The development of anticancer drugs to treat triple-negative breast cancer (TNBC) is an ongoing challenge. Immunogenic cell death (ICD) has garnered considerable interest worldwide as a promising synergistic modality for cancer chemoimmunotherapy. However, only few drugs or treatment modalities can trigger an ICD response and none of them exert a considerable clinical effect against TNBC. Therefore, new agents with potentially effective chemoimmunotherapeutic response are required. In this study, five new cyclometalated Ir(III) complexes containing isoquinoline alkaloid CˆN ligands were designed and synthesized. Among them, Ir-1 exhibited the highest in vitro cytotoxicity. Mechanistically, Ir-1 could trigger autophagy-dependent ferroptosis and a subsequent ferroptosis-dependent ICD response as well as indoleamine 2,3-dioxygenase (IDO) inhibition via reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress in MDA-MB-231 cells. When immunocompetent BALB/c mice were vaccinated with Ir-1-treated dying TNBC cells, antitumor CD8⁺ T-cell response and Foxp3⁺ T-cell depletion were induced, resulting in long-lasting antitumor immunity in TNBC cells. Moreover, combination therapy with Ir-1 and anti-PD1 could substantially augment in vivo therapeutic effects. Based on these results, Ir-1 is a promising candidate for chemoimmunotherapy against TNBC and its effects are mediated synergistically via ICD induction and IDO blockage.

Protein liquid-liquid phase separation (LLPS), a pivotal phenomenon intricately linked to cellular processes, is regulated by various other proteins. However, there is still a lack of high-throughput methods for screening protein regulators of LLPS in target proteins. Here, we developed a CRISPR/Cas9-based screening method to identify protein phase separation regulators by integrating bimolecular fluorescence complementation (BiFC) and fluorescence-activated cell sorting (FACS). Using this newly developed method, we screened the RNA-binding proteins that regulate PABPN1 phase separation and identified the tumor suppressor QKI as a promoter of PABPN1 phase separation. Furthermore, QKI exhibits decreased expression levels and diminished nuclear localization in colorectal cancer cells, resulting in reduced PABPN1 phase separation, which, in turn, promotes alternative polyadenylation (APA), cell proliferation, and migration in colorectal cancer.
Humans ; Colorectal Neoplasms/genetics* ; RNA-Binding Proteins/genetics* ; Poly(A)-Binding Protein I/genetics* ; CRISPR-Cas Systems ; Flow Cytometry ; Cell Proliferation ; Cell Line, Tumor ; Cell Movement

OBJECTIVE: The relationship between fish consumption and stroke is inconsistent, and it is uncertain whether this association varies across predicted stroke risks. METHODS: A cohort study comprising 95,800 participants from the Prediction for Atherosclerotic Cardiovascular Disease Risk in China project was conducted. A standardized questionnaire was used to collect data on fish consumption. Participants were stratified into low- and moderate-to-high-risk categories based on their 10-year stroke risk prediction scores. Hazard ratios ( HRs) and 95% confidence intervals ( CIs) were estimated using Cox proportional hazard models and additive interaction by relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). RESULTS: During 703,869 person-years of follow-up, 2,773 incident stroke events were identified. Higher fish consumption was associated with a lower risk of stroke, particularly among moderate-to-high-risk individuals ( HR = 0.53, 95% CI: 0.47-0.60) than among low-risk individuals ( HR = 0.64, 95% CI: 0.49-0.85). A significant additive interaction between fish consumption and predicted stroke risk was observed (RERI = 4.08, 95% CI: 2.80-5.36; SI = 1.64, 95% CI: 1.42-1.89; AP = 0.36, 95% CI: 0.28-0.43). CONCLUSION Higher fish consumption was associated with a lower risk of stroke, and this beneficial association was more pronounced in individuals with moderate-to-high stroke risk.
Humans ; China/epidemiology* ; Male ; Female ; Stroke/etiology* ; Middle Aged ; Prospective Studies ; Incidence ; Aged ; Animals ; Fishes ; Risk Factors ; Diet ; Seafood ; Adult ; Cohort Studies

OBJECTIVE: The aim of this study is to analyze the clinical features and genetic etiology of a patient with multiple morphological abnormalities of the sperm flagella (MMAF) retrospectively. METHODS: A severely oligospermic patient from the Reproductive Center of the First Affiliated Hospital of Ningbo University was selected as the study subject. Clinical data and examination results were collected. High-throughput sequencing and bioinformatics were used to analyze the genetic etiology. And Sanger sequencing was employed to validate findings in the family. Transmission electron microscopy (TEM) was used to observe the sperm ultrastructure, and immunofluorescence analysis was performed to examine the localization of FSIP2 protein in the sperm. RESULTS: The patient presented with severe oligospermia, and sperm morphology displayed MMAF. TEM revealed fibrous sheath and 9+2 microtubule structural disruptions in the sperm. Sequencing identified compound heterozygous variants in the FSIP2 gene (c.17798C > T, c.5927T > G), inherited from the father and mother, respectively. According to the guidelines of the American College of Medical Genetics and Genomics, the variants were classified as pathogenic. The patient's spouse underwent intracytoplasmic single sperm injection, resulting in one embryo, but no clinical pregnancy occurred after embryo transfer. CONCLUSION This study reported the mutation of FSIP2 gene c.17798C > T, c.5927T > G in a patient with MMAF. These findings expand the mutational spectrum of the FSIP2 gene and provide insights for genetic and assisted reproductive counseling for patients with MMAF.
Humans ; Male ; Sperm Tail/pathology* ; Heterozygote ; Oligospermia/genetics* ; Spermatozoa ; Mutation ; Infertility, Male/genetics* ; Adult ; Pedigree ; Retrospective Studies ; Sperm Injections, Intracytoplasmic

Objective To investigate the types of diseases examined by ultrasonography in a certain island clinic,and to summarize the experience of ultrasound medical support in island area.Methods The ultrasound examination results of patients who were admitted to a certain island clinic from January 2017 to August 2022 were reviewed,and the types and characteristics of diseases examined by ultrasound were analyzed.Results A total of 2 043 patients underwent ultrasound examination.There were 76 disease categories and 1 579 diseases.The top five diseases were fatty liver(13.24%),kidney crystals(12.10%),kidney stones(10.70%),gallbladder polyps(6.33%)and ureteral stones with hydronephrosis(6.02%).Ultrasound could predict the pathological types of appendicitis and guide the clinical decision by observing the width of the appendiceal lumen and the layers of the appendiceal wall.Doppler-assessed ureteric jet could be used to determine the renal function of the affected side of ureteral calculi.Conclusion There are wide and varied disease categories in islands.Sonographers should have comprehensive abilities and qualities.This study can provide reference for the follow-up medical support on island area.

Objective: To explore the effect of different obesity indicators in predicting cardiovascular and cerebrovascular diseases (CVD) risk among patients with type 2 diabetes mellitus (T2DM), so as to provide the evidence for the early identification of CVD risk among T2DM patients. Methods: The patients with T2DM under community management in Qingpu District, Shanghai Municipality were selected as the study subjects in January 2025. Basic information such as gender, age, and blood glucose control status were collected through the Shanghai Chronic Disease Information Management System, while history of CVD were obtained from residents' electronic health records and the Shanghai Disease Control Information Platform. Obesity was assessed using body mass index (BMI), waist circumference (WC), BMI combined with WC, waist-to-height ratio (WHtR), and triglyceride (TG) combined with WC indicators. The association between obesity and CVD was analyzed using multivariable logistic regression models. The predictive effect of each obesity indicators for CVD was evaluated using the area under the receiver operating characteristic curve (AUC). Results: A total of 4 367 patients with T2DM were included, including 2 121 males (48.57%) and 2 246 females (51.43%). The average age was (68.71±8.05) years. The prevalence of CVD was 44.49%. Multivariable logistic regression analysis showed that after adjusting for age, education level, history of hypertension, duration of T2DM, use of glucose-lowering medications, renal function, and blood glucose control status, obese T2DM patients had a 389.4% increased risk of CVD compared to those with normal BMI; centrally obese T2DM patients had a 100.4% increased risk compared to those with normal WC; T2DM patients with isolated general obesity and compound obesity had 161.0% and 241.1% increased risks of CVD, respectively, compared to those with normal BMI and WC; centrally obese T2DM patients had a 100.4% increased risk compared to those with normal WHtR; T2DM patients with normal TG-high WC and high TG-high WC phenotypes had 83.1% and 68.8% increased risks of CVD, respectively, compared to those with normal TG and normal WC (all P<0.05). BMI had the highest AUC, at 0.714, with sensitivity and specificity of 0.675 and 0.642, respectively. This was followed by BMI combined with WC, which had an AUC of 0.707, with sensitivity and specificity of 0.635 and 0.679, respectively. Conclusions Obesity defined by BMI, WC, BMI combined with WC, WHtR, and TG combined with WC increases the risk of CVD among patients with T2DM. BMI and BMI combined with WC have better predictive effect in predicting CVD risk among patients with T2DM, and can be used as the primary obesity indicators for CVD risk screening.

Objective To investigate the application value of spectral CT multi-quantitative parameters combined with clinical characteristics in predicting high-risk gastroesophageal varices(GOV)in patients with liver cirrhosis.Methods The results of upper abdominal spectral CT enhancement and electronic gastroscopy in 112 patients diagnosed with liver cirrhosis were analyzed retrospec-tively,and the clinical data were collected.According to the gastroscopic manifestations,the patients were divided into high-risk GOV group(n=74)and low-risk GOV group(n=38).Univariate analysis was used to compare the spectral CT quantitative parameters and clinical characteristics between the two groups.Multivariate logistic regression analysis was used to screen the independent risk factors for high-risk GOV.R software was used to construct a nomogram model for predicting high-risk GOV,and the differentia-tion,calibration and clinical practicability of the prediction model were evaluated.Results The normalized iodine concentration(NIC)of liver left lobe,prothrombin time(PT),albumin(ALB)and liver function grading were independent risk factors for high-risk GOV(P＜0.05).The area under the curve(AUC)of receiver operating characteristic(ROC)curve of predicting high-risk GOV in nomo-gram model was 0.893.Calibration curve showed that the predicted results were basically consistent with the actual results.Decision curve analysis(DCA)showed that the prediction model had good clinical practicability.Conclusion The nomogram model based on NIC of liver left lobe,PT,ALB and liver function grading is helpful to predict patients with high-risk GOV in liver cirrhosis,and pro-vides a reference for clinical prevention and treatment of esophagogastric variceal bleeding(EVB).

Depression is a highly heterogeneous psychiatric disorder with complex pathogenesis influenced by the interplay of biological,psychological,and social-environmental factors.Based on the 2021 edition of the Chinese Guidelines for the Prevention and Treatment of Depressive Disorders,which explicitly identify gender as a significant risk factor for depression onset,this paper systematically reviews the gender-differentiated pathogenesis and therapeutic advances in depression from both traditional Chinese medicine(TCM)and Western medical perspectives.In Western medicine,a large number of studies have demonstrated the sex-specific mechanism of estrogen/testosterone fluctuations and monoamine transmitter system regulation.While in TCM,although the constitution theory proposes that there are significant gender differences in congenital constitution and that qi depression and qi deficiency are associated with susceptibility to depression,current evidence primarily relies on cross-sectional surveys and lacks validation through high-quality RCTs.Compared with Western medicine,the direct research on gender-differentiated antidepressant effects in TCM remains relatively underdeveloped.In future study,it may be possible to deepen and improve the research on anti-depression in TCM from the biological markers of particular constitutions in the gender dimension.This paper advocates establishing a bio-psycho-social integrated intervention model,advancing mechanistic exploration through prospective cohort studies and multi-omics technologies,and promoting precision diagnosis and treatment systems based on gender differences,and to form a three-dimensional diagnosis and treatment and research system that covers biomarkers,social role assessment,and TCM constitution identification,in order to provide a new theoretical framework and a practical pathway for the precise medical treatment of depression.

Objective:To investigate the effects of different post space parameters and scanning aid material on the trueness of digital impressions of post spaces obtained by two intraoral scanners, thereby providing a reference for clinically determining the conditions under which post spaces are suitable for digital impression technology.Methods:This study varied three variables of post space models of residual crowns: opening diameter, post space depth and adjacent tooth status,with specific settings: opening diameter were set at two levels (2.0 and 2.5 mm);post space depth was set at three levels (8.0, 10.0, and 12.0 mm); and adjacent tooth status were set at three levels [bilateral adjacent teeth present (A), unilateral adjacent tooth present (B), and bilateral adjacent teeth absent (C)]. A total of 18 model groups were prepared. Eighteen samples were printed using a three-dimensional printing instrument. Combined with scanning aid material, direct in vitro scanning of these post space models was performed using intraoral scanners (IOS) A (Trios 5) and B (Primescan connect), with 10 replicates per group ( n=10). The scanned data were sequentially imported into reverse engineering software. The original design data of the models served as true values, and best-fit comparisons were performed. By calculating the average root mean square error (RMSE) values, the trueness of digital impressions of post spaces with different morphologies obtained by the two scanners was evaluated, both with and without the use of scanning aid material. Results:Under the experimental conditions set in this study, for IOS A, only the sample groups with opening diameter-post space depth-adjacent tooth status combinations of (2.0-8.0-ABC, 2.5-8.0-ABC, 2.5-10.0-ABC) could be identified, with RMSE results ranging from 46.5 to 365.0 μm. After adding scanning aid materials,RMSE results ranging from 46.0 to 185.0 μm, the trueness of the sample groups (2.0-8.0-A, 2.5-10.0-A) was significantly improved by more than 100 μm, and an additional sample group (2.5-12.0-C) could be identified. For IOS B, the identifiable sample groups included all 18 sample groups, with RMSE results ranging from 38.8 to 106.0 μm. After the addition of scanning aid materials, RMSE results ranging from 37.6 to 110.2 μm, the identifiable sample groups remained unchanged. Post space opening diameter, post space depth, and adjacent tooth status all had significant effects on the trueness of post space digital impressions for both IOS A and IOS B (all P<0.05). Scanning aid materials had a significant effect on IOS A ( P<0.05), but no significant effect on IOS B ( P>0.05). Conclusions:IOS B exhibited superior post space scanning performance compared to IOS A, and its trueness for clinically common post spaces could meet clinical requirements. IOS A has certain requirements for post space opening diameter, post space depth, and adjacent tooth status. For narrow and long post spaces, scanning aid materials can be used to improve the scanning trueness.

Objective:To investigate the effects of different post space parameters and scanning aid material on the trueness of digital impressions of post spaces obtained by two intraoral scanners, thereby providing a reference for clinically determining the conditions under which post spaces are suitable for digital impression technology.Methods:This study varied three variables of post space models of residual crowns: opening diameter, post space depth and adjacent tooth status,with specific settings: opening diameter were set at two levels (2.0 and 2.5 mm);post space depth was set at three levels (8.0, 10.0, and 12.0 mm); and adjacent tooth status were set at three levels [bilateral adjacent teeth present (A), unilateral adjacent tooth present (B), and bilateral adjacent teeth absent (C)]. A total of 18 model groups were prepared. Eighteen samples were printed using a three-dimensional printing instrument. Combined with scanning aid material, direct in vitro scanning of these post space models was performed using intraoral scanners (IOS) A (Trios 5) and B (Primescan connect), with 10 replicates per group ( n=10). The scanned data were sequentially imported into reverse engineering software. The original design data of the models served as true values, and best-fit comparisons were performed. By calculating the average root mean square error (RMSE) values, the trueness of digital impressions of post spaces with different morphologies obtained by the two scanners was evaluated, both with and without the use of scanning aid material. Results:Under the experimental conditions set in this study, for IOS A, only the sample groups with opening diameter-post space depth-adjacent tooth status combinations of (2.0-8.0-ABC, 2.5-8.0-ABC, 2.5-10.0-ABC) could be identified, with RMSE results ranging from 46.5 to 365.0 μm. After adding scanning aid materials,RMSE results ranging from 46.0 to 185.0 μm, the trueness of the sample groups (2.0-8.0-A, 2.5-10.0-A) was significantly improved by more than 100 μm, and an additional sample group (2.5-12.0-C) could be identified. For IOS B, the identifiable sample groups included all 18 sample groups, with RMSE results ranging from 38.8 to 106.0 μm. After the addition of scanning aid materials, RMSE results ranging from 37.6 to 110.2 μm, the identifiable sample groups remained unchanged. Post space opening diameter, post space depth, and adjacent tooth status all had significant effects on the trueness of post space digital impressions for both IOS A and IOS B (all P<0.05). Scanning aid materials had a significant effect on IOS A ( P<0.05), but no significant effect on IOS B ( P>0.05). Conclusions:IOS B exhibited superior post space scanning performance compared to IOS A, and its trueness for clinically common post spaces could meet clinical requirements. IOS A has certain requirements for post space opening diameter, post space depth, and adjacent tooth status. For narrow and long post spaces, scanning aid materials can be used to improve the scanning trueness.