Disrupted bone morphogenetic protein type 2 receptor (BMPR2) signaling in endothelial cells drives pulmonary arterial hypertension (PAH). However, targeted recovery of this signaling pathway by lipid nanoparticles (LNPs) has not been explored as a therapy. Here, we employed Design of Experiments to optimize the delivery efficiency of LNPs targeting pulmonary endothelial cells developed by our laboratory, resulting in a remarkable 35-fold increase in a simplified three-component formulation without helper lipids. Administration of BMPR2 mRNA LNPs effectively reversed established PAH in two experimental rat models (monocrotaline or SU5416-hypoxia) by reversing pulmonary vascular remodeling. Specifically, BMPR2 mRNA LNPs replenished the expression of BMPR2 protein and subsequently activated downstream pathways, as confirmed by elevated levels of p-SMAD1/5/9 and ID1 proteins. The relief of pulmonary arterial occlusion was demonstrated by thinned pulmonary arterial media and decreased proportion of full muscularized vessels. Alleviation of right ventricular hypertrophy was indicated by declined Fulton index, the cross-sectional area of right ventricular cardiomyocytes as well as collagen deposition. Effective recovery of right ventricular function was evidenced by increased pulmonary artery flow acceleration time/pulmonary artery flow ejection time ratio. These findings underscore the potential of restoring BMPR2 signaling through pulmonary endothelial cell-specific LNPs for treating PAH.

OBJECTIVES: To analyze the differential expression and biological functions of circRNAs in the anterior lens capsules of high myopic patients with cataract and their pathogenic roles in the development of this condition. METHODS: Anterior lens capsule specimens were collected intraoperatively from 36 patients with age-related cataract (ARC) and 36 high myopic patients with cataract. Among these, 18 specimens from each group were selected for whole transcriptome sequencing and biological analysis, and the remaining 36 specimens were used for validation of circPDGFRA, circFOXJ3, hsa_circ_0004767, hsa_circ_0007528, ciCRIM1, circMAN1A2, circSLC5A3, and circPTK2 expressions using RT-qPCR. hsa_circ_0007528 was selected for cell experiments to examine its effects on proliferation, migration, and apoptosis of lens epithelial cells (LECs). RESULTS: A total of 16 192 circRNAs were detected in the specimens from both groups, among which 62 circRNAs were differentially expressed (29 upregulated and 33 downregulated). GO and KEGG analyses revealed that the differentially expressed circRNAs were primarily localized in the cytoplasm, nucleoplasm, and endoplasmic reticulum, and were involved in signaling pathways associated with Gap junction and the PI3K-Akt, NF-κB, Jak-STAT, HIF-1, and MAPK signaling pathways. The ceRNA network predicted multiple target genes. RT-qPCR validation results were consistent with the sequencing data. In the LECs, upregulation of hsa_circ_0007528 significantly inhibited cell proliferation and migration and obviously promoted cell apoptosis. CONCLUSIONS The expression profile of circRNAs in the anterior lens capsule of high myopic patients with cataract differs from that of ARC patients. Upregulation of hsa_circ_0007528 inhibits LEC proliferation and migration and promotes cell apoptosis.
Humans ; Cataract/complications* ; RNA, Circular ; Myopia/genetics* ; Apoptosis ; Cell Proliferation ; Epithelial Cells ; Cell Movement ; Anterior Capsule of the Lens/metabolism* ; Male ; Female

Digital technologies have become an integral part of complete denture restoration. With advancement in computer-aided design and computer-aided manufacturing (CAD/CAM), tools such as intraoral scanning, facial scanning, 3D printing, and numerical control machining are reshaping the workflow of complete denture restoration. Unlike conventional methods that rely heavily on clinical experience and manual techniques, digital technologies offer greater precision, predictability, and efficacy. They also streamline the process by reducing the number of patient visits and improving overall comfort. Despite these improvements, the clinical application of digital complete denture restoration still faces challenges that require further standardization. The major issues include appropriate case selection, establishing consistent digital workflows, and evaluating long-term outcomes. To address these challenges and provide clinical guidance for practitioners, this expert consensus outlines the principles, advantages, and limitations of digital complete denture technology. The aim of this review was to offer practical recommendations on indications, clinical procedures and precautions, evaluation metrics, and outcome assessment to support digital restoration of complete denture in clinical practice.
Humans ; Denture, Complete ; Computer-Aided Design ; Denture Design/methods* ; Consensus ; Printing, Three-Dimensional

Objective This study aimed to investigate the correlation of cerebral perfusion and cognitive function status in patients with minor stroke(MS)or transient ischemic attack(TIA)complicated by severe intracranial arterial stenosis or occlusion(hereafter referred to as ICAS-MSTIA).Methods Retrospectively enrol consecutive ICAS-MSTIA patients admitted to the Department of Neurology,the First Affiliated Hospital of Xi'an Jiaotong University,from June 2023 to May 2024.In the meantime,healthy controls were openly recruited.The ICAS-MSTIA patients were divided into two groups based on the side of intracranial large artery stenosis or occlusion:the left intracranial large artery involvement group and the right intracranial large artery involvement group.All patients with intracranial large artery stenosis or occlusion underwent MR scanning within 2 weeks after the first episode of TIA or MS,while there was no specific time requirement for MR examination in the healthy control group.On the day of MR scanning,the Montreal cognitive assessment(MoCA)scale was used to evaluate the participants'global cognitive function and performance in various cognitive domains,including visuospatial/executive function,naming,attention,language,abstraction,delayed recall,and orientation.General information of all participants was collected,including age,sex,educational level,body mass index,and history of smoking and alcohol consumption.Clinical data were collected from both left and right intracranial large artery involvement groups,including cerebrovascular risk factors(such as,diabetes mellitus,hypertension,and hyperlipidemia),National Institutes of Health stroke scale(NIHSS)score at admission,responsible stenotic or occluded arteries(internal carotid artery,middle cerebral artery),degree of stenosis in the responsible vessel(severe stenosis[stenosis rate 70%-99%],occlusion[stenosis rate100%])and non-responsible vessel(no stenosis[0],mild stenosis[stenosis rate＞0-49%]),collateral circulation compensation(American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology[ASTIN/SIR]collateral circulation classification),and responsible events(TIA,MS).General data and MoCA scale scores were compared across the three groups,while clinical data were compared between the left and right intracranial large artery involvement groups.Statistical parametric mapping 12(SPM 12)was used to perform voxel-wise independent samples t-tests on cerebral blood flow(CBF)differences among the left ICAS-MSTIA group,right ICAS-MSTIA group,and healthy control group,with cluster-level family-wise error(FWE)correction applied for adjustment.Multiple linear regression analysis was conducted to evaluate the relationship between global CBF values and total MoCA scores in ICAS-MSTIA patients with left or right intracranial large artery involvement.Results A total of 33 ICAS-MSTIA patients and 33 healthy controls were enrolled in the study.Among the ICAS-MSTIA patients,21 had left intracranial large artery involvement and 12 had right involvement.(1)Among the three groups,statistically significant differences were observed in the proportions of individuals with reported smoking history(P=0.024)and alcohol consumption history(P=0.011).The left intracranial large artery involvement group had a higher NIHSS score(0[0,2]vs.0[0,0],P=0.044)and a higher proportion of patients with internal carotid artery involvement(13/21 cases vs.2/12 cases,P=0.027)compared with the right side group.No statistically significant differences were observed in other general or clinical data across the three groups or between the two non-control groups(all P＞0.05).(2)Statistically significant differences were found across the three groups in the MoCA scale total score and scores of visuospatial/executive function,attention,language,abstraction,delayed recall,and orientation cognitive domains(all P＜0.05),while no significant difference was noted in the naming score(P=0.063).The left intracranial large artery involvement group had lower total MoCA score and lower scores in visuospatial/executive function,attention,language,abstraction,delayed recall,and orientation in comparison to the healthy control group(all P＜0.016 7).The right intracranial large artery involvement group had significantly lower scores in language,abstraction,and orientation domains than the healthy control group(all P＜0.016 7).Additionally,the left side group had a lower attention domain score than the right side group(P＜0.016 7).No other statistically significant differences were found in pairwise comparisons(all P＞0.016 7).(3)Patients in both the left and right intracranial large artery involvement groups exhibited a significant decrease in CBF in extensive regions on the affected side,including the temporal lobe,dorsolateral prefrontal cortex,and occipital lobe.Furthermore,after correction,in the left involvement group CBF was higher in the contralateral lingual gyrus,cuneus,and calcarine sulcus compared with the healthy control group(P＜0.05).While in the right involvement group,no regions had increased CBF compared to the healthy control group.(4)Multiple linear regression showed positive correlation between CBF in ipsilateral precentral gyrus and superior temporal gyrus,and the total MoCA score in patients with left intracranial large artery involvement(FWE-corrected,P＜0.05).In contrast,there was no correlation between CBF and total MoCA score in patients with right intracranial large artery involvement.Conclusions ICAS-MSTIA patients exhibited various degrees of impairment in cerebral perfusion and cognitive function.A significant positive correlation is observed between these two impairments in patients with left intracranial large artery involvement.

Objective:To explore the incidence of Crohn's disease-like pouch (CDP) after ileal pouch-anal anastomosis (IPAA) and analyze the clinical characteristics and risk factors in ulcerative colitis (UC) patients.Methods:A retrospective cohort study was conducted. One hundred and eighty-two UC patients undergoing IPAA at Jinling Hospital affiliated to Nanjing University from November 2003 to November 2024 were enrolled. Patients were categorized into CDP and non-CDP groups. Clinical features and prognosis were compared, and multivariate Cox regression was performed to identify risk factors for CDP.Results:A total of 182 UC patients were included, with a median follow-up time of 45.00 (30.00, 75.25) months. The patients were divided into two groups based on the diagnosis of CDP, with 23 patients (12.64%) in the CDP group and 159 patients (87.30%) in the non-CDP group. Compared to the non-CDP group, patients in the CDP group had a lower body mass index (BMI) ( Z=-2.87, P=0.004), and were more likely to develop early postoperative pouchitis (χ 2=4.50, P=0.034). The median time from ileostomy closure to the development of CDP was 12 .00 (6.00, 28.00) months. Cox regression analysis showed that a preoperative BMI<18.5 kg/m 2 ( HR=2.84, 95% CI: 1.24~6.49, P=0.013) and early postoperative pouchitis ( HR=3.11, 95% CI: 1.22~7.93, P=0.018) were associated with an increased risk of CDP. Conclusions:Preoperative low BMI and pouchitis occurring within 3 months postoperatively are significant risk factors for CDP. Close monitoring and early intervention are recommended for high-risk patients.

Objective:To explore the time variations of the influence of the ultra-high dose rate irradiation (FLASH irradiation, FLASH-IR) and conventional dose rate irradiation (CONV-IR) of electron beams under different doses on the energy metabolism of triple-negative breast cancer cells MDA-MB-231.Methods:The basal metabolism of the MDA-MB-231 cells and normal breast epithelial cells MCF-10A was compared using a Seahorse XF Pro Metabolic Analyzer. Based on an irradiation platform with a thermionic cathode electron accelerator (6 MeV), the MDA-MB-231 cells were exposed to FLASH-IR (106 Gy/s) and CONV-IR (0.1 Gy/s) at 2 and 14 Gy, respectively. Meanwhile, a sham irradiation group was established under identical culture conditions. The mitochondrial metabolism and glycolytic metabolism of the cells at 4, 24, and 48 h post-irradiation were analyzed.Results:Compared to the MCF-10A cells, the MDA-MB-231 cells exhibited a greater reliance on glycolytic metabolism. Compared to those of the sham irradiation group, MDA-MB-231 cells in the 2 Gy CONV-IR group showed up-regulated ATP-linked respiration at 4, 24, and 48 h post-irradiation ( t = 2.69-3.70, P < 0.05). Their glycolytic level and glycolytic capacity were up-regulated only at 4 h post-irradiation and were down-regulated at 48 h ( t = 2.79, -4.44, P < 0.05). In contrast, there was no statistically significant difference in these indicators between the FLASH-IR and CONV-IR groups ( P > 0.05). However, the proton leak of the MDA-MB-231 cells in the FLASH-IR group was relatively down-regulated at 4 h post-irradiation and was significantly up-regulated at 24 h and 48 h post-irradiation compared with the CONV-IR group ( t = -2.45, 3.19, 6.51, P < 0.05). At 14 Gy, the MDA-MB-231 cells in the CONV-IR group showed progressively increased mitochondrial and glycolytic metabolism across all time points ( t = 2.48-12.14, P < 0.05). Notably, compared with the CONV-IR group, the MDA-MB-231 cells in the FLASH-IR group exhibited more significantly up-regulated basal respiration, ATP-linked respiration, and non-mitochondrial oxygen consumption ( t = 2.56-6.51, P < 0.05), as well as a higher glycolytic capacity at 24 h post-irradiation ( t = 2.86, P < 0.05). Conclusions:Low-dose (2 Gy) FLASH-IR induces relatively up-regulated proton leak in breast cancer cells MDA-MB-231 at 24 h post-irradiation. In contrast, under high-dose (14 Gy) FLASH-IR, the MDA-MB-231 cells show more pronounced mitochondrial metabolic stress and a higher demand for energy metabolism.

Objective To investigate the neurovascular coupling(NVC)status in the acute phase of patients with minor ischemic stroke(MIS)or transient ischemic attack(TIA)due to intracranial large artery moderate-to-severe stenosis or occlusion using multimodal MRI techniques and to explore its correlation with quality of life(QoL).Methods This prospective,consecutive study enrolled patients with MIS or TIA due to intracranial large artery moderate-to-severe stenosis or occlusion form the Department of Neurology,the First Affiliated Hospital of Xi'an Jiaotong University,between June 2022 and October 2023.Recruit healthy subjects with matched age,sex,and handedness form the community during the same period.Patients were divided into left-sided involvement and right-sided involvement groups based on the affected side of the responsible vessel,while the healthy subjects were set as the healthy control group.Post-hoc power analysis was performed using G*Power 3.1 software.General characteristics(age,gender,body mass index,education level)were collected and compared across all three groups.Clinical data and QoL assessment were collected and compared between the two patient groups.Collected clinical data including type of cerebrovascular events(TIA,MIS),the National Institutes of Health stroke scale(NIHSS)score at admission,the responsible vessel(internal carotid artery,middle cerebral artery)and its side location,the degree of responsibility artery stenosis(moderate-severe stenosis[50%-99%stenosis rate],occlusion[100%stenosis rate]),the intracranial collateral circulation status(American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology[ASITN/SIR]collateral circulation grading),cerebrovascular risk factors(hypertension,diabetes,hyperlipidemia,smoking history),and the laboratory test indicators at admission(glycated hemoglobin,triglycerides,total cholesterol,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,blood uric acid,blood homocysteine).QoL was assessed using the stroke impact scale(SIS),covering eight functional domains and a patient-reported overall recovery item.Multimodal MR data were acquired for all subjects.Whole-brain cerebral blood flow(CBF)images were generated using statistics parameter mapping 12(SPM 12)software,while regional homogeneity(ReHo)images were generated using DPABI software.The voxel-wise ratio of CBF to ReHo(CBF/ReHo)was calculated as the regional NVC parameter.Differences in regional NVC characteristics were compared between patient groups and the healthy control group.Correlations between NVC parameters and SIS scores within patient groups were explored.Results(1)A total of 38 patients with MIS or TIA due to intracranial large artery moderate-to-severe stenosis or occlusion were included(26 males,12 females,aged 36-69 years,with mean age of[52±11]years),with 23 in the left-sided involvement group and 15 in the right-sided involvement group.Nineteen healthy subjects were included(10 males,9 females,aged 37-67 years,with mean age of[53±10]years).Post-hoc power analysis showed statistical power of 0.808 for comparing the left-sided involvement group with the healthy control group and 0.762 for comparing the right-sided involvement group with control group.(2)No statistically significant differences were found on gender,age,education level,or body mass index across the three groups(all P＞0.05).No statistically significant differences were observed on the type of cerebrovascular event,cerebrovascular risk factors,distribution of the responsible vessel,degree of stenosis in the responsible vessel,admission NIHSS score,or laboratory test results between the two patient groups(all P＞0.05).There were no statistically significant differences in the total SIS score and the scores of subscales between the two patient groups(all P＞0.05).(3)Compared with the healthy control group,the left-sided involvement group exhibited reduced CBF/ReHo values in the left superior and middle temporal gyri,supramarginal gyrus,middle and inferior frontal gyri,precentral gyrus,angular gyrus,postcentral gyrus,insula,and posterior cerebellar lobe(FDR-corrected,all P＜0.05).In the right-sided involvement group,reduced CBF/ReHo values were observed in the right supramarginal gyrus,right postcentral gyrus,inferior temporal gyrus,and insula(FDR-corrected,all P＜0.05).(4)Correlation analysis revealed that the SIS total score in the left-sided involvement group negatively correlated with CBF/ReHo values in the right inferior frontal gyrus(T=-5.91)and the right middle temporal gyrus(T=-6.65,FDR-corrected,both P＜0.05).The SIS subscale score for activities of daily living in the left-sided involvement group showed negative correlations with CBF/ReHo values in the right angular gyrus(T=-7.36),right medial superior frontal gyrus(T=-6.97),right orbitofrontal cortex(T=-8.99),and left thalamus(T=-7.51,FDR-corrected,all P＜0.05).No significant correlation was observed between the SIS total score and CBF/ReHo values in patients with right-sided involvement group.The SIS subscale for communication score in the right-sided involvement group correlated with CBF/ReHo in the left lingual gyrus(T=-12.15),left olfactory cortex(T=-7.68),and right anterior cingulate and paracingulate cortex(T=-9.46,FDR-corrected,all P＜0.05).Conclusions Patients with MIS or TIA due to intracranial large artery moderate-to-severe stenosis or occlusion show abnormal NVC in the acute phase,especially those with left hemisphere involvement,who exhibit more extensive impairments.QoL in left-sided involvement patients is strongly linked to NVC in the right orbitofrontal cortex and right middle temporal gyrus.These findings require further validation in larger-scale studies.

Objective:To investigate the clinical characteristics, postoperative complications, and risk factors for pouchitis in surgical patients with ulcerative colitis (UC).Methods:This was a retrospective observational study. The clinical data of 336 UC patients who had undergone surgical treatment at the Inflammatory Bowel Disease Center of the Department of General Surgery, Jinling Hospital Affiliated to Nanjing University Medical School from February 2014 to February 2024 were enrolled. The study patients were stratified into 2014-2019 ( n = 158) and 2020–2024 groups ( n = 178), these being the periods before and after biologics were covered for treatment of UC by national insurance in China in 2020. Clinical characteristics and surgical complications were analyzed and compared between the 2014-2019 and 2020-2024 groups. Multivariable logistic regression was performed to identify the risk factors associated with pouchitis in UC patients undergoing total proctocolectomy with ileal pouch-anal anastomosis (TPC-IPAA). Results:The study cohort comprised 336 UC patients, 193 (57.4%) of whom were men. The median preoperative disease course was 48.0 months and the mean age at colectomy was 46.4±15.4 years. TPC-IPAA had been performed on 275 patients (81.8%), 129 in the 2014-2019 group and 146 in the 2020-2024 group. Sixty-one patients had undergone total or subtotal colectomy, 29 in the 2014-2019 group and 32 in the 2020-2024 group. 262 (78.0%) UC patients underwent surgery due to medical refractory. Ninety-nine (29.5%) had used biopharmaceuticals within 2 months prior to surgery, 63 (18.8%) of them having received infliximab. A smaller proportion of patients had undergone surgery for UC that was refractory to medications in the 2020–2024 group than in the 2014–2019 group (73.0% [130/178] vs. 83.5% [132/158], χ 2=5.384, P=0.020), the patients were older at colectomy (48.0±15.4 years vs. 44.6±15.2 years, t=-2.008, P=0.045), the body mass index was higher (20.2±3.1 kg/m 2 vs. 19.4±3.2 kg/m 2, t=-2.201, P=0.028), the Mayo score prior to surgery was lower ( M[ Q1, Q3]: 11.0 [9.2, 12.0 points] vs. 12.0 [11.0, 12.0) points, Z=-4.242, P=0.001), the rate of Charlson Comorbidity Index ≥ 3 scores was higher (27.0% [48/178] vs. 17.1% [27/158], χ 2=5.384, P=0.020), a greater percentage of patients had received biologics prior to surgery (41.0% [73/178) vs. 16.5% [26/158], χ 2=24.285, P<0.001), and intraoperative blood loss was greater ( M[ Q1, Q3]: 100.0 [100.0, 150.0] ml vs. 50.0 [30.0, 100.0] ml, Z=-7.054, P<0.001) despite the operation time being shorter (253.8±74.6 minutes vs. 315.2±96.8 minutes, t=6.265, P<0.001). Among the 275 patients undergoing TPC-IPAA, 95 (34.6%) had early complications (within 30 days after surgery), 20 (7.3%) of which were Clavien-Dindo Grade III–IV complications. Among these patients, 50 (18.2%) had ileus or small bowel obstruction, 11 in the 2014-2019 group and 39 in the 2020-2024 group; this difference is statistically significant (χ 2=15.225, P<0.001). Ninety-one patients (33.1%) had late complications (more than 30 days after surgery), 75 (27.3%) being pouchitis (36 in the 2014-2019 group and 39 in the 2020-2024 group); this difference is not statistically significant (χ 2=0.049, P=0.824). Five patients (1.8%) had undergone pouch excision with permanent ileostomy. Among the 61 patients who had undergone total or subtotal colectomy, 26 (42.6%) developed early postoperative complications, including 10 (16.4%) Clavien-Dindo Grade III-IV complications and one death (1.6%), the last being attributable to multiorgan dysfunction. Three patients (4.9%) had late complications; the difference in incidence of postoperative complications between the 2014-2019 and 2020-2024 groups is not statistically significant (both P>0.05). Multivariable analysis identified intraoperative blood transfusion (OR: 2.12, 95% CI: 1.19–3.75, P=0.010) and interval to stoma closure > 120 days (OR: 2.05, 95%CI: 1.16-3.62, P = 0.013) as independent risk factors for development of pouchitis in UC patients undergoing TPC-IPAA. Conclusion:Surgical treatment of UC remains safe in the biologics era. Proactive strategies to reduce intraoperative blood transfusion and achieve timely stoma closure may reduce the risk of pouchitis in UC patients undergoing TPC-IPAA.

Objective This study aimed to investigate the correlation of cerebral perfusion and cognitive function status in patients with minor stroke(MS)or transient ischemic attack(TIA)complicated by severe intracranial arterial stenosis or occlusion(hereafter referred to as ICAS-MSTIA).Methods Retrospectively enrol consecutive ICAS-MSTIA patients admitted to the Department of Neurology,the First Affiliated Hospital of Xi'an Jiaotong University,from June 2023 to May 2024.In the meantime,healthy controls were openly recruited.The ICAS-MSTIA patients were divided into two groups based on the side of intracranial large artery stenosis or occlusion:the left intracranial large artery involvement group and the right intracranial large artery involvement group.All patients with intracranial large artery stenosis or occlusion underwent MR scanning within 2 weeks after the first episode of TIA or MS,while there was no specific time requirement for MR examination in the healthy control group.On the day of MR scanning,the Montreal cognitive assessment(MoCA)scale was used to evaluate the participants'global cognitive function and performance in various cognitive domains,including visuospatial/executive function,naming,attention,language,abstraction,delayed recall,and orientation.General information of all participants was collected,including age,sex,educational level,body mass index,and history of smoking and alcohol consumption.Clinical data were collected from both left and right intracranial large artery involvement groups,including cerebrovascular risk factors(such as,diabetes mellitus,hypertension,and hyperlipidemia),National Institutes of Health stroke scale(NIHSS)score at admission,responsible stenotic or occluded arteries(internal carotid artery,middle cerebral artery),degree of stenosis in the responsible vessel(severe stenosis[stenosis rate 70%-99%],occlusion[stenosis rate100%])and non-responsible vessel(no stenosis[0],mild stenosis[stenosis rate＞0-49%]),collateral circulation compensation(American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology[ASTIN/SIR]collateral circulation classification),and responsible events(TIA,MS).General data and MoCA scale scores were compared across the three groups,while clinical data were compared between the left and right intracranial large artery involvement groups.Statistical parametric mapping 12(SPM 12)was used to perform voxel-wise independent samples t-tests on cerebral blood flow(CBF)differences among the left ICAS-MSTIA group,right ICAS-MSTIA group,and healthy control group,with cluster-level family-wise error(FWE)correction applied for adjustment.Multiple linear regression analysis was conducted to evaluate the relationship between global CBF values and total MoCA scores in ICAS-MSTIA patients with left or right intracranial large artery involvement.Results A total of 33 ICAS-MSTIA patients and 33 healthy controls were enrolled in the study.Among the ICAS-MSTIA patients,21 had left intracranial large artery involvement and 12 had right involvement.(1)Among the three groups,statistically significant differences were observed in the proportions of individuals with reported smoking history(P=0.024)and alcohol consumption history(P=0.011).The left intracranial large artery involvement group had a higher NIHSS score(0[0,2]vs.0[0,0],P=0.044)and a higher proportion of patients with internal carotid artery involvement(13/21 cases vs.2/12 cases,P=0.027)compared with the right side group.No statistically significant differences were observed in other general or clinical data across the three groups or between the two non-control groups(all P＞0.05).(2)Statistically significant differences were found across the three groups in the MoCA scale total score and scores of visuospatial/executive function,attention,language,abstraction,delayed recall,and orientation cognitive domains(all P＜0.05),while no significant difference was noted in the naming score(P=0.063).The left intracranial large artery involvement group had lower total MoCA score and lower scores in visuospatial/executive function,attention,language,abstraction,delayed recall,and orientation in comparison to the healthy control group(all P＜0.016 7).The right intracranial large artery involvement group had significantly lower scores in language,abstraction,and orientation domains than the healthy control group(all P＜0.016 7).Additionally,the left side group had a lower attention domain score than the right side group(P＜0.016 7).No other statistically significant differences were found in pairwise comparisons(all P＞0.016 7).(3)Patients in both the left and right intracranial large artery involvement groups exhibited a significant decrease in CBF in extensive regions on the affected side,including the temporal lobe,dorsolateral prefrontal cortex,and occipital lobe.Furthermore,after correction,in the left involvement group CBF was higher in the contralateral lingual gyrus,cuneus,and calcarine sulcus compared with the healthy control group(P＜0.05).While in the right involvement group,no regions had increased CBF compared to the healthy control group.(4)Multiple linear regression showed positive correlation between CBF in ipsilateral precentral gyrus and superior temporal gyrus,and the total MoCA score in patients with left intracranial large artery involvement(FWE-corrected,P＜0.05).In contrast,there was no correlation between CBF and total MoCA score in patients with right intracranial large artery involvement.Conclusions ICAS-MSTIA patients exhibited various degrees of impairment in cerebral perfusion and cognitive function.A significant positive correlation is observed between these two impairments in patients with left intracranial large artery involvement.

Objective·To explore the antitumor effects and potential mechanisms of combining phosphoinositide 3-kinase,FYVE-type zinc finger containing(PIKfyve)inhibitor YM201636 with the stimulator of interferon genes(STING)agonist diABZI in STING pathway-deficient melanoma.Methods·The mRNA and protein expression levels of STING in human cancer cell lines were obtained from the Cancer Cell Line Encyclopedia(CCLE)and UniProt databases.Based on median expression values,melanoma cell lines with high STING mRNA but low protein expression were identified.Quantitative real-time PCR(qRT-PCR)and Western blotting were performed to validate STING mRNA and protein expression in human melanoma cells.The murine melanoma cell line YUMM1.7,characterized by low STING protein expression,was selected through Western blotting.The ability of YM201636 to restore STING protein expression in YUMM1.7 cells was evaluated.STING agonist diABZI was then applied in combination with YM201636 to analyze the synergistic tumor cell-killing effect through CCK-8 assay.Western blotting was used to detect the phosphorylation of TANK-binding kinase 1(TBK1)and interferon regulatory factor 3(IRF3),and qRT-PCR was used to evaluate type Ⅰ interferon expression.A mouse melanoma model was established and treated with YM201636,diABZI,or their combination.Tumor volume was measured,and treatment efficacy was assessed.RNA sequencing and immunofluorescence staining were performed to analyze immune cell infiltration in the tumor microenvironment.Results·Database analyses,qRT-PCR,and Western blotting confirmed that some human melanoma cell lines exhibited high STING mRNA expression but low STING protein levels.YM201636 significantly increased STING protein expression in YUMM1.7 cells(P<0.001).Combined treatment with YM201636 and diABZI significantly enhanced phosphorylation of TBK1 and IRF3(P<0.05),indicating effective activation of the STING signaling pathway.This combination also promoted the expression of type Ⅰ interferons(P<0.001)and enhanced tumor cell killing in vitro.In vivo,the combination therapy markedly suppressed melanoma growth compared to monotherapy.Immune profiling of the tumor microenvironment revealed significantly increased infiltration of CD4? T cells and CD8? T cells in the combination treatment group(P<0.05).Conclusion·The PIKfyve inhibitor YM201636 could restore STING protein expression in STING-deficient melanoma and enhance the antitumor efficacy of the STING agonist diABZI,offering a promising therapeutic strategy for tumors with defective STING signaling.