Monocytes Release Pro-Cathepsin D to Drive Blood-to-Brain Transcytosis in Diabetes.

BACKGROUND: Microvascular complications are the major outcome of type 2 diabetes progression, and the underlying mechanism remains to be determined. METHODS: High-throughput RNA sequencing was performed using human monocyte samples from controls and diabetes. The transgenic mice expressing human CTSD (cathepsin D) in the monocytes was constructed using CD68 promoter. In vivo 2-photon imaging, behavioral tests, immunofluorescence, transmission electron microscopy, Western blot analysis, vascular leakage assay, and single-cell RNA sequencing were performed to clarify the phenotype and elucidate the molecular mechanism. RESULTS: Monocytes expressed high-level CTSD in patients with type 2 diabetes. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied by cognitive deficit. Mechanistically, the monocytes release nonenzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low-density LRP1 (lipoprotein receptor-related protein 1). Importantly, genetic ablation of CTSD in the monocytes exhibited a protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. CONCLUSIONS: These findings uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is a potential target for the intervention of microvascular complications in diabetes.

Long Noncoding RNA KCNQ1OT1 Confers Gliomas Resistance to Temozolomide and Enhances Cell Growth by Retrieving PIM1 From miR-761.

Many studies have found that the dysregulation of long noncoding RNA (lncRNA) contributed to cancer initiation, progression, and recurrence via multiple signaling pathways. However, the underlying mechanisms of lncRNA in temozolomide (TMZ)-resistant gliomas were not well understood, hindering the improvement of TMZ-based therapies. The present study demonstrated that the lncRNA KCNQ1OT1 increased in TMZ-resistant glioma cells compared to the TMZ-sensitive cells. The introduction of KCNQ1OT1 promoted cell viability, clonogenicity, and rhodamine 123 efflux while hampering TMZ-induced apoptosis. Moreover, KCNQ1OT1 directly sponged miR-761, which decreased in TMZ-resistant sublines. The overexpression of miR-761 attenuated cell viability and clonogenicity, while triggering apoptosis and rhodamine 123 accumulation post-TMZ exposure, leading to a response to TMZ. The interaction between miR-761 and 3'-untranslated region of PIM1 attenuated PIM1-mediated signaling cascades. Furthermore, the knockdown of KCNQ1OT1 augmented the TMZ-induced tumor regression in TMZ-resistant U251 mouse models. Briefly, the present study evaluated that KCNQ1OT1 conferred TMZ resistance by releasing PIM1 expression from miR-761, resulting in the upregulation of PIM-mediated MDR1, c-Myc, and Survivin. The present findings demonstrated that the interplay of KCNQ1OT1: miR-761: PIM1 regulated chemoresistance in gliomas and provided a promising therapeutic target for TMZ-resistant glioma patients.

Risk Factors of Psychological Responses of Chinese University Students During the COVID-19 Outbreak: Cross-sectional Web-Based Survey Study.

BACKGROUND: COVID-19 is a highly contagious and highly pathogenic disease caused by a novel coronavirus, SARS-CoV-2, and it has become a pandemic. As a vulnerable population, university students are at high risk during the epidemic, as they have high mobility and often overlook the severity of the disease because they receive incomplete information about the epidemic. In addition to the risk of death from infection, the epidemic has placed substantial psychological pressure on the public. In this respect, university students are more prone to psychological problems induced by the epidemic compared to the general population because for most students, university life is their first time outside the structure of the family, and their mental development is still immature. Internal and external expectations and academic stress lead to excessive pressure on students, and unhealthy lifestyles also deteriorate their mental health. The outbreak of COVID-19 was a significant social event, and it could potentially have a great impact on the life and the mental health of university students. Therefore, it is of importance to investigate university students' mental health status during the outbreak of COVID-19. OBJECTIVE: The principal objective of this study was to investigate the influencing factors of the psychological responses of Chinese university students during the COVID-19 outbreak. METHODS: This study used data from a survey conducted in China between February 21 and 24, 2020, and the data set contains demographic information and psychological measures including the Self-Rating Anxiety Scale, the Self-Rating Depression Scale, and the compulsive behaviors portion of the Yale-Brown Obsessive-Compulsive Scale. A total of 2284 questionnaires were returned, and 2270 of them were valid and were used for analysis. The Mann-Whitney U test for two independent samples and binary logistic regression models were used for statistical analysis. RESULTS: Our study surveyed 563 medical students and 1707 nonmedical students. Among them, 251/2270 students (11.06%) had mental health issues. The results showed that contact history of similar infectious disease (odds ratio [OR] 3.363, P=.02), past medical history (OR 3.282, P<.001), and compulsive behaviors (OR 3.525, P<.001) contributed to the risk of mental health issues. Older students (OR 0.928, P=.02), regular daily life during the epidemic outbreak (OR 0.410, P<.001), exercise during the epidemic outbreak (OR 0.456, P<.001), and concern related to COVID-19 (OR 0.638, P=.002) were protective factors for mental health issues. CONCLUSIONS: According to the study results, mental health issues have seriously affected university students, and our results are beneficial for identifying groups of university students who are at risk for possible mental health issues so that universities and families can prevent or intervene in the development of potential mental health issues at the early stage of their development.

Which is the best treatment for melanoma brain metastases? A Bayesian network meta-analysis and systematic review.

OBJECTIVE: Melanoma has a high degree of central nervous system tropism, and there are many treatment modalities for melanoma brain metastases (MBM). The efficacy and toxicity of various treatments are still controversial. Therefore, they were evaluated by direct and indirect comparison to assist clinical decision-making in this study. METHOD: A total of 7 therapeutic modalities for MBM were studied. Retrieval was conducted through Embase, PubMed, Cochrane Library and Web of science databases and the quality of the included literature was evaluated. Meta-analysis and Bayesian network meta-analysis were performed using Review Manager and R language. RESULTS: A total of 10 articles were included with 836 MBM patients. Direct comparison showed that stereotactic radiotherapy combined with immunotherapy (SRS + IT) was superior to IT (HR = 0.66, 95%CI = 0.52-0.84) or SRS (HR = 0.81, 95%CI = 0.63-1.03) alone in improving intracranial progression-free survival (PFS). In terms of overall survival (OS), SRS + IT was superior to SRS alone (HR = 0.64, 95%CI = 0.49-0.83), or IT (HR = 0.59, 95%CI = 0.29-1.21). Rank probability and surface under the cumulative ranking curve (SUCRA) by indirect comparison showed that SRS + IT had the best effect on improving intracranial PFS (0.88) and OS (0.98). Additionally, various combination therapies, especially SRS + IT (0.72), increased the incidence of radiation necrosis (RN). In direct comparisons, SRS + IT (RR = 0.93, 95%CI = 0.47-1.83) and SRS + TT (targeted therapy) (RR = 0.24, 95%CI = 0.10-0.56) did not increase intracranial hemorrhage (ICH) compared with SRS. CONCLUSIONS: SRS + IT treatment was the best choice for MBM patients in both intracranial PFS and OS, even though it also led to an increased probability of RN.

The recent two decades of traumatic brain injury: a bibliometric analysis and systematic review.

BACKGROUND: Traumatic brain injury (TBI) is a serious public health burden worldwide, with a mortality rate of 20-30%; however, reducing the incidence and mortality rates of TBI remains a major challenge. This study provides a multidimensional analysis to explore the potential breakthroughs in TBI over the past two decades. MATERIALS AND METHODS: The authors used bibliometric and Latent Dirichlet Allocation (LDA) analyses to analyze publications focusing on TBI published between 2003 and 2022 from the Web of Science Core Collection (WOSCC) database to identify core journals and collaborations among countries/regions, institutions, authors, and research trends. RESULTS: Over the past 20 years, 41 545 articles on TBI from 3043 journals were included, with 12 916 authors from 20 449 institutions across 145 countries/regions. The annual number of publications has increased 10-fold compared to previous publications. This study revealed that high-income countries, especially the United States, have a significant influence. Collaboration was limited to several countries/regions. The LDA results indicated that the hotspots included four main areas: 'Clinical finding', 'Molecular mechanism', 'Epidemiology', and 'Prognosis'. Epidemiological research has consistently increased in recent years. Through epidemiological topic analysis, the main etiology of TBI has shifted from traffic accidents to falls in a demographically aging society. CONCLUSION: Over the past two decades, TBI research has developed rapidly, and its epidemiology has received increasing attention. Reducing the incidence of TBI from a preventive perspective is emerging as a trend to alleviate the future social burden; therefore, epidemiological research might bring breakthroughs in TBI.

Impacts of Statin Therapy Strategies on Incidence of Ischemic Cerebrovascular Events in Patients With Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Bayesian Network Meta-Analysis.

BACKGROUND: The exacerbation of neurological outcomes often occurs in aneurysmal subarachnoid hemorrhage (aSAH). Statins have been commonly used for aSAH; however, there is lack of evidence of the pharmacological efficacy of different dosages and types of statins. OBJECTIVE: To apply the Bayesian network meta-analysis to analyze the optimal dosage and type of statins for the amelioration of ischemic cerebrovascular events (ICEs) in patients with aSAH. METHODS: We developed the Bayesian network meta-analysis and systemic review to analyze the effects of statins on functional prognosis and the impacts of optimal dosage and type of statins on ICEs in patients with aSAH. The outcome variables of the analysis were the incidence of ICEs and functional prognosis. RESULTS: A total of 2569 patients with aSAH across 14 studies were included. Analysis of 6 randomized controlled trials showed that statin use significantly improved functional prognosis in patients with aSAH (risk ratio [RR], 0.73; 95% CI, 0.55-0.97). Statins significantly reduced the incidence of ICEs (RR, 0.78; 95% CI, 0.67-0.90). Pravastatin (40 mg/d) decreased the incidence ICEs compared with placebo (RR, 0.14; 95% CI, 0.03-0.65) and was ranked the most effective, presenting with a significantly lower rate of the incidence ICEs than the worst-ranked simvastatin (40 mg/d) (RR, 0.13; 95% CI, 0.02-0.79). CONCLUSION: Statins could significantly diminish the incidence of ICEs and enhance functional prognosis in patients with aSAH. Various types and dosages of statins show distinct efficacies.

Immunotherapeutic Value of MAP1LC3C and Its Candidate FDA-Approved Drugs Identified by Pan-Cancer Analysis, Virtual Screening and Sensitivity Analysis.

Background: The autophagy pathway within the tumour microenvironment can be regulated to inhibit or promote tumour development. In the fight against tumour growth, immunotherapy induces an anti-tumour immune response, whereas autophagy modulates this immune response. A key protein in the autophagy pathway, microtubule-associated protein 1 light chain 3 (MAP1LC3), has recently become a hotspot for tumour research. As a relatively novel member, the function of MAP1LC3C in tumours still need to be investigated. Therefore, the goal of this study was to look into the possible link between MAP1LC3C and immunotherapy for 33 kinds of human malignancies by using pan-cancer analysis. Methods: High-throughput sequencing data from The Cancer Genome Atlas, Genotype-Tissue Expression Project and Cancer Cell Line Encyclopedia databases, combined with clinical data, were used to analyze the expression of MAP1LC3C in 33 types of cancer, as well as patient prognosis and neoplasm staging. Activity scores were calculated using ssGSEA to assess the MAP1LC3C activity in pan-cancer. Associations between MAP1LC3C and the tumour microenvironment, including immune cell infiltration and immunomodulators, were analyzed. Moreover, tumour tissue ImmuneScores and StromalScores were analyzed using the ESTIMATE algorithm. Additionally, associations between MAP1LC3C and tumour mutational burden/microsatellite instability, were investigated. Finally, based on the expression and structure of MAP1LC3C, the United States Food and Drug Administration (FDA)-approved drugs, were screened by virtual screening, molecular docking and NCI-60 drug sensitivity analysis. Results: Our study found that MAP1LC3C was differentially expressed in tumour and normal tissues in 23 of 33 human cancer types, among which MAP1LC3C had prognostic effects in 12 cancer types, and MAP1LC3C expression was significantly correlated with tumour stage in four cancer types. In addition, MAP1LC3C activity in 14 cancer types was consistent with changes in transcription levels. Moreover, MAP1LC3C strongly correlated with immune infiltration, immune modulators and immune markers. Finally, a number of FDA-approved drugs were identified via virtual screening and drug sensitivity analysis. Conclusion: Our study investigated the prognostic and immunotherapeutic value of MAP1LC3C in 33 types of cancer, and several FDA-approved drugs were identified to be highly related to MAP1LC3C and can be potential cancer therapeutic candidates.

Disulfiram in glioma: Literature review of drug repurposing.

Gliomas are the most common malignant brain tumors. High-grade gliomas, represented by glioblastoma multiforme (GBM), have a poor prognosis and are prone to recurrence. The standard treatment strategy is tumor removal combined with radiotherapy and chemotherapy, such as temozolomide (TMZ). However, even after conventional treatment, they still have a high recurrence rate, resulting in an increasing demand for effective anti-glioma drugs. Drug repurposing is a method of reusing drugs that have already been widely approved for new indication. It has the advantages of reduced research cost, safety, and increased efficiency. Disulfiram (DSF), originally approved for alcohol dependence, has been repurposed for adjuvant chemotherapy in glioma. This article reviews the drug repurposing method and the progress of research on disulfiram reuse for glioma treatment.

Modulation of Tumor Immune Microenvironment and Prognostic Value of Ferroptosis-Related Genes, and Candidate Target Drugs in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most common type of malignant brain tumor, among which IDH1-wild type GBM has a poor prognosis. Recent studies have shown that ferroptosis-related genes (FRGs) are correlated with the development and progression of cancer. In GBM, the role of FRGs associated with IDH1 status as biological indicators and therapeutic targets remains to be clarified. Ten of FRGs (STEAP3, HSPB1, MAP1LC3A, SOCS1, LOX, CAPG, CP, GDF15, CDKN1A, and CD44) associated with IDH1 status in GBM were identified as key genes through screening by survival analysis and Random Forest using The Cancer Genome Atlas (TCGA) datasets, and the protein expressions of key genes were verified. Transwell and qPCR results showed that ferroptosis promoted the migration of glioblastoma cells and affected the expression of key genes. Our study established the ferroptosis-related prognostic model for GBM patients based on ten key genes by a different modeling method from previous study, the GSVA algorithm. Further, we took the methods of functional enrichment analysis, clinical characteristics, immune cell infiltration, immunomodulator, ESTIMATE and single nucleotide variant (SNV) analysis to study the molecular mechanisms of prognostic model and key genes. The results showed that ten key genes were strongly associated with immune-related factors and were significantly involved in the p53 signaling pathway, senescence and autophagy in cancer, and in the negative regulation of protein kinase activity. Moreover, potential therapeutic drugs were identified by Virtual Screening and Molecular Docking. Our study indicated that the novel ferrotosis-related prognostic model for GBM patients and key genes possessed the prognostic and therapeutic values.

Optimal Course of Statins for Patients With Aneurysmal Subarachnoid Hemorrhage: Is Longer Treatment Better? A Meta-Analysis of Randomized Controlled Trials.

Statins are used in clinical practice to prevent from complications such as cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (aSAH). However, the efficacy and safety of statins are still controversial due to insufficient evidence from randomized controlled trials and inconsistent results of the existing studies. This meta-analysis aimed to systematically review the latest evidence on the time window and complications of statins in aSAH. The randomized controlled trials in the databases of The Cochrane Library, PubMed, Web of Science, Embase, CNKI, and Wanfang from January 2005 to April 2021 were searched and analyzed systematically. Data analysis was performed using Stata version 16.0. The fixed-effects model (M-H method) with effect size risk ratio (RR) was used for subgroups with homogeneity, and the random-effects model (D-L method) with effect size odds ratio (OR) was used for subgroups with heterogeneity. The primary outcomes were poor neurological prognosis and all-cause mortality, and the secondary outcomes were cerebral vasospasm (CVS) and statin-related complications. This study was registered with PROSPERO (International Prospective Register of Systematic Reviews; CRD42021247376). Nine studies comprising 1,464 patients were included. The Jadad score of the patients was 5-7. Meta-analysis showed that poor neurological prognosis was reduced in patients who took oral statins for 14 days (RR, 0.73 [0.55-0.97]; I 2 = 0%). Surprisingly, the continuous use of statins for 21 days had no significant effect on neurological prognosis (RR, 1.04 [0.89-1.23]; I 2 = 17%). Statins reduced CVS (OR, 0.51 [0.36-0.71]; I 2 = 0%) but increased bacteremia (OR, 1.38 [1.01-1.89]; I 2 = 0%). In conclusion, a short treatment course of statins over 2 weeks may improve neurological prognosis. Statins were associated with reduced CVS. Based on the pathophysiological characteristics of CVS and the evaluation of prognosis, 2 weeks could be the optimal time window for statin treatment in aSAH, although bacteremia may increase.