Glioblastoma (GBM) is a lethal tumor, but few biomarkers and molecular subtypes predicting prognosis are available. This study was aimed to identify prognostic subtypes and multi-omics signatures for ...GBM. Using oncopression and TCGA-GBM datasets, we identified 80 genes most associated with GBM prognosis using correlations between gene expression levels and overall survival of patients. The prognostic score of each sample was calculated using these genes, followed by assigning three prognostic subtypes. This classification was validated in two independent datasets (REMBRANDT and Severance). Functional annotation revealed that invasion- and cell cycle-related gene sets were enriched in poor and favorable group, respectively. The three GBM subtypes were therefore named invasive (poor), mitotic (favorable), and intermediate. Interestingly, invasive subtype showed increased invasiveness, and MGMT methylation was enriched in mitotic subtype, indicating need for different therapeutic strategies according to prognostic subtypes. For clinical convenience, we also identified genes that best distinguished the invasive and mitotic subtypes. Immunohistochemical staining showed that markedly higher expression of PDPN in invasive subtype and of TMEM100 in mitotic subtype (P < 0.001). We expect that this transcriptome-based classification, with multi-omics signatures and biomarkers, can improve molecular understanding of GBM, ultimately leading to precise stratification of patients for therapeutic interventions.
Abstract
Premature ventricular contraction (PVC), a common arrhythmia affecting 1–2% of the general population, has been considered to have a benign clinical course. However, people with PVC often ...develop heart failure and ventricular arrhythmias such as ventricular tachycardia. We aimed to clarify the risk of heart failure and lethal ventricular arrhythmias in people with PVC. The Korean National Health Insurance Service database was used for this study. People who underwent nationwide health check-ups in 2009 were enrolled in this study and clinical follow-up data until December 2018 were analyzed. Newly diagnosed PVC in 2009 (≥ 1 inpatient or outpatient claim) were identified and cumulative incidence of heart failure (≥ 1 inpatient claim) and ventricular arrhythmias (≥ 1 inpatient or outpatient claim) were compared. A total of 4515 people were first diagnosed with PVC in 2009 among 9,743,582 people without prior history of PVC, heart failure, or ventricular arrhythmias. People with newly diagnosed PVC in 2009 had a significantly higher incidence of heart failure compared to those without PVC adjusted hazard ratio (HR) 1.371; 95% confidence interval (CI) 1.177–1.598;
p
< 0.001. Significant interaction was observed between age and PVC with young age people at greater risk of developing heart failure for having PVC. The incidence of ventricular arrhythmia was also significantly increased in people with PVC (HR 5.588; 95% CI 4.553–6.859;
p
< 0.001). Age and chronic kidney disease had significant interactions with PVC. In conclusion, the incidence of heart failure and ventricular arrhythmia was significantly increased in people with PVC. Outpatient follow-up of people with PVC can be helpful to detect early signs of heart failure or advanced forms of ventricular arrhythmia.
Patient‐specific cancer therapies can evolve by vitalizing the mother tissue‐like cancer niche, cellular profile, genetic signature, and drug responsiveness. This evolution has enabled the ...elucidation of a key mechanism along with development of the mechanism‐driven therapy. After surgical treatment, glioblastoma (GBM) patients require prompt therapy within 14 days in a patient‐specific manner. Hence, this study approaches direct culture of GBM patient tissue (1 mm diameter) in a microchannel network chip. Cancer vasculature‐mimetic perfusion can support the preservation of the mother tissue‐like characteristic signatures and microenvironment. When temozolomide and radiation are administered within 1 day, the responsiveness of the tissue in the chip reflected the clinical outcomes, thereby overcoming the time‐consuming process of cell and organoid culture. When the tissue chip culture is continued, the intact GBM signature gets lost, and the outward migration of stem cells from the tissue origin increases, indicating a leaving‐home effect on the family dismantle. Nanovesicle production using GBM stem cells enables self‐chasing of the cells that escape the temozolomide effect owing to quiescence. The anti‐PTPRZ1 peptide display and temozolomide loading to nanovesicles awakes cancer stem cells from the quiescent stage to death. This study suggests a GBM clinic‐driven avatar platform and mechanism‐learned nanotherapy for translation.
Glioblastoma niche and drug responsiveness are preserved by culturing patient tissues in microchannel chips. As cancer stem cells migrate from the tissue following channels, cancer RNA signature of the tissue disappear. Nanovesicles are produced using glioblastoma stem cells with temozolomide loading and stem cell targeting peptide display, which chases to have committed the suicide of cancer stem cells by awakening their quiescence.
Targeted approaches for treating glioblastoma (GBM) attempted to date have consistently failed, highlighting the imperative for treatment strategies that operate on different mechanistic principles. ...Bioenergetics deprivation has emerged as an effective therapeutic approach for various tumors. We have previously found that cancer cells preferentially utilize cytosolic NADH supplied by aldehyde dehydrogenase (ALDH) for ATP production through oxidative phosphorylation (OxPhos). This study is aimed at examining therapeutic responses and underlying mechanisms of dual inhibition of ALDH and OxPhos against GBM.
For inhibition of ALDH and OxPhos, the corresponding inhibitors, gossypol and phenformin were used. Biological functions, including ATP levels, stemness, invasiveness, and viability, were evaluated in GBM tumorspheres (TSs). Gene expression profiles were analyzed using microarray data. In vivo anticancer efficacy was examined in a mouse orthotopic xenograft model.
Combined treatment of GBM TSs with gossypol and phenformin significantly reduced ATP levels, stemness, invasiveness, and cell viability. Consistently, this therapy substantially decreased expression of genes associated with stemness, mesenchymal transition, and invasion in GBM TSs. Supplementation of ATP using malate abrogated these effects, whereas knockdown of ALDH1L1 mimicked them, suggesting that disruption of ALDH-mediated ATP production is a key mechanism of this therapeutic combination. In vivo efficacy confirmed remarkable therapeutic responses to combined treatment with gossypol and phenformin.
Our findings suggest that dual inhibition of tumor bioenergetics is a novel and effective strategy for the treatment of GBM.
Purpose
Glioblastoma (GBM) is a rapidly growing tumor in the central nervous system with altered metabolism. Depleting the bioenergetics of tumors with biguanides have been suggested as an effective ...therapeutic approach for treating GBMs. The purpose of this study was to determine the effects of IM1761065, a novel biguanide with improved pharmacokinetics, on GBM-tumorspheres (TSs).
Methods
The biological activities of IM1761065 on GBM-TSs, including their effects on viability, ATP levels, cell cycle, stemness, invasive properties, and transcriptomes were examined. The in vivo efficacy of IM1761065 was tested in a mouse orthotopic xenograft model.
Results
IM1761065 decreased the viability and ATP levels of GBM-TSs in a dose-dependent manner, and reduced basal and spare respiratory capacity in patient-derived GBM-TS, as measured by the oxygen consumption rate. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TSs were also significantly suppressed by IM1761065. A gene-ontology comparison of IM1761065-treated groups showed that the expression levels of stemness-related, epithelial mesenchymal transition-related, and mitochondrial complex I genes were also significantly downregulated by IM1761065. An orthotopic xenograft mouse model showed decreased bioluminescence in IM1761065-treated cell-injected mice at 5 weeks. IM1761065-treated group showed longer survival than the control group (
P
= 0.0289, log-rank test).
Conclusion
IM1761065 is a potent inhibitor of oxidative phosphorylation. The inhibitory effect of IM1761065 on the bioenergetics of GBM-TS suggests that this novel compound could be used as a new drug for the treatment of GBM.
Abstract
Forkhead Box M1 (FOXM1) is known to regulate cell proliferation, apoptosis and tumorigenesis. The lignan, (−)-(2R,3R)-1,4-O-diferuloylsecoisolariciresinol (DFS), from
Alnus japonica
has ...shown anti-cancer effects against colon cancer cells by suppressing FOXM1. The present study hypothesized that DFS can have anti-cancer effects against glioblastoma (GBM) tumorspheres (TSs). Immunoprecipitation and luciferase reporter assays were performed to evaluate the ability of DFS to suppress nuclear translocation of β-catenin through β-catenin/FOXM1 binding. DFS-pretreated GBM TSs were evaluated to assess the ability of DFS to inhibit GBM TSs and their transcriptional profiles. The in vivo efficacy was examined in orthotopic xenograft models of GBM. Expression of FOXM1 was higher in GBM than in normal tissues. DFS-induced FOXM1 protein degradation blocked β-catenin translocation into the nucleus and consequently suppressed downstream target genes of FOXM1 pathways. DFS inhibited cell viability and ATP levels, while increasing apoptosis, and it reduced tumorsphere formation and the invasiveness of GBM TSs. And DFS reduced the activities of transcription factors related to tumorigenesis, stemness, and invasiveness. DFS significantly inhibited tumor growth and prolonged the survival rate of mice in orthotopic xenograft models of GBM. It suggests that DFS inhibits the proliferation of GBM TSs by suppressing FOXM1. DFS may be a potential therapeutic agent to treat GBM.
Despite aggressive clinical treatment, recurrence of glioblastoma multiforme (GBM) is unavoidable, and the clinical outcome is still poor. A convincing explanation is the phenotypic transition of GBM ...cells upon aggressive treatment such as radiotherapy. However, the microenvironmental factors contributing to GBM recurrence after treatment remain unexplored. Here, it is shown that radiation‐treated GBM cells produce soluble intercellular adhesion molecule‐1 (sICAM‐1) which stimulates the infiltration of macrophages, consequently enriching the tumor microenvironment with inflammatory macrophages. Acting as a paracrine factor, tumor‐derived sICAM‐1 induces macrophages to secrete wingless‐type MMTV integration site family, member 3A (WNT3A), which promotes a mesenchymal shift of GBM cells. In addition, blockade of either sICAM‐1 or WNT3A diminishes the harmful effect of radiation on tumor progression. Collectively, the findings indicate that cellular crosstalk between GBM and macrophage through sICAM‐1‐WNT3A oncogenic route is involved in the mesenchymal shift of GBM cells after radiation, and suggest that radiotherapy combined with sICAM‐1 targeted inhibition would improve the clinical outcome of GBM patients.
This study identifies the functional role of soluble intercellular adhesion molecule‐1 (sICAM‐1) for the mesenchymal shift of glioblastoma multiforme (GBM) in the tumor microenvironment. Importantly, the shedding of ICAM‐1 is increased in GBM following radiation and recruited macrophages for GBM progression. Taken together, the findings suggest sICAM‐1 as a molecular target to enhance the efficacy of radiotherapy.
Ionizing radiation is widely used for patient with glioblastoma (GBM). However, the effect of radiation on patient survival is marginal and upon recurrence tumors frequently shift toward mesenchymal ...subtype adopting invasiveness. Here, we show that ionizing radiation affects biomechanical tension in GBM microenvironment and provides proinvasive extracellular signaling cue, hyaluronic acid (HA)-rich condition. In response to radiation, HA production was increased in GBM cells by HA synthase-2 (HAS2) that was transcriptionally upregulated by NF-ĸB. Notably, NF-ĸB was persistently activated by IL-1α-feedback loop, making HA abundance in tumor microenvironment after radiation. Radiation-induced HA abundance causally has been linked to invasiveness of GBM cells by generating movement track as an extracellular matrix, and by acting as a signaling ligand for CD44 receptor, leading to SRC activation, which is sufficient for mesenchymal shift of GBM cells. Collectively, our findings provide an explanation for the frequent brain tumor relapse after radiotherapy, and potential therapeutic targets to block mesenchymal shift upon relapse.
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•Cu/CeO2 catalysts were prepared using different impregnation orders for Cu and Ce.•Cu–Ce/CeO2 (prepared by co-impregnation) exhibited the highest catalytic activity.•Cu dispersion ...and Cu particle size are important factors in reaction < 280 °C.•Oxygen vacancy concentration and active Cu species are important factors > 360 °C.
To investigate the effect of Cu/CeO2 catalysts preparation methods for low temperature water−gas shift reaction, Cu/CeO2 catalysts were prepared with various impregnation sequences and applied to the water−gas shift reaction at a high gas hourly space velocity of 36,080 mL/g·h. The catalyst preparation method affected both the Cu−Ce synergistic effect and the physico−chemical properties of the Ce promoted Cu/CeO2 catalysts, such as specific surface area, Cu particle size, Cu dispersion, amount of active Cu species and oxygen vacancy concentration. Among the prepared catalysts, Cu–Ce/CeO2 showed the highest CO conversion because of the high contents of active Cu species and high concentration of oxygen vacancies.
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