Inhibition of CTR1 expression improves hypoxia/reoxygenation-induced myoblast injury by blocking cuproptosis.

Skeletal muscle ischemia-reperfusion injury (IRI) is a common severe disease with a complex pathological process. This study found that copper chloride (CuCl2) inhibited cell viability in a concentration dependent manner, increased intracellular copper levels and downregulated copper transporter 1 (CTR1) expression. CTR1 upregulation promoted copper uptake by myoblasts and then enhanced cuproptosis, leading to a significant increase in the levels of dihydrolipoamide S-acetyltransferase (DLAT) oligomers, while a significant decrease in the levels of lipoylated (Lip)-dihydrolipoamide S-succinyltransferase (DLST) and Lip-DLAT, ultimately inhibiting cell viability and inducing cell injury. Inducing cuproptosis with elesclomol plus CuCl2 (ES + Cu) further confirmed that "ES + Cu" treatment significantly reduced the contents of adenosine triphosphate (ATP) and glutathione (GSH), decreased the activities of mitochondrial complex I and III, and increased the contents of lactate (LA), malondialdehyde (MDA), creatine kinase (CK) and lactate dehydrogenase (LDH); when tetrathiomolybdate (TTM) was added to inhibit cuproptosis, myoblast injury was recovered significantly. Meanwhile, hypoxia/reoxygenation (H/R) induced CTR1 expression, increased the levels of intracellular copper, DLAT oligomers, LA, MDA, CK and LDH, reduced the levels of Lip-DLST, Lip-DLAT, ATP and GSH, and weakened the activities of mitochondrial complex I and III; after knocking down CTR1 expression, the levels of intracellular copper and the activation of cuproptosis pathway were decreased, and cell viability, injury and inflammation levels were significantly improved. Therefore, cuproptosis can promote myoblast injury, while H/R enhances copper uptake by inducing CTR1 expression, thereby enhancing cuproptosis and inducing cell injury, indicating that cuproptosis is a new mechanism of H/R-induced myoblast injury.

The lncRNA LINC01605 promotes the progression of pancreatic ductal adenocarcinoma by activating the mTOR signaling pathway.

BACKGROUND: This study investigated the molecular mechanism of long intergenic non-protein coding RNA 1605 (LINC01605) in the process of tumor growth and liver metastasis of pancreatic ductal adenocarcinoma (PDAC). METHODS: LINC01605 was filtered out with specificity through TCGA datasets (related to DFS) and our RNA-sequencing data of PDAC tissue samples from Renji Hospital. The expression level and clinical relevance of LINC01605 were then verified in clinical cohorts and samples by immunohistochemical staining assay and survival analysis. Loss- and gain-of-function experiments were performed to estimate the regulatory effects of LINC01605 in vitro. RNA-seq of LINC01605-knockdown PDAC cells and subsequent inhibitor-based cellular function, western blotting, immunofluorescence and rescue experiments were conducted to explore the mechanisms by which LINC01605 regulates the behaviors of PDAC tumor cells. Subcutaneous xenograft models and intrasplenic liver metastasis models were employed to study its role in PDAC tumor growth and liver metastasis in vivo. RESULTS: LINC01605 expression is upregulated in both PDAC primary tumor and liver metastasis tissues and correlates with poor clinical prognosis. Loss and gain of function experiments in cells demonstrated that LINC01605 promotes the proliferation and migration of PDAC cells in vitro. In subsequent verification experiments, we found that LINC01605 contributes to PDAC progression through cholesterol metabolism regulation in a LIN28B-interacting manner by activating the mTOR signaling pathway. Furthermore, the animal models showed that LINC01605 facilitates the proliferation and metastatic invasion of PDAC cells in vivo. CONCLUSIONS: Our results indicate that the upregulated lncRNA LINC01605 promotes PDAC tumor cell proliferation and migration by regulating cholesterol metabolism via activation of the mTOR signaling pathway in a LIN28B-interacting manner. These findings provide new insight into the role of LINC01605 in PDAC tumor growth and liver metastasis as well as its value for clinical approaches as a metabolic therapeutic target in PDAC.

Targeting the PI3K/mTOR pathway in idiopathic pulmonary fibrosis: Advances and therapeutic potential.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease characterized by irreversible tissue scarring, leading to severe respiratory dysfunction. Despite current treatments with the drugs Pirfenidone and Nintedanib, effective management of IPF remains inadequate due to limited therapeutic benefits and significant side effects. This review focuses on the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway, a critical regulator of cellular processes linked to fibrosis, such as fibroblast proliferation, inflammation, and epithelial-mesenchymal transition (EMT). We discuss recent advances in understanding the role of the PI3K/mTOR pathway in IPF pathogenesis and highlight emerging therapies targeting this pathway. The review compiles evidence from both preclinical and clinical studies, suggesting that PI3K/mTOR inhibitors may offer new hope for IPF treatment by modulating fibrosis and improving patient outcomes. Moreover, it outlines the potential for these inhibitors to be developed into effective, personalized treatment options, underscoring the importance of further research to explore their efficacy and safety profiles comprehensively.

Unsupervised corneal contour extraction algorithm with shared model for dynamic deformation videos: improving accuracy and noise resistance.

BACKGROUND: In this study, an automatic corneal contour extraction algorithm with a shared model is developed to extract contours from dynamic corneal videos containing noise, which improves the accuracy of corneal biomechanical evaluation and clinical diagnoses. The algorithm does not require manual labeling and completes the unsupervised semantic segmentation of each frame in corneal dynamic deformation videos based on a fully convolutional deep-learning network using corneal geometry and texture information. RESULTS: We included 1027 corneal videos at Tianjin Eye Hospital (Nankai University Affiliated Eye Hospital) from May 2020 to November 2021. The videos were obtained by the ultra-high-speed Scheimpflug camera, and then we used the shared model mechanism to accelerate the segmentation of corneal regions in videos, effectively resist noise, determine corneal regions based on shape factors, and finally achieve automatic and accurate extraction of corneal region contours. The Intersection over Union (IoU) of the extracted and real corneal contours using this algorithm reached 95%, and the average overlap error was 0.05, implying that the extracted corneal contour overlapped almost completely with the real contour. CONCLUSIONS: Compared to other algorithms, the method introduced in this study does not require manual annotation of corneal contour data in advance and can still extract accurate corneal contours from noisy corneal videos with good repeatability.

Effects of fine particulate matter mass and chemical components on oxidative DNA damage in human early placenta.

The effects of chemical components of ambient fine particulate matter (PM2.5) on human early maternal-fetal interface are unknown. We estimated the associations of PM2.5 and component exposures with placental villi 8-hydroxy-2'-deoxyguanosine (8-OHdG) in 142 normal early pregnancy (NEP) and 142 early pregnancy loss (EPL) from December 2017 to December 2022. We used datasets accessed from the Tracking Air Pollution in China platform to estimate maternal daily PM2.5 and component exposures. Effect of average PM2.5 and component exposures during the post-conception period (i.e., from ovulation to villi collection) on the concentration of villi 8-OHdG were analyzed using multivariable linear regression models. Distributed lag and cumulative effects of PM2.5 and component exposures during the periovulatory period and within ten days before villi collection on villi 8-OHdG were analyzed using distributed lag non-linear models combined with multivariable linear regression models. Per interquartile range increase in average PM2.5, black carbon (BC), and organic matter (OM) exposures during the post-conception period increased villi 8-OHdG in all subjects (ß = 34.48% [95% CI: 9.33%, 65.42%], ß = 35.73% [95% CI: 9.08%, 68.89%], and ß = 54.71% [95% CI: 21.56%, 96.91%], respectively), and in EPL (ß = 63.37% [95% CI: 16.00%, 130.10%], ß = 47.43% [95% CI: 4.30%, 108.39%], and ß = 72.32% [95% CI: 18.20%, 151.21%], respectively), but not in NEP. Specific weekly lag effects of PM2.5, BC, and OM exposures during the periovulatory period increased villi 8-OHdG in all subjects. Ten-day cumulative and lag effects of PM2.5, BC, and OM increased villi 8-OHdG in all subjects and EPL, but not in NEP; and the effects of OM were robust after adjusting for BC, ammonium, nitrate, or sulfate in two-pollutant models. In conclusion, placental oxidative DNA damage in early pregnancy was associated with maternal exposure to PM2.5, especially its chemical components BC and OM.

Minocycline-loaded nHAP/PLGA microspheres for prevention of injury-related corneal angiogenesis.

BACKGROUND: Corneal neovascularization (CoNV) threatens vision by disrupting corneal avascularity, however, current treatments, including pharmacotherapy and surgery, are hindered by limitations in efficacy and adverse effects. Minocycline, known for its anti-inflammatory properties, could suppress CoNV but faces challenges in effective delivery due to the cornea's unique structure. Therefore, in this study a novel drug delivery system using minocycline-loaded nano-hydroxyapatite/poly (lactic-co-glycolic acid) (nHAP/PLGA) nanoparticles was developed to improve treatment outcomes for CoNV. RESULTS: Ultra-small nHAP was synthesized using high gravity technology, then encapsulated in PLGA by a double emulsion method to form nHAP/PLGA microspheres, attenuating the acidic by-products of PLGA degradation. The MINO@PLGA nanocomplex, featuring sustained release and permeation properties, demonstrated an efficient delivery system for minocycline that significantly inhibited the CoNV area in an alkali-burn model without exhibiting apparent cytotoxicity. On day 14, the in vivo microscope examination and ex vivo CD31 staining corroborated the inhibition of neovascularization, with the significantly smaller CoNV area (29.40% ± 6.55%) in the MINO@PLGA Tid group (three times daily) than that of the control group (86.81% ± 15.71%), the MINO group (72.42% ± 30.15%), and the PLGA group (86.87% ± 14.94%) (p < 0.05). Fluorescein sodium staining show MINO@PLGA treatments, administered once daily (Qd) and three times daily (Tid) demonstrated rapid corneal epithelial healing while the Alkali injury group and the DEX group showed longer healing times (p < 0.05). Additionally, compared to the control group, treatments with dexamethasone, MINO, and MINO@PLGA were associated with an increased expression of TGF-ß as evidenced by immunofluorescence, while the levels of pro-inflammatory cytokines IL-1ß and TNF-α demonstrated a significant decrease following alkali burn. Safety evaluations, including assessments of renal and hepatic biomarkers, along with H&E staining of major organs, revealed no significant cytotoxicity of the MINO@PLGA nanocomplex in vivo. CONCLUSIONS: The novel MINO@PLGA nanocomplex, comprising minocycline-loaded nHAP/PLGA microspheres, has shown a substantial capacity for preventing CoNV. This study confirms the complex's ability to downregulate inflammatory pathways, significantly reducing CoNV with minimal cytotoxicity and high biosafety in vivo. Given these findings, MINO@PLGA stands as a highly promising candidate for ocular conditions characterized by CoNV.

Corneal biomechanics in early diagnosis of keratoconus using artificial intelligence.

Keratoconus is a blinding eye disease that affects activities of daily living; therefore, early diagnosis is crucial. Great efforts have been made toward an early diagnosis of keratoconus. Recent studies have shown that corneal biomechanics is associated with the occurrence and progression of keratoconus. Hence, detecting changes in corneal biomechanics may provide a novel strategy for early diagnosis. However, an early keratoconus diagnosis remains challenging due to the subtle and localized nature of its lesions. Artificial intelligence has been used to help address this problem. Herein, we reviewed the literature regarding three aspects of keratoconus (keratoconus, early keratoconus, and keratoconus grading) based on corneal biomechanical properties using artificial intelligence. Furthermore, we summarized the current research progress, limitations, and possible prospects.

Effects of Long-Term Simulated Weightlessness on Retinal Microcirculation and Visual Electrophysiology.

Objective: To investigate the mechanisms of ocular injuries in astronauts due to gravity deficit by examining changes in retinal microcirculation and visual electrophysiology in macaques subjected to simulated weightlessness. Methods: The head-down recumbency of macaques was used to simulate the movement of blood to the side of the head that occurs without microgravity. Head-down recumbency was performed with the head tilted downwards at a recommended angle of 10°. The macaques in the control group were similarly tethered to the rope but could be held in a normal position. The whole experiment lasted for 6 weeks and retinal microcirculation and visual electrophysiology information was collected at weeks 0, 3 and 6. Results: The retinal microcirculation of macaques was affected by 3 weeks of weightlessness. This includes morphological changes, such as dilation and tortuosity of the retinal microvasculature in macaques at day 21. OCT and OCTA results showed an increase in retinal and choroidal thickness and a significant decrease in vessel length density within 6×6 mm of the macula. Sustained simulated weightlessness (42 days) significantly exacerbated retina-related damage. This was evidenced by a significant decrease in the perfusion density of microcirculatory vessels, such as the macular 3×3 mm mesial vessels and the macular 6*6 mm central and medial vessels. The FAZ density in the macula 3×3 mm area began to increase. Retinal oxygen saturation testing showed a slight increase in arterial oxygen saturation. Simultaneous changes in visual electrophysiology occurred, including a significant decrease in a- and b-wave amplitudes on the dark-vision electroretinogram and a significant decrease in the amplitude of the bright-vision negative wave response. The peak timing of the flash visual evoked potential component P1 was significantly delayed compared to its baseline and time-matched control. Conclusions: Sustained simulated weightlessness (42 days) significantly exacerbated retina-related damage, with both reduced macular blood supply and increased FAZ density suggesting the development of retinal ischemic changes, which disrupt visual electrophysiology. Retinal damage in human astronauts under long-term outer space conditions may be prevented by intervening in ischemic changes in the retina during the early stages of weightlessness.

The Influence of Nonlinear High-Intensity Dynamic Processes on the Standing Wave Precession of a Non-Ideal Hemispherical Resonator.

The properties of small size, low noise, high performance and no wear-out have made the hemispherical resonator gyroscope a good choice for high-value space missions. To enhance the precision of the hemispherical resonator gyroscope for use in tasks with large angular velocities and angular accelerations, this paper investigates the standing wave precession of a non-ideal hemispherical resonator under nonlinear high-intensity dynamic conditions. Based on the thin shell theory of elasticity, a dynamic model of a hemispherical resonator is established by using Lagrange's second kind equation. Then, the dynamic model is equivalently transformed into a simple harmonic vibration model of a point mass in two-dimensional space, which is analyzed using a method of averaging that separates the slow variables from the fast variables. The results reveal that taking the nonlinear terms about the square of the angular velocity and the angular acceleration in the dynamic equation into account can weaken the influence of the 4th harmonic component of a mass defect on standing wave drift, and the extent of this weakening effect varies with the dimensions of the mass defects, which is very important for steering the development of the high-precision hemispherical resonator gyroscope.

Analysis of cuproptosis-related lncRNA signature for predicting prognosis and tumor immune microenvironment in pancreatic cancer.

Pancreatic cancer (PC) is a highly malignant digestive tract tumor, with a dismal 5-year survival rate. Recently, cuproptosis was found to be copper-dependent cell death. This work aims to establish a cuproptosis-related lncRNA signature which could predict the prognosis of PC patients and help clinical decision-making. Firstly, cuproptosis-related lncRNAs were identified in the TCGA-PAAD database. Next, a cuproptosis-related lncRNA signature based on five lncRNAs was established. Besides, the ICGC cohort and our samples from 30 PC patients served as external validation groups to verify the predictive power of the risk signature. Then, the expression of CASC8 was verified in PC samples, scRNA-seq dataset CRA001160, and PC cell lines. The correlation between CASC8 and cuproptosis-related genes was validated by Real-Time PCR. Additionally, the roles of CASC8 in PC progression and immune microenvironment characterization were explored by loss-of-function assay. As showed in the results, the prognosis of patients with higher risk scores was prominently worse than that with lower risk scores. Real-Time PCR and single cell analysis suggested that CASC8 was highly expressed in pancreatic cancer and related to cuproptosis. Additionally, gene inhibition of CASC8 impacted the proliferation, apoptosis and migration of PC cells. Furthermore, CASC8 was demonstrated to impact the expression of CD274 and several chemokines, and serve as a key indicator in tumor immune microenvironment characterization. In conclusion, the cuproptosis-related lncRNA signature could provide valuable indications for the prognosis of PC patients, and CASC8 was a candidate biomarker for not only predicting the progression of PC patients but also their antitumor immune responses.

ß-Carboline Alkaloids Resist the Aggregation and Cytotoxicity of Human Islet Amyloid Polypeptide.

ß-Carboline alkaloids have a variety of pharmacological activities, such as antitumor, antibiosis and antidiabetes. Harmine and harmol are two structurally similar ß-carbolines that occur in many medicinal plants. In this work, we chose harmine and harmol to impede the amyloid fibril formation of human islet amyloid polypeptide (hIAPP) associated with type 2 diabetes mellitus (T2DM), by a series of physicochemical and biochemical methods. The results indicate that harmine and harmol effectively prevent peptide fibril formation and alleviate toxic oligomer species. In addition, both small molecules exhibit strong binding affinities with hIAPP mainly through hydrophobic and hydrogen bonding interactions, thus reducing the cytotoxicity induced by hIAPP. Their distinct binding pattern with hIAPP is closely linked to the molecular configuration of the two small molecules, affecting their ability to impede peptide aggregation. The study is of great significance for the application and development of ß-carboline alkaloids against T2DM.

Effect of concomitant Renal DeNervation and cardiac ablation on Atrial Fibrillation recurrence - RDN+AF study.

BACKGROUND: Renal denervation (RDN) can reduce cardiac sympathetic activity maintained by arterial hypertension (aHT). Its potential antiarrhythmic effect on rhythm outcome in patients with multi-drug resistant aHT undergoing catheter ablation for atrial fibrillation (AF) is unclear. METHODS: The RDN+AF study was a prospective, randomized, two-center trial. Patients with paroxysmal or persistent AF and uncontrolled aHT (mean systolic 24-h ambulatory BP > 135 mmHg) despite taking at least three antihypertensive drugs were enrolled. Patients were 1:2 randomized to either RDN+AF ablation or AF-only ablation. Primary endpoint was freedom from any AF episode > 2 min at 12 months assessed by implantable loop recorder (ILR) or 7d-holter electrocardiogram. Secondary endpoints included rhythm outcome at 24 months, blood pressure control, periprocedural complications, and renovascular safety. RESULTS: The study randomized 61 patients (mean age 65 ± 9 years, 53% men). At 12 months, RDN+AF patients tended to have a greater decrease in ambulatory BPs but did not reach statistical significance. No differences in rhythm outcome were observed. Freedom from AF recurrence in the RDN+AF and AF-only group measured 61% versus 53% p = .622 at 12 months and 39% versus 47% p = .927 at 24 months, respectively. Periprocedural complications occurred in 9/61 patients (15%). No patient died. CONCLUSION: Among patients with multidrug-resistant aHT and paroxysmal or persistent AF, concomitant RDN+AF ablation was not associated with better blood pressure control or rhythm outcome in comparison to AF-only ablation and medical therapy.

Association between Triglyceride-Glucose Index and 1-year Recurrent Stroke after Acute Ischemic Stroke: Results from the Xi'an Stroke Registry Study of China.

INTRODUCTION: The triglyceride-glucose (TyG) index is reported to be related to poor functional outcomes and all-cause mortality post-stroke. However, the association between TyG index and recurrent stroke after acute ischemic stroke (AIS) has not been well described. We aimed to identify whether the TyG index was associated with 1-year recurrent stroke after AIS. METHODS: Baseline patient information was collected at admission, and the TyG index was calculated. Recurrent stroke events were followed up at 1, 3, 6, and 12 months after diagnosis. We then examined the association between the TyG index and risk of 1-year recurrent stroke using multivariable Cox regression models and restricted cubic spline analyses. RESULTS: Among 2,288 participants, the mean TyG index was 8.8  0.7. Those in the fourth quartile (Q4) demonstrated higher recurrent stroke risk than those in Q1 (adjusted hazard ratio [HR] = 1.63; 95% confidence interval [CI], 0.98-2.72; p = 0.059). Subgroup analysis revealed a sex-specific association between TyG index and recurrent stroke (p for interaction = 0.022). Additionally, restricted cubic splines analyses showed a non-linear association between the TyG index and 1-year recurrent stroke. In females, patients in the Q4 had a 2.95-fold increased recurrent stroke risk than did patients in the Q1 (adjusted HR =2.95; 95% CI, 1.09-7.94; p = 0.032); the risk increased when the TyG index was > 8.73. However, no significant correlation was observed in males. CONCLUSION: A non-linear association was found between the TyG index and 1-year recurrent stroke risk. Subsequently, a high TyG index could predict an increased 1-year recurrent stroke risk in female AIS patients.

Banxia Xiexin decoction ameliorates dextran sulfate sodium (DSS)-induced ulcerative colitis via inhibiting serine-threonine protein kinase (Akt)/mitogen-activated protein kinase (MAPK) signaling pathway.

Banxia Xiexin decoction (BXD), a traditional Chinese medicine, was widely used in treating ulcerative colitis (UC). However, the active components of BXD and its mechanism in UC remain elusive. Therefore, we used network pharmacology in vivo experiments, molecular docking, and surface plasmon resonance strategy (SPR) to uncover BXD's potential mechanism. A UC rat model was established by orally administering 7% dextran sulfate sodium (DSS) in drinking water, BXD and palmatine were orally administered for 7 days. Network pharmacology was used to investigate the main bioactive components and crucial targets of BXD in treating UC. Molecular docking was used to investigate interactions between components and crucial targets, verifying the results by SPR. By network pharmacology predicting, 20 active components and 44 candidate anti-UC targets of BXD were identified, and the crucial proteins were screeded from PPI network, including extracellular regulated protein kinases (ERK), AKT1, and tumor necrosis factor-α (TNF). In addition, some key active components (palmatine, sexangularetin, and skullcapflavone II) were screened out from the active components-targets network. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and in vivo experiments showed that protein-serine-threonine kinase (Akt)/MAPK pathway was involved in BXD treatment for UC; BXD and palmatine significantly ameliorated the severity of DSS-induced UC in rats. Our study might assist in further investigation of the active components in Chinese medicine.

Biomechanical properties analysis of forme fruste keratoconus and subclinical keratoconus.

PURPOSE: To analyze the biomechanical properties of the eye in patients with unilateral keratoconus with normal (forme fruste keratoconus [FFKC]) or abnormal topography (subclinical keratoconus [SKC]). METHODS: This study included 153 eyes of 153 participants, including 95 eyes of patients with unilateral keratoconus, and 58 eyes of 58 healthy controls. Contralateral eyes with unilateral keratoconus were divided into two groups according to clinical manifestations and global consensus: FFKC (n = 30) and SKC (n = 65). The biomechanical characteristics were analyzed using non-parametric tests; further analysis thereof was performed after adjusting for confounding factors (i.e., intraocular pressure, age, and corneal thickness). Receiver operating characteristic curve (ROC) was used to analyze the ability of the biomechanical parameters to distinguish FFKC from SKC. RESULTS: Statistically significant differences between the FFKC and SKC groups were found in 9 of the 18 corneal biomechanical parameters analyzed using non-parametric tests. After adjusting for confounding factors, the multivariate analysis still revealed significant statistical differences in A1-time (P = 0.017), integrated radius (IR) (P = 0.024), and tomographic and biomechanical index (TBI, P < 0.001) between the FFKC and SKC groups. Stiffness parameter at first applanation (SP-A1) (Area under ROC [AUROC] = 0.765) demonstrated the strongest distinguishing ability, except for TBI (AUROC = 0.858) and Corvis Biomechanical Index (AUROC = 0.849), however, there was no statistically significant difference in SP-A1 (P = 0.366) between FFKC and SKC. CONCLUSIONS: Biomechanical parameters A1-time and IR have a high diversity between FFKC and SKC, besides TBI, and may reflect more subtle changes in corneal biomechanical properties (BPs) preceding SP-A1. The BPs of SKC are weaker than FFKC, which might be a basic and clue for the classification and diagnosis of the severity of early keratoconus in terms of biomechanics.

Elevated non-HDL-C/HDL-C ratio increases the 1-year risk of recurrent stroke in older patients with non-disabling ischemic cerebrovascular events: results from the Xi'an Stroke Registry Study of China.

BACKGROUND: Few studies have explored the prognostic role of nontraditional lipid-related indicators in non-disabling ischemic cerebrovascular events (NICE). In this study, we aimed to investigate the relationship between the ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (non-HDL-C/HDL-C) and the1-year risk of recurrent stroke in patients with NICE. METHODS: Total cholesterol (TC), HDL-C, and patient information were collected at admission. Recurrent stroke events were followed up 3, 6, and 12 months after onset. Non-HDL-C levels were calculated by subtracting HDL-C from TC. The non-HDL-C/HDL-C ratio was treated as a continuous variable and in quartiles (Q1-Q4). Stratified multivariate Cox regression was used to investigate the relationship between the non-HDL-C/HDL-C ratio and the 1-year risk of recurrent stroke in patients with NICE. RESULTS: Overall, 1,659 patients with NICE were enrolled. For each unit increase in the non-HDL-C/HDL-C ratio, the 1-year risk of recurrent stroke in patients aged ≥ 65 years (older patients) with NICE increased by 64% in the adjusted model (hazard ratio [HR]: 1.64, 95%confidence interval [CI]:1.18-2.27, P = 0.003), and the HRs were 3.21 and 4.24 times higher in the Q3 and Q4 groups than that in the Q1 group, which was considered to be the reference (adjusted model Q3: HR: 3.21, 95%CI: 1.05-9.83, P = 0.041; adjusted model Q4: HR: 4.24, 95%CI: 1.30-13.85, P = 0.017). However, there was no significant difference in patients younger than 65 years. Both curve fitting and Kaplan-Meier cumulative risk analysis showed that an elevated non-HDL-C/HDL-C ratio significantly increased the 1-year risk of recurrent stroke in older patients with NICE. The optimal range for the non-HDL-C/HDL-C ratio should be no higher than the Q2 group (2.256-2.939). Stratified Cox regression analysis showed that these results tended to be stable for different comorbidities (all P for interaction > 0.05). CONCLUSIONS: Elevated non-HDL-C/HDL-C ratios significantly increased the 1-year risk of recurrent stroke in older patients with NICE. Therefore, clinicians need to pay more attention to this indicator when managing older patients with NICE.

Topographic Differences in Superficial Macular Vessel Density in Eyes with Early Primary Open-Angle Glaucoma and Normal Tension Glaucoma.

INTRODUCTION: The aim of the study was to compare macular vascular microcirculation in early primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), and normal subjects. METHODS: 99 patients with early glaucoma (99 eyes: 60 POAG and 39 NTG) and 78 normal subjects were included. All subjects underwent optical coherence tomography angiography scan at 6 × 6 mm macular area. Macular vessel density (VD) and perfusion density (PD) and 9 sectors were compared between the controls, POAG, and NTG groups. Linear regression analysis was used to investigate the relationship between VD and other variables including macular PD, signal strength (SS), and mean macular ganglion cell-inner plexiform layer (mGCIPL) thickness. RESULTS: Significant losses in total area of VD and PD were detected in POAG and NTG groups compared to the controls (all p < 0.01). There were no significant differences in all inner sectors of macular VD and PD between POAG and controls (all p > 0.05). Except for outer-nasal sector, all other outer sectors of macular VD and PD were significantly lower in POAG than in the controls (all p < 0.01). The inferior-inner sector and all outer sectors of VD and PD were significantly lower in NTG than in the controls (all p < 0.01). Macular VD was significantly correlated with macular PD (r = 0.99, p < 0.001), SS (r = 0.60, p < 0.001), and mGCIPL thickness (r = 0.51, p < 0.001). CONCLUSIONS: Macular microcirculation declined significantly in early POAG and NTG patients. Macular microcirculation loss in the NTG group was more central and nasal compared with that in the POAG group. A decrease in macular VD was correlated with lower macular PD, lower SS, and thinner mGCIPL thickness.

Overexpressed LAMC2 promotes trophoblast over-invasion through the PI3K/Akt/MMP2/9 pathway in placenta accreta spectrum.

BACKGROUND: Placenta accreta spectrum (PAS) is an ongoing major iatrogenic public health challenge with devastating obstetric complications, but its underlying molecular pathogenesis remains poorly illuminated. LAMC2 is reported to regulate tumor cells proliferation and invasion, yet has not been explored in placenta trophoblast cells. This study investigated LAMC2 expression and its contribution in the etiology of PAS. METHODS: Quantitative polymerase chain reaction, western blot, and immunohistochemistry were performed to detect the expression of LAMC2 in placentas. Cell proliferation, invasion, migration, and apoptosis were monitored by CCK8 assay, wound healing assay, transwell invasion assay, and flow cytometry assay. Western blot was conducted to confirm the pertinent proteins level of PI3K/Akt/MMP2/9 pathway in HTR8/SVneo cells. RESULTS: LAMC2 was predominantly expressed in placental villous syncytiotrophoblasts and cytotrophoblasts. LAMC2 mRNA and protein expression were substantially upregulated in placental tissues with PAS compared to those with pernicious placenta previa without PAS. LAMC2 overexpression eminently boosted HTR8/SVneo cells proliferation, invasion, and migration, but inhibited apoptosis, accompanied by elevated protein expression of MMP2, MMP9, and phosphorylated Akt (pAkt). Knockdown of LAMC2 yielded the converse results. Additionally, when treated with LY294002, the effects of LAMC2 overexpression on proliferation, migration, invasion, and apoptosis of HTR8/SVneo cells were abolished and concomitantly the elevated pAkt, MMP2, and MMP9 proteins induced by LAMC2 overexpression were eliminated. CONCLUSION: Our study highlighted the involvement of LAMC2 in the pathogenesis of PAS by activating the PI3K/Akt/MMP2/9 signaling pathway to stimulate trophoblast over-invasion. These findings provide a new target for the diagnosis and disease stratification of PAS.

ADAMTS12 promotes migration and epithelial-mesenchymal transition and predicts poor prognosis for pancreatic cancer.

BACKGROUND: ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) family, a group of extracellular multifunctional enzymes, has been proven to play a pivotal role in the tumor. In pancreatic cancer, the role and mechanism of this family remain unclear. The present study aimed to figure out the hub gene of ADAMTSs and explore the exact roles in the prognosis and biological functions in pancreatic ductal adenocarcinoma (PDAC). METHODS: We used several databases to analyze the ADAMTS family and then screen out the hub genes. The expression of ADAMTS12 in 106 pairs of PDAC tumors and adjacent normal tissues was examined by immunohistochemistry, and its correlations with clinical parameters were further analyzed. The impacts of ADAMTS12 on the migration of PDAC cells were predicted by gene set enrichment analysis and confirmed by transwell assays. The potential impacts of ADAMTS12 on the epithelial-mesenchymal transition (EMT) were identified by database analysis and experimental proof of real-time quantitative polymerase chain reaction (qPCR) and Western blotting. RESULTS: Our study found that ADAMTS12 was a crucial gene in PDAC, and it was highly expressed in tumor tissues when compared to that in the adjacent tissues. ADATMS12 had predictive value of a poor prognosis for PDAC. The elevation of ADAMTS12 was parallel to the progression of PDAC. Inhibition of ADAMTS12 suppressed the migration of PDAC cells and interfered with the process of EMT. CONCLUSIONS: ADAMTS12 is a crucial member of ADAMTSs in PDAC and a predictor of poor prognosis. Additionally, based on its impacts on migration and metastasis in PDAC and the relationship with EMT, ADAMTS12 plays a role of an oncogene in PDAC and may be a promising target for treatment.

Renal hemodynamic evaluation protocol based on the pathophysiological mechanism of acute kidney injury: Critical Care UltraSound Guided-A(KI)BCDE.

The multiple etiological characteristics of acute kidney injury (AKI) have brought great challenges to its clinical diagnosis and treatment. Renal injury in critically ill patients always indicates hemodynamic injury. The Critical Care UltraSound Guided (CCUSG)-A(KI)BCDE protocol developed by the Chinese Critical Ultrasound Study Group (CCUSG), respectively, includes A(KI) diagnosis and risk assessment and uses B-mode ultrasound, Color doppler ultrasound, spectral Doppler ultrasound, and contrast Enhanced ultrasound to obtain the hemodynamic characteristics of the kidney so that the pathophysiological mechanism of the occurrence and progression of AKI can be captured and the prognosis of AKI can be predicted combined with other clinical information; therefore, the corresponding intervention and treatment strategies can be formulated to achieve targeted, protocolized, and individualized therapy.