefore, these multifunctional α ₂-adrenergic antagonists-butyrylcholinesterase inhibitors, exemplified by lead compound 8, present an innovative, small molecule-based, disease-modifying approach to treatment of AD.

Objective:To effectively quantify and evaluate the quality of different deformation registration algorithms, in order to enhance the possibility of implementing deformation registration in clinical practice.Methods:The Jacobian determinant mean (JDM) is proposed based on the Jacobian determinant (JD) of displacement vector field (DVF), and the Jacobian determinant error (DJDE) is introduced by incorporating the JD of the inverse DVF. The optical flow method (OF-DIR) and fast demons method with elastic regularization (FD-DIR) were tested on nasopharyngeal and lung cancer datasets. Finally, JDM and DJDE with the Jacobian determinant negative percentage (JDNP), inverse consistency error (ICE) and normalized mean square error (NMSE) were used to evaluate the registration algorithms and compare the differences evaluation indicators in different tumor images and different algorithms, and the receiver operating curve (ROC) was analyzed in evaluation.Results:In lung cancer, OF-DIR outperformed FD-DIR in terms of JDM, NMSE, DJDE and ICE, and the difference was statistically significant( z = -2.24, -4.84, t = 4.01, 6.54, P<0.05). In nasopharyngeal carcinoma, DJDE, ICE and NMSE of OF-DIR were superior to FD-DIR, and the difference was statistically significant ( t = 4.46, -7.49, z = -2.22, P<0.05), but there was no significant difference in JDM ( P>0.05). In lung cancer and nasopharyngeal carcinoma, JDNP of OF-DIR was worse than that of FD-DIR, and the difference was statistically significant ( z = -4.29, -4.02, P<0.01). In addition, DJDE is more specific and sensitive on ROC curve (AUC=0.77), and has different performance result for tumor images at different sites. Conclusions:The JDM and DJDE evaluation metrics proposed are effective for deformation registration algorithms. OF-DIR is suitable for both lung cancer and nasopharyngeal carcinoma, while the influence of organ motion on the registration effect should be considered when using FD-DIR.

Objective:To explore the effect of "Internet plus" exercise prescription intervention on upper limb dysfunction and quality of life of breast cancer patients at home after surgery, so as to provide reference for health management of breast cancer patients after surgery.Methods:Adopting a prospective randomized controlled trial research method. From November 2021 to January 2023, 124 breast cancer patients in the breast and thyroid surgery department of Xiang′an Hospital Affiliated to Xiamen University were selected for the study. According to the random number table method, they were randomly divided into an intervention group (62 cases) and a control group (62 cases). The control group patients were given routine training, and the intervention group patients received routine training in the first four weeks after operation, and "Internet plus" exercise prescription intervention in the fifth week after operation. The upper limb dysfunction, quality of life before and after the intervention and motor compliance after the intervention between the two groups were compared.Results:A total of 117 patients were ultimately included, and they were all female, with 58 patients in the intervention group aged (51.01 ± 9.77) years old and 59 patients in the control group aged (51.47 ± 9.85) years old. There was no statistically significant difference in upper limb dysfunction and quality of life between the two groups of patients before intervention ( P>0.05). After the intervention, the degree of upper limb dysfunction in the intervention group was (63.55 ± 7.02) points, which were lower than that in the control group (67.13 ± 7.25) points, and the difference was statistically significant ( t = 2.71, P<0.01). After the intervention, the total score of quality of life and the scores of physiological status, social/family status, emotional status, functional status and additional attention of breast cancer patients in the intervention group were (115.27 ± 17.35), (22.65 ± 4.53), (22.79 ± 4.36), (20.96 ± 3.95), (19.56 ± 4.22), (29.31 ± 5.24) points, which were higher than those in the control group (104.28 ± 17.04), (20.57 ± 4.48), (20.85 ± 4.23), (18.75 ± 4.04), (17.18 ± 4.06), (26.93 ± 5.21) points, the differences were statistically significant ( t values were 2.44-3.46, all P<0.05). In terms of exercise compliance of breast cancer patients in the intervention group, the aerobic exercise completion rate was 91.38% (53/58), muscle strength training completion rate was 77.59% (45/58), stretching exercise completion rate was 86.21% (50/58), exercise frequency was (3.96 ± 1.13) times/week, exercise duration was (29.51 ± 7.64) min/time, which was superior to 77.97% (46/59), 57.63% (34/59), 69.49% (41/59), (3.38 ± 0.94) times/week, (23.96 ± 7.33) min/time in the control group, the differences were statistically significant ( χ2 = 4.04, 5.31, 4.73, t = 3.02, 4.01, all P<0.05). Conclusions:"Internet plus" exercise prescription intervention has the characteristics of convenience, intuition and strong operability, which is conducive to improving the upper limb dysfunction, quality of life and exercise compliance of breast cancer patients at home after surgery. It is recommended to be popularized and applied clinically.

Objective To analyze the research hotspots and trends in the field of cancer pain drugs based on literature.Methods This article included research literature related to cancer pain and drugs published in the China National Knowledge Infrastructure(CNKI)and Web of Science databases.The visual analysis of the literature was performed by software of VOS-viewer 1.6.18 and CiteSpace 6.2.R3,including drawing the graphs and comparing the number of published articles,journals,institutions,authors and keywords were also analyzed.Results A total of 4 774 literatures were included.The journals with the largest number of articles published were the Chinese Journal of Pain Medicine and the Journal of Pain and Symptom Management.The authors with the highest number of articles published were Liu Duanqi and Bruera Eduardo.The institutions with the highest number of publications were Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology,and the University of Texas Anderson Cancer Center.The most frequent keyword was cancer pain.The keywords with the strongest citation bursts included Clinical efficacy average daily cost,and primary care.Conclusion Since the beginning of the 21st century,the research on cancer pain drugs has gradually heated up,and the number of papers has shown an upward trend.From 2019 to 2022,the research on cancer pain drugs at home and abroad mainly focused on the clinical efficacy and average daily cost.This article has clarified the research hotspots of cancer pain drugs in recent years to a certain extent and has certain reference significance for future research.

Background and objective Pembrolizumab(PEM)has been shown to be effective in clinical trials for the treatment of advanced non-small cell lung cancer(NSCLC),but clinical trials were based on cohorts of patients selected on specific criteria,and whether the findings are consistent with real-world patients is debatable.The aim of this study is to evaluate the efficacy and safety of PEM in the treatment of advanced NSCLC based on real-world data.Methods A retro-spective collection of real-world data from patients with advanced NSCLC receiving PEM was conducted.Propensity score matching was used to eliminate inter-group differences and assess the efficacy and safety of PEM compared to chemotherapy.Results Among 450 matched patients,the incidence rates of any-grade adverse events were 79.87％in the PEM group and86.71％inthe chemotherapy group,while the incidence rates of grade＞3 adverse events were 4.03％and 7.31％,respectively.The objective response rates were 48.63％for PEM and 36.00％for chemotherapy(P=0.011).The median progression-free survival was 15.5 months for PEM and 8.8 months for chemotherapy(P＜0.001),and the median overall survival was not reached for PEM and 26.2 months for chemotherapy(P＜0.001).Conclusion PEM treatment for advanced NSCLC demonstrates favorable survival outcomes and acceptable safety in real-world clinical practice.

Objective:To investigate the application value of 0.9% sodium chloride injection for a balloon catheter in bedside Doppler ultrasound-guided percutaneous dilatational tracheostomy in critically ill patients.Methods:A randomized controlled study was conducted involving 54 critically ill patients who were scheduled for tracheostomy at the Intensive Care Medicine, Jilin Province People's Hospital, from September 2022 to April 2024. These patients were randomly divided into a conventional group ( n = 27) and an ultrasound group ( n = 27) using the random number table method. The conventional group underwent empirical extubation, while the ultrasound group received extubation guided by a balloon catheter filled with 0.9% sodium chloride injection under ultrasound guidance. The following parameters were observed in both groups: duration of operation, incidence of blood oxygen saturation < 90%, incidence of puncturing the endotracheal tube or balloon catheter, distance from extubation site to the incisors, dosage of propofol, length of incision, and amount of bleeding. Results:Both groups of patients successfully completed the procedure on the first attempt, with no significant complications such as extensive bleeding, vascular injury, thyroid damage, or pneumothorax. In the ultrasound group, the incidence of puncturing the endotracheal tube or balloon catheter, duration of operation, and dosage of propofol were 3.7% (1/27), (6.2 ± 1.4) minutes, and 40 (40, 40) mg, respectively, all of which were superior to those in the conventional group [48.1% (13/27), (9.8 ± 2.7) minutes, 80 (70, 80) mg, χ2 = 23.19, t = 6.11, Z = -6.29, all P < 0.05]. The incidence of hypoxemia in the ultrasound group was 0, which was significantly lower than that in the conventional group [29.6% (8/27), P < 0.05]. The distance from extubation site to the incisors in the ultrasound group was 18 (17, 18) cm, which was significantly different from 18 cm of the conventional group ( Z = -2.62, P < 0.05). There were no statistically significant differences in length of incision and amount of bleeding between the two groups ( P = 0.652, 0.878). Conclusion:Performing PDT under bedside Doppler ultrasound guidance with a 0.9% sodium chloride injection-filled balloon catheter in patients requiring mechanical ventilation can reduce procedure duration, lower the incidence of hypoxemia and puncturing of the endotracheal tube or balloon catheter, decrease the use of sedative medications, and enhance the accuracy and safety of the procedure.

Objective To observe the correlations of chest CT quantitative parameters in patients with acute exacerbation of chronic obstructive pulmonary disease(AECOPD)with blood eosinophil(EOS)level.Methods Chest CT data of 162 AECOPD patients with elevated eosinophils were retrospectively analyzed.The patients were divided into low EOS group(n=105)and high EOS group(n=57)according to the absolute counting of blood EOS.The quantitative CT parameters,including the number of whole lung bronchi and the volume of blood vessels,low-attenuation area percentage(LAA％)of whole lung,of left/right lung and each lobe of lung,as well as the luminal diameter(LD),wall thickness(WT),wall area(WA)and WA percentage of total bronchial cross-section(WA％)of grade 3 to 8 bronchi were compared between groups.Spearman correlations were performed to analyze the correlations of quantitative CT parameters with blood EOS level.Results LAA％of the whole lung,of the left/right lung and each lobe of lung,as well as of the upper lobe of right lung LDgrade4,middle lobe of right lung WTgrade5,upper lobe of right lung WAgrade4,middle lobe of right lung WAgrade5 and lower lobe of left lung WAgrade3 in low EOS group were all higher than those in high EOS group(all P＜0.05).Except for the upper lobe of right lung LDgrade4,the above quantitative CT indexes being significant different between groups were all weakly and negatively correlated with blood EOS level(r=-0.335 to-0.164,all P＜0.05).Conclusion Chest CT quantitative parameters of AECOPD patients were correlated with blood EOS level,among which LAA％,a part of WT and WA were all weakly negatively correlated with blood EOS level.

Objective: To investigate the clearance effect of photodynamic therapy (PDT) with an oxygen-releasing photosensitizer methylene blue (MB) formula on Enterococcus faecalis in the root canal. Methods : Groups were divided into the MB group and oxygen release MB group. Samples in the MB group were mixed with 50 μmol/L MB solution, and samples in the oxygen release MB group were mixed with 50 μmol/L MB in oxygen release emulsion. N-acetyl-L-tryptophan amide (NATA) and 1,3-diphenylisobenzofuran (DPBF) were used to detect the oxidative activity and singlet oxygen generation of different formulas of MB (MB group, oxygen-releasing MB group), and the oxygen-releasing capacity of the oxygen-releasing photosensitizer formula was analyzed. The single root canal anterior teeth were collected, and the Enterococcus faecalis root canal infection model of isolated teeth was constructed. The distribution of Enterococcus faecalis in the root canal was observed by scanning electron microscopy. The isolated teeth with Enterococcus faecalis root canal infection were divided into three groups: the conventional root canal therapy group, MB-PDT therapy group, and oxygen-releasing MB-PDT therapy group, with 10 teeth in each group. Bacterial samples in the root canals of each group were obtained, the number of colonies was analyzed(CFU/mL) after 24 h of in vitro culture, and the clearance rate of Enterococcus faecalis in the root canal by photodynamic therapy was evaluated. The remaining isolated teeth with Enterococcus faecalis root canal infection were divided into 3 groups, with 5 samples in each group. Bacterial samples at a depth of 1 000 μm in the dentin tubules of the upper root, middle root and lower root segment were obtained and cultured in vitro for 24 h for calculations. The number of colonies (CFU/mL) was analyzed, and the clearance rate of Enterococcus faecalis in the dentin tubules of different segments of the root canals in each group was analyzed. Results : The oxidation activity and singlet oxygen generation capacity in the oxygen-releasing MB group were stronger than those in the MB group. Scanning electron microscope detection showed that Enterococcus faecalis was distributed in dentinal tubules, indicating that the model of root canal infection in vitro was successfully constructed. The clearance rate of Enterococcus faecalis in the oxygen-releasing MB-PDT therapy group was higher than that in the conventional therapy group and the MB-PDT therapy group (P<0.05). Oxygen-releasing PDT significantly improved the bactericidal effect in the lower dentinal tubules, and the clearance rate of Enterococcus faecalis was better than in the other two groups (P<0.05). Conclusion Photodynamic therapy with the oxygen-releasing photosensitizer MB can achieve a better root canal bactericidal effect and can significantly improve the clearance effect of Enterococcus faecalis in the deep dentin of the lower root segment.

Objective:To investigate the differences in the expression profiles of cyclic RNA (circRNA) in peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) and its clinical significance.Methods:Venous blood were collected from 4 patients with RA (group T) and 4 healthy subjects (group C). The expression profiles of circRNA in PBMCs of the two groups were detected by Arraystar circRNA microarray, and the differentially expressed circRNA was analyzed by clustering analysis. The binding sites for interaction between differentially expressed circRNA and miRNA were predicted, and functional analysis such as geneontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed. quantitative real-time polymerase chain reaction (RT-qPCR) was used to verify the expression of partially differentially expressed circRNA in the two groups of PBMCs, and a circRNA-miRNA-mRNA regulatory network (ceRNA network) was constructed for the target circRNA with significantly differential expression. A receiver operating characteristic curve [receiver operating characteristic curve (ROC)] was established to analyze the potential diagnostic value of target circRNA. SPSS Statistics 23.0 and Graphpad Prism 8.0 were used to analyze the data, and the independent t test was used to analyze the difference between the two groups. Results:① Microarray results showed that, compared with group C, a total of 399 [fold of difference (FC)>1.5, and P<0.05] circRNA were abnormally expressed in PBMCs of group T; including 149 up-regulated and 250 down-regulated. ② Bioinformatics analysis: The prediction of the binding site of circRNA and miRNA suggested that the differentially expressed circRNA in RA might affect the inflammatory response by targeting miR-140-5p, miR-338-5p, and miR-9-5p. GO analysis showed that the differentially expressed circRNA was mainly involved in the intimal-binding organelles, protein metabolism and binding, etc. KEGG pathway analysis showed that most of the involved pathways were related to infection and human immune dysregulation. ③ The results of multi-sample RT-qPCR validation showed that the expression level of hsa_circRNA_009012 in group T was significantly higher than that in group C ( t=-4.417, P<0.01), the expression level of hsa_circRNA_101328 was significantly lower than that in group C ( t=-1.042, P<0.01), and the expression of hsa_circRNA_058230 had no significant change ( t=4.691, P>0.05). ④ ROC curve analysis indicated that hsa_circRNA_009012 had potential value in the diagnosis of RA [area under curve=0.96]. Conclusion:The expression of circRNA in PBMCs of patients with RA is imbalanced, and it may participate in the regulation of the development of RA. Among them, hsa_circRNA_009012 is expected to become a new biological marker for the diagnosis and treatment of RA.

Objective:To investigate the effect of metformin on the microRNA (miRNA) expression and screen potential target with network pharmacology analysis in patients with type 2 diabetes.Methods:Fifteen patients with new diagnosed type 2 diabetes admitted to our hospital were selected, who received metformin during hospitalization and after discharge. The expression of serum matrix metalloproteinase (MMP)-9, transforming growth factor (TGF)-β1, and myocardial fibrosis related miRNAs were compared before and 6 month after metformin treatment. In addition, gene ontology (GO) and KEGG pathway enrichment analysis were applied to analyze differential expression miRNAs showing statistical significance. Meanwhile, the network figure was established to reflect the target gene messenger RNA (mRNA) corresponding to differentially expressed miRNA.Results:Compared with pre-medication, the serum level of MMP-9 was significantly decreased after treatment ( P<0.05). Besides, the expression of homo sapiens microRNA (hsa-miR)29a-3p, hsa-miR133a-5p, hsa-miR21-5p, hsa-miR30c-5p, and hsa-miR1-3p in patients with type 2 diabetes were dramatically down-regulated by metformin ( P<0.05 or P<0.01). Results of GO analysis and KEGG pathway enrichment analysis showed that differentially expressed miRNAs were mainly concentrated in endoplasmic reticulum lumen, synapse, basement membrane and other cell components. The molecular functions such as Rho GTPase binding and participation in extracellular matrix structural constituent were exerted through biological processes such as collagen catabolic process, regulation of short-term neuronal synaptic plasticity, and axon extension, which were mainly enriched in advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) signaling pathway in diabetic complications, tumor necrosis factor (TNF) signaling pathway, and Wnt signaling pathway, etc. The outcome of miRNA-mRNA network analysis demonstrated that there were 230 target genes mRNAs corresponding to differentially expressed miRNA. Conclusion:Metformin could play its role in the treatment of type 2 diabetes by down regulating the expression of miRNA, participating in the transduction of related cellular signaling pathways, regulating chromatin, nucleic acid binding, and enzyme activities.