Urinary D-asparagine level is decreased by the presence of glioblastoma
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ABSTRACT:
SUBMITTER: Nakade Y
PROVIDER: S-EPMC11337596 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundIsocitrate dehydrogenase wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, yet only 27% of isocitrate dehydrogenase WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood.MethodsWe investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests.ResultsWe demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knock down or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; hazard ratio = 3.94, 95% confidence interval = 1.87 to 8.28; P < .001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, P = .03), which decreased dramatically after surgery.ConclusionsOur results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM.
| S-EPMC7156939 | biostudies-literature
Project description:A comparison of expression changes between AEP RNAi and U87 control cell lines
2019-10-01 | GSE104806 | GEO
Project description:While the prognosis of patients with glioblastoma (GBM) remains poor despite recent therapeutic advances, variable survival times suggest wide variation in tumor biology and an opportunity for stratified intervention. We used volumetric analysis and morphometrics to measure the spatial relationship between subventricular zone (SVZ) proximity and survival in a cohort of 39 newly diagnosed GBM patients. We collected T2-weighted and gadolinium-enhanced T1-weighted magnetic resonance images (MRI) at pre-operative, post-operative, pre-radiation therapy, and post-radiation therapy time points, measured tumor volumes and distances to the SVZ, and collected clinical data. Univariate and multivariate Cox regression showed that tumors involving the SVZ and tumor growth rate during radiation therapy were independent predictors of shorter progression-free and overall survival. These results suggest that GBMs in close proximity to the ependymal surface of the ventricles convey a worse prognosis-an observation that may be useful for stratifying treatment.
| S-EPMC3151407 | biostudies-literature
Project description:Epilepsy at presentation is an independent favorable prognostic factor in glioblastoma (GBM). In this study, we analyze the oncologic signaling pathways that associate with epilepsy in human GBMs, and that can underlie this prognostic effect. Following ethical approval and patient consent, fresh frozen GBM tissue was obtained from 76 patient surgeries. Hospital records were screened for the presence of seizures at presentation of the disease. mRNA and miRNA expression-based and gene set enrichment analyses were performed on these tissues, to uncover candidate oncologic pathways that associate with epilepsy. We performed qPCR experiments and immunohistochemistry on tissue microarrays containing 286 GBMs to further explore the association of these candidate pathways and of markers of mesenchymal transformation (NF-κB, CEBP-β, STAT3, STAT5b, VEGFA, SRF) with epilepsy. Gene sets involved in hypoxia/HIF-1α, STAT5, CEBP-β and epithelial-mesenchymal transformation signaling were significantly downregulated in epileptogenic GBMs. On confirmatory protein expression analyses, epileptogenic tumors were characterized by a significant downregulation of phospho-STAT5b, a target of HIF-1α. Epilepsy status did not associate with molecular subclassification or miRNA expression patterns of the tumors. Epileptogenic GBMs correlate with decreased hypoxia/ HIF-1α/STAT5b signaling compared to glioblastomas that do not present with epilepsy.
| S-EPMC6356242 | biostudies-literature
Project description:Esophageal cancer (EC) including esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) generally exhibits poor prognosis; hence, a noninvasive biomarker enabling early detection is necessary. Age- and sex-matched 150 healthy controls (HCs) and 43 patients with ESCC were randomly divided into two groups: 9 individuals in the discovery cohort for microarray analysis and 184 individuals in the training/test cohort with cross-validation for qRT-PCR analysis. Using 152 urine samples (144 HCs and 8 EACs), we validated the urinary miRNA biomarkers for EAC diagnosis. Among eight miRNAs selected in the discovery cohort, urinary levels of five miRNAs (miR-1273f, miR-619-5p, miR-150-3p, miR-4327, and miR-3135b) were significantly higher in the ESCC group than in the HC group, in the training/test cohort. Consistently, these five urinary miRNAs were significantly different between HC and ESCC in both training and test sets. Especially, urinary miR-1273f and miR-619-5p showed excellent values of area under the curve (AUC) ≥ 0.80 for diagnosing stage I ESCC. Similarly, the EAC group had significantly higher urinary levels of these five miRNAs than the HC group, with AUC values of approximately 0.80. The present study established novel urinary miRNA biomarkers that can early detect ESCC and EAC.
| S-EPMC8058072 | biostudies-literature
Project description:BackgroundIt is important to understand clinical features of bacteremic urinary tract infection (bUTI), because bUTI is a serious infection that requires prompt diagnosis and antibiotic therapy. Escherichia coli is the most common and important uropathogen. The objective of our study was to characterize the clinical presentation of E coli bUTI.MethodsRetrospective cohort study of consecutive adult patients admitted for community acquired E. coli bacteremia from January 1, 2015 to December 31, 2016 was conducted at 4 acute care academic and community hospitals in Toronto, Ontario, Canada. Logistic regression models were developed to identify E coli bUTI cases without urinary symptoms.ResultsOf 462 patients with E. coli bacteremia, 284 (61.5%) patients had a urinary source. Of these 284 patients, 161 (56.7%) had urinary symptoms. In a multivariable model, bUTI without urinary symptoms were associated with older age (age < 65 years as reference, age 65-74 years had OR of 2.13 95% CI 0.99-4.59 p = 0.0523; age 75-84 years had OR of 1.80 95% CI 0.91-3.57 p = 0.0914; age > =85 years had OR of 2.95 95% CI 1.44-6.18 p = 0.0036) and delirium (OR of 2.12 95% CI 1.13-4.03 p = 0.0207). Sepsis by SIRS criteria was present in 274 (96.5%) of all bUTI cases and 119 (96.8%) of bUTI cases without urinary symptoms.ConclusionThe majority of patients with E. coli bacteremia had a urinary source. A significant proportion of bUTI cases had no urinary symptoms elicited on history. Elderly and delirious patients were more likely to have bUTI without urinary symptoms. In elderly and delirious patients with sepsis by SIRS criteria but without a clear infectious source, clinicians should suspect, investigate, and treat for bUTI.
| S-EPMC7576869 | biostudies-literature
Project description:Natural killer (NK) cells are functionally suppressed in the glioblastoma multiforme (GBM) tumor microenvironment. We have recently shown that survival and differentiation of cancer stem-like cells (CSCs)/poorly differentiated tumors are controlled through two distinct phenotypes of cytotoxic and non-cytotoxic/split anergized NK cells, respectively. In this paper, we studied the function of NK cells against brain CSCs/poorly differentiated GBM and their NK cell-differentiated counterparts. Brain CSCs/poorly differentiated GBM, differentiated by split anergized NK supernatants (supernatants from NK cells treated with IL-2 + anti-CD16mAb) expressed higher levels of CD54, B7H1 and MHC-I and were killed less by the NK cells, whereas their CSCs/poorly differentiated counterparts were highly susceptible to NK cell lysis. Resistance to NK cells and differentiation of brain CSCs/poorly differentiated GBM by split anergized NK cells were mediated by interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Brain CSCs/poorly differentiated GBM expressed low levels of TNFRs and IFN-γRs, and when differentiated and cultured with IL-2-treated NK cells, they induced increased secretion of pro-inflammatory cytokine interleukin (IL)-6 and chemokine IL-8 in the presence of decreased IFN-γ secretion. NK-induced differentiation of brain CSCs/poorly differentiated GBM cells was independent of the function of IL-6 and/or IL-8. The inability of NK cells to lyse GBM tumors and the presence of a sustained release of pro-inflammatory cytokines IL-6 and chemokine IL-8 in the presence of a decreased IFN-γ secretion may lead to the inadequacy of NK cells to differentiate GBM CSCs/poorly differentiated tumors, thus failing to control tumor growth.
| S-EPMC4996719 | biostudies-literature
Project description:Glioblastoma (GBM) remains one of the most aggressive cancers, partially due to its ability to migrate into the surrounding brain. The sphingolipid balance, or the balance between ceramides and sphingosine-1-phosphate, contributes to the ability of GBM cells to migrate or invade. Of the ceramidases which hydrolyze ceramides, acid ceramidase (ASAH1) is highly expressed in GBM samples compared to non-tumor brain. ASAH1 expression also correlates with genes associated with migration and focal adhesion. To understand the role of ASAH1 in GBM migration, we utilized shRNA knockdown and observed decreased migration that did not depend upon changes in growth. Next, we inhibited ASAH1 using carmofur, a clinically utilized small molecule inhibitor. Inhibition of ASAH1 by carmofur blocks in vitro migration of U251 (GBM cell line) and GBM cells derived from patient-derived xenografts (PDXs). RNA-sequencing suggested roles for carmofur in MAPK and AKT signaling. We found that carmofur treatment decreases phosphorylation of AKT, but not of MAPK. The decrease in AKT phosphorylation was confirmed by shRNA knockdown of ASAH1. Our findings substantiate ASAH1 inhibition using carmofur as a potential clinically relevant treatment to advance GBM therapeutics, particularly due to its impact on migration.
| S-EPMC9221433 | biostudies-literature
Project description:BackgroundRecently, new concepts about obesity and normal weight subtypes with metabolic conditions are rising and ketone bodies are emerging as a significant indicator of metabolic health. This study aimed to find a relationship between ketonuria and those subtypes.MethodsThe data of 19,036 subjects were analyzed in this cross-sectional study (2013-2017 Korea National Health and Nutrition Examination Survey, KNHANES). Based on body mass index and adult treatment panel III with modification of waist circumference, individuals were categorized into 4 groups: metabolically healthy normal weight (MHNW), metabolically healthy obese (MHO), metabolically unhealthy normal weight (MUNW), and metabolically unhealthy obese (MUO). Individuals were divided into 2 groups, positive and negative ketonuria groups, and the metabolic parameters were compared.ResultsThe metabolic indicators of the positive ketonuria group showed better results than those of the negative ketonuria group and the MHNW group showed the highest proportion of positive ketonuria. The MHNW group showed higher urinary ketones than the MUO group (odds ratio [OR], 0.391; 95% confidence interval [CI], 0.254-0.601) in men. In women, OR of having ketonuria was 0.698 (95% CI, 0.486-1.002) in the MHO group and 0.467 (95% CI, 0.226-0.966) in the MUNW group compared to the MHNW group, respectively.ConclusionCompared to the MHNW group, the MUO group showed lower presence of ketonuria in men, and tendency to have less ketonuria in women.
| S-EPMC7416001 | biostudies-literature
Project description:Social restrictions reduced the rates of respiratory infections in 2020, but studies on the rates of urinary tract infections (UTIs) during lockdown have had conflicting results. This study aimed to report UTI incidence during the first and second waves of COVID-19 pandemic in Finland. We conducted a retrospective register-based cohort study. The whole Finnish pediatric population (children under the age of 15 years, N = 860,000) was included. The yearly and monthly incidences of UTIs per 100,000 children in 2020 were compared to that of three previous years (2017-2019) by incidence rate ratios (IRRs) with 95% confidence intervals (CIs). A total of 10,757 cystitis and 4873 pyelonephritis cases were included. The yearly incidence of cystitis was 12% lower (IRR 0.88, CI 0.83-0.94) among children aged 1-6 in 2020 and 11% (IRR 0.89, CI 0.83-0.95) lower among children aged 7-14 in 2020 compared with previous years. The yearly incidence of pyelonephritis was 16% lower (IRR 0.84, CI 0.76-0.94) among children aged 1-6. No significant decrease were observed among children aged < 1 and 7-14.ConclusionThe incidence of cystitis and pyelonephritis during a period of social restrictions was lower than during 2017-2019, especially in children aged 1-6 years. These results raise the possibility of reducing the occurrence of urinary tract infections in children by improving hygiene measures.What is known• Social restrictions have reduced the rate of common respiratory infections globally. • Previous studies have presented a decreased or unchanged incidence of urinary tract infections during the COVID-19 pandemic.What is new• During the pandemic, there was a decrease in the incidence of urinary tract infections in Finnish children and the most prominent decrease was in daycare-aged children. • Improved hygiene measures and social restrictions may have influenced the transmission of uropathogens.
| S-EPMC8801286 | biostudies-literature