Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the Aβ-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how Aβ mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric Aβ (o-Aβ) bound to microglial Kv2.1 and promoted Kv2.1-dependent potassium efflux to activate NLRP3 inflammasome resulting in neuronal tauopathy by using Kv2.1 inhibitor drofenine (Dfe) as a probe. The underlying mechanism has been intensively investigated by assays with Kv2.1 knockdown in vitro (si-Kv2.1) and in vivo (AAV-ePHP-si-Kv2.1). Dfe deprived o-Aβ of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-κB pathway while improving the cognitive impairment of 5×FAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-Aβ-driven microglial NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Dfe as a Kv2.1 inhibitor shows potential in the treatment of AD.

OBJECTIVES: To explore the mechanism by which Pulsatilla saponin D (PSD) inhibits invasion and metastasis of triple-negative breast cancer (TNBC). METHODS: The public databases were used to identify the potential targets of PSD and the invasion and metastasis targets of TNBC to obtain the intersection targets between PSD and TNBC. The "PSD-target-disease" interaction network was constructed and protein-protein interaction (PPI) analysis was performed to obtain the core targets, which were analyzed for KEGG pathway and GO functional enrichment. Molecular docking study of the core targets and PSD was performed, and the therapeutic effect and mechanism of PSD were verified using Transwell assay and Western blotting in cultured TNBC cells. RESULTS: Network pharmacology analysis identified a total of 285 potential PSD targets and 26 drug-disease intersection core targets. GO analysis yielded 175 entries related to the binding of biomolecules (protein, DNA and RNA), enzyme activities, and regulation of gene transcription. KEGG analysis yielded 46 entries involving pathways in cancer, chemical carcinogenesis-receptor activation, microRNAs in cancer, chemical carcinogenesis-reactive oxygen species, PD-L1 expression and PD-1 checkpoint pathway in cancer. Molecular docking showed high binding affinities of PSD to MTOR, HDAC2, ABL1, CDK1, TLR4, TERT, PIK3R1, NFE2L2 and PTPN1. In cultured TNBC cells, treatment with PSD significantly inhibited cell invasion and migration and lowered the expressions of MMP2, MMP9, N-cadherin and the core proteins p-mTOR, ABL1, TERT, PTPN1, HDAC2, PIK3R1, CDK1, TLR4 as well as NFE2L2 expressionin the cell nuclei. CONCLUSIONS The inhibitory effects of PSD on TNBC invasion and metastasis are mediated by multiple targets and pathways.
Humans ; Triple Negative Breast Neoplasms/metabolism* ; Saponins/pharmacology* ; Pulsatilla/chemistry* ; Female ; Molecular Docking Simulation ; Cell Line, Tumor ; Neoplasm Invasiveness ; Protein Interaction Maps ; Neoplasm Metastasis ; Signal Transduction/drug effects* ; Cell Movement/drug effects*

To improve the evaluation indicators of medical quality in TCM hospitals; To realize objective, fair, and accurate evaluation of the quality of TCM. Based on relevant literature on medical quality in traditional Chinese medicine hospitals research and thematic group discussions, 21 evaluation indicators for TCM characteristics were formed. A questionnaire survey was conducted among 40 experts, and 37 were effectively collected, with a positive coefficient of 92.50%. After two rounds of expert consultation, the evaluation indicators were determined to be: the intensity of outpatient use of TCM decoction pieces (utilization rate of TCM decoction pieces, prescription number of TCM decoction pieces, dosage of TCM decoction pieces, and service price of TCM decoction pieces), the intensity of the use of TCM technology (proportion of TCM technology, number of TCM projects, cost of TCM technology, and course of treatment). Case studies were conducted on relevant data from 10 departments using the operational decision support system (BI) platform of Yueyang Integrated Traditional Chinese and Western Medicine Hospital affiliated with Shanghai University of Traditional Chinese Medicine to verify the rationality of indicators. The 10 departments were analyzed and evaluated, and the results obtained were basically consistent with the actual medical quality situation of the hospital. The indicators used in this study can reflect the actual medical quality situation, and have a certain degree of scientificity, feasibility, and applicability, providing reference for improving the medical quality evaluation indicators of TCM hospitals.

Objective:To evaluate auditory spatial discrimination capabilities in patients with mild to moderately severe symmetrical sensorineural hearing loss (SNHL) and to compare the impact of different psychophysical testing methods on Minimum Audible Angle (MAA) and test duration.Methods:A total of 105 symmetrical SNHL patients aged from 18 to 60 years old were enrolled from April to July 2023, including 56 males and 49 females. They were divided into three groups based on PTA: mild, moderate, and moderately severe hearing loss, with 35 individuals in each group. Additionally, a control group of 35 individuals with normal hearing was tested, including 18 males and 17 females. Participants underwent four distinct psychophysical discrimination tests: the block up-down, 1-up/1-down, 1-up/2-down, and 1-up/3-down procedures. We recorded the MAA and test duration for each. We employed repeated measures of ANOVA to compare the MAA and test duration across different methods and groups, and Pearson′s correlation to assess the relationship between MAA and degree of hearing loss.Results:MAA of sound localization in patients with symmetrical SNHL was significantly positively correlated with the degree of hearing loss ( r=0.59, P<0.01). Significant deterioration in MAA was observed as hearing loss progressed to the moderate level (PTA≥35 dBHL, P<0.01). The testing methods significantly influenced MAA and testing duration ( F=24.02, P<0.01; F=75.56, P<0.01) and the 1-up/1-down method was the quickest, averaging only (0.69±0.32) mins. Conclusions:The horizontal plane auditory spatial discrimination abilities in patients with symmetrical SNHL is impaired progressively with increasing hearing loss, notably beyond moderate hearing loss levels. Different psychophysical methods influence both MAA and test duration, the quicker 1-up/1-down method is recommended for assessing MAA in symmetrical SNHL patients.

Purpose To explore the value of the new generation tau PET tracer 18F-Florzolotau in Alzheimer's disease(AD)at different stages.Materials and Methods Twenty-five MCI patients and sixty-one AD patients with positive β-amyloid status in Huashan Hospital,Fudan University from February 2020 to January 2022 were retrospectively enrolled with 18F-Florzolotau PET imaging and demographic and clinical data.The pre-processed PET images were analyzed by SPM two-sample t-test between MCI and AD groups,and the standardized uptake value ratios(SUVR)were extracted from the region of interest defined by SPM analysis(P＜0.001);scaled subprofile model/principal component analysis was used to construct the different tau related patterns(MCItauRP,ADtauRP)and calculate the corresponding expression values.The classification efficiency of SUVR and MCItauRP,ADtauRP expression values was evaluated by receiver operating characteristic curve.Results Compared with MCI patients,tau protein deposition of AD patients was increased mainly in the bilateral temporal,occipital lobe(P＜0.001),and the SUVR of these brain region in the AD group was higher than that in the MCI group(Z=-3.164,P＜0.00l);the expression values of MCItauRP and ADtauRP were significantly different between the AD group and MCI group(t=3.72,Z=-3.51;both P＜0.001),and these expression values of AD patients were higher than those in the MCI group;the accuracy of tauRP expression values and SUVR for the differentiation between the AD and MCI group were 61.63％,65.12％and 65.12％,respectively;the sensitivity was 88.00％,96.00％and 100.00％,respectively;the specificity was 50.82％,52.46％and 50.82％,respectively.Conclusion The new tau PET can identify and distinguish the differences in tau protein deposition between AD and MCI patients.However,the classification and diagnosis efficiency is not high.In the future,it is necessary to find a more ideal analysis method.

Objective:To compare the effects of different reference brain regions on the semi-quantitative SUV ratio (SUVR) of 18F-Florzolotau PET images of Alzheimer′s disease (AD). Methods:The 18F-Florzolotau PET images of 28 (13 males, 15 females, age (57.3±9.5) years) normal controls (NC), 19 patients (4 males, 15 females, age (73.3±7.3) years) with β-amyloid (Aβ)-positive mild cognitive impairment (MCI) and 40 patients (19 males, 21 females, age (61.9±9.1) years) with AD were collected from Huashan Hospital, Fudan University between November 2018 and July 2020. Six semi-quantitative reference brain regions were defined, including whole cerebellum (WC), cerebellar gray matter (GM), cerebellar white matter (WM), parametric estimation of reference signal intensity (PERSI), WC after partial volume correction (WC_pvc), cerebellar GM after partial volume correction (GM_pvc). SUVR was calculated for 14 ROIs, which included the whole brain defined by the automated anatomical labeling (AAL) template, fusiform, inferior temporal, lingual, middle temporal, occipital, parahippocampal, parietal, posterior cingulate, precuneus defined by the AAL template, and Meta ROI composed of the above brain regions, and braak_Ⅰ-Ⅱ, braak_Ⅲ-Ⅳ, braak_Ⅴ-Ⅵ defined by the Desikan Killiany template. AUC was used to evaluate the classification ability of SUVR, and the correlation between SUVR and clinical scale scores were assessed by Spearman rank correlation analysis. Results:The SUVRs of most brain regions showed a steady upward trend in the AD disease spectrum. In the classification task of NC and MCI, the overall performance of SUVR based on WC_pvc was relatively optimal (AUCs: 0.975-1.000). In the classification task of NC and AD, SUVRs of 10 ROIs based on the WC_pvc method showed the relatively best performance (AUCs: 0.976-1.000). The correlation between SUVR of fusiform based on cerebellar WM and mini-mental state examination (MMSE) score was the strongest ( rs=-0.72, P<0.001), and the SUVR of precuneus based on WC_pvc showed the strongest correlation with clinical dementia rating (CDR) score ( rs=0.78, P<0.001). Conclusion:The SUVR based on WC_pvc method performs well in classification and correlation tasks, and is recommended to be used in semi-quantification of 18F-Florzolotau PET images of AD.

Objective:A voxel-level quantification method based on the tau IQ algorithm and Braak staging, excluding β-amyloid (Aβ) imaging, was developed to achieve specific tau quantification. Methods:This cross-sectional study included 92 subjects (35 males, 57 females; age (62.9±10.4) years) from the Nuclear Medicine/PET Center of Huashan Hospital, Fudan University between November 2018 and July 2020. The cohort comprised 28 cognitively normal (CN) individuals, 20 patients with mild cognitive impairment (MCI), and 44 patients with Alzheimer′s disease (AD). All participants underwent 18F-florzolotau PET imaging, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR) scoring. A longitudinal tau dataset was constructed based on Braak staging. Voxel-level logistic regression fitting provided a baseline matrix, decomposed via least squares to yield the Tau load coefficient. One-way analysis of variance (with post hoc Tukey) was used to compare Tau load and SUV ratio (SUVR) among groups. ROC curve analysis was used to evaluate classification between CN, MCI and AD. Spearman rank correlation was used to assess the relationships between Tau load, SUVR, and MMSE scores or CDR scores. Results:The Tau load in the CN group was close to 0 and significantly lower than that in the MCI and AD groups ( F=55.03, P<0.001; post hoc tests all P<0.001). Significant differences were also observed in the SUVR across all ROIs ( F values: 36.46-55.38, all P<0.001). Compared to SUVR, Tau load demonstrated greater intergroup differences. In ROC curve analyses between each pair of CN, MCI, and AD groups, Tau load consistently achieved the highest AUC (0.754-1.000). Both Tau load and SUVR for each ROI were negatively correlated with MMSE scores ( rs values: from -0.698 to -0.583, all P<0.05) and positively correlated with CDR scores ( rs values: 0.648-0.783, all P<0.05), with Tau load showing the highest absolute correlation coefficients. Conclusion:Compared to the traditional semi-quantitative SUVR method, the Braak-tau IQ algorithm does not require a specific reference brain region to achieve specific tau quantification.

OBJECTIVE Alzheimer disease(AD)is a neurodegenerative disease with clinical hallmarks of pro-gressive cognitive impairment.Synergistic effects of Aβ-tau cascade reaction are tightly implicated in AD patholo-gy,and microglial NLRP3 inflammasome activation drives neuronal tauopathy through microglia and neurons cross-talk.However,the underlying mechanism of how Aβ medi-ates NLRP3 inflammasome remains unclear.Shab related potassium channel member 1(Kv2.1)as a voltage gated po-tassium channel widely distributed in the central nervous system and plays an important role in regulating the out-ward potassium flow in neurons and glial cells.In current work,we aimed to explore the underlying mechanism of Kv2.1 in regulating Aβ/NLRP3 inflammasome/tau axis by using a determined Kv2.1 inhibitor drofenine(Dfe).METHODS Cell-based assays including Western blot-ting and immunofluorescence staining against primary microglia or neurons were carried out to expound the role of Kv2.1 channel in NLRP3 inflammasome activa-tion and subsequent neuronal tau hyperphosphorylation.For animal studies,new object recognition,Y-maze and Morris water maze were performed to evaluate the ame-lioration of Kv2.1 inhibition through either Kv2.1 inhibitor Dfe treatment or adeno-associated virus AAV-ePHP-si-Kv2.1injectionon5×FADADmodel mice.Assays of histol-ogy and immunostaining of tissue sections and Western blotting of brain tissues were performed to verify the con-clusion of cellular assays.RESULTS We reported that oligomeric Aβ(o-Aβ)bound to microglial Kv2.1 and pro-moted Kv2.1-dependent potassium leakage to activate NLRP3 inflammasome through JNK/NF-κB pathway sub-sequently resulting in neuronal tauopathy.Treatment of either Kv2.1 inhibitor Dfe or AAV-ePHP-si-Kv2.1 for brain-specific Kv2.1 knockdown deprived o-A β of its capability in inducing microglial NLRP3 inflammasome activation and neuronal tau hyperphosphorylation,while improved the cognitive impairment of 5×FAD AD model mice.CONCLUSION Our results have highly addressed that Kv2.1 channel is required for o-Aβ driving NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Kv2.1 inhibition is a prom-ising therapeutical strategy for AD and Dfe as a Kv2.1 inhibitor shows potential in the treatment of this disease.

ObjectiveTo compare the annual and age trends of the age-standard incidence rate （ASIR） and the age-standard mortality rate （ASMR） of lung cancer in countries with different human development index （HDI） from 1990 to 2019. MethodsThe data were collected from the global burden of disease study and GLOBOCAN 2020. The average annual percentage change （AAPC） and age trends of ASIR and ASMR in lung cancer were analyzed by the Joinpoint regression model， and the comparison between the four groups was analyzed by Kruskale-Wallis analysis. ResultsIn 2020， the incidence and mortality of lung cancer gradually increased with age and HDI grade. From 1990 to 2019， the global ASIR and ASMR of lung cancer decreased， and the ASIR of lung cancer among male decreased， while the ASIR of lung cancer among female increased. The results showed that ASIR of lung cancer in female residents in countries with very high HDI increased significantly from 1996 to 2011， resulting in an overall upward trend in female ASIR， while the other groups showed a downward trend. It was found that ASIR and ASMR of lung cancer in China and India were on the rise， while ASIR and ASMR of lung cancer in Russia and the United States were on the decline. ConclusionAlthough very high/high HDI countries face a higher burden of lung cancer occurrence and death， the accumulation of lung cancer burden is completed in the transitioning period. Therefore， lung cancer prevention measures in countries in transition are critical for global lung cancer control.

ObjectiveTo determine the influence of COVID-19 prevention and control on the epidemic characteristics and dynamics of notifiable infectious diseases in the first quarters， Zhejiang Province， and to explore more effective countermeasures against infectious diseases. MethodsDescriptive epidemiology was conducted to determine the change in notifiable infectious diseases during the prevention and control of COVID-19 in Zhejiang Province by retrieving the data of notifiable infectious diseases from 2017 to 2022 in the Chinese information system for disease control and prevention. Cumulative reported new cases of notifiable infectious diseases in the first quarters of 2017‒2019 were compared with that of 2020‒2022. ResultsA total of 546 753 cases of notifiable infectious diseases were newly reported in the first quarters of 2017‒2019， with an average incidence of 321.92/10⁵. In contrast， a total of 509 908 cases of notifiable infectious diseases were newly reported in the first quarters of 2020‒2022， during which the COVID-19 epidemic occurred， with an average incidence of 270.39/10⁵. The incidence in 2020‒2022 significantly declined by 51.53/10⁵， compared with that in 2017‒2019 （χ²=8 072.06， P<0.001）. In the first quarters of 2020‒2022， the average incidence of zoonotic diseases and vector-borne diseases decreased by more than 50%. In addition， the incidence of respiratory， enteric， blood-borne， and sexually transmitted diseases declined to certain degree. ConclusionThe decline in the newly reported cases of non-COVID-19 notifiable infectious diseases in the first quarters of 2020‒2022 indicates that the countermeasures against COVID-19 epidemic， such as multi-disease co-prevention， multi-sectoral collaboration， societal mobilization and personal hygiene and protection， may also decrease the incidence of multiple infectious diseases. It suggests the countermeasures are effective， which would provide evidence for routine prevention and control of infectious diseases in future.