Atrial fibroblast activation is a central cellular event driving atrial fibrotic remodeling, which plays a critical role in the initiation and maintenance of atrial fibrillation (AF). Our previous studies have identified the intermediate-conductance Ca2+-activated potassium channel KCa3.1 as a key mediator of reactive atrial fibrosis. However, the upstream mechanisms regulating its expression under pro-fibrotic stimulation remain incompletely defined. The present study aimed to investigate whether NADPH oxidase (NOX)-derived reactive oxygen species (ROS) regulate KCa3.1 expression and function in atrial fibroblasts. Primary rat atrial fibroblasts were stimulated with angiotensin II (Ang II). Ang II markedly increased intracellular ROS generation through AT1 receptor-dependent activation of NOX. Pharmacological inhibition with Diphenyleneiodonium (DPI) or CRISPR-mediated deletion of NOX2 or NOX4 significantly suppressed Ang II-induced upregulation of KCa3.1 expression and channel activity. Exposure to hydrogen peroxide (H2O2) alone was sufficient to enhance KCa3.1 expression and TRAM-34-sensitive currents. Functionally, pharmacological blockade or genetic deletion of KCa3.1 markedly attenuated ROS-induced fibroblast proliferation, migration, and myofibroblast differentiation. Mechanistically, ROS activated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of either pathway suppressed KCa3.1 promoter activity and expression. Collectively, these findings identify a NOX-ROS-JNK/ERK-KCa3.1 signaling axis that drives atrial fibroblast activation and may represent a potential therapeutic target in oxidative stress-associated atrial remodeling.

Kidney organoids are important tools for modeling human development and disease, especially in chronic kidney disease (CKD), which is a global health challenge. Current treatment strategies focus on delaying disease progression by managing underlying causes, and in this regard, kidney organoids offer a platform for mechanism-based therapeutics. Advances in the understanding of human induced pluripotent stem cells (hiPSCs) and sophisticated 3D organ culture methods have enabled researchers to replicate human kidney development and disease mechanisms in vitro, thereby opening new avenues for drug testing. Although the methods for generating renal cell lineages are well established, new protocols for inducing lineages, such as the ureteric bud and collecting ducts, have emerged over the past 5 years. Patient-derived or genetically edited kidney organoids have been used to successfully model various genetic kidney diseases, notably polycystic kidney disease, and to generate kidney tissues that closely mimic the morphology of real organs. However, achieving more complex disease modeling and generating transplantable synthetic kidneys still has notable challenges. The present review discusses the application of hiPSC-derived 3D organoids in CKD research and addresses the limitations of current organ culture methods. The present review also examines the impact of CRISPR/Cas9 technology, and investigates potential future directions.

BACKGROUND:Porokeratosis is a rare, genetically heterogeneous group of dyskeratotic dermatoses with an incompletely understood pathogenesis. Accumulating evidence shows that pathogenic variants in mevalonate pathway-related genes play a central role in the aetiology of the disease. Previous studies have established partial genotype-phenotype correlations, although the biological mechanisms underlying these associations remain incompletely characterized. OBJECTIVES:To analyse the germline and somatic variant spectrum of porokeratosis, unravel gene subtype-specific 'second-hit' mechanisms, and establish genotype-phenotype correlations via a large cohort, providing evidence to guide clinical practice. METHODS:We sequenced peripheral blood samples from 69 patients with porokeratosis and performed whole-exome sequencing on 37 lesional epidermis samples from 29 patients, to detect somatic second-hit changes. We reviewed the germline genotypes and phenotypes of 572 patients reported in 46 studies retrieved from PubMed and ClinVar, and analysed genotype-phenotype correlations. RESULTS:In 69 Chinese patients with porokeratosis, 22 pathogenic variants were detected in MVK, PMVK, MVD and FDPS, including 7 novel variants, 4 of which were validated via the 'second-hit' mechanism. By integrating this information with literature data, we summarized 10 common variants and identified novel genotypephenotype correlations: 100% (n = 6/6) of patients with porokeratosis plus nonmelanoma skin cancer and 71% (n = 17/24) of those with linear porokeratosis (LP) harboured MVD variants; MVK, MVD and PMVK variants were detected in patients with porokeratosis ptychotropica (PP). Somatic second-hit changes were identified in 81% (n = 55/68) of patients, mostly copy-neutral loss of heterozygosity (CN-LOH) with gene subtype specificity: most MVK-related porokeratosis showed chromosome 12-wide CN-LOH, while most MVD-related porokeratosis had 16q CN-LOH. CONCLUSIONS:Our large cohort study expands the genetic variant spectrum of porokeratosis, clarifies gene subtype-specific somatic 'second-hit' mechanisms and establishes clinically relevant genotype-phenotype correlations. These findings enable porokeratosis subtyping guided by genetic testing and provide a foundation for developing molecularly integrated scoring systems to refine risk-stratified management.

IntroductionCardiovascular disease (CVD) is the leading cause of death in patients receiving dialysis, and accurate risk prediction at dialysis initiation remains limited. We developed and validated a machine learning model integrating CT-derived body composition features to predict CVD-related mortality in initial dialysis patients.MethodsPatients initiating dialysis between 2014 and 2020 from three tertiary hospitals were used for model training and internal validation, with patients from a fourth center for external validation. Clinical characteristics and laboratory variables were collected, and body composition parameters were assessed using opportunistic CT scans. Feature selection was performed using univariable logistic regression and LASSO regression. Eight machine learning algorithms were trained, and model performance was assessed using discrimination, calibration, and decision curve analysis. Model interpretability was evaluated using Shapley Additive Explanations (SHAP), and a web-based risk calculator was developed.ResultsAmong 1051 incident dialysis patients, 645 were assigned to the training and internal validation cohorts and 406 to the external validation cohort. Eight key predictors were identified, including age, diabetes, CVD, history of cardiac intervention, dialysis modality, skeletal muscle density, hemoglobin, and serum creatinine. CatBoost demonstrated the best performance, with an area under the receiver operating characteristic curve of 0.843 in internal validation and 0.799 in external validation, along with good calibration and clinical net benefit. SHAP analysis identified CVD, skeletal muscle density, and hemoglobin as major contributors.DiscussionAn explainable machine learning model incorporating CT-derived body composition features accurately predicts CVD-related mortality in initial dialysis patients. This model may facilitate early risk stratification and targeted prevention strategies at dialysis initiation.

Glial scar formation is one of the major pathological mechanisms following ischemic stroke. Rapamycin is a potent specific mTOR inhibitor and an autophagy activator. Although it has neuroprotective effects against acute ischemic stroke, it is unknown whether delayed administration of rapamycin can reduce ischemic stroke-induced pathogenesis such as glial scar formation, independent on its effects of acute administration. We recently reported that matrilin-3, an extracellular matrix component, provides neuroprotection in ischemic stroke by suppressing astrocyte-mediated neuroinflammation and glial scar formation. Here, in rat models of middle cerebral artery occlusion and reperfusion (I/R), rapamycin was administered for consecutive 7 or 14 days starting at day 1 post-reperfusion; and in an oxygen-glucose deprivation and reoxygenation (OGD/Re)-induced primary astrocyte or human astrocyte injury model, rapamycin was given upon reoxygenation. We found that rapamycin improved I/R-mediated rats' neurological dysfunction, accompanied by reduced glial scar formation and neuronal loss. To our surprise, rapamycin increased the levels of matrilin-3 in the peri-infarct region of rats and in OGD/Re-treated astrocytes associating with restoring autophagic flux. In contrast, the autophagy inhibitors wortmannin and bafilomycin A1 blocked autophagic flux, decreased the levels of matrilin-3 and enhanced glial scar formation, respectively. Overexpression of matrilin-3 significantly reduced the glial scar formation. Mechanistically, rapamycin could decrease the ADAMTS-4 and ADAMTS-5 levels, two hydrolases responsible for the breakdown of matrilin-3, thus upregulating the matrilin-3 levels. Our results reveal that delayed administration of rapamycin suppresses the glial scar formation by upregulating the astrocytic matrilin-3 related to restoring autophagic flux in ischemic stroke.

Gestational diabetes mellitus (GDM) is one of the most common endocrine-related complications during pregnancy, and its prevalence has increased over the past three decades. GDM adversely affects the maternal cardiovascular system, umbilical–placental blood perfusion, and fetal blood flow. We conducted a comprehensive literature search and systematically evaluated and synthesized cardiovascular changes in the mothers, umbilical–placental circulation, and the progeny following exposure to GDM. Multiple pathophysiological mechanisms underlying cardiovascular alteration were investigated, including endothelial dysfunction, insulin resistance, oxidative stress, ion channel abnormalities, inflammation, angiogenic imbalance, and epigenetic modifications. These findings provide valuable insights for developing early intervention strategies and therapeutic approaches to mitigating cardiovascular risks in both mothers and offspring following GDM exposure.

BACKGROUND:To explore the associations of age, intramuscular adipose tissue index (IATI), and serum albumin with survival status in initial dialysis patients and the mediating effects. METHODS:Totally 1,044 Chinese initial dialysis patients from four hospitals (2014-2020) were eventually enrolled and followed up to December 31, 2022 or until death in this retrospective cohort study. IATI was defined as the ratio of low attenuation muscle density to skeletal muscle density assessed by CT at the first lumbar vertebra level. Multivariate Cox regression and two-piecewise Cox proportional hazards models were used to determine the risk factors for all-cause mortality and to perform stratified analysis. Mediation analysis was conducted to identify mediators. RESULTS:High IATI, age > 60 years, and low serum albumin were significant independent risk factors for all-cause mortality. The association between IATI and all-cause mortality remained significant in female patients, and those with low neutrophil/lymphocyte ratios, or without coronary heart disease. When age and IATI were categorical variables, age had a significant indirect effect on all-cause mortality (0.015) and survival time (-1.262) via IATI, while IATI indirectly influenced all-cause mortality through serum albumin (0.012). CONCLUSIONS:Age > 60 years and high IATI are risk factors for all-cause mortality while serum albumin is protective in initial dialysis patients. The relationship between age and survival status may be mediated by IATI, while the effect of IATI on all-cause mortality may be mediated by serum albumin.

BackgroundMyosteatosis is associated with adverse prognosis in diseases. We aimed to establish thresholds for myosteatosis, assess its association with all-cause and cardiac mortality in initial dialysis patients, and construct a myosteatosis-based survival nomogram. assessed the predictive value of myosteatosis with all-cause and cardiac mortality in initial-dialysis patients, and constructed a myosteatosis-based survival nomogram.MethodsThis multicentric retrospective study included 383 initial-dialysis patients (1/2014–12/2019). Endpoints include all-cause and cardiac mortality. Skeletal Muscle Index (SMI, cm2/m2) and Skeletal Muscle Density (SMD, Hounsfield Units [HU]) were measured at the third lumbar vertebra (L3) level by computed tomography (CT). Sex-specific SMI and SMD thresholds predicted all-cause mortality through the receiver operating characteristic (ROC) curves. The Cox models assessed myosteatosis-associated mortality risks. Survival prediction models were built using univariate and multivariate Cox proportional hazards regression in the training cohort, followed by internal and external validation.ResultsPatients were predominantly aged 18–65 years (n = 298, 77.81%), with males comprising 60.84% (n = 233). All-cause mortality was 22.72% (n = 87), of which 52.87% (n = 46) were attributed to cardiac causes. Sex-specific SMD cutoffs for predicting all-cause mortality were 32.46 HU (AUC = 0.707) in males and 34.58 HU (AUC = 0.690) in females (both P < 0.05). Myosteatosis was associated with higher all-cause (36.7%) and cardiac mortality (19.8%) (both P < 0.001), and independently predicted both outcomes (all-cause mortality: HR = 3.203, 95% CI:1.937–5.296; cardiac mortality: HR = 3.418, 95% CI:1.718–6.802). The myosteatosis-based nomogram achieved a C-index of 0.761, validated in real-world data.ConclusionSex-specific myosteatosis thresholds (males: SMD ≤32.46 HU; females: ≤34.58 HU) derived from L3-CT independently predicted all-cause and cardiac mortality in initial-dialysis patients. The myosteatosis-based survival nomogram demonstrated moderate-to-good predictive accuracy and potential clinical utility.

To investigate the associations of systemic inflammation, lipid metabolism, bone metabolism markers, and muscle quality with thoracic aortic calcification (TAC) in patients undergoing maintenance dialysis. This multicenter cross-sectional research involved 1916 patients aged 18–80 years who underwent maintenance dialysis across four tertiary hospitals in China between January 2020 and June 2023. Non-contrast chest CT scans were performed to assess TAC and skeletal muscle density (SMD). Associations of TAC with SMD, monocyte-lymphocyte ratio (MLR), and high-density lipoprotein (HDL), apolipoprotein (apo) A1, alkaline phosphatase (ALP) were explored via multivariate regression models. Stratified analysis was further done to investigate the effect of SMD on TAC. Mediation analyses were conducted to identify the mediators. Multivariate linear regression analysis demonstrated significant positive associations between TAC and MLR (β = 0.43; 95

Background The creatinine muscle index (CMI, mg/day/1.73m²) may be a potential indicator for evaluating muscle mass. We aimed to assess the correlation between CMI and muscle mass and investigate the association of CMI with CVD. Methods Participants aged 45–65 years from the 2011 China Health and Retirement Longitudinal Study were included and followed until 2020. CMI was calculated using serum creatinine and cystatin C-estimated glomerular filtration rate. Spearman’s correlation was used to assess the relationship between CMI and appendicular skeletal muscle mass (ASMM). Cox proportional hazards regression models and restricted cubic splines (RCS) were employed to analyze the association between CMI and CVD. Results Among the 5122 participants, 1100 participants developed CVD. CMI was correlated with ASMM in males (r = 0.60, P < 0.001) and females (r = 0.53, P < 0.001). After adjusting for multiple factors, higher CMI (tertile 3 versus 1) was associated with reduced risks of CVD in males (HR [95% CI]: 0.74 [0.57–0.95]) and females (HR [95% CI]: 0.79 [0.64–0.97]). RCS revealed a linear relationship between CMI and CVD (all P for non-linearity > 0.05). Conclusions CMI may is a practical indicator of muscle mass, and higher CMI levels are associated with lower CVD risk.

Gestational hypertension (PIH), especially pre-eclampsia (PE), is a common complication of pregnancy. This condition poses significant risks to the health of both the mother and the fetus. Emerging evidence suggests that epigenetic modifications, particularly DNA methylation, may play a role in initiating the earliest pathophysiology of PIH. This article describes the relationship between DNA methylation and placental trophoblast function, genes associated with the placental microenvironment, the placental vascular system, and maternal blood and vascular function, abnormalities of umbilical cord blood and vascular function in the onset and progression of PIH, as well as changes in DNA methylation in the progeny of PIH, in terms of maternal, fetal, and offspring. We also explore the latest research on DNA methylation-based early detection, diagnosis and potential therapeutic strategies for PIH. This will enable the field of DNA methylation research to continue to enhance our understanding of the epigenetic regulation of PIH genes and identify potential therapeutic targets.

In this study, palmoplantar keratosis in four patients with variants in the LSS gene showed various degrees of improvement after 4-16 weeks of therapy using simvastatin and cholesterol ointment, while keratosis in a patient with MBTPS2 variant displayed poor response.

The utilization of ultrapure dialysate has been shown to decrease dialysate contamination and mitigate inflammatory responses. The central dialysate delivery system (CDDS) has the potential to attain a level of purity similar to ultrapure dialysate. Nevertheless, there is limited research examining the impact of CDDS on inflammation in comparison to single-patient dialysis fluid delivery system(SPDDS). This study aims to investigate the effects of CDDS utilizing ultrapure dialysate on ameliorating the microinflammatory state in hemodialysis patients. A retrospective cohort clinical study enrolled a total of 125 hemodialysis patients, with 58 patients from the CDDS unit and 67 patients from the SPDDS unit. Each participant was monitored for a period of 6 months, and the repeated measurement data was analyzed using a generalized linear mixed models (GLMM). The average age of the studty cohort was 56.22 ± 12.64 years. The GLMM analysis showed a significant time*group interaction effect on hs-CRP changes over the follow-up period (β = -1.966, FTime* CDDS group = 13.389, P < 0.001). A linear mixed model analysis with random slope showed that a different slope was observed between CDDS group and SPDDS group (βCDDS =—0.793; βSPDDS = 0.791), indicating a decreased hs-CRP levels in CDDS group, while increased in the SPDDS group over the follow-up period. However, no significant time*group interaction effect were observed on albumin and β2-microglobulin levels during follow-up period(β2-microglobulin: β = -0.658, FTime* CDDS group = 1.228, P = 0.269; albumin: β = 0.012, FTime* CDDS group = 1.429, P = 0.233). Using ultrapure dialysate in the CDDS is associated with an improvement in hs-CRP levels compared to standard dialysate, which might confer long-term clinical advantages.

Background: Ichthyosis follicularis, atrichia and photophobia (IFAP) syndrome is a rare genetic genodermatosis. According to previous reports, in addition to MBTPS2 variants, variants in SREBF1 (encoding SREBP1) can also cause IFAP syndrome. SREBF1 variants can also result in hereditary mucoepithelial dysplasia (HMD). These two diseases exhibit some similar clinical features. Objectives: We report two cases of IFAP syndrome with atypical clinical features associated with the c.1670G>A variant in the SREBF1 gene, and review the clinical characteristics of all reported cases of IFAP syndrome and HMD patients with SREBF1 variants to date. Materials & Methods: Whole-exome sequencing was performed for the two patients, and immunohistochemistry was performed on samples from psoriatic-like plaques on the right lower limb of one of the patients. A PubMed search was conducted to identify all patients with IFAP syndrome and HMD with SREBF1 variants. Results: A missense variant c.1670G>A in SREBF1 was identified in our two patients. The heterozygous SREBF1 variant was not identified in their parents. Immunohistochemistry of samples from the psoriatic-like plaques on the lower limb from one of the patients showed enhanced staining for IL-17A and S100A8, with reduced nuclear translocation of SREBP1. Conclusion: We describe two cases of IFAP syndrome without apparent photophobia, one of which exhibited severe psoriasis-like plaques limited to the extensor sides of both lower limbs. Immunohistochemical results of the lower limb lesions showed partial resemblance to psoriatic lesions. In addition, a comparative review of the clinical features of all published HMD and IFAP syndrome cases is presented.

PurposeIn this study, we identified and diagnosed a novel inherited condition called Dyschromatosis, Ichthyosis, Deafness, and Atopic Disease (DIDA) syndrome. We present a series of studies to clarify the pathogenic variants and specific mechanism.MethodsExome sequencing and Sanger sequencing was conducted in affected and unaffected family members. A variety of human and cell studies were performed to explore the pathogenic process of keratosis.ResultsOur finding indicated that DIDA syndrome was caused by compound heterozygous variants in the oxysterol-binding protein-related protein 2 (OSBPL2) gene. Furthermore, our findings revealed a direct interaction between OSBPL2 and Phosphoinositide phospholipase C-beta-3 (PLCB3), a key player in hyperkeratosis. OSBPL2 effectively inhibits the ubiquitylation of PLCB3, thereby stabilizing PLCB3. Conversely, OSBPL2 variants lead to enhanced ubiquitination and subsequent degradation of PLCB3, leading to epidermal hyperkeratosis, characterized by aberrant proliferation and delayed terminal differentiation of keratinocytes.ConclusionsOur study not only unveiled the association between OSBPL2 variants and the newly identified DIDA syndrome but also shed light on the underlying mechanism.

ABSTRACT Background The discovery of phospholipase A2 receptor (PLA2R) and its antibody (aPLA2Rab) has paved the way for diagnosing PLA2R-associated membranous nephropathy (PLA2R-MN) with a high specificity of 98%. However, the sensitivity was only 40% to 83.9%, and there is ongoing discussion around determining the optimal threshold for diagnosis. Recent advancements in the use of exosomes, a novel form of “liquid biopsy,” have shown great promise in identifying markers for various medical conditions. Methods Protein mass spectrometry and western blot were applied to verify the existence of PLA2R antigen in the urine exosome. We then evaluated the efficacy of urinary exosomal PLA2R antigen alone or combined with serum aPLA2Rab level to diagnose PLA2R-MN. Results The urinary exosomes contained a high abundance of PLA2R antigen as evidenced by protein mass spectrometry and western blot in 85 PLA2R-MN patients vs the disease controls (14 secondary MN patients, 22 non-MN patients and 4 PLA2R-negative MN patients) and 20 healthy controls. Of note, urinary exosomal PLA2R antigen abundance also had a good consistency with the PLA2R antigen level in the renal specimens of PLA2R-MN patients. The sensitivity of urinary exosomal PLA2R for diagnosing PLA2R-MN reached 95.4%, whereas the specificity was 63.3%. Combining detection of the urinary exosomal PLA2R and serum aPLA2Rab could develop a more sensitive diagnostic method for PLA2R-MN, especially for patients with serum aPLA2Rab ranging from 2 to 20 RU/mL. Conclusions Measurement of urinary exosomal PLA2R could be a sensitive method for the diagnosis of PLA2R-MN.

Porokeratosis encompasses a group of keratinization disor-ders with distinct clinical variants,including porokeratosis of Mibelli,disseminated superficial actinic porokeratosis,porokeratosis plantaris,palmaris et disseminata,and linear porokeratosis(LP).1 Familial porokeratosis has been asso-ciated with pathogenic variants in genes of the mevalonate pathway(such as MVK,PMVK,MVD,and FDPS),a vital metabolic pathway responsible for synthesizing sterols and isoprenoid metabolites.1-3

BACKGROUND: We have shown that the late-pregnant (LP) rodent exhibits a higher susceptibility to myocardial ischemia-reperfusion injury (IRI) compared to non-pregnant (NP). The molecular mechanisms remain unclear. The dysregulation of multiple microRNAs (miRs) in IRI suggests their potential as promising targets for therapeutic interventions. Methods: Female Sprague-Dawley rats in both NP and LP states underwent occlusion of the left anterior descending coronary artery (LAD) for a duration of 45 minutes, followed by reperfusion for 3 hours or 24 hours. Expression of miR was assessed via fluorescent in situ hybridization. MicroRNA-microarray profiling was conducted on hearts of NP and LP rats subjected to IRI. Female H9c2 rat cardiomyoblast cells were transfected with miR mimics and inhibitors, and subjected to hypoxia/reoxygenation. Blood samples were obtained from NP, LP, and ischemic heart disease (IHD) patients. MiR98 inhibitor was administered at the initiation of reperfusion. Results: MicroRNA-microarray analysis revealed upregulation of microRNA-98-5p (miR-98) in LV of LP at baseline, and a further upregulation after IRI. The expression of Stat3 and Pgc-1α were decreased in LV of LP rats compared to NP rats upon IRI. Fluorescent in situ hybridization revealed expression of miR-98 in cardiomyocytes in NP rats, which was increased in LP rats. Overexpression of miR-98 in vitro in female H9c2 cells decreased Stat3 and Pgc-1α levels, and promoted apoptosis, oxidative stress, and inflammatory markers. MiR-98 inhibitor in LP rats at the onset of reperfusion reduced infarct size, apoptosis, oxidative stress, and inflammatory markers and was associated with upregulation of Stat3 and Pgc-1α. In humans, plasma miR-98 levels were significantly higher in healthy LP compared to healthy NP individuals and even higher in LP patients with IHD patients. CONCLUSIONS: We show the detrimental effects of miR-98 by promoting cardiomyocyte oxidative stress, inflammation, and apoptosis via its targets Stat3 and Pgc-1α in the context of late pregnancy. MiR-98 could be a novel cardio-protective strategy or biomarker in late pregnancy.

目的:探讨散结镇痛胶囊联合屈螺酮炔雌醇片治疗子宫腺肌症(ADS)对患者卵巢储备功能、血管内皮生长因子(VEGF)、脂联素(APN)、血管生成素-2(Ang-2)水平的影响.方法:选取本院2019年2月1日-2021年2月1日收治的ADS患者180例,随机分为中医组、西医组和中西医组各60例,分别给予散结镇痛胶囊、屈螺酮炔雌醇片-Ⅱ及结镇痛胶囊+屈螺酮炔雌醇片-Ⅱ治疗.比较治疗前后子宫体积、卵巢储备功能激素指标及血管生成相关因子水平.结果:治疗后,3组子宫体积、抗苗勒管激素、促卵泡激素、黄体生成素、雌激素、VEGF、APN均有不同程度降低,Ang-2水平不同程度升高,但中西医组变化幅度大于另外两组(均P<0.05).治疗总有效率中西医组(83.3％)大于中医组(66.7％)和西医组(65.0％),3组治疗期间均未出现明显不良反应.结论:散结镇痛胶囊联合屈螺酮炔雌醇片治疗ADS,可有效改善患者卵巢储备功能、子宫状况和临床症状,降低血清VEGF、Ang-2水平,升高APN水平,疗效更佳,安全性较好.