Abstract
The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (
IDH
) wild-type glioblastoma (GBM) is currently limited due to high ...molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of
IDH
wild-type GBM tumors derived from a quantitative proteomic analysis of 39
IDH
wild-type GBMs as well as
IDH
mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (
FKBP9
). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (
PHGDH
). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.
The primary purpose was to examine the relationship between the muscle architectural characteristics of short and long-distance cyclist-including muscle thickness, fascicle angle, and fascicle ...length-of the anterior thigh and posterior leg and its impact in 20-s cycling power. The secondary purpose was to clarify the muscle variables that predict the cycling power by using ultrasonography to measure the muscle architectural characteristics. Twenty-four varsity cyclists participated in this study, of whom 12 were short-distance cyclists and 12 were long-distance cyclists. B-mode ultrasonography was used to measure muscle architecture parameters. A cycle ergometer was used to measure the cycling power. The rectus femoris, vastus medialis, and medial head of gastrocnemius were significantly thicker in short-distance cyclists than in long-distance cyclists at every site (p < 0.05). Our analysis revealed that the rectus femoris fascicle length at the 30% level of the thigh was a significant independent predictor of the 20-s cycling power in short-distance cyclists, while the rectus femoris fascicle angle at the 50% level was that of the 20-s cycling power in long-distance cyclists. These findings highlight the significance of rectus femoris muscle architecture to cycling power.
Although many reports have revealed dysfunction of endothelial cells in aging, resulting in blood-brain barrier (BBB) breakdown, the underlying mechanism or mechanisms remain to be explored. Here, we ...find that acid sphingomyelinase (ASM) is a critical factor for regulating brain endothelial barrier integrity. ASM is increased in brain endothelium and/or plasma of aged humans and aged mice, leading to BBB disruption by increasing caveolae-mediated transcytosis. Genetic inhibition and endothelial-specific knockdown of ASM in mice ameliorated BBB breakdown and neurocognitive impairment during aging. Using primary mouse brain endothelial cells, we found that ASM regulated the caveolae-cytoskeleton interaction through protein phosphatase 1-mediated ezrin/radixin/moesin (ERM) dephosphorylation and apoptosis. Moreover, mice with conditional ASM overexpression in brain endothelium accelerated significant BBB impairment and neurodegenerative change. Overall, these results reveal a novel role for ASM in the control of neurovascular function in aging, suggesting that ASM may represent a new therapeutic target for anti-aging.
•ASM activity is upregulated in brain and/or plasma of aged humans and mice•Brain endothelial cell is a main contributor of increased ASM in aging•Increased ASM in aging causes BBB impairment and neuronal dysfunction•It is regulated by caveolae-mediated transcytosis and ERM dephosphorylation
Park et al. demonstrate that ASM activity is increased in brain endothelial cells and/or plasma in aged mice, leading to BBB leakage by caveolae-mediated transcytosis via ERM dephosphorylation. Moreover, specific ASM overexpression in brain endothelium accelerates BBB and neuronal dysfunction.
The source apportionment of volatile organic compounds (VOCs) was examined using receptor models (positive matrix factorization and chemical mass balance) and a chemical transport model (CTM). The ...receptor model-based analysis was performed using the datasets collected from four different sites from the megacity of Seoul during the years 2013–2015. The contributions of VOC emission sources to ozone (O3) and PM2.5 concentrations and the subsequent health effects in the study area were also assessed during a photochemically active period (June 2015) using a three-dimensional CTM, Community Multi-scale Air Quality (CMAQ), and the Environmental Benefits Mapping and Analysis Program (BenMAP). The solvent use and the on-road mobile emission sources were found to exert dominant controls on the VOC levels observed in the target city. VOCs transported from regions outside of Seoul accounted for a significant proportion (up to approximately 35%) of ambient VOC levels during the study period. The solvent use accounted for 3.4% of the ambient O3 concentrations during the day (daily mean of 2.6%) and made insignificant contributions to PM2.5 (<1%) during the simulation period. Biogenic VOC made insignificant contributions to O3 (<1%) and a small contribution to PM2.5 during the day (5.6% with a daily mean of 2.4%). The number of premature deaths attributed indirectly (O3 and PM2.5 formations via the oxidation of VOCs) to solvent use is expected to be significant.
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•The solvent use and the on-road mobile emission sources exert dominant controls on the VOC levels.•VOCs transported from regions outside of Seoul accounted for a significant proportion of ambient VOC levels.•Biogenic VOC made insignificant contributions to O3 and PM2.5•The number of premature deaths attributed indirectly to solvent use is expected to be significant.
Objective We explored the clinical significances of the relationships among sphenoid sinus aeration, intersphenoid sinus septum (ISS), and internal carotid artery (ICA). Methods We retrospectively ...reviewed the preoperative paranasal sinus computed tomography scans and the medical charts of 490 patients who were treated by the endoscopic endonasal transsphenoidal approach. We analyzed sphenoid sinus pneumatization, number of ISS, and positional relationships between the ICA and ISS (including ICA prominence and the thickness of surrounding bone). Results ISS were often present in the ICAs of patients with presellar pneumatization (36.2%; p = 0.042). Sphenoid sinus pneumatization status significantly differed according to number of ISS (p < 0.001), ICA prominence (p < 0.001), ISS insertion into the ICA (p = 0.042), and distance from ISS to ICA (p = 0.004). When sphenoid sinus aeration was poor, the ICA was not prominent, and the ISS were attached to or lay close to the paraclival ICA. Conclusions Patients with presellar pneumatization exhibited less prominent ICAs, and more ISS attached to or near the paraclival ICA, than did other patients. Therefore, particular caution is required when using the endoscopic endonasal transsphenoidal approach to treat patients with poor sphenoid sinus aeration.
Centrality metrics have been studied in the network science research. They have been used in various networks, such as communication, social, biological, geographic, or contact networks under ...different disciplines. In particular, centrality metrics have been used in order to study and analyze targeted attack behaviors and investigated their effect on network resilience. Although a rich volume of centrality metrics has been developed from 1940s, only some centrality metrics (e.g., degree, betweenness, or cluster coefficient) have been commonly in use. This paper aims to introduce various existing centrality metrics and discusses their applicabilities in various networks. In addition, we conducted extensive simulation study in order to demonstrate and analyze the network resilience of targeted attacks using the surveyed centrality metrics under four real network topologies. We also discussed algorithmic complexity of centrality metrics surveyed in this work. Through the extensive experiments and discussions of the surveyed centrality metrics, we encourage their use in solving various computing and engineering problems in networks.
Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we ...find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in ∼14% of cases with significantly worse prognosis. Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.
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•Characterization of the mutational landscape of secondary glioblastoma•Clonal and subclonal METex14 promote glioma progression and mark worse prognosis•PLB-1001 is a highly selective, efficient, and BBB-permeable MET kinase inhibitor•PLB-1001 provides a safe and efficacious therapeutic approach for glioma treatment
A new MET inhibitor shows preliminary efficacy for treatment of patients with secondary glioblastoma.
Memory is supported by a specific collection of neurons distributed in broad brain areas, an engram. Despite recent advances in identifying an engram, how the engram is created during memory ...formation remains elusive. To explore the relation between a specific pattern of input activity and memory allocation, here we target a sparse subset of neurons in the auditory cortex and thalamus. The synaptic inputs from these neurons to the lateral amygdala (LA) are not potentiated by fear conditioning. Using an optogenetic priming stimulus, we manipulate these synapses to be potentiated by the learning. In this condition, fear memory is preferentially encoded in the manipulated cell ensembles. This change, however, is abolished with optical long-term depression (LTD) delivered shortly after training. Conversely, delivering optical long-term potentiation (LTP) alone shortly after fear conditioning is sufficient to induce the preferential memory encoding. These results suggest a synaptic plasticity-dependent competition rule underlying memory formation.
This study determined the effects of anti-diabetic medication adherence on the long-term all-cause mortality and hospitalization for cerebrovascular disease and myocardial infarction among newly ...diagnosed patients. The study used retrospective cohort from the National Health Insurance Service. Study participants were 65,076 newly diagnosed type 2 diabetes mellitus patients aged ≥40 years. The medication adherence was evaluated from the proportion of days covered (PDC) between 2006 and 2007. Outcome variables were mortality, newly diagnosed cerebrovascular disease (CVD) and myocardial infarction (MI) in 2008-2017. Cox-proportional hazard regression analysis was performed. After adjusting for sex, age, monthly contribution, insurance type, medical institution type, Charlson comorbidity index score, disability, hypertension, and active ingredients of oral hypoglycemic agents, the adjusted hazard ratio (aHR) for all-cause-mortality of the lowest PDC group (<0.20) was 1.45 (95% confidence interval CI = 1.36-1.54) as compared to the highest PDC (≥0.8). The aHR for all-cause-mortality associated with PDC levels of 0.60-0.79, 0.40-0.59, and 0.20-0.39 were 1.19, 1.26, and 1.34, respectively (P
< 0.001). Compared to the highest PDC group, diabetic patients with the lowest PDC had elevated risk for CVD (aHR = 1.41; 95% CI = 1.30-1.52; P
< 0.001). Improving anti-diabetic medication adherence among newly diagnosed type 2 diabetes mellitus patients is essential to the reduce risk for cardiovascular disease and long-term all-cause mortality.
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