Prolonged sleep deprivation induces a cytokine-storm-like syndrome in mammals.

Most animals require sleep, and sleep loss induces serious pathophysiological consequences, including death. Previous experimental approaches for investigating sleep impacts in mice have been unable to persistently deprive animals of both rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS). Here, we report a "curling prevention by water" paradigm wherein mice remain awake 96% of the time. After 4 days of exposure, mice exhibit severe inflammation, and approximately 80% die. Sleep deprivation increases levels of prostaglandin D2 (PGD2) in the brain, and we found that elevated PGD2 efflux across the blood-brain-barrier-mediated by ATP-binding cassette subfamily C4 transporter-induces both accumulation of circulating neutrophils and a cytokine-storm-like syndrome. Experimental disruption of the PGD2/DP1 axis dramatically reduced sleep-deprivation-induced inflammation. Thus, our study reveals that sleep-related changes in PGD2 in the central nervous system drive profound pathological consequences in the peripheral immune system.

Prolonged myelin deficits contribute to neuron loss and functional impairments after ischaemic stroke.

Ischaemic stroke causes neuron loss and long-term functional deficits. Unfortunately, effective approaches to preserving neurons and promoting functional recovery remain unavailable. Oligodendrocytes, the myelinating cells in the CNS, are susceptible to oxygen and nutrition deprivation and undergo degeneration after ischaemic stroke. Technically, new oligodendrocytes and myelin can be generated by the differentiation of oligodendrocyte precursor cells (OPCs). However, myelin dynamics and their functional significance after ischaemic stroke remain poorly understood. Here, we report numerous denuded axons accompanied by decreased neuron density in sections from ischaemic stroke lesions in human brain, suggesting that neuron loss correlates with myelin deficits in these lesions. To investigate the longitudinal changes in myelin dynamics after stroke, we labelled and traced pre-existing and newly-formed myelin, respectively, using cell-specific genetic approaches. Our results indicated massive oligodendrocyte death and myelin loss 2 weeks after stroke in the transient middle cerebral artery occlusion (tMCAO) mouse model. In contrast, myelin regeneration remained insufficient 4 and 8 weeks post-stroke. Notably, neuronal loss and functional impairments worsened in aged brains, and new myelin generation was diminished. To analyse the causal relationship between remyelination and neuron survival, we manipulated myelinogenesis by conditional deletion of Olig2 (a positive regulator) or muscarinic receptor 1 (M1R, a negative regulator) in OPCs. Deleting Olig2 inhibited remyelination, reducing neuron survival and functional recovery after tMCAO. Conversely, enhancing remyelination by M1R conditional knockout or treatment with the pro-myelination drug clemastine after tMCAO preserved white matter integrity and neuronal survival, accelerating functional recovery. Together, our findings demonstrate that enhancing myelinogenesis is a promising strategy to preserve neurons and promote functional recovery after ischaemic stroke.

A Fast-Charge Graphite Anode with a Li-Ion-Conductive, Electron/Solvent-Repelling Interface.

Graphite has been serving as the key anode material of rechargeable Li-ion batteries, yet is difficultly charged within a quarter hour while maintaining stable electrochemistry. In addition to a defective edge structure that prevents fast Li-ion entry, the high-rate performance of graphite could be hampered by co-intercalation and parasitic reduction of solvent molecules at anode/electrolyte interface. Conventional surface modification by pitch-derived carbon barely isolates the solvent and electrons, and usually lead to inadequate rate capability to meet practical fast-charge requirements. Here we show that, by applying a MoOx-MoNx layer onto graphite surface, the interface allows fast Li-ion diffusion yet blocks solvent access and electron leakage. By regulating interfacial mass and charge transfer, the modified graphite anode delivers a reversible capacity of 340.3 mAh g-1 after 4000 cycles at 6 C, showing promises in building 10-min-rechargeable batteries with a long operation life.

A map of the spatial distribution and tumour-associated macrophage states in glioblastoma and grade 4 IDH-mutant astrocytoma.

Tumour-associated macrophages (TAMs) abundantly infiltrate high-grade gliomas and orchestrate immune response, but their diversity in isocitrate dehydrogenase (IDH)-differential grade 4 gliomas remains largely unknown. This study aimed to dissect the transcriptional states, spatial distribution, and clinicopathological significance of distinct monocyte-derived TAM (Mo-TAM) and microglia-derived TAM (Mg-TAM) clusters across glioblastoma-IDH-wild type and astrocytoma-IDH-mutant-grade 4 (Astro-IDH-mut-G4). Single-cell RNA sequencing was performed on four cases of human glioblastoma and three cases of Astro-IDH-mut-G4. Cell clustering, single-cell regulatory network inference, and gene set enrichment analysis were performed to characterize the functional states of myeloid clusters. The spatial distribution of TAM subsets was determined in human glioma tissues using multiplex immunostaining. The prognostic value of different TAM-cluster specific gene sets was evaluated in the TCGA glioma cohort. Profiling and unbiased clustering of 24,227 myeloid cells from glioblastoma and Astro-IDH-mut-G4 identified nine myeloid cell clusters including monocytes, six Mo/Mg-TAM subsets, dendritic cells, and proliferative myeloid clusters. Different Mo/Mg-TAM clusters manifest functional and transcriptional diversity controlled by specific regulons. Multiplex immunostaining of subset-specific markers identified spatial enrichment of distinct TAM clusters at peri-vascular/necrotic areas in tumour parenchyma or at the tumour-brain interface. Glioblastoma harboured a substantially higher number of monocytes and Mo-TAM-inflammatory clusters, whereas Astro-IDH-mut-G4 had a higher proportion of TAM subsets mediating antigen presentation. Glioblastomas with a higher proportion of monocytes exhibited a mesenchymal signature, increased angiogenesis, and worse patient outcome. Our findings provide insight into myeloid cell diversity and its clinical relevance in IDH-differential grade 4 gliomas, and may serve as a resource for immunotherapy development. © 2022 The Pathological Society of Great Britain and Ireland.

Electrochemical ammonia synthesis under ambient conditions using TM-embedded porphine-fused sheets as single-atom catalysts.

In this research, we systematically investigated the reaction mechanism and electrocatalytic properties of transition metal anchored two-dimensional (2D) porphine-fused sheets (TM-Por) as novel single-atom catalysts (SACs) for the electrochemical nitrogen reduction reaction (eNRR) under ambient conditions. Using high-throughput screening and first-principles calculations based on the density functional theory (DFT) method, three eNRR catalyst candidates, i.e. Mo-Por, Tc-Por, and Nb-Por, were screened out, with the eNRR onset potentials on them being -0.36, -0.53, and -0.74 V, respectively. Furthermore, these catalyst candidates all have good stability and selectivity. Analyzing the band structures found that these catalyst candidates all are metallic, which is needed for good electrocatalysts. Ab initio molecular dynamics (AIMD) simulations show that these catalyst candidates have good stability at 500 K. It is hoped that our work will open up new possibilities for the experimental synthesis of electrochemical ammonia catalysts.

How anthropogenic factors influence the dissolved oxygen in surface water over three decades in eastern China?

The aquatic environment, linked to the sustainable development of human existence and ecological environment, is influenced comprehensively by anthropogenic and natural activities. In light of the continuously low concentration of dissolved oxygen (DO) in surface water in plain river networks and the phenomenon of delay in the improvement of surface water quality, this research aims to introduce a method that may be utilized in identifying the critical driving forces of DO in surface water and their lagging characteristics, which will contribute to the assessment and adjustment of water quality drivers and/or policies. The research analyzes a typical small watershed in a river network region of the Yangtze River Delta plain as the study area, collecting 35-year (1986-2020) data on several water quality parameters, decades of anthropogenic activities, and two natural factors. The time series methods of vector autoregressive model, Granger causality tests, forecast error variance decompositions, and impulse response functions (hereinafter referred to as VAR+), which are rarely applied in related research, were employed in this study and proved helpful for screening out pivotal drivers and capturing the lagging responses of DO level to driving forces at each lagged time. Results show that there exists a fluctuating drop in DO level in surface water from 1986 to 2008 and a steady climb from 2008 to 2020, with the lowest DO level being present in 2008. The impulsive perturbations of phosphate fertilizer consumption (PFC), motor vessel number, and precipitation minimally increase DO concentration, while the impulsive perturbation of gross domestic product (GDP) causes the sharpest drop in DO level. With these perturbations, the driving force of PFC persists for approximately seven years, and the driving forces of water temperature, permanent population, and GDP persist for only five years. Future research could be conducted with spatial hysteresis, selection of lag order and variable quantity within the model, as well as intermediate variables between drivers and DO level for exploring driving pathways and mechanisms.

Forecasting oil consumption with attention-based IndRNN optimized by adaptive differential evolution.

Accurate prediction of oil consumption plays a dominant role in oil supply chain management. However, because of the effects of the coronavirus disease 2019 (COVID-19) pandemic, oil consumption has exhibited an uncertain and volatile trend, which leads to a huge challenge to accurate predictions. The rapid development of the Internet provides countless online information (e.g., online news) that can benefit predict oil consumption. This study adopts a novel news-based oil consumption prediction methodology-convolutional neural network (CNN) to fetch online news information automatically, thereby illustrating the contribution of text features for oil consumption prediction. This study also proposes a new approach called attention-based JADE-IndRNN that combines adaptive differential evolution (adaptive differential evolution with optional external archive, JADE) with an attention-based independent recurrent neural network (IndRNN) to forecast monthly oil consumption. Experimental results further indicate that the proposed news-based oil consumption prediction methodology improves on the traditional techniques without online oil news significantly, as the news might contain some explanations of the relevant confinement or reopen policies during the COVID-19 period.

Engineering at Subatomic Scale: Achieving Selective Catalytic Pathways via Tuning of the Oxidation States in Functionalized Single-Atom Quantum Catalysts.

Regulating the catalytic pathways of single-atom sites in single atom catalysts (SACs) is an exciting debate at the moment, which has redirected the research towards understanding and modifying the single-atom catalytic sites through various strategies including altering the coordination environment of single atom for desirable outcomes as well as increasing their number. One useful aspect concerning the tunability of the catalytic pathways of SACs, which has been overlooked, is the oxidation state dynamics of the single atoms. In this study, iron single-atoms (FeSA) with variable oxidation states, dependent on the precursors, are harnessed inside a nitrogen-rich functionalized carbon quantum dots (CQDs) matrix via a facile one-step and low-temperature synthesis process. Dynamic electronic properties are imparted to the FeSAs by the simpler carbon dots matrix of CQDs in order to achieve the desired catalytic pathways of reactive oxygen species (ROS) generation in different environments, which are explored experimentally and theoretically for an in-depth understanding of the redox chemistry that drives the alternative catalytic pathways in FeSA@CQDs. These alternative and oxidation state-dependent catalytic pathways are employed for specific as well as cascade-like activities simulating natural enzymes as well as biomarkers for the detection of cancerous cells.

Incoherent coded aperture correlation holographic imaging with fast adaptive and noise-suppressed reconstruction.

Fast and noise-suppressed incoherent coded aperture correlation holographic imaging is proposed, which is utilized by employing an annular sparse coded phase mask together with adaptive phase-filter cross-correlation reconstruction method. Thus the proposed technique here is coined as adaptive interferenceless coded aperture correlation holography (AI-COACH). In AI-COACH, an annular sparse coded phase mask is first designed and generated by the Gerchberg-Saxton algorithm for suppressing background noise during reconstruction. In order to demonstrate the three-dimensional and sectional imaging capabilities of the AI-COACH system, the imaging experiments of 3D objects are designed and implemented by dual-channel optical configuration. One resolution target is placed in the focal plane of the system as input plane and ensured Fourier transform configuration, which is employed as reference imaging plane, and moved the other resolution target to simulate different planes of a three-dimensional object. One point spread hologram (PSH) and multiple object-holograms without phase-shift at different axial positions are captured by single-exposure sequentially with the annular sparse CPMs. A complex-reconstruction method is developed to obtain adaptively high-quality reconstructed images by employing the cross-correlation of PSH and OH with optimized phase filter. The imaging performance of AI-COACH is investigated by imaging various type of objects. The research results show that AI-COACH is adaptive to different experimental conditions in the sense of autonomously finding optimal parameters during reconstruction procedure and possesses the advantages of fast and adaptive imaging with high-quality reconstructions.

Presenilin1 inhibits glioblastoma cell invasiveness via promoting Sortilin cleavage.

BACKGROUND: Alzheimer's disease (AD) and glioblastoma are the most common and devastating diseases in the neurology and neurosurgery departments, respectively. Our previous research reports that the AD-related protein Presenilin1 represses cell proliferation by inhibiting the Wnt/ß-catenin pathway in glioblastoma. However, the function of Presenilin1 and the underlying mechanism need to be further investigated. METHODS: The correlations of two genes were conducted on the R2 microarray platform and CGGA. Wound healing, Transwell assays and glioblastoma transplantation were performed to detect invasion ability. Phalloidin staining was employed to show cell morphology. Proximity ligation assays and protein docking assays were employed to detect two protein locations. We also employed western blotting to detect protein expression. RESULTS: We found that Presenilin1 clearly repressed the migration, invasion and mesenchymal transition of glioblastoma cells. Intriguingly, we observed that the expression of Presenilin1 was positively correlated with Sortilin, which is identified as a pro-invasion molecule in glioma. Furthermore, Presenilin1 interacted with Sortilin at the transmembrane domain and repressed Sortilin expression by cleaving it in glioblastoma cells. First, we found that Sortilin introduced the function of Presenilin1 in phosphorylating ß-catenin and repressing invasion in glioblastoma cells. Last, Presenilin1 stimulation sharply suppressed the invasion and mesenchymal transition of glioblastoma in mouse subcutaneous and intracranial transplantation models. CONCLUSIONS: Our study reveals that Sortilin mediates the regulation of ß-catenin by Presenilin1 and transduces the anti-invasive function of Presenilin1, which may provide novel therapeutic targets for glioblastoma treatment. Video Abstract.

The Inhibitory Effect of miR-345 on Glioma Progression Is Closely Related to circRNA-hsa_circ_0073237 and HDGF.

Glioma is the most common primary malignant tumor of the central nervous system and has a poor prognosis. Therefore, exploring the key molecular targets is a new opportunity for basic research and clinical treatment of glioma. Previous studies found that circRNA-hsa_circ_0073237 was upregulated in gliomas. Our further analyses of the biological function and molecular mechanism of hsa_circ_0073237 showed that hsa_circ_0073237 was also upregulated in glioma cell lines and could combine with miR-345 to inhibit its expression. miR-345 was downregulated in glioma tissues and cells, and targeted to regulate the expression of hepatoma-derived growth factor (HDGF), while HDGF expression was enhanced in glioma. Hsa_circ_0073237 promoted the expression of HDGF in glioma cells by adsorbing miR-345. Hsa_circ_0073237 siRNA, miR-345, and HDGF siRNA effectively inhibited cell viability and invasion and promoted cell apoptosis. When expression of hsa_circ_0073237 and miR-345 was inhibited simultaneously, cell viability, apoptosis, and invasion did not change significantly; however, after transfection with HDGF overexpression vector, the effects of hsa_circ_0073237 siRNA and miR-345 on glioma cell viability, apoptosis, and invasion were obviously reversed. Further construction of glioma xenograft models in nude mice confirmed that the introduction of miR-345 in vivo effectively inhibited tumor growth, significantly reduced tumor diameter and weight, and obviously decreased the expression of HDGF. Therefore, hsa_circ_0073237 can regulate the biological functions of glioma cells through miR-345/HDGF, thereby affecting the progression of tumors, indicating that the hsa_circ_0073237/miR-345/HDGF pathway may be a key target for the treatment of glioma.

Completed absorption of coronavirus disease 2019 (COVID-19) pneumonia lesions: a preliminary study.

Background: Complete absorption of coronavirus disease 2019 (COVID-19) pneumonia in a short term was not detailedly reported. We aimed to investigate the clinical and imaging characteristics of COVID-19 patients with complete absorption of pulmonary lesions. Methods: Retrospectively collected the clinical and chest CT data of 224 patients with COVID-19 in one regional medical center. Currently, pulmonary lesions in 37 patients were completely absorbed. The clinical manifestations, laboratory examinations, and CT findings of lesions for these patients were summarized. Results: Among the 37 patients (age, 39.0 ± 12.4 [14-63] years, 20 males), disease in 36 (97.3%) was mild and in 1 (2.7%) was from severe to mild. The most common symptoms were cough (24/37, 64.9%) and fever (23/37, 62.2%). Their laboratory indicators at admission were usually normal, while the white blood cell and neutrophil count significantly increased at discharge (p = 0.004, p = 0.006). On initial CT images, all patients had various pulmonary lesions (mean involved lobes: 2.8 ± 1.5, range: 1-5; mean involved segments: 6.6 ± 4.3, range: 1-16), which mainly manifested as multiple patchy and or spherical ground glass opacities (GGOs) (30/37, 81.1%) with fibrous strips (19/30, 63.3%) or consolidation (11/30, 36.7%). After treatment, lesions in most (33/37, 89.2%) patients were continuously absorbed. At discharge, previous lesions were mostly absorbed in 11 patients (11/37, 29.7%), the main residues were GGOs (24/37, 64.9%), followed by fibrous strips (13/37, 35.1%). On the latest CT, all the pulmonary lesions were completely absorbed, the duration of lesions was 31.6 ± 11.4 days (range: 5-50 days). Conclusion: The pulmonary lesions in some mild COVID-19 patients (generally with normal laboratory indicators at admission, GGOs as the main manifestation on initial CT, and representation of continuous absorption after treatment) could be completely absorbed with a mean duration of 31.6 days.

A novel de novo TSC2 nonsense mutation detected in a pediatric patient with tuberous sclerosis complex.

PURPOSE: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by hamartomas in multiple organ systems. The TSC1 and TSC2 genes have been identified as the genetic basis of TSC. Two gene tests were used for definitive genetic diagnosis. METHODS: In our study, the case of a Chinese pediatric patient with seizures, hypomelanotic macules, hyperpigmented patches, multiple parenchymal lesions in the ventricle, and developmental retardation is detailed. Whole-genome sequencing (WGS) and multiplex ligation-dependent probe amplification (MLPA) were employed to detect genetic variations and copy number variations of TSC1 and TSC2. RESULTS: A novel heterozygous nonsense mutation in the TSC2 gene (c.3751A>T, p.Lys1251Ter) was identified in a Chinese pediatric patient suffering from TSC, whose unaffected parents did not carry this mutation. The mutation was classified as "pathogenic" according to the American College of Medical Genetics (ACMG) guidelines. CONCLUSION: WGS was carried out to definitively diagnose and detect variations in the exon and noncoding region of the gene and copy number variations in the whole genome simultaneously. For diseases with complex genetic mechanisms, WGS as the first-line test can be efficient and cost-effective for clinical diagnosis.

Relationship between the sodium fluorescein yellow fluorescence boundary and the actual boundary of high-grade gliomas during surgical resection.

OBJECTIVE: Resection of high-grade glioma with sodium fluorescein can improve the resection rate of the glioma and improve survival. However, it is unclear whether the yellow fluorescence boundary of the high-grade glioma is consistent with the actual boundary of the tumor. This study explores the yellow fluorescence boundary and the actual tumor boundary in high-grade glioma surgery. METHODS: This is a retrospective analysis of 10 patients with high-grade gliomas who underwent tumor visualization with sodium fluorescein. After staining of the tumor, random selections of both developed and non-developed yellow fluorescent border tissue at the fluorescence chromogenic boundary were made, followed by pathological examination. Claudin-5, an important component of the tight connections between vascular endothelial cells, was assessed by immunohistochemistry and qRT-PCR in the tumor and surrounding tissues in order to determine the tumor cell content of the tissue, blood-brain barrier damage, and vascular proliferation. The yellow fluorescence boundary was compared with the actual tumor boundary and the results analyzed. RESULTS: Tumor cells were still detected outside the yellow fluorescence boundary during high-grade glioma surgery (P < 0.05). Claudin-5 expression was higher in high-grade gliomas than in adjacent normal tissues (P < 0.05), while disconnected Claudin-5 expression was associated with intraoperative yellow fluorescence imaging (r = 0.67). CONCLUSIONS: There is a difference between the yellow fluorescence boundary and the actual boundary of the tumor in high-grade glioma, and there are glioma cell infiltrations in the brain tissue of the undeveloped yellow fluorescent border. To ensure patient recovery and function, it is recommended that tumor resection be expanded based on yellow fluorescence visualization. Claudin-5 is overall up-regulated in high-grade gliomas, but some Claudin-5 expression is disconnected. This Claudin-5 expression pattern may be related to the development of yellow fluorescence.

CCL8 secreted by tumor-associated macrophages promotes invasion and stemness of glioblastoma cells via ERK1/2 signaling.

Tumor-associated macrophages (TAMs) constitute a large population of glioblastoma and facilitate tumor growth and invasion of tumor cells, but the underlying mechanism remains undefined. In this study, we demonstrate that chemokine (C-C motif) ligand 8 (CCL8) is highly expressed by TAMs and contributes to pseudopodia formation by GBM cells. The presence of CCL8 in the glioma microenvironment promotes progression of tumor cells. Moreover, CCL8 induces invasion and stem-like traits of GBM cells, and CCR1 and CCR5 are the main receptors that mediate CCL8-induced biological behavior. Finally, CCL8 dramatically activates ERK1/2 phosphorylation in GBM cells, and blocking TAM-secreted CCL8 by neutralized antibody significantly decreases invasion of glioma cells. Taken together, our data reveal that CCL8 is a TAM-associated factor to mediate invasion and stemness of GBM, and targeting CCL8 may provide an insight strategy for GBM treatment.

Krüppel-like factor 4 (KLF4) induces mitochondrial fusion and increases spare respiratory capacity of human glioblastoma cells.

Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor critical for the regulation of many cellular functions in both normal and neoplastic cells. Here, using human glioblastoma cells, we investigated KLF4's effects on cancer cell metabolism. We found that forced KLF4 expression promotes mitochondrial fusion and induces dramatic changes in mitochondrial morphology. To determine the impact of these changes on the cellular functions following, we analyzed how KLF4 alters glioblastoma cell metabolism, including glucose uptake, glycolysis, pentose phosphate pathway, and oxidative phosphorylation. We did not identify significant differences in baseline cellular metabolism between control and KLF4-expressing cells. However, when mitochondrial function was impaired, KLF4 significantly increased spare respiratory capacity and levels of reactive oxygen species in the cells. To identify the biological effects of these changes, we analyzed proliferation and survival of control and KLF4-expressing cells under stress conditions, including serum and nutrition deprivation. We found that following serum starvation, KLF4 altered cell cycle progression by arresting the cells at the G2/M phase and that KLF4 protected cells from nutrition deprivation-induced death. Finally, we demonstrated that methylation-dependent KLF4-binding activity mediates mitochondrial fusion. Specifically, the downstream targets of KLF4-mCpG binding, guanine nucleotide exchange factors, serve as the effector of KLF4-induced mitochondrial fusion, cell cycle arrest, and cell protection. Our experimental system provides a robust model for studying the interactions between mitochondrial morphology and function, mitochondrial dynamics and metabolism, and mitochondrial fusion and cell death during tumor initiation and progression.

Isovitexin (IV) induces apoptosis and autophagy in liver cancer cells through endoplasmic reticulum stress.

Liver cancer is a leading cause of cancer death worldwide, and novel chemotherapeutic drugs to suppress liver cancer are urgently required. Isovitexin (IV), a glycosylflavonoid, is extracted from rice hulls of Oryza sativa, and has various biological activities. However, the anti-tumor effect of IV against liver cancer has not yet been demonstrated in vitro or in vivo. In the present study, we showed that IV significantly suppressed the growth of liver cancer cells. Mechanistic studies indicated that IV induced apoptosis by the mitochondrial apoptotic pathway, as evidenced by the increase of Bax, cleaved Caspase-3, poly (ADP-ribose) polymerase (PARP), and cytoplasm Cyto-c released from mitochondria. In addition, IV resulted in autophagy in liver cancer cells, supported by the enhancement of LC3II, autophagy-related protein (Atg) 3, Atg5 and Beclin1. Suppressing autophagy using bafilomycin A1 (BFA) or siRNA Atg-5 reduced apoptotic cells in IV-treated cells, demonstrating that autophagy induction regulated apoptosis. Moreover, IV was found to cause endoplasmic reticulum (ER) stress in liver cancer cells, along with the promotion of ER stress-related molecules, including inositol-requiring enzyme 1α (IRE1α), X-box-binding protein-1s (XBP-1s), C/EBP homologous protein (CHOP) and glucose-regulated protein (GRP)-78. Of note, inhibition of ER stress by use of its inhibitor, tauroursodeoxycholate (TUDCA), significantly reversed IV-induced apoptosis and autophagy. In vivo, IV treatment showed significant tumor growth inhibition compared to the non-treated group. IV could therefore be a strong candidate for liver cancer prevention.

Krüppel-like factor 9 and histone deacetylase inhibitors synergistically induce cell death in glioblastoma stem-like cells.

BACKGROUND: The dismal prognosis of patients with glioblastoma (GBM) is attributed to a rare subset of cancer stem cells that display characteristics of tumor initiation, growth, and resistance to aggressive treatment involving chemotherapy and concomitant radiation. Recent research on the substantial role of epigenetic mechanisms in the pathogenesis of cancers has prompted the investigation of the enzymatic modifications of histone proteins for therapeutic drug targeting. In this work, we have examined the function of Krüppel-like factor 9 (KLF9), a transcription factor, in chemotherapy sensitization to histone deacetylase inhibitors (HDAC inhibitors). METHODS: Since GBM neurosphere cultures from patient-derived gliomas are enriched for GBM stem-like cells (GSCs) and form highly invasive and proliferative xenografts that recapitulate the features demonstrated in human patients diagnosed with GBM, we established inducible KLF9 expression systems in these GBM neurosphere cells and investigated cell death in the presence of epigenetic modulators such as histone deacetylase (HDAC) inhibitors. RESULTS: We demonstrated that KLF9 expression combined with HDAC inhibitor panobinostat (LBH589) dramatically induced glioma stem cell death via both apoptosis and necroptosis in a synergistic manner. The combination of KLF9 expression and LBH589 treatment affected cell cycle by substantially decreasing the percentage of cells at S-phase. This phenomenon is further corroborated by the upregulation of cell cycle inhibitors p21 and p27. Further, we determined that KLF9 and LBH589 regulated the expression of pro- and anti- apoptotic proteins, suggesting a mechanism that involves the caspase-dependent apoptotic pathway. In addition, we demonstrated that apoptosis and necrosis inhibitors conferred minimal protective effects against cell death, while inhibitors of the necroptosis pathway significantly blocked cell death. CONCLUSIONS: Our findings suggest a detailed understanding of how KLF9 expression in cancer cells with epigenetic modulators like HDAC inhibitors may promote synergistic cell death through a mechanism involving both apoptosis and necroptosis that will benefit novel combinatory antitumor strategies to treat malignant brain tumors.

The rise of soluble platelet-derived growth factor receptor ß in CSF early after subarachnoid hemorrhage correlates with cerebral vasospasm.

Platelet-derived growth factor ß (PDGFß) has been proposed to contribute to the development of cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH), and soluble PDGFRß (sPDGFRß) is considered to be an inhibitor of PDGF signaling. We aimed at determining the sPDGFRß concentrations in the cerebrospinal fluid (CSF) of patients with aneurysmal SAH (aSAH) and analyzing the relationship between sPDGFRß level and CVS. CSF was sampled from 32 patients who suffered aSAH and five normal controls. Enzyme-linked immunosorbent assay was performed to determine the sPDGFRß concentrations in the CSF. Functional outcome was assessed using modified Rankin scale (mRS) at 6 months after aSAH. CVS was identified using transcranial Doppler or angio-CT or DSA. The cutoff of sPDGFRß for CVS was defined on the ROC curve. The concentrations of sPDGFRß following aSAH were both higher than those of normal controls on days 1-3 and 4-6, and peaked on days 7-9 post-SAH. The cutoff value of sPDGFRß level on days 1-3 for CVS was defined as 975.38 pg/ml according to the ROC curve (AUC = 0.680, p = 0.082). In addition, CSF sPDGFRß concentrations correlated with CVS (r = 0.416, p = 0.018), and multivariate analysis indicated that sPDGFRß level higher than 975.38 pg/ml on days 1-3 was an independent predictor of CVS (p = 0.001, OR = 19.22, 95% CI: 3.27-113.03), but not for unfavorable outcome after aSAH in the current study. CSF sPDGFRß level increases after aSAH and is higher in patients who developed CVS, and sPDGFRß level higher than 975.38 pg/ml on days 1-3 is a potential predictor for CVS after SAH.

Blood-Brain Barrier Disruption, Sodium Fluorescein, And Fluorescence-Guided Surgery Of Gliomas.

PURPOSE: Sodium fluorescein (SF) is an ideal dye for intraoperative guided-resection of high-grade gliomas (HGGs). However, it is not well understood whether the SF-guided technique is suitable for different grades of gliomas, and the correlation between fluorescence and pathology is also not yet clear. MATERIALS AND METHODS: In this study, we investigated 28 patients, including 23 patients with HGG and 5 patients with low-grade glioma (LGG). All patients were treated using the SF-guided technique on a Pentero 900 microscope (Carl Zeiss, Oberkochen, Germany). Claudin-5 immunohistochemical (IHC) staining for the tumours and peritumour tissues was analyzed. RESULTS: Intraoperative yellow fluorescence was noted in all the HGGs but not in the LGGs. Claudin-5 expression in the blood brain barrier endothelial cells was downregulated and disconnected in the HGGs (p < 0.05), but had no difference or slightly decreased in the LGGs (p > 0.05). CONCLUSIONS: The SF-guided technique is suitable for HGG surgery but not for LGG surgery. Downregulation of claudin-5 expression may contribute to the presence of yellow fluorescence in the glioma in SF-guided surgery.