19 cinnamamide/ester-triazole compounds were designed, synthesized and evaluated for their anti-Alzheimer's disease (AD) activity. Among them, compound 4f displayed excellent anti-β-amyloid protein (Aβ)-mediated cytotoxicity (EC₅₀ = 2.03 ± 2.45 μmol·L^-1) in APPswe cells and acetylcholinesterase inhibiton (IC₅₀ = 4.88 ± 4.70 μmol·L^-1). Further study indicated that, at dosages of (1, 5 and 25 mg·kg^-1), compound 4f was effective in improving spatial learning and memory deficits in Aβ_1-42-impaired mice, which was achieved by promoting the nonamyloidogenic signaling and inhibiting the amyloidogenic pathway, along with the suppression of Aβ-induced Tau phosphorylation. All animal experiments in this study were approved by the Experimental Animal Care and Use Committee of the Institute of Medicinal Biotechnology (IMB-20220908D701). In conclusion, compound 4f holds promise as a lead candidate for AD treatment, and the present study lays the foundation for its subsequent development.

Objective:To explore the clinical, imaging, and pathological features of glottic squamous cell carcinoma of the larynx and their relationship with prognosis. Methods:A retrospective analysis was conducted on the clinical, imaging, and pathological data of 130 patients with glottic squamous cell carcinoma of the larynx who were treated at the First People's Hospital of Yinchuan and the General Hospital of Ningxia Medical University from January 2018 to March 2023. Imaging examinations （CT and MRI） were used to evaluate the lesion boundary clarity, density, enhancement nature, and enhancement degree. Postoperative pathological examination was used to determine the pathological nature, immunohistochemistry, etc. Statistical methods such as χ² test, Spearman correlation analysis, multivariate logistic regression analysis, and Kaplan-Meier method were used to analyze the data. Results:Among the 130 patients, 127 were male and 3 were female, with an average age of （61.92±9.595） years. There was a correlation between clinical, imaging, and pathological features. Multivariate analysis showed that heterogeneous MRI density （OR=12.414;P=0.019） and squamous cell carcinoma as a subtype were correlated. The initial symptom of non-hoarseness （HR=6.045;P=0.010） and unclear MRI boundary （HR=12.559; P=0.029） were independent risk factors for poor prognosis in patients with glottic squamous cell carcinoma of the larynx. Conclusion:There is a correlation between the clinical, imaging, and pathological features of patients with glottic squamous cell carcinoma of the larynx, and they can affect prognosis. The initial symptom of non-hoarseness and unclear MRI boundary of the tumor are independent risk factors for poor prognosis.
Humans ; Laryngeal Neoplasms/diagnosis* ; Prognosis ; Male ; Female ; Retrospective Studies ; Middle Aged ; Carcinoma, Squamous Cell/diagnosis* ; Magnetic Resonance Imaging ; Glottis/pathology* ; Tomography, X-Ray Computed ; Aged

Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

Objective To investigate the effects and mechanism of β2 adrenergic receptors(ADRB2)in ferroptosis and autophagy induced by erastin(Era)in prostate cancer.Methods PC-3 cells were infected with lentivirus or control and set to sh-NC group(normal culture),sh-NC+Era group(10 μmol/L Era treatment for 24 h),sh-ADRB2 group(normal culture),and sh-ADRB2+Era group(10 μmol/L Era treatment for 24 h).The viability of the cells treated with Era and ferrostatin-1(Fer-1)was measured by CCK-8 assay.The cell morphology was analyzed by transmission electron microscopy.The malondialdehyde(MDA)content was measured by the Lipid Oxidation Detection Kit and the iron level by Iron Colorimetric Assay.Western blotting was used to detect the expressions of cystine-glutamate exchanger(XCT),ferritin heavy chain 1(FTH1),glutathione peroxidase 4(GPX4),p62,LC3,JNK,c-Jun,and p-c-Jun.PC-3 cells with ADRB2 knockdown were injected into nude mice to construct a xenograft model and then treated with Era.The animals were divided into sh-NC group,sh-NC+Era group,sh-ADRB2 group,and sh-ADRB2+Era group,with 4 mice in each group.The tumor volumes were recorded every other day and the final tumor weight was measured at study termination.The expressions of ADRB2,JNK,c-Jun,and p-c-Jun were detected by immunohistochemistry(IHC).Results The viability of PC-3 cells decreased after Era treatment(P<0.01)and recovered after Fer-1 treatment(P<0.01).Morphological changes of ferroptosis and autophagy were observed in Era-treated cells,and MDA and iron ion contents up-regulated(P<0.05 or P<0.01).Knockdown of ADRB2 and Era treatment further inhibited PC-3 cell viability(P<0.05),and MDA and iron ion contents up-regulated(P<0.01).The expressions of ferroptosis-related proteins FTH1,XCT,GPX4,and LC3 down-regulated(P<0.05 or P<0.05),p62 and JNK pathway-related proteins JNK,c-Jun,and p-c-Jun were up-regulated(P<0.01).After JNK inhibitor treatment,the expressions of FTH1,XCT,and LC3 increased,and p62 decreased(P<0.01).In the PC-3 xenograft model,tumor volume in sh-ADRB2+Era group was significantly smaller than those in sh-NC+Era group and sh-ADBR2 group(P<0.05 or P<0.01).IHC showed that compared with sh-NC group,ADRB2 protein expression level was down-regulated in sh-ADRB2 group(P<0.05),while JNK,c-Jun,and p-c-Jun protein expression levels were elevated(P<0.01).Compared with sh-NC+Era group,the ADRB2 protein expression level in sh-ADRB2+Era group was down-regulated,while JNK,c-Jun,and p-c-Jun protein expression levels were up-regulated(P<0.05).Conclusion ADRB2 regulated ferroptosis and autophagy induced by Era via JNK/c-Jun pathway in prostate cancer.

OBJECTIVE To establish the drug use evaluation(DUE) standard of ticagrelor, and to provide a reference for the rational clinical application of ticagrelor. METHODS Based on the ticagrelor drug label, related guidelines and literature, combined with clinical expert consultation results, DUE standard from three levels (indications, medications and medication results) was established. A retrospective survey was conducted to evaluate the inpatients using ticagrelor from January 2021 to December 2021 in the Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine. RESULTS The DUE of ticagrelor was divided into three levels, including 3 first-level indexes, 14 second-level indexes and 60 third-level indexes. A total of 263 cases of using ticagrelor were included, of which the irrational rate was 72.62%. The irrational cases were mainly off-label use (60.08%), inappropriate drug conversion(14.83%) and unreasonable usage and dosage(5.70%), etc. CONCLUSION The established DUE standard of ticagrelor is scientific, practical and feasible, which can provide reference for clinical rational drug use and prescription evaluation.

OBJECTIVE To investigate the implementation effects of the national centralized drug volume-based procurement policy （abbreviated as “national centralized procurement policy”） in Guangxi Zhuang Autonomous Region prefecture， and to provide a reference for the future centralized drug procurement work of the medical institution. METHODS Drug procurement data before and after policy implementation were included in the study. The six secondary indicators （such as availability， affordability， and drug safety） and eighteen third-level indicators （such as completion rate of agreed purchase volume， affordability level， drug revenue proportion） were introduced， guided by the policy objectives and issues of concern to policy beneficiaries. Descriptive statistics was adopted to analyze the data before and after policy implementation （in 2019 and 2020） in terms of differences and change trends. RESULTS In terms of accessibility， the participation rate of medical institutions in Guangxi Zhuang Autonomous Region was 92.55%， the proportion of diseases involved and median completed procurement rate were 40.16%， and 287.82% respectively， and the total centralized delivery rate was 97.20%. In terms of affordability， the total reduction amplitude in drug price was 74.80% from 2019 to 2022； the charge for medicine per capita in hospitalization， the proportion of medicine used for outpatient service and hospitalization， decreased by 17.61%， 10.22%， and 20.10% in order； the burden levels on medical fares for patients were all below 1 in addition to chronic diseases， and anti-tumor drugs. In terms of the impact on medicine， the ratio of adverse drug reaction event cases in 2022 was 66.00%， an increase of 1.29% compared to the previous； since the implementation of the policy， 12 drugs from local pharmaceutical enterprises from Guangxi Zhuang Autonomous Region had passed the consistency evaluation， and the market concentration rate of the top 8 pharmaceutical companies was less than 20.00%. In terms of the impact on healthcare and medical insurance， the public medical institutions achieved generic substitution for originator drugs mostly until 2022； about 9.12% of drugs that were non- centrally purchased in the same category were used； 63.39% of people under investigation did not show a need for a second dressing change； drug expenditure decreased by 2.459 billion yuan. CONCLUSIONS The national centralized procurement policy achieves a significant effect in Guangxi Zhuang Autonomous Region. On the other hand， attention should be paid to these suggestions as follows: expanding the category of drugs used in clinic， conducting clinically comprehensive evaluation of selected drugs， and improving reasonable allocation strategy， etc.

Objective:To explore the effects of G protein-coupled receptor 55 (GPR55) antagonist CID16020046 on renal fibrosis in mice, and provide a new method and idea for the treatment of renal fibrosis.Methods:(1) GPR55 overexpression and GPR55 antagonist CID16020046 were used in renal fibroblasts (NRK-49F) of rats, respectively. Meanwhile,transforming growth factor-β1 (TGF-β1) was applied in the NRK-49F cells to observe the expression of fibrosis-related factors and inflammatory factors. (2) A mouse model of renal fibrosis with unilateral ureteral obstruction (UUO) was established in vivo. Eight-week-old male C57BL/6J mice (20-25 g) were randomly divided into three groups according to the random number table method: sham group ( n=6), model group (UUO group, n=7), model + CID16020046 drug (UUO+CID group, n=8). The drug CID16020046 (10 mg/kg) was intraperitoneally injected 1 day before modeling, on the day of modeling and every day after surgery in UUO+CID group, and the corresponding dose of 0.9% normal saline was injected intraperitoneally in sham and UUO groups.The mice were sacrificed for sampling 7 days after UUO surgery, and their renal function indicators, liver transaminase, and cardiac markers were examined. Western blotting and quantitative real-time PCR were used to detect the expression of renal fibrosis-related factors and inflammatory factors. Immunohistochemistry staining, Sirius red staining and Masson trichrome staining were used to detect the pathological changes of renal tissues. Results:(1) After NRK-49F cells were stimulated by TGF-β1, the mRNA and protein expression levels of GPR55 were significantly increased (both P<0.05). There was no statistically significant difference in the mRNA expression of fibrosis-related factors fibronectin and collagen Ⅰ, and inflammatory factors interleukin-1β and tumor necrosis factor-α between TGF-β1 group and TGF-β1 + GPR55 overexpression group (all P>0.05). Compared with the TGF-β1 group, the protein expression levels of fibrosis-related factors alpha-smooth muscle actin (α-SMA) and vimentin, and the mRNA expression levels of collagen Ⅰ and α-SMA were lower in the TGF-β1 + CID group (all P<0.05). (2) Compared with sham group, the mRNA and protein expression levels of GPR55 in UUO group were higher (both P<0.05). The serum creatinine in the UUO+CID group was lower compared to the UUO group ( P<0.05). There was no statistically significant difference in blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and creatine kinase isoenzyme between UUO group and UUO+CID group (all P>0.05). Compared with the UUO group, the protein expression levels of renal fibrosis-related factors fibronectin, collagen Ⅰ and vimentin, and the mRNA expression levels of fibronectin, collagen Ⅰ, collagen Ⅲ and α-SMA were lower in the UUO+CID group (all P<0.05). The degree of renal tubular dilation and interstitial collagen fiber deposition in the UUO+CID group was significantly reduced compared to the UUO group (all P<0.05). Conclusions:CID16020046 can reduce serum creatinine in UUO mice, protect renal function, and simultaneously decrease the expression of fibrosis-related factors in renal fibroblasts and mouse kidney tissues, thereby alleviating renal fibrosis.

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.
Female ; Humans ; Male ; Aged ; Middle Aged ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy* ; Prognosis ; Lymphoma, B-Cell ; Immunohistochemistry ; Immunoglobulin Heavy Chains/therapeutic use*

Cohort study is one of the important research methods in analytical epidemiology because of its clear time sequence relationship, which is better than other observational studies in demonstrating causal association. However, screening diagnosis or other methods are often used to exclude the individuals with outcome events during the enrollment process of the subjects in cohort studies. The accuracy of screening diagnosis and the effectiveness of exclusion will affect the accuracy of the baseline status assessment of the subjects included in the study, which may lead to the causal time sequence reversal of exposure-outcome in the estimation of causal effect. Landmark analysis can be used to control reverse causality by excluding subjects with potentially unknown expose-outcome timing. In this paper, we describe the basic principles and analytical steps of landmark analysis, and use data from the Chinese Longitudinal Healthy Longevity Survey to explore the relationship between physical activity and frailty, and introduce the specific application of landmark analysis for the purpose of facilitating its application and inferring causal effects more accurately in cohort studies.

With completing a baseline survey of a large natural population cohort, conducting regular follow-up has become a key factor in further improving the quality of cohort construction and ensuring its sustainable development. Typical cohort follow-up methods include repeat surveys, routine monitoring, and community-oriented surveillance. However, in practical applications, there are often issues such as high costs, difficulty, and high error rates. Telephone follow-up is an important supplementary method to the methods mentioned above, as it has the characteristics of low cost, fast response, and high quality. However, the with difficult organization, quality control is challenging, response rates are low, and management levels vary widely, which limits its widespread use in large-scale population cohort studies. Given the above problems, this study draws on customer relationship management based on the actual needs of the China Northwest Cohort follow-up. It relies on the REDCap electronic data collection platform to build a telephone follow-up management and quality control system. Targeted solutions are provided for key issues in telephone follow-up implementation, including organizational structure, project management, data collection, and process quality control, to improve the quality control level of telephone follow-up comprehensively and thereby enhance the quality and efficiency of follow-up. We hope to provide standardized follow-up programs and efficient quality control tools for newly established and existing cohort studies.