Decreased PDLIM1 expression in endothelial cells contributes to the development of intracranial aneurysm.

INTRODUCTION: Intracranial aneurysm (IA) is a common vascular enlargement that occurs in the wall of cerebral vessels and frequently leads to fatal subarachnoid hemorrhage. PDZ and LIM domain protein 1 (PDLIM1) is a cytoskeletal protein that functions as a platform for multiple protein complex formation. However, whether PDLIM is involved in the pathogenesis of IA remains poorly understood. METHODS: Loss-of-function and gain-of-function strategies were employed to determine the in vitro roles of PDLIM1 in vascular endothelial cells (VECs). A rat model of IA was generated to study the role of PDLIM1 in vivo. Gene expression profiling, Western blotting, and dual luciferase reporter assays were performed to uncover the underlying cellular mechanism. Clinical IA samples were used to determine the expression of PDLIM1 and its downstream signaling molecules. RESULTS: PDLIM1 expression was reduced in the endothelial cells of IA and was regulated by Yes-associated protein 1 (YAP1). Genetic silencing of PDLIM1 inhibited the viability, migratory ability, and tube formation ability of VECs. Opposite results were obtained by ectopic expression of PDLIM1. Additionally, PDLIM1 overexpression mitigated IA in vivo. Mechanistic investigations revealed that PDLIM1 promoted the transcriptional activity of ß-catenin and induced the expression of v-myc myelocytomatosis viral oncogene homolog (MYC) and cyclin D1 (CCND1). In clinical settings, reduced expression of PDLIM1 and ß-catenin downstream target genes was observed in human IA samples. CONCLUSION: Our study indicates that YAP1-dependent expression of PDLIM1 can inhibit IA development by modulating the activity of the Wnt/ß-catenin signaling pathway and that PDLIM1 deficiency in VECs may represent a potential marker of aggressive disease.

Proteomic landscape of primary and metastatic brain tumors for heterogeneity discovery.

PURPOSE: Despite recent advancements in our understanding of driver gene mutations and heterogeneity within brain tumors, whether primary or metastatic (also known as secondary), our comprehension of proteomic changes remains inadequate. The aim of this study is to provide an informative source for brain tumor researches, and distinguish primary brain tumors and secondary brain tumors from extracranial origins based on proteomic analysis. EXPERIMENTAL DESIGN: We assembled the most frequent brain tumors as follows: gliomas from WHO grade 2 to 4, with IDH1 mutations and wildtypes; brain metastases (BrMs) originating from lung cancer (LC), breast cancer (BC), ovarian cancer (OC), and colorectal cancer (CC). A total of 29 tissue samples were analyzed by label free quantitative mass spectrometry-based proteomics. RESULTS: In total, 8165 protein groups were quantified, of which 4383 proteins were filtered at 50% valid intensity values for downstream analysis. Proteomic analysis of BrMs reveals conserved features shared among multiple origins. While proteomic heterogeneities were found for discriminating different grades of gliomas, as well as IDH1 mutant and wildtype gliomas. In addition, notable distinctions were observed at the pathway level between BrMs and gliomas. Specifically, BrMs exhibited characteristic pathways focused on proliferation and immunomodulation after colonizing the brain, whereas gliomas primarily engaged in invasion processes. CONCLUSIONS AND CLINICAL RELEVANCE: We characterized an extensive proteomic landscape of BrMs and gliomas. These findings have promising implications for the development of targeted therapies for BrMs and gliomas.

Association between cardiopulmonary function, health-related quality of life and cognitive impairment among the older nursing home residents in Shanghai, China.

BACKGROUND: This study aimed to examine the association between cardiopulmonary function, health-related quality of life (HRQOL) and cognitive function among nursing home residents aged 80 years and over. METHODS: A nursing home-based, cross-sectional study was implemented among 677 aged over 80 years in Shanghai, China. A total of 197 participants underwent effective cardiopulmonary function examinations. Mini-Mental Status Examination (MMSE) and Short Form-36 scales (SF-36) were used to assess cognitive function and HRQOL, respectively. RESULTS: Decline in left ventricular ejection fractions (LVEF) [adjusted odds ratio (AOR), 1.98; 95% confidential interval (CI), 1.03-3.81)] and vital capacity (VC) (AOR, 2.08; 95%CI, 1.07-4.04) was associated with cognitive impairment. After adjusting confounding factors, relationships between cognitive function and physical functioning (PF) (AOR, 0.98; 95%CI, 0.97-0.99) still existed. CONCLUSIONS: Healthcare professionals should pay more attention to cardiopulmonary health and HRQOL in the nursing home residents. Actions of public health strategies focus on the improvement of cardiopulmonary function, and PF among older nursing home residents with cognitive impairment is required.

Outbreak of SARS-CoV-2 Omicron Infection in a Centralized Quarantine Location in Hangzhou, China.

This cohort study assesses whether transmission of COVID-19 occurred among individuals staying on different floors at a hotel used as a centralized quarantine location in Hangzhou, China.

Circulating proteomic panels for risk stratification of intracranial aneurysm and its rupture.

The prevalence of intracranial aneurysm (IA) is increasing, and the consequences of its rupture are severe. This study aimed to reveal specific, sensitive, and non-invasive biomarkers for diagnosis and classification of ruptured and unruptured IA, to benefit the development of novel treatment strategies and therapeutics altering the course of the disease. We first assembled an extensive candidate biomarker bank of IA, comprising up to 717 proteins, based on altered proteins discovered in the current tissue and serum proteomic analysis, as well as from previous studies. Mass spectrometry assays for hundreds of biomarkers were efficiently designed using our proposed deep learning-based method, termed DeepPRM. A total of 113 potential markers were further quantitated in serum cohort I (n = 212) & II (n = 32). Combined with a machine-learning-based pipeline, we built two sets of biomarker combinations (P6 & P8) to accurately distinguish IA from healthy controls (accuracy: 87.50%) or classify IA rupture patients (accuracy: 91.67%) upon evaluation in the external validation set (n = 32). This extensive circulating biomarker development study provides valuable knowledge about IA biomarkers.

Comprehensive mass spectrometry for development of proteomic biomarkers of intracranial aneurysms.

Protein biomarkers of intracranial aneurysm (IA) are essential for early detection and prediction of its rupture to facilitate the diagnosis and clinical management of the disease, monitor treatment response and detect recurrence. Here, we developed a comprehensive strategy for IA biomarker discovery by analyzing tissues from an animal model (n = 4) and serum from human patients (n = 60) using isobaric tandem mass tags-based quantitative proteomics. A total of 4811 and 562 proteins were identified from aneurysm tissue and serum samples, respectively. The 223 candidate protein biomarkers were further validated in an independent serum cohort (n = 30) by multiple reaction monitoring analysis. Combined with a logistic regression model, we built a diagnostic classifier P2 (FCN2 & RARRES2) to differentiate IA from healthy controls with accuracy of 93.3%, as well as a diagnostic classifier P7 (ADAM12, APOL3, F9, C3, CEACAM1, ICAM3, KLHDC7A) to classify ruptured IA from unruptured IA with accuracy of 95.0%. Taken together, our results suggest a valuable strategy for biomarker discovery and patient stratification in IA.

Mitochondrial Transplantation Attenuates Cerebral Ischemia-Reperfusion Injury: Possible Involvement of Mitochondrial Component Separation.

BACKGROUND: Mitochondrial dysfunctions play a pivotal role in cerebral ischemia-reperfusion (I/R) injury. Although mitochondrial transplantation has been recently explored for the treatment of cerebral I/R injury, the underlying mechanisms and fate of transplanted mitochondria are still poorly understood. METHODS: Mitochondrial morphology and function were assessed by fluorescent staining, electron microscopy, JC-1, PCR, mitochondrial stress testing, and metabolomics. Therapeutic effects of mitochondria were evaluated by cell viability, reactive oxygen species (ROS), and apoptosis levels in a cellular hypoxia-reoxygenation model. Rat middle cerebral artery occlusion model was applied to assess the mitochondrial therapy in vivo. Transcriptomics was performed to explore the underlying mechanisms. Mitochondrial fate tracking was implemented by a variety of fluorescent labeling methods. RESULTS: Neuro-2a (N2a) cell-derived mitochondria had higher mitochondrial membrane potential, more active oxidative respiration capacity, and less mitochondrial DNA copy number. Exogenous mitochondrial transplantation increased cellular viability in an oxygen-dependent manner, decreased ROS and apoptosis levels, improved neurobehavioral deficits, and reduced infarct size. Transcriptomic data showed that the differential gene enrichment pathways are associated with metabolism, especially lipid metabolism. Mitochondrial tracking indicated specific parts of the exogenous mitochondria fused with the mitochondria of the host cell, and others were incorporated into lysosomes. This process occurred at the beginning of internalization and its efficiency is related to intercellular connection. CONCLUSIONS: Mitochondrial transplantation may attenuate cerebral I/R injury. The mechanism may be related to mitochondrial component separation, altering cellular metabolism, reducing ROS, and apoptosis in an oxygen-dependent manner. The way of isolated mitochondrial transfer into the cell may be related to intercellular connection.

Surgical Clipping of Previously Coiled Recurrent Intracranial Aneurysms: A Single-Center Experience.

Objective: This study reviews our experiences in surgical clipping of previously coiled aneurysms, emphasizing on recurrence mechanism of intracranial aneurysms (IAs) and surgical techniques for different types of recurrent IAs. Method: We performed a retrospective study on 12 patients who underwent surgical clipping of aneurysms following endovascular treatment between January 2010 and October 2020. The indications for surgery, surgical techniques, and clinical outcomes were analyzed. Result: Twelve patients with previously coiled IAs were treated with clipping in this study, including nine females and three males. The reasons for the patients having clipping were as follows: early surgery (treatment failure in two patients, postoperative early rebleeding in one patient, and intraprocedural aneurysm rupture during embolization in one patient) and late surgery (aneurysm recurrence in five patients, SAH in one, mass effect in one, and aneurysm regrowth in one). All aneurysms were clipped directly, and coil removal was performed in four patients. One patient died (surgical mortality, 8.3%), 1 patient (8.3%) experienced permanent neurological morbidity, and the remaining 10 patients (83.4%) had good outcomes. Based on our clinical data and previous studies, we classified the recurrence mechanism of IAs into coil compaction, regrowth, coil migration, and coil loosening. Then, we elaborated the specific surgical planning and timing of surgery depending on the recurrence type of IAs. Conclusion: Surgical clipping can be a safe and effective treatment strategy for the management of recurrent coiled IAs, with acceptable morbidity and mortality in properly selected cases. Our classification of recurrent coiled aneurysms into four types helps to assess the optimal surgical approach and the associated risks in managing them.

Prevalence and Associated Risk Factors of Hypertension in Adults with Disabilities: A Cross-Sectional Study in Shanghai, China.

BACKGROUND: Although hypertension is highly prevalent in China, epidemiologic data of hypertension among people with disabilities remain largely unknown. This study aims to examine the prevalence and associated risk factors of hypertension in patients with disabilities. METHODS: A cross-sectional study was carried out among 7348 adults with disabilities from February to December 2018 in Shanghai, and patient data from physical, imageological and routine blood examinations were collected and analyzed. Logistic regression models were performed to determine the associated risk factors of hypertension in adults with disabilities. RESULTS: Among the 7348 disabled patients, the prevalence of hypertension, rate of receiving treatment, and blood pressure control were 42.5%, 85.0% and 46.0%, respectively. Increases in the levels of age, physical disability, body mass index (BMI), fasting plasma glucose (FBG), total triglyceride (TG), hyperuricemia (hyper-UA), serum urea (SU), and estimated creatinine clearance (eCrCl <80 µmol/L) were independently correlated with hypertension. CONCLUSION: Patients with physical disabilities have a significantly higher prevalence of hypertension compared to the normal population. Patients with intellectual or mental disabilities have lower rates of blood pressure control compared to other types of disabilities. Assessment of associated risk factors highlights an increased likelihood of potential renal dysfunction among hypertensive disabled patients.

One-stage coiling versus clipping of multiple intracranial aneurysms in elderly patients.

OBJECTIVES: Although multiple intracranial aneurysms (MIAs) are frequent and disastrous, determining treatment strategy for them is often complicated, especially in elderly patients (≥60 years old). We evaluated the safety and effectiveness of one-stage coiling versus surgical clipping for MIAs in elderly patients. METHODS: All elderly patients who underwent one-stage embolization or surgical clipping for more than two aneurysms were identified in our hospital between January 2012 and June 2018. Patient characteristics and clinical outcomes at discharge and follow-up were retrospectively evaluated. RESULTS: A total of 32 patients with 76 IAs underwent one-stage coiling and 21 patients with 46 IAs underwent one-stage clipping were enrolled in this study. Patients who underwent clipping were younger (mean age 64.1 versus 67.2, P = 0.006) and had lower total hospital costs (mean14764 $ versus 24,620 $, P < 0.001) compared with patients who underwent coiling. Immediate posttreatment angiography showed complete occlusion in 56 aneurysms, near complete in 11 and incomplete in 2 in coiling group. Aneurysms wrapping was performed in 2, incomplete clipping in 1 and complete clipping in 41 aneurysms in clipping group. At discharge, 49 (92.5 %) patients were in a good condition (GOS score 4 and 5), 4 (7.5 %) were disabled. At 12 months after discharge, 25 (92.6 %) and 16 (94.1 %) patients had favorable outcomes in the coiling and clipping groups, respectively. CONCLUSIONS: Both one-stage coiling and surgical clipping are safe, effective methods for treating MIAs in elderly patients.

Predicting the Poor Recovery Risk of Aneurysmal Subarachnoid Hemorrhage: Clinical Evaluation and Management Based on a New Predictive Nomogram.

PURPOSE: To develop and validate a model for identifying the risk factors of poor recovery in patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS: A prediction model was developed using training data obtained from 1577 aSAH patients from multiple centers. The patients were followed for 6 months on average and assessed using the modified Rankin Scale; patient information was collected with a prospective case report form. The least absolute shrinkage and selection operator regression were applied to optimize factor selection for the poor recovery risk model. Multivariable logistic regression, incorporating the factors selected in the previous step, was used for model predictions. Predictive ability and clinical effectiveness of the model were evaluated using C-index, receiver operating characteristic curve, and decision curve analysis. Internal validation was performed using the C-index, taking advantage of bootstrapping validation. RESULTS: The predictors included household income per capita, hypertension, smoking, migraine within a week before onset, Glasgow Coma Scale at admission, average blood pressure at admission, modified Fisher score at admission, treatment method, and complications. Our newly developed model made satisfactory predictions; it had a C-index of 0.796 and an area under the receiver operating characteristic curve of 0.784. The decision curve analysis showed that the poor recovery nomogram was of clinical benefit when an intervention was decided at a poor recovery threshold between 2% and 50%. Internal validation revealed a C-index of 0.760. CONCLUSION: Our findings indicate that the novel poor recovery nomogram may be conveniently used for risk prediction in aSAH patients. For patients with intracranial aneurysms, migraine needs to be vigilant. Quitting smoking and blood pressure management are also beneficial.

Intracranial Pseudoaneurysms: Evaluation and Management.

Intracranial pseudoaneurysms account for about 1% of intracranial aneurysms with a high mortality. The natural history of intracranial pseudoaneurysm is not well-understood, and its management remains controversial. This review provides an overview of the etiology, pathophysiology, clinical presentation, imaging, and management of intracranial pseudoaneurysms. Especially, this article emphasizes the factors that should be considered for the most appropriate management strategy based on the risks and benefits of each treatment option.

Mfsd2a and Spns2 are essential for sphingosine-1-phosphate transport in the formation and maintenance of the blood-brain barrier.

To maintain brain homeostasis, a unique interface known as the blood-brain barrier (BBB) is formed between the blood circulation and the central nervous system (CNS). Major facilitator superfamily domain-containing 2a (Mfsd2a) is a specific marker of the BBB. However, the mechanism by which Mfsd2a influences the BBB is poorly understood. In this study, we demonstrated that Mfsd2a is essential for sphingosine-1-phosphate (S1P) export from endothelial cells in the brain. We found that Mfsd2a and Spinster homolog 2 (Spns2) form a protein complex to ensure the efficient transport of S1P. Furthermore, the S1P-rich microenvironment in the extracellular matrix (ECM) in the vascular endothelium dominates the formation and maintenance of the BBB. We demonstrated that different concentrations of S1P have different effects on BBB integrity. These findings help to unravel the mechanism by which S1P regulates BBB and also provide previously unidentified insights into the delivery of neurological drugs in the CNS.

Using apelin-based synthetic Notch receptors to detect angiogenesis and treat solid tumors.

Angiogenesis is a necessary process for solid tumor growth. Cellular markers for endothelial cell proliferation are potential targets for identifying the vasculature of tumors in homeostasis. Here we customize the behaviors of engineered cells to recognize Apj, a surface marker of the neovascular endothelium, using synthetic Notch (synNotch) receptors. We designed apelin-based synNotch receptors (AsNRs) that can specifically interact with Apj and then stimulate synNotch pathways. Cells engineered with AsNRs have the ability to sense the proliferation of endothelial cells (ECs). Designed for different synNotch pathways, engineered cells express different proteins to respond to angiogenic signals; therefore, angiogenesis can be detected by cells engineered with AsNRs. Furthermore, T cells customized with AsNRs can sense the proliferation of vascular endothelial cells. As solid tumors generally require vascular support, AsNRs are potential tools for the detection and therapy of a variety of solid tumors in adults.

A Prevascularization Strategy Using Novel Fibrous Porous Silk Scaffolds for Tissue Regeneration in Mice with Spinal Cord Injury.

Spinal cord injury (SCI) represents an extremely debilitating condition for which no efficacious treatment is available. Because spinal cord does not have satisfactory capacity for revascularization after injury, it seems to be a promising way to modulate the lesion environment by reperfusion to promote a regenerative phenotype. Although engineered scaffolds provide a platform to deliver therapeutic cells and neurotrophic factors, slow and insufficient vascularization of large tissue constructs negatively impacts the survival and function of these transplanted cells. In this study, we cocultured our fibrous porous silk scaffold (FPSS) with ADAMTS13-overexpressing human umbilical vein endothelial cells (HUVECs) in vitro and transplanted this prevascularized construct into an SCI mouse model. The prevascularized system exhibited a tube-like structure in vitro, promoted vascular infiltration and microvascular network formation after transplantation, and recruited more neural cells to the lesion site. Twenty-eight days later, behavioral analysis showed that locomotor recovery was significantly improved in treated animals compared with control animals. Taken together, our results suggest that the FPSS-HUVECs system promoted neovascularization, guided axon growth at the injury site, and improved the microenvironment. Therefore, this prevascularization system may provide a better therapeutic option for SCI.

Neurogenic Niche Conversion Strategy Induces Migration and Functional Neuronal Differentiation of Neural Precursor Cells Following Brain Injury.

Glial scars formed after brain injuries provide permissive cues for endogenous neural precursor/stem cells (eNP/SCs) to undergo astrogenesis rather than neurogenesis. Following brain injury, eNP/SCs from the subventricular zone leave their niche, migrate to the injured cortex, and differentiate into reactive astrocytes that contribute to glial scar formation. In vivo neuronal reprogramming, directly converting non-neuronal cells such as reactive astrocytes or NG2 glia into neurons, has greatly improved brain injury repair strategies. However, reprogramming carries a high risk of future clinical applications such as tumorigenicity, involving virus. In this study, we constructed a neural matrix to alter the adverse niche at the injured cortex, enabling eNP/SCs to differentiate into functional neurons. We found that the neural matrix functioned as a "glial trap" that largely concentrated and limited reactive astrocytes to the core of the lesion area, thus altering the adverse niche. The eNP/SCs migrated toward the injured cortex and differentiated into functional neurons. In addition, regenerated neurites extended across the boundary of the injured cortex. Mice treated with the neural matrix demonstrated significant behavioral recovery. For the first time, we induced eNP/SC-derived functional neurons in the cortex after brain injury without the use of viruses, microRNAs, or small molecules. Our novel strategy of applying this "glial trap" to obtain functional neurons in the injured cortex may provide a safer and more natural therapeutic alternative to reprogramming in future clinical applications.

Potential Therapeutic Strategies for Intracranial Aneurysms Targeting Aneurysm Pathogenesis.

Subarachnoid hemorrhage resulting from intracranial aneurysms (IAs) is associated with high rates of morbidity and mortality. Although trigger mechanisms in the pathogenesis of IAs have not been fully elucidated, accumulating evidence has demonstrated that inflammation acts as a critical contributor to aneurysm pathogenesis. IAs is initiated by disruption and dysfunction of endothelial cells (ECs) caused by abnormal wall shear stress (WSS). Subsequently, vascular inflammation can trigger a series of biochemical reactions resulting in vascular smooth muscle cell (VSMC) apoptosis and migration, accompanied by inflammatory cell infiltration, secretion of various cytokines, and inflammatory factors. These changes result in degradation of vascular wall, leading to the progression and eventual rupture of IAs. Increasing our knowledge of the pathogenesis of these lesions will offer physicians new options for prevention and treatment. In this study, we review aneurysmal pathogenesis to seek for safe, effective, and non-invasive therapeutic strategies.

Aloin attenuates cognitive impairment and inflammation induced by d-galactose via down-regulating ERK, p38 and NF-κB signaling pathway.

Oxidative stress is considered as major culprit for neurodegenerative diseases and triggers cognitive and memory impairments. The present study mainly aimed to study the protective effects and underlying mechanisms of aloin on d-galactose (d-gal) induced ageing mice. Our results demonstrated that chronic administration of d-gal (150 mg kg-1) in mice caused spontaneous and cognitive impairments, as determined by open-field test and Morris water-maze test. Aloin treatment significantly ameliorated histopathological damage, attenuated the microglia activation and reduced levels of inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 in the hippocampus. Moreover, it effectively suppressed the level of reactive oxygen species (ROS) and increased antioxidant enzymes activities. Further data showed that these protective effects were accompanied by inhibition of the activation of nuclear factor kappa B and the phosphorylation of p38 and ERK. In conclusion, the present study suggests that aloin can ameliorate d-gal induced oxidative stress, cognitive impairment and inflammation, possibly via mediating the ERK, p38 and NF-κB signaling pathways.