Diabetic Retinopathy and Brain Structure, Cognition Function, and Dementia: A Bidirectional Mendelian Randomization Study.

BACKGROUND: Accumulating evidence has demonstrated that hyperglycemia is a possible risk factor for mild cognitive impairment or Alzheimer's disease. Diabetic retinopathy (DR) has been identified as a risk factor for dementia in patients with diabetes. OBJECTIVE: This study aimed to investigate the causal relationships between DR and brain structure, cognitive function, and dementia. METHODS: We performed bidirectional two-sample Mendelian randomization for DR, brain structure, cognitive function, and dementia using the inverse-variance weighted method. RESULTS: Inverse-variance weighted analysis showed the association of DR with vascular dementia (OR = 1.68, 95% CI: 1.01-2.82), and dementia was significantly associated with the increased risk of non-proliferative DR (NPDR) (OR = 1.76, 95% CI: 1.04-2.98). Furthermore, better cognitive performance was significantly associated with a reduced risk of NPDR (OR = 0.85, 95% CI: 0.74-0.98). No association was observed between DR and brain structure. CONCLUSIONS: These findings suggest that the association of DR with vascular dementia. The reciprocal effect of cognitive performance and dementia on NPDR risk highlights the potential benefits of dementia prevention for reducing the burden of DR.

LncNFYB promotes the proliferation of rheumatoid arthritis fibroblast-like synoviocytes via LncNFYB/ANXA2/ERK1/2 axis.

Long noncoding RNAs (lncRNAs) are specifically expressed in different diseases and regulate disease progression. To explore the functions of rheumatoid arthritis (RA)-specific lncRNA, we determined the lncRNA expression profile of fibroblast-like synoviocytes (FLS) obtained from patients with RA and osteoarthritis (OA) using a LncRNA microarray and identified up-regulated LncNFYB in RA as a potential therapeutic target. Using gain- and loss-of-function studies, LncNFYB was proven to promote FLS proliferation and cell cycle progress but not affect their invasion, migration, and apoptotic abilities. Further investigation discovered that LncRNA could combine with annexin A2 (ANXA2) and enhance the level of phospho-ANXA2 (Tyr24) in the plasma membrane area, which induced the activation of ERK1/2 to promote proliferation. These findings provide new insights into the biological functions of LncNFYB on modification of FLS, which may be exploited for the therapy of RA.

Cancer Stem Cells in Tumours of the Central Nervous System in Children: A Comprehensive Review.

Cancer stem cells (CSCs) are a subgroup of cells found in various kinds of tumours with stem cell characteristics, such as self-renewal, induced differentiation, and tumourigenicity. The existence of CSCs is regarded as a major source of tumour recurrence, metastasis, and resistance to conventional chemotherapy and radiation treatment. Tumours of the central nervous system (CNS) are the most common solid tumours in children, which have many different types including highly malignant embryonal tumours and midline gliomas, and low-grade gliomas with favourable prognoses. Stem cells from the CNS tumours have been largely found and reported by researchers in the last decade and their roles in tumour biology have been deeply studied. However, the cross-talk of CSCs among different CNS tumour types and their clinical impacts have been rarely discussed. This article comprehensively reviews the achievements in research on CSCs in paediatric CNS tumours. Biological functions, diagnostic values, and therapeutic perspectives are reviewed in detail. Further investigations into CSCs are warranted to improve the clinical practice in treating children with CNS tumours.

Association between serum uric acid level and systemic lupus erythematosus kidney outcome: An observational study in Southern Chinese population and a meta-analysis.

OBJECTIVE: The study aimed to explore the effect of serum uric acid (SUA) level on the progression of kidney function in systemic lupus erythematosus (SLE) patients. METHODS: A total of 123 biopsy-proven lupus nephritis (LN) patients were included in this retrospective observational study. Cox proportional hazard regression analyses as well as restricted cubic spline analyses were performed to identify predictors of renal outcome in LN patients. We also performed a systematic review and meta-analysis for SUA and overall kidney outcomes in SLE patients. RESULTS: Based on the laboratory tests at renal biopsy, 72 (58.5%) of the 123 patients had hyperuricemia. The median (IQR) follow-up duration was 3.67 years (1.79-6.63 years), and a total of 110 (89.4%) patients experienced progression of LN. Increased serum uric acid level, whether analyzed as continuous or categorical variable, was associated with higher risk of LN progression in Cox proportional hazard regression model (hazard ratio [HR]: 1.003, 95% confidence interval [CI]: 1.001-1.005; HR: 1.780, 95% CI: 1.201-2.639, respectively). This relationship maintained in women (HR: 1.947, 95% CI: 1.234-3.074) but not men (HR: 2.189, 95% CI: 0.802-5.977). The meta-analysis showed a similar result that both continuous and categorical SUA were positively associated with the risk of kidney function progression in LN (weighted mean difference [WMD]: 1.73, 95% CI: 0.97-2.49; odds ratio [OR]: 1.55, 95% CI: 1.20-2.01, respectively). CONCLUSIONS: Our study found overall and especially in women that higher SUA in LN patients were associated with increased risk of renal progression. Meta-analysis yielded consistent results. Future studies are required to establish if uric acid can be used as a biomarker for risk assessment and/or as a novel therapeutic target in SLE.

＜Editors' Choice＞ Advantages of gasless single-port transumbilical extracorporeal laparoscopic-assisted appendectomy in the treatment of uncomplicated acute appendicitis in children in China: a multi-institutional retrospective study.

Gasless transumbilical extracorporeal laparoscopic-assisted appendectomy is an approach used increasingly to treat uncomplicated acute appendicitis (UAA). However, there is limited information on its clinical effects and value in the Chinese pediatric population. This study retrospectively reviewed patients with UAA treated in two pediatric institutions from January 2018 through October 2021. Enrolled patients were divided into two groups by operative technique: gasless transumbilical laparoscopic-assisted appendectomy (gasless-TULAA, n=142) and conventional laparoscopic appendectomy (CLA, three-port, n=126). The perioperative clinical data, including age, sex, body mass index (BMI), operation time, time to postoperative ambulation, time to first postoperative exhaust, hospitalization expenses, and postoperative complications (incision infection, intestinal obstruction, and residual abdominal abscess), were compared between the two groups. Operations in both groups were successfully conducted without converting to open surgery. There were no significant differences (p > 0.05) in age and BMI in the two groups. Compared with CLA, gasless-TULAA showed significantly shorter operation time, earlier postoperative ambulation, shorter postoperative exhaust time, and lower hospital cost (p < 0.001). All patients were followed for 3 months, and postoperative complications were observed in three patients: two patients in the gasless-TULAA group (one with surgical wound effusion, one with intra-abdominal abscess), and one patient in the CLA group (surgical wound infection); there was no significant difference between the groups. Notably, 38 patients initially treated by gasless-TULAA were converted because of intraoperative factors. The gasless-TULAA technique had potential benefits: shortened operation time, better outcome, and greater cost-efficiency. These superiorities are worthy of future large-scale prospective study.

Association of kidney function and brain health: A systematic review and meta-analysis of cohort studies.

OBJECTIVE: This study aimed to evaluate the bidirectional association between the kidney dysfunction and the brain health, including structural and functional abnormalities. DESIGN: Systematic review and meta-analysis with network meta-analysis for outcomes with different estimated glomerular filtration rate (eGFR) ranges. DATA SOURCES: PubMed, Embase database, Cochrane library and Web of Science (up to Dec. 2021). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Longitudinal studies that provided evidence of the impact of kidney function estimated from eGFR and urine albumin-to-creatinine ratio (UACR) or chronic kidney disease (CKD) on structural and functional brain abnormalities, and those that provided evidence of the opposite relationship. Studies with study population mean age under 18 years old were excluded. MAIN OUTCOME MEASURES: Two independent reviewers screened the included studies, extracted the data, and assessed the risk of bias. We performed a random-effects meta-analysis and a network meta-analysis for outcomes with compatible data. We assessed the risk of bias using the Newcastle-Ottawa Quality Assessment Scale criteria (NOS). Subgroup and sensitivity analyses were conducted to explore heterogeneity in the meta-analyses. Inconsistency analyses using the node-splitting method were performed to confirm the results of network meta-analysis. RESULTS: A total of 53 studies with 3037,357 participants were included in the current systematic review. Among these, 16 provided evidence of structural brain abnormalities, and 38 provided evidence of cognitive impairment and dementia. Analysis of evidence of categorical kidney function showed a positive association between kidney dysfunction and cerebral small vessel disease (cSVD) (relative risk (RR) 1.77, 95% confidence interval (CI) 1.40-2.24, I2 = 0.0%), but such results were not found in the analyses of evidence where the kidney function was measured as a continuous variable. Meanwhile, analysis of 28 prior longitudinal studies with 194 compatible sets of data showed that the worse kidney function as categorical variables was related to a greater risk of global brain cognitive disorder (RR 1.28, 95% CI 1.20-1.36, I2 = 82.5%). CONCLUSIONS: In this systematic review and meta-analysis, we found a positive association between CKD and functional brain disorders. However, the relationship between the kidney dysfunction and structural abnormalities in the brain remains controversial. As for the opposite relationship, structural brain abnormalities, especially cerebral microbleeds and silent infarction, but not functional brain abnormalities, are associated with worse renal function. In addition, a higher UACR, but not a lower eGFR, was associated with a higher risk of Alzheimer's disease and vascular dementia.

Establishment and verification of a prognostic model of liver cancer by RNA-binding proteins based on the TCGA database.

Background: Globally, liver cancer is one of the most common malignant tumors and is the third leading cause of cancer deaths. RNA-binding protein (RBP) is a general term for a class of proteins that bind to RNA to regulate metabolic processes. The expression of RNA-binding proteins is related to the prognosis of liver cancer patients. Methods: The RBP gene expression data of liver cancer were extracted from the TCGA database. First, the differentially expressed RBPs (DE RBPs) were selected through enrichment analysis and volcano mapping. Then, the prognosis-related RBP genes were selected through single-factor Cox regression analysis. The key prognosis-related RBPs were further screened by multifactor Cox regression analysis, and a formula for the patient's risk coefficient was obtained. Finally, based on the patient's risk score, a nomogram was established and verified. Results: We extracted 374 cancer tissue samples and 50 normal tissue samples with the clinical information from each sample. Through enrichment analysis, we screened 208 upregulated RBPs and 122 downregulated RBPs. Prognosis-related high-risk genes were EEF1E1, NOP56, UPF3B, SF3B4, SMG5, CD3EAP, BRCA1, BARD1, XPO5, CSTF2, EZH2, EXO1, RRP12, PRIM1, LIN28B, NROB1 and TCOF1, and the low-risk genes were MRPL46, RCL1, MRPL54, CPEB3, IFIT5, PPARGC1A, EIF2AK4, SEPSECS, ACO1, SECISBP2 L and ZCCHC24. Further multivariate Cox regression analysis was performed on the prognosis-related RBPs, and the three key prognosis-related RBPs were screened out, which were BARD1, NR0B1 and EIF2AK4. A patient risk coefficient calculation formula was obtained: risk score = (1.207×BARD1 Exp) + (0.483×NR0B1 Exp) + (-0.720×EIF2AK4 Exp). Finally, a nomogram was established based on the risk score to predict the survival time of patients from 1 to 5 years. Conclusions: The nomogram has good predictive value for the survival time of liver cancer patients.

LncRNA DLGAP1-AS1 accelerates glioblastoma cell proliferation through targeting miR-515-5p/ROCK1/NFE2L1 axis and activating Wnt signaling pathway.

INTRODUCTION: Glioblastoma (GBM), the primary malignant tumor in the central nervous system, features high aggressiveness and mortality. Long noncoding RNAs (lncRNAs) can exert the crucial function in regulating various human diseases, including GBM. However, the function and mechanism of lncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) in GBM remain still unknown. METHODS: DLGAP1-AS1 expression in GBM cells was detected by RT-qPCR. Functional assays were conducted to determine GBM cell proliferation and apoptosis. RIP, RNA pull down, and luciferase reporter assay were applied for measuring the interplay of DLGAP1-AS1 with other RNAs. RESULTS: DLGAP1-AS1 was distinctly upregulated in GBM cells. DLGAP1-AS1 depletion inhibited cell proliferation, but induced apoptosis. MiR-515-5p could be sponged by DLGAP1-AS1 in GBM cells and to repress cell proliferation in GBM. Further, Rho-associated coiled-coil containing protein kinase 1 (ROCK1) and Nuclear factor erythroid-2 like 1 (NFE2L1) were confirmed as the target gene of miR-515-5p. Wnt signaling pathway could be activated by DLGAP1-AS1 via regulating ROCK1 and NFE2L1 expression. Rescue assays proved that overexpression of both ROCK1 and NFE2L1 could totally reverse the inhibitory effect of silencing DLGAP1-AS1 on GBM cell proliferation. CONCLUSION: LncRNA DLGAP1-AS1 accelerated cell proliferation in GBM via targeting miR-515-5p/ROCK1/NFE2L1 axis and activating Wnt signaling pathway.

Relationship between obesity and structural brain abnormality: Accumulated evidence from observational studies.

We aimed to evaluate the relationship between obesity and structural brain abnormalities assessed by magnetic resonance imaging using data from 45 observational epidemiological studies, where five articles reported prospective longitudinal results. In cross-sectional studies' analyses, the pooled weighted mean difference for total brain volume (TBV) and gray matter volume (GMV) in obese/overweight participants was -11.59 (95 % CI: -23.17 to -0.02) and -10.98 (95 % CI: -20.78 to -1.18), respectively. TBV was adversely associated with BMI and WC, GMV with BMI, and hippocampal volume with BMI, WC, and WHR. WC/WHR are associated with a risk of lacunar and white matter hyperintensity (WMH). In longitudinal studies' analyses, BMI was not statistically associated with the overall structural brain abnormalities (for continuous BMI: RR = 1.02, 95 % CI: 0.94-1.12; for categorial BMI: RR = 1.18, 95 % CI: 0.75-1.85). Small sample size of prospective longitudinal studies limited the power of its pooled estimates. A higher BMI is associated with lower brain volume while greater WC/WHR, but not BMI, is related to a risk of lacunar infarct and WMH. Future longitudinal research is needed to further elucidate the specific causal relationships and explore preventive measures.

Effective Inhibition of MYC-Amplified Group 3 Medulloblastoma Through Targeting EIF4A1.

PURPOSE: In medulloblastoma (MB), group 3 (G3) patients with MYC amplification tend to exhibit worse prognosis, thus creating a need for novel effective therapies. As the driver and crucial dependency for MYC-amplified G3-MB, MYC has been proven to be a prospective therapeutic target. Here, we aimed to identify novel effective therapeutic strategies against MYC-amplified G3-MB via targeting MYC translation. MATERIALS AND METHODS: Major components of translation initiation complex eIF4F were subjected to MB tumor dataset analysis, and EIF4A1 was identified to be a potential therapeutic target of MYC-amplified G3-MB. Validation was performed through genetic or pharmacological approaches with multiple patient-derived tumor models of MYC-amplified G3-MB in vitro and in vivo. Underlying mechanisms were further explored by Western blot, quantitative real-time PCR and mass spectrometry (MS) analyses. RESULTS: MB tumor datasets analyses showed that EIF4A1 was significantly up-regulated in G3-MB patients relative to normal cerebella, positively correlated with MYC in G3-MB at transcriptional level and a crucial cancer dependency in MYC-amplified G3-MB cells. Targeting EIF4A1 with a CRISPR/Cas9 approach or small-molecule inhibitor silvestrol effectively attenuated growth in multiple preclinical models of MYC-amplified G3-MB via blocking proliferation and inducing apoptosis. Mechanistically, EIF4A1 inhibition effectively impeded MYC expression at translational level, and its potency was positively associated with MYC level. Whole-proteome MS analysis of silvestrol-treated cells further unveiled other biological functions and pathways influenced by EIF4A1 inhibition. CONCLUSION: Our investigation shows that interrupting MYC translation by EIF4A1 inhibition could be a potential effective therapeutic approach when treating patients with MYC-amplified G3-MB.

Effective inhibition of MYC-amplified group 3 medulloblastoma by FACT-targeted curaxin drug CBL0137.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor that can be categorized into four major molecular subgroups. Group 3 MB with MYC amplification (MYCamp-G3-MB) has been shown to be highly aggressive and exhibited worst prognosis, indicating the need for novel effective therapy most urgently. A few epigenetic targeted therapeutic strategies have recently been proven to effectively treat preclinical models of MYCamp-G3-MB, including BET inhibition, HDAC inhibition and SETD8 inhibition, unveiling a promising direction for further investigation. In this study, we carried out systemic bioinformatic analyses of public-available MB datasets as well as functional genomic screening datasets of primary MYCamp-G3-MB lines to search for other potential therapeutic targets within epigenetic modulators. We identified SSRP1, a subunit of histone-chaperone FACT complex, to be the top drug target candidate as it is highly cancer-dependent in whole-genome CRISPR-Cas9 screening across multiple MYCamp-G3-MB lines; significantly upregulated in MYCamp-G3-MB compared to normal cerebellum and most of the rest MB subtypes; its higher expression is correlated with worse prognosis; and it has a blood-brain-barrier penetrable targeted drug that has entered early phase human clinical trials already. Then we utilized RNA-interference approach to verify the cancer-dependency of SSRP1 in multiple MYCamp-G3-MB lines and further confirmed the therapeutic efficacy of FACT-targeted curaxin drug CBL0137 on treating preclinical models of MYCamp-G3-MB in vitro and in vivo, including an orthotopic intracranial xenograft model. Mechanistically, transcriptome analyses showed CBL0137 preferentially suppressed cell-cycle and DNA-repair related biological processes. Moreover, it selectively disrupted transcription of MYC and NEUROD1, two critical oncogenic transcription factors of MYCamp-G3-MB, via depleting FACT complex from their promoter regions. In summary, our study demonstrates FACT-targeted CBL0137 works effectively on treating MYCamp-G3-MB, presenting another promising epigenetic-targeted therapeutic strategy against the most devastating form of MB.

Cytoplasm protein GFAP magnetic beads construction and application as cell separation target for brain tumors.

BACKGROUND: It is very important to develop a highly efficient cerebrospinal fluid (CSF) detection system with diagnosis and prediction function, for which the detection of circulating tumor cells (CTCs) in CSF is a good choice. In contrast to the past use of epithelial EpCAM as CTCs separation target, a cytoplasm protein of GFAP antibody was first selected to construct highly-sensitive immunomagnetic liposome beads (IMLs). The validation and efficiency of this system in capturing CTCs for brain tumors were measured both in vitro and in vivo. The associations between the numbers of CTCs in patients with their clinical characteristics were further analyzed. RESULTS: Our data show that CTCs can be successfully isolated from CSF and blood samples from 32 children with brain tumors. The numbers of CTCs in CSF were significantly higher than those in blood. The level of CTCs in CSF was related to the type and location of the tumor rather than its stage. The higher the CTCs number is, the more possibly the patient will suffer from poor prognosis. Genetic testing in GFAP CTC-DNA by sanger sequencing, q-PCR and NGS methods indicated that the isolated CTCs (GFAP+/EGFR+) are the related tumor cell. For example, the high expression of NPR3 gene in CSF CTCs was consistent with that of tumor tissue. CONCLUSIONS: The results indicated that GFAP-IML CTCs isolation system, combined with an EGFR immunofluorescence assay of antitumor marker, can serve as a brand-new method for the identification of CTCs for brain tumors. Via lumbar puncture, a minimally invasive procedure, this technique may play a significant role in the clinical diagnosis and drug evaluation of brain tumors.

Air pollution and gestational diabetes mellitus: evidence from cohort studies.

Exposure to different air pollutants has been linked to type 2 diabetes mellitus, but the evidence for the association between air pollutants and gestational diabetes mellitus (GDM) has not been systematically evaluated. We systematically retrieved relevant studies from PubMed, Embase, and the Web of Science, and performed stratified analyses and regression analyses. Thirteen studies were analyzed, comprising 1 547 154 individuals from nine retrospective studies, three prospective studies, and one case-control study. Increased exposure to particulate matter ≤2.5 µm in diameter (PM2.5) was not associated with the increased risk of GDM (adjusted OR 1.03, 95% CI 0.99 to 1.06). However, subgroup analysis showed positive correlation of PM2.5 exposure in the second trimester with an increased risk of GDM (combined OR 1.07, 95% CI 1.00 to 1.13). Among pollutants other than PM2.5, significant association between GDM and nitrogen dioxide (NO2) (OR 1.05, 95% CI 1.01 to 1.10), nitrogen oxide (NOx) (OR 1.03, 95% CI 1.01 to 1.05), and sulfur dioxide (SO2) (OR 1.09, 95% CI 1.03 to 1.15) was noted. There was no significant association between exposure to black carbon or ozone or carbon monoxide or particulate matter ≤10 µm in diameter and GDM. Thus, systematic review of existing evidence demonstrated association of exposure to NO2, NOx, and SO2, and the second trimester exposure of PM2.5 with the increased risk of GDM. Caution may be exercised while deriving conclusions from existing evidence base because of the limited number and the observational nature of studies.

Prediabetes and structural brain abnormalities: Evidence from observational studies.

Type 2 diabetes mellitus has been linked to structural brain abnormalities, but evidence of the association among prediabetes and structural brain abnormalities has not been systematically evaluated. Comprehensive searching strategies and relevant studies were systematically retrieved from PubMed, Embase, Medline and web of science. Twelve articles were included overall. Stratified analyses and regression analyses were performed. A total of 104 468 individuals were included. The risk of infarct was associated with continuous glycosylated haemoglobin (HbA1c ) [adjusted odds ratio (OR) 1.19 (95% confidence interval [CI]: 1.05-1.34)], or prediabetes [adjusted OR 1.13 (95% CI: 1.00-1.27)]. The corresponding ORs associated with white matter hyperintensities were 1.08 (95%CI: 1.04-1.13) for prediabetes, and 1.10 (95%CI: 1.08-1.12) for HbA1c . The association was significant between the decreased risk of brain volume with continuous HbA1c (the combined OR 0.92, 95% CI: 0.87-0.98). Grey matter volume and white matter volume were inversely associated with prediabetes [weighted mean deviation (WMD), -9.65 (95%CI: -15.25 to -4.04) vs WMD, -9.25 (95%CI: -15.03 to -3.47)]. There were no significant association among cerebral microbleeds, hippocampal volume, continuous total brain volume, and prediabetes. Our findings demonstrated that (a) both prediabetes and continuous HbA1c were significantly associated with increasing risk of infarct or white matter hyperintensities; (b) continuous HbA1c was associated with a decreased risk of brain volume; (c) prediabetes was inversely associated with grey matter volume and white matter volume. To confirm these findings, further studies on early diabetes onset and structural brain abnormalities are needed.

Clinical Significance of Baseline Neutrophil-to-Lymphocyte Ratio in Patients With Ischemic Stroke or Hemorrhagic Stroke: An Updated Meta-Analysis.

Background and purpose: Stroke is a leading cause of death and acquired disability in adults today. Inflammation plays an important role in the pathophysiology of stroke. The peripheral neutrophil-to-lymphocyte ratio (NLR) is an important global inflammatory indicator becoming more mainstream in stroke care. This meta-analysis aims to evaluate the relationship between the baseline NLR and acute ischemic and hemorrhagic stroke, as well as define the clinical significance of NLR in subtypes of ischemic stroke. Methods: This meta-analysis was registered in PROSPERO with the number CRD42018105305. We went through relevant articles from PubMed Central (PMC) and EMBASE. Prospective and retrospective studies were included if related to baseline NLR levels prior to treatment in patients with ischemic or hemorrhagic stroke. Studies were identified up until April 2019. The cutoff value for NLR and the sources of odds ratios (ORs)/risk ratios (RRs) were measured. Modified Rankin Scale (mRS) was used to investigate the outcomes during clinical follow-up. Predefined criteria were used to evaluate the risk of bias in eligible studies. P-values < 0.05 were considered statistically significant. STATA version 14.0 (STATA, College Station, TX) was used in all statistical analyses. Results: Thirty-seven studies with 43,979 individuals were included in the final analysis. Higher NLR levels were correlated with increased risk of ischemic stroke (ORs/RRs = 1.609; 95% CI = 1.283-2.019), unfavorable functional outcome at 3 months (ORs/RRs = 1.851; 95% CI = 1.325-2.584), and increased mortality in patients with ischemic stroke (ORs/RRs = 1.068; 95% CI = 1.027-1.111). While in terms of hemorrhagic stroke (including SAH and ICH), elevated NLR levels only had deleterious effects on mortality (ORs/RRs = 1.080; 95% CI = 1.018-1.146). Conclusions: Baseline NLR level is a promising predictor of the clinical outcomes in both ischemic and hemorrhagic stroke. In addition, elevated NLR is also associated with a high risk of ischemic stroke occurrence. However, future studies are needed to demonstrate the underlying mechanisms and further explain this association.

Integrative analysis of gene expression and DNA methylation through one-class logistic regression machine learning identifies stemness features in medulloblastoma.

Most human cancers develop from stem and progenitor cell populations through the sequential accumulation of various genetic and epigenetic alterations. Cancer stem cells have been identified from medulloblastoma (MB), but a comprehensive understanding of MB stemness, including the interactions between the tumor immune microenvironment and MB stemness, is lacking. Here, we employed a trained stemness index model based on an existent one-class logistic regression (OCLR) machine-learning method to score MB samples; we then obtained two stemness indices, a gene expression-based stemness index (mRNAsi) and a DNA methylation-based stemness index (mDNAsi), to perform an integrated analysis of MB stemness in a cohort of primary cancer samples (n = 763). We observed an inverse trend between mRNAsi and mDNAsi for MB subgroup and metastatic status. By applying the univariable Cox regression analysis, we found that mRNAsi significantly correlated with overall survival (OS) for all MB patients, whereas mDNAsi had no significant association with OS for all MB patients. In addition, by combining the Lasso-penalized Cox regression machine-learning approach with univariate and multivariate Cox regression analyses, we identified a stemness-related gene expression signature that accurately predicted survival in patients with Sonic hedgehog (SHH) MB. Furthermore, positive correlations between mRNAsi and prognostic copy number aberrations in SHH MB, including MYCN amplifications and GLI2 amplifications, were detected. Analyses of the immune microenvironment revealed unanticipated correlations of MB stemness with infiltrating immune cells. Lastly, using the Connectivity Map, we identified potential drugs targeting the MB stemness signature. Our findings based on stemness indices might advance the development of objective diagnostic tools for quantitating MB stemness and lead to novel biomarkers that predict the survival of patients with MB or the efficacy of strategies targeting MB stem cells.

Incidence of metastatic disease and survival among patients with newly diagnosed primary CNS tumors in the United States from 2004-2013.

Background: Population-based estimates of the incidence and prognosis of metastatic disease at the initial diagnosis of primary central nervous system (CNS) tumors are currently lacking. Methods: A total of 43,455 patients diagnosed with a primary CNS tumor were enrolled to evaluate metastatic rates utilizing the data from the Surveillance, Epidemiology, and End Results (SEER) program. We used multivariate logistic regression to analyze the risk factors associated with the presence of metastasis at the first visit of patients with metastatic medulloblastoma (MB), atypical teratoid/rhabdoid tumor (ATRT), glioblastoma multiforme (GBM), or pilocytic astrocytoma (PA). Hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific death (CSD) of patients with these four CNS tumors were analyzed using multivariate Cox regression. Results: In patients with primary CNS embryonal tumors, the metastatic rates of patients with MB and ATRT were 14.51% and 19.25%, respectively. The metastatic rate for MB patients aged 0 to 18 years was 16.69%. In the patients with glioma, the metastatic rates of patients with PA and GBM were 1.55% and 1.39%, respectively. On multivariate logistic regression among patients with glioma, GBM (vs PA; OR, 2.12; 95% CI, 1.37 to 3.30; P=0.001) was associated with greater odds of having metastatic disease at diagnosis. On multivariate logistic regression among patients with GBM, MB, or ATRT, MB (vs GBM; OR, 4.66; 95% CI, 2.81 to 7.72; P<0.001) and ATRT (vs GBM; OR, 5.65; 95% CI, 3.27 to 9.75; P<0.001) were associated with greater odds of having metastatic disease at diagnosis. In the multivariate Cox proportional hazards model for CSD among patients with metastatic GBM or MB at diagnosis, gross total resection/total lobectomy (vs partial resection/partial lobectomy) was not related to a decreased or an increased risk of CSD. In patients with metastatic ATRT, compared to no surgery, gross total resection/total lobectomy or partial resection/partial lobectomy was not associated with a decreased risk of CSD. Conclusions: The findings in this study provide a population-based estimate of the incidence and prognosis of metastatic disease at the initial diagnosis of primary CNS tumors. These survival outcomes are relevant because they will help to prioritize future research directions to improve the treatment strategies of these metastatic CNS tumors.

Urine NGAL as an early biomarker for diabetic kidney disease: accumulated evidence from observational studies.

Objectives: Urine neutrophil gelatinase-associated lipocalin (NGAL) was found to increase in diabetic kidney disease (DKD). However, the clinical value of urine NGAL as diagnostic indicators in DKD remains to be clarified. Methods: Relevant studies were systematically retrieved from PubMed, Embase, Web of Science, and the Cochrane Library. Stratified analyses and regression analyses were performed. Results: Fourteen studies with 1561 individuals were included in our analysis, including 1204 cross-sectional participants and 357 cohort participants. For the cross-sectional studies, the pooled sensitivity and specificity of NGAL in the diagnosis of DKD were 0.82 (95% confidence interval (CI): 0.75-0.87) and 0.81 (95% CI: 0.68-0.90), respectively. The pooled diagnostic odds ratio was 19 (95% CI: 11-33), and the overall area under the curve was 0.88 (95% CI: 0.84-0.90). For the cohort studies, the pooled sensitivity and specificity of NGAL in the diagnosis of DKD were 0.96 (95% CI: 0.91-0.98) and 0.89 (95% CI: 0.84-0.92), respectively. The overall area under the curve was 0.98, indicating good discriminative ability of NGAL as biomarkers for DKD. Conclusions: Urine NGAL, as the early diagnostic marker of DKD, might have the high diagnostic value, especially in cohort studies.