BACKGROUND:Endothelial cell (EC) senescence is intimately linked to the development and progression of atherosclerosis. The FGFR2 (fibroblast growth factor receptor 2) signaling is crucial in regulating the phenotype of ECs. Recent studies have revealed that cell phenotype-specific alternative splicing of FGFR2 premRNA (precursor mRNA) results in the mutually exclusive inclusion of either exon IIIb or IIIc, leading to critical differences in receptor function. This study aimed to investigate the role of FGFR2 alternative splicing in EC senescence and atherosclerosis development, and to elucidate the underlying mechanisms. METHODS:Clinical samples and animal models were used to assess the association between FGFR2-IIIc isoform expression and EC senescence as well as atherosclerotic plaque formation. The mechanisms underlying FGFR2-IIIc-induced EC senescence were elucidated through a combination of in vivo and in vitro investigations. In addition, genetically engineered mice with endothelial-specific overexpression or knockdown of FGFR2-IIIc were utilized to investigate the impact of FGFR2-IIIc on vascular endothelial senescence and the progression of atherosclerosis. RESULTS:Elevated expression of the FGFR2-IIIc isoform was detected in clinical samples and animal models of aging and atherosclerosis, where it correlated with both EC senescence and atherosclerotic plaque formation. Mechanistically, the alternative splicing-mediated switch from FGFR2-IIIb to FGFR2-IIIc established an FGF2-FGFR2-IIIc autocrine feedback loop, which drove ECs toward a senescence-associated secretory phenotype via the PKC (protein kinase C) ε/STAT3 (signal transducer and activator of transcription) pathway. Senescence-inducing stimuli promoted the binding of the splicing factor hnRNP H1 (heterogeneous nuclear ribonucleoprotein H1) to exon IIIb of the FGFR2 gene, leading to skipping of this exon. Notably, EC-specific knockout of FGFR2-IIIc in ApoE-/- mice reduced plaque area, suppressed senescence-associated secretory phenotype gene expression, and attenuated cellular senescence compared with controls. CONCLUSIONS:This study reveals that FGFR2 splicing mediated by hnRNP H1 promotes EC senescence and atherosclerosis via an FGF2-FGFR2-IIIc autocrine loop. These findings identify FGFR2-IIIc as a potential therapeutic target for age-related atherosclerosis.

Patients with end-stage renal disease often require arteriovenous fistula (AVF) creation for hemodialysis. However, nearly 40% of patients develop aneurysmal dilatation of AVF (AVFA) after surgery, which can lead to prolonged bleeding at puncture sites, increased infection risk, and even potential rupture. Despite its high incidence, research on AVFA remains remarkably limited. This study makes an innovative discovery by establishing a link between AVFA formation and alternative splicing of fibronectin (FN), a crucial extracellular matrix component. Specifically, we demonstrate that increased inclusion of the EDA exon in FN within vascular smooth muscle cells triggers phenotypic switching to a synthetic state and extracellular matrix remodeling through the ITGB1/FAK/Src/RUNX2 pathway. These changes ultimately reduce vascular mechanical strength and contribute to AVFA development. Furthermore, we identify the splicing factor SRSF5 as a key regulator of EDA inclusion and characterize its potential binding sites, providing potential therapeutic targets for AVFA prevention.

To investigate the utility of blood oxygenation level-dependent (BOLD) MRI to reflect oxygenation dynamics related to microvascular function in critical limb-threatening ischemia (CLTI), and to examine its associations with clinical and angiographic findings as well as its short-term responsiveness to revascularization. Twenty-seven CLTI patients scheduled for percutaneous transluminal angioplasty (PTA) and 15 age-matched healthy controls underwent calf BOLD MRI with a standardized ischemia–hyperemia paradigm. CLTI patients also underwent BOLD MRI after PTA. Curve parameters, including ischemic minimum value (IMV), time to peak (TTP), gradient during reactive hyperemia (Grad), and peak hyperemic value (HPV), were analyzed. The Bollinger score and collateral number were determined from pre-PTA digital subtraction angiography. Statistical analyses assessed parameter differences between CLTI patients and controls, as well as between pre- and post-PTA, and correlations with the ankle-brachial index (ABI), Rutherford classification, and angiographic findings. Compared with controls, CLTI patients demonstrated less negative IMV (P ≤ 0.04), prolonged TTP (P < 0.001), and reduced Grad (P ≤ 0.008) in all muscle groups. Following PTA, IMV improved, TTP shortened, and Grad increased in CLTI patients (all P < 0.05). TTP correlated negatively with ABI both before and after PTA (R=-0.58, P = 0.002 and R=-0.69, P < 0.001, respectively), and Grad and HPV were positively associated with collateral number (R = 0.41, P = 0.03 and R = 0.54, P = 0.004, respectively). No significant associations were found between BOLD MRI parameters and Rutherford classification or Bollinger scores. BOLD MRI can noninvasively reflect oxygenation dynamics related to microvascular function in CLTI, reveal short-term hemodynamic responses following revascularization, and provide insights into collateral circulation.

The arteriovenous fistula (AVF), the preferred vascular access for hemodialysis, is limited by neointimal hyperplasia. Although proprotein convertase subtilisin/kexin type 6 (PCSK6) is involved in vascular smooth muscle cell (VSMC) activation, its role in AVF stenosis is unclear. PCSK6 expression was significantly upregulated in VSMCs of human and murine stenotic AVFs and correlated with the severity of neointimal hyperplasia. In vitro, PCSK6 overexpression promoted VSMC proliferation, migration, contractility, and extracellular matrix (ECM) synthesis, whereas PCSK6 knockdown suppressed these processes. Mechanistically, PCSK6 directly interacted with STAT1 and enhanced its phosphorylation, with STAT1 inhibition reversing PCSK6-driven effects. In vivo, smooth muscle cell-specific PCSK6 knockout in mice on a high-glucose diet attenuated neointimal formation, improved AVF lumen diameter and blood flow, and enhanced vasodilation. In conclusion, PCSK6 drives AVF neointimal hyperplasia by binding and activating STAT1 to promote VSMC phenotypic switching and ECM remodeling, identifying the PCSK6/STAT1 axis as a novel mechanism and potential therapeutic target for preventing AVF failure.

OBJECTIVE:Real-world evidence comparing dual-pathway inhibition (DPI) with dual antiplatelet therapy (DAPT) after endovascular revascularization for acute or nonacute limb ischemia is limited. This study aims to compare the 24-month effectiveness and safety outcomes of DPI versus DAPT in this setting. METHODS:This prospective, multicenter observational study from the RESOLVE registry used propensity score matching (PSM) to analyze patients receiving DPI or DAPT after endovascular revascularization. The primary endpoint was 24-month major adverse events (MAE) including recurrent acute limb ischemia, major amputation, myocardial infarction, ischemic stroke, or cardiovascular death. Secondary endpoints included major adverse limb events (MALE), major adverse cardiovascular events (MACE), and all-cause death. RESULTS:After PSM, 109 matched pairs were analyzed. The DPI group had significantly lower 24-month MAE incidence than the DAPT group (11.47% vs 28.45%; HR = 2.83; P < .01), as well as lower MALE (16.83% vs 28.40%; HR = 1.83; P = .04) and all-cause death (2.94% vs 11.65%; HR = 4.28; P = .02). MACE showed a trend toward lower incidence with DPI (2.00% vs 7.77%; HR = 4.22; P = .07). No major bleeding events were observed in either group. Modified SVS run-off score >10 and chronic limb-threatening ischemia predicted greater DPI benefit (P for interaction=.020 and .031). CONCLUSIONS:In this PSM analysis, DPI was associated with significantly lower 24-month rates of MAE, MALE, and all-cause death compared with DAPT. No major bleeding events were observed in either group. These findings suggest a potentially favorable efficacy profile for DPI but warrant confirmation in further randomized controlled trials.

BACKGROUND:Endovascular therapy is the preferred option for arteriovenous fistula dysfunction. The aim of this trial is to compare the 12-month efficacy and safety outcomes of cutting balloon with the drug-coated balloon. METHODS AND ANALYSIS:The DRAGON study is a multicenter, prospective, observational cohort study. One hundred and eighty patients with stenosis of the venous segment of arteriovenous fistula will be recruited for treatment with the cutting balloon or the drug-coated balloon. The primary efficacy endpoint is the 12-month target-lesion primary patency rate. The secondary efficacy endpoints are the 3- and 6-month target-lesion primary patency rate, the 6- and 12-month access-circuit primary patency rate, the total number of target-lesion reintervention, the 12-month target-lesion reintervention rate, and the 12-month access-circuit thrombosis rate. The safety endpoints included complications and death. ETHICS AND DISSEMINATION:The Dragon study has been registered at www. CLINICALTRIALS:gov (registration number: NCT06527963). The study protocol has been approved by the Institutional review board and Human Research Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University (Approved number: LY2024-102-B). The results will be disseminated by publication in a peer-reviewed journal.

OBJECTIVE:The study aimed to compare ultrasound-guided brachial plexus block (BPB) with local anesthesia (LA) on efficacy, safety and 12-month patency rate for percutaneous transluminal angioplasty (PTA) treatment of dysfunctional arteriovenous fistula (AVF). METHODS:Consecutive patients with dysfunctional AVF who underwent PTA from January 2021 to December 2022 were included. Overlap weighting was performed to adjust for significant differences between the two groups. The primary efficacy outcomes included visual analogue scale (VAS) score and 12-month target-lesion primary patency rate. The secondary efficacy outcomes included target-lesion primary-assisted patency rate, secondary patency rate, access-circuit thrombosis rate, access-circuit reintervention rate, and number of reinterventions within 12 months. Univariate analysis and multivariate analysis by log-binomial regression were used to identify the independent factors associated with intraoperative pain. RESULTS:218 patients were included in the study: 82 patients underwent PTA under BPB and 136 patients underwent PTA under LA. After overlap weighting, the baseline, lesion characteristics and intraoperative details had no significant difference between the two groups. Patients under BPB had significantly lower VAS scores than those under LA (2.4 ± 1.4 vs 5.1 ± 1.9, p < 0.001). The 12-month target-lesion primary patency rate was significantly higher in the BPB group than that in the LA group (58.3% vs 40.0%, p = 0.037). The 12-month target-lesion primary-assisted patency rate and access-circuit secondary patency rate were significantly higher in the BPB group than those in the LA group (p = 0.023 and p = 0.028). The access-circuit thrombosis rate was significantly lower in the BPB group (10.0%) than that in the LA group (28.3%) (p = 0.011). BPB was the only independent factor associated with mild pain (p < 0.001, OR: 0.037, 95%CI: 0.011-0.119). CONCLUSIONS:BPB could decrease the intraoperative pain and improve the 12-month primary patency rates compared with LA for patients underwent PTA treatment of dysfunctional AVF.

OBJECTIVE:This study aimed to investigate the outcomes of profunda femoris vein thrombosis evaluation and clearance (PFV-TEC) by percutaneous mechanical thrombectomy (PMT) for acute iliofemoral deep vein thrombosis (DVT). METHODS:This study retrospectively analysed data from the CODA study (NCT06124768) from January 2021 to December 2022. Consecutive patients with acute iliofemoral DVT treated by PMT were included. Patients were categorised into two treatment groups: PMT with PFV-TEC and PMT without PFV-TEC. The primary efficacy outcome was the 24 month incidence of post-thrombotic syndrome (PTS). RESULTS:Ninety-three patients were included: 43 patients underwent PMT with PFV-TEC and 50 patients without PFV-TEC. In the PMT with PFV-TEC group, 39 patients had profunda femoris vein (PFV) thrombosis and successfully underwent PMT. The 24 month iliofemoral vein and PFV patency rates were 90% and 89% in the PMT with PFV-TEC group, which were statistically significantly higher than those in the PMT without PFV-TEC group (p = .033 and p = .001, respectively). The 24 month incidence of PTS was statistically significantly lower in the PMT with PFV-TEC group than in the PMT without PFV-TEC group (11% vs. 32%; p = .020). Multivariable analysis identified iliofemoral vein patency (hazard ratio [HR] 0.07, 95% confidence interval [CI] 0.02 - 0.38; p = .002) and PFV patency (HR 0.07, 95% CI 0.01 - 0.61; p = .017) as independent protective factors against PTS. CONCLUSION:PMT with PFV-TEC improved iliofemoral and PFV patency and decreased the incidence of PTS. PFV-TEC is recommended in PMT treatment for acute iliofemoral DVT.

Background::The development of thoracic aortic dissection (TAD) is closely associated with the loss of vascular smooth muscle cells (VSMCs). Androgen receptor (AR) signaling has increasingly been recognized as an important regulator of cell death in prostate cancer. However, the role of AR signaling in the development of TAD in men remains unknown.Methods::The expression of AR was analyzed in clinical specimens obtained from TAD patients undergoing surgical aortic replacement and control subjects receiving heart transplantation. Using β-aminopropionitrile (BAPN)-induced aortic dissection mouse models, we systematically investigated the protective role of AR through multiple approaches. Histopathological evaluation was performed using immunohistochemistry and immunofluorescence. Primary vascular smooth muscle cells were isolated for functional studies including AR knockdown, ferroptosis assessment, and metabolic profiling. Mechanistic insights were gained through chromatin immunoprecipitation, luciferase reporter assays, and RNA stability tests. Seahorse extracellular flux analysis and targeted metabolomics were employed to characterize metabolic alterations. Results::The expression of AR in VSMCs was downregulated in both clinical samples and animal models of TAD. Using in vitro and in vivo models, we demonstrated a novel function of AR that inhibited ferroptosis in VSMC by promoting excessive lipid peroxidation. Mechanistically, we showed that AR counter-regulated the expression levels of acyl-CoA synthetases ACSL3 and ACSL4 in VSMCs. AR acted as a transcriptional regulator to promote the transcription of ACSL3 gene while inhibiting the transcription of the ACSL4 gene, both of which inhibited lipid peroxidation and ferroptosis. Importantly, activating AR signaling was beneficial in preventing TAD from developing and progressing in the animal model. Conclusions::Our results reveal a previously unrecognized role of AR in TAD pathogenesis and uncover the opposite yet complementary regulation of ACSL3/ACSL4 levels involved in lipid peroxidation-driven ferroptosis in VSMCs.

BACKGROUND:This study was performed to evaluate the early outcomes of the WeFlow-JAAA off-the-shelf (OTS) endograft system for the treatment of juxtarenal and pararenal abdominal aortic aneurysms (JR/PR-AAAs). METHODS:We conducted a prospective, multicenter study involving 115 patients diagnosed with JR/PR-AAAs. The inclusion criteria were a distance of ≥4 mm from the inferior edge of the superior mesenteric artery (SMA) to the aneurysm and a proximal landing zone angulation of <60°. All participants underwent endovascular repair using the WeFlow-JAAA system. The primary end points were clinical success and major adverse events (MAEs) within 30 days postprocedure. The secondary end points were all-cause mortality, secondary interventions, endoleaks, target vessel patency, and preservation of renal function during the first 30 days. RESULTS:The patients' mean age was 69.1 years, and 94.8% were male. The average maximum aneurysm diameter was 62.7 mm. The mean proximal neck length below the SMA was 20.3 ± 8.3 mm (range: 5-50 mm). Technical success was achieved in 99.1% of patients, with a target vessel patency rate of 99.4% within 30 days. One patient (0.9%) developed an early type I endoleak. MAEs occurred in 3.5% of patients, including 1 all-cause death due to cardiac arrest and three cases of minor ischemic stroke, all of which resolved. No significant aneurysm growth or stent migration was observed. CONCLUSION:The WeFlow-JAAA OTS endograft system demonstrated high technical success and low complication rates in the early treatment of JR/PR-AAAs. The occurrence of type II endoleaks and minor adverse events highlights areas for improvement. Future studies should focus on reducing type II endoleak risk and assessing long-term durability.

OBJECTIVE:The aim of this study was to assess the 24-month clinical outcome of endovascular therapy (EVT) for femoropopliteal (FP) lesions in patients with lifestyle-limiting claudication in a current real-world setting. METHODS:We retrospectively analyzed data from a clinical database formed by TALENT (Impact Of Tibial Run Off On Clinical Outcome Of Endovascular Therapy In Femoropopliteal Lesions), a prospective, multicenter patient registry. We selected 980 patients (1010 limbs) with symptomatic intermittent claudication (IC) undergoing FP intervention from the TALENT registry between December 1, 2020, and May 1, 2023. The observational end points included the incidence of clinically driven target lesion revascularization (CD-TLR), major adverse limb events (MALEs), major adverse cardiovascular events (MACEs), all-cause of mortality, progression to chronic limb threatening ischemia (CLTI), and changes in self-reported quality-of-life (QOL) measures (Vascular Quality of Life 25). Prognostic predictors for MALE, MACE, CD-TLR, and progression to CLTI were elucidated by Cox proportional hazard regression analysis. RESULTS:A total of 1010 targeted limbs in 980 patients with IC treated with EVT were included in this study. The median follow-up time was 24 months (interquartile range, 24-36 months). At the 24-month follow-up, the cumulative incidence of CD-TLR was 7.15% (95% confidence interval [CI], 5.45%-8.85%), whereas progression to CLTI occurred in only 2.20% of limbs (95% CI, 1.18%-3.22%). Incidence of MALE and MACE were 7.59% (95% CI, 5.85%-9.34%) and 2.04% (95% CI, 1.10%-2.98%), respectively. The all-cause of mortality rate was 5.85% (95% CI, 4.29%-7.41%) and VascuQOL scores showed sustained improvement throughout the follow-up period (3.17 ± 0.84 vs 5.71 ± 1.19; P < .001). Cox regression analysis identified chronic renal insufficiency (CRI) (defined as a glomerular filtration rate of <30 mL/min/1.73 m2), Trans-Atlantic Inter-Society Consensus Document (TASC) II C/D FP lesions, and a history of previous lower extremity intervention as independent risk factors for CD-TLR. Female sex, TASC II C/D FP lesions, and poor pedal runoff (pedal runoff score = 2-3) were identified as independent risk factors for progression to CLTI within 24 months. CRI and TASC II C/D FP lesions were independent risk factors for MALEs. CRI and chronic obstructive pulmonary disease were independent risk factors for MACEs within 24 months. CONCLUSIONS:The 24-month clinical outcomes of EVT for FP lesions in patients with lifestyle-limiting IC demonstrated acceptable results, with sustained enhancements in health-related QOL.

BACKGROUND:Blood oxygenation level-dependent (BOLD) MRI can noninvasively quantify lower extremity perfusion in peripheral artery disease (PAD) patients. However, its ability to reflect perfusion change in response to lower extremity revascularization (LER) and its prognostic value for clinical outcomes are not fully understood. PURPOSE:To evaluate BOLD MRI response to LER and its predictive value for major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in PAD patients. STUDY TYPE:Prospective. POPULATION:Forty-one patients (median age, 73 years; 29 men) undergoing LER for symptomatic PAD. FIELD STRENGTH/SEQUENCE:3.0 T/BOLD MRI with a multi-echo gradient-recalled echo sequence. ASSESSMENT:Pre- and post-LER BOLD MRI was performed under an ischemia-hyperemia paradigm. Normalized T2* time course curves were generated in each of 5 calf muscle compartments (anterior, lateral, deep posterior, soleus, and gastrocnemius) and times to peak (TTP), minimum/maximum values, and gradients during hyperemia (Grad) analyzed. Follow-up was every 6-12 months via hospital records and telephone interviews for MACE and MALE outcomes. Model 1 (clinical factors) and Model 2 (+BOLD MRI) were compared. STATISTICAL TESTS:Chi-square test or Fisher's exact test, Student's t-test or Wilcoxon rank-sum test, area under the receiver operating characteristic curve (AUC), Kaplan-Meier survival analysis, and Cox proportional hazards regression analysis. Significance was set at p < 0.05. RESULTS:During a median 38-month follow-up, 9 patients experienced MACE and 20 experienced MALE. Successful LER improved TTP and Grad in all muscle compartments. Grad change (ΔGradsol ) and post-LER TTP (TTPsol ) in the soleus muscle achieved the highest AUC values of 0.92 and 0.80 in predicting MACE and MALE, respectively. In multivariable Cox regression analysis, ΔGradsol and TTPsol were independent predictors of MACE (hazard ratio [HR] per standard deviation [SD] increase, 0.23) and MALE (HR per SD increase, 1.62), respectively. BOLD MRI added incremental prognostic value to clinical factors, increasing C-index by 0.06 for MACE and 0.05 for MALE. DATA CONCLUSION:BOLD MRI showed perfusion changes in skeletal muscles following revascularization and provided incremental prognostic value in PAD patients. EVIDENCE LEVEL:2. TECHNICAL EFFICACY:Stage 4.

Objective: The study aimed to investigate the early results of directional femoral ultrasound-guided compression technique (UCT) using in percutaneous mechanical thrombectomy (PMT) for acute deep vein thrombosis (DVT). Methods: Consecutive single-center patients with acute iliofemoral DVT who underwent PMT from January 2020 to December 2021 were included. Directional femoral UCT was used to adjust the PMT catheter into the residual thrombus in the inguinal region by ultrasound compression to improve the thrombus clearance rate. Patients were retrospectively analyzed and divided into 2 groups based on PMT with or without directional femoral UCT. The primary efficacy outcome was the incidence of post-thrombotic syndrome (PTS) at 24-month follow-up. The secondary efficacy outcomes included common femoral venous thrombus removal grade, total thrombus removal grade, venous primary patency rate, and incidence of moderate-to-severe PTS at 24-month follow-up. The safety outcomes included complications, major bleeding events, and death at 24-month follow-up. Results: A total of 96 patients were included in the study: 42 patients underwent PMT with directional femoral UCT and 54 patients underwent PMT without UCT. There was no significant difference in baseline characteristics between the 2 groups. The percentages of patients achieved common femoral venous thrombus removal grade 3 and total thrombus removal grade 3 were significantly higher in the PMT with UCT group than those in the PMT without UCT group (p<0.001). The 24-month primary patency rate was significantly higher in the PMT with UCT group than that in the PMT without UCT group (90.0% vs 71.2%, p=0.027). The incidence of PTS was significantly lower in the PMT with UCT group (10.0%) than that in the PMT without UCT group (28.8%) (p=0.027). Conclusion: PMT with directional femoral UCT could improve the thrombus clearance rate and primary patency rate of acute iliofemoral DVT and might decrease the incidence of PTS compared to traditional PMT treatment without UCT. Clinical Impact Residual thrombus in common femoral vein is a difficult problem associated with higher incidence of PTS. Few studies have focused on common femoral venous thrombus clearance. PMT with directional femoral UCT could improve the thrombus clearance rate and primary patency rate of acute iliofemoral DVT, and might decrease the incidence of PTS compared to traditional PMT treatment without UCT. Directional femoral UCT is recommended in PMT treatment of acute iliofemoral DVT.

Background: The coronary no-reflow (NR) phenomenon is an independent predictor of major adverse cardiac events (MACEs). This study aimed to establish a clinical and comprehensive nomogram for predicting NR in acute myocardial infarction (AMI) patients after primary percutaneous coronary intervention (pPCI). Methods: The multivariable logistic regression analysis was performed to determine the NR-related factors. A nomogram was established via several clinical and biochemical factors, and the performance was evaluated via discrimination, calibration, and clinical factors. Results: The study consisted of 3041 AMI patients after pPCI, including 2129 patients in the training set (70%) and 912 patients in the validation set (30%). The NR event was 238 in the training set and 87 in the validation set. The level of N-terminal prohormone B-type natriuretic peptide (NT-proBNP), basophil count (BASO), neutrophil count (NEUBC), D-dimer, hemoglobin (Hb), and red blood cell distribution width (RDW.CV) in NR patients showed statistically significant differences. In the training set, the C-index was 0.712, 95% CI 0.677 to 0.748. In the validation set, the C-index was 0.663, 95% CI 0.604 to 0.722. Conclusions: A nomogram that may predict NR in AMI patients undergoing pPCI was established and validated. We hope this nomogram can be used for NR risk assessment and clinical decision-making and significantly prevent potentially impaired reperfusion associated with NR.

Androgen deprivation therapy (ADT) is the first line of treatment for metastatic prostate cancer (PCa) that effectively delays the tumor progression. However, it also increases the risk of venous thrombosis event (VTE) in patients, a leading cause of mortality. How a pro-thrombotic cascade is induced by ADT remains poorly understood. Here, we report that protein disulfide isomerase A2 (PDIA2) is upregulated in PCa cells to promote VTE formation and enhance PCa cells resistant to ADT. Using various in vitro and in vivo models, we demonstrated a dual function of PDIA2 that enhances tumor-mediated pro-coagulation activity via tumor-derived extracellular vehicles (EVs). It also stimulates PCa cell proliferation, colony formation, and xenograft growth androgen-independently. Mechanistically, PDIA2 activates the tissue factor (TF) on EVs through its isomerase activity, which subsequently triggers a pro-thrombotic cascade in the blood. Additionally, TF-containing EVs can activate the Src kinase inside PCa cells to enhance the AR signaling ligand independently. Androgen deprivation does not alter PDIA2 expression in PCa cells but enhances PDIA2 translocation to the cell membrane and EVs via suppressing the clathrin-dependent endocytic process. Co-recruitment of AR and FOXA1 to the PDIA2 promoter is required for PDIA2 transcription under androgen-deprived conditions. Importantly, blocking PDIA2 isomerase activity suppresses the pro-coagulation activity of patient plasma, PCa cell, and xenograft samples as well as castrate-resistant PCa xenograft growth. These results demonstrate that PDIA2 promotes VTE and tumor progression via activating TF from tumor-derived EVs. They rationalize pharmacological inhibition of PDIA2 to suppress ADT-induced VTE and castrate-resistant tumor progression.

Diabetic foot ulcer (DFU) is among the most frequent complications of diabetes and is associated with significant morbidity and mortality. Excessive neutrophil extracellular traps (NETs) delay wound healing in diabetic patients. Therefore, interventions targeting NET release need to be developed to effectively prevent NET-based wound healing impairment. Gasdermin D (GSDMD), a pore-forming protein acts as a central executioner of inflammatory cell death and can activate inflammasomes in neutrophils to release NETs. A precise understanding of the mechanism underlying NET-mediated delay in diabetic wound healing may be valuable in identifying potential therapeutic targets to improve clinical outcomes. In this study, we reported that neutrophils were more susceptible to NETosis in diabetic wound environments of patients with DFU. By in vitro experiments and using in vivo mouse models of diabetic wound healing (wide-type, Nlrp3-/-, Casp-1-/-, and Gsdmd-/- mice), we demonstrated that NLRP3/caspase-1/GSDMD pathway on activation controls NET release by neutrophils in diabetic wound tissue. Furthermore, inhibition of GSDMD with disulfiram or genic deletion of Gsdmd abrogated NET formation, thereby accelerating diabetic wound healing. Disulfiram could inhibit NETs-mediated diabetic foot ulcer healing impairment by suppressing the NLRP3/Caspase-1/GSDMD pathway. In summary, our findings uncover a novel therapeutic role of disulfiram in inhibiting NET formation, which is of considerable value in accelerating wound healing in patients with DFU.

PURPOSE:This paper was aimed at estimating the prevalence and risk factors of hearing loss (HL) among the middle-aged and elderly in China. METHODS:Databases including the CQVIP (VIP) Database, Chinese National Knowledge Infrastructure (CNKI), China Biology Medicine disc (CBMdisc), Wanfang, PubMed, Web of Science, Excerpta Medica Database (Embase) and the Cochrane Library were comprehensively searched. In this review, random-effect models were used for pooling the prevalence of HL and the odds ratios (ORs) of potential risk factors. RESULTS:34 studies were included in the meta-analysis. HL among the middle-aged and elderly in China had a pooled prevalence of 45% (95% confidence interval (CI) 40-51%). There were significant differences in the prevalence of HL between males and females (47% vs. 42%), between different screening methods by self-report and pure-tone audiometry (44% vs. 46%), between the middle-aged and the elderly (18% vs. 52%), and between the uneducated and the educated (49% vs. 36%). In urban areas, the prevalence was slightly higher than that in rural areas (50% vs. 48%). The findings suggested that the middle-aged and elderly in the South Central China region (61%, 95% CI 45-78%) and Northwest China (57%, 95% CI 55-58%) were more likely to develop HL. In addition, it was confirmed that advanced age, being male, noise exposure history, hypertension and hyperglycemia were related to a higher prevalence of HL among middle-aged and older adults. CONCLUSION:The prevalence of HL among the middle-aged and older population in China is 45%, nearly half of the total population. It is urgent to take great efforts to raise people's awareness of HL prevention and early hearing screening.

PURPOSE To evaluate the safety and efficacy of Innospring® stent, a novel self-expanding interwoven nitinol stent, in treating femoropopliteal atherosclerotic lesions. METHODS A prospective, single-center, single-arm, first-in-human study enrolled 15 patients (mean age 73.1 years; 13 men) to evaluate the safety and efficacy of the Innospring® stent monitored by core laboratories. The inclusion criteria were claudication or ischemic rest pain, de novo lesions or nonstented restenosis, >70% stenosis, lesion length <20 cm, and a reference vessel diameter of 4-7 mm. The primary safety endpoint was 30-day major adverse events. The primary efficacy end point was stent patency at 12 months. Follow-up evaluations were conducted at 30 days, 6 months, and 12 months. RESULTS The lesion length was 6.1 ± 3.5 mm. Fourteen (93.3%) patients had lesions of the superficial femoral artery and 3 (20.0%) patients had lesions of the popliteal artery. Nine (60.0%) patients had moderate-to-severe calcified lesion. Technical and procedural success was 100%. No patients experienced major adverse events in the first 30 days. The Rutherford category showed significant and sustained improvement at 6 and 12 months. The 12-month follow-up radiographs obtained in 13 patients confirmed the absence of stent fractures in 100% of examinations. The cumulative primary stent patency rate at 6 and 12 months were 93.3% and 84.6%, respectively. CONCLUSION Stenting of the superficial femoral and popliteal arteries using the Innospring® stent is safe and effective. This competing interwoven nitinol stent may provide superior stent integrity and fracture-resistance as well as serve areas under extreme mechanical stress. CLINICAL IMPACT Endovascular recanalization is a widely accepted and recommended treatment for symptomatic peripheral artery diseases. The Innospring® stent is a novel self-expanding interwoven stent containing eight nitinol wires with additional radial force, fracture-resistance, and visibility under fluoroscopy. This first-in-human study using the Innospring® stent in patients with femoropopliteal occlusive disease reported that stenting of the superficial femoral and popliteal arteries using the Innospring® stent is safe and effective. This competing interwoven nitinol stent may provide an impressive stent integrity and fracture-resistance as well as serve areas under extreme mechanical stress.

Objective To form a Chinese version visual vascular quality of life questionnaire（VascuQoL） through cultural adaptation and visualization of English version VascuQoL, and to observe its value for evaluating life quality of patients with peripheral artery disease（PAD） in China. Methods Cross-cultural adaptation and visualization were performed based on original English version VascuQoL to form Chinese version visual VascuQoL. The life qualities of 251 patients with PAD in China were evaluated with Chinese version visual VascuQoL. Item analysis and validity analysis were performed according to ankle brachial index（ABI） and European quality of life 5-dimensions 5-levels questionnaire（EQ-5D-5L） to observe the reliability and validity of Chinese version visual VascuQoL. Results The Cronbach’s α coefficient of Chinese version visual VascuQoL was 0.969, the Kaiser-Meyer-Olkin（KMO） test value was 0.783, the Bartlett’s spherical test value was 1 040.15（P＜0.01）, and the cumulative variance interpretation rate was 78.40%. Before transluminal intervention, ABI of the affected side of PAD was positively correlated with the scores of Chinese version visual VascuQoL（r=0.56, P＜0.000 1）. The r value between the "pain" dimension of Chinese version visual VascuQoL and EQ-5D-5L after operation was 0.41. Conclusion The reliability and validity of Chinese version visual VascuQoL for evaluating life quality of PAD patients in China were both good.