Expert opinion on translational research for advanced glioblastoma treatment

Malignant gliomas are known to be one of the most difficult diseases to diagnose and treat because of the infiltrative growth pattern,rapid progression,and poor prognosis.Many antitumor drugs are not ideal for the treatment of gliomas due to the blood-brain barrier.Temozolomide(TMZ)is a DNA alkylating agent that can cross the blood-brain barrier.As the only first-line chemotherapeutic drug for malignant gliomas at present,TMZ is widely utilized to provide a survival benefit;however,some patients are inherently insensitive to TMZ.In addition,patients could develop acquired resistance during TMZ treatment,which limits antitumor efficacy.To clarify the mechanism underlying TMZ resistance,numerous studies have provided multilevel solutions,such as improving the effective concentration of TMZ in tumors and developing novel small molecule drugs.This review discusses the in-depth mechanisms underlying TMZ drug resistance,thus aiming to provide possibilities for the establishment of personalized therapeutic strategies against malignant gliomas and the accelerated development and transformation of new targeted drugs.

Identification of the E2F1-RAD51AP1 axis as a key factor in MGMT-methylated GBM TMZ resistance

Objective:Epidermal growth factor receptor variant III(EGFRvIII)is a constitutively-activated mutation of EGFR that contributes to the malignant progression of glioblastoma multiforme(GBM).Temozolomide(TMZ)is a standard chemotherapeutic for GBM,but TMZ treatment benefits are compromised by chemoresistance.This study aimed to elucidate the crucial mechanisms leading to EGFRvIII and TMZ resistance.Methods:CRISPR-Cas13a single-cell RNA-seq was performed to thoroughly mine EGFRvIII function in GBM.Western blot,realtime PCR,flow cytometry,and immunofluorescence were used to determine the chemoresistance role of E2F1 and RAD51-associated protein 1(RAD51AP1).Results:Bioinformatic analysis identified E2F1 as the key transcription factor in EGFRvIII-positive living cells.Bulk RNA-seq analysis revealed that E2F1 is a crucial transcription factor under TMZ treatment.Western blot suggested enhanced expression of E2F1 in EGFRvIII-positive and TMZ-treated glioma cells.Knockdown of E2F1 increased sensitivity to TMZ.Venn diagram profiling showed that RAD51AP1 is positively correlated with E2F1,mediates TMZ resistance,and has a potential E2F1 binding site on the promoter.Knockdown of RAD51AP1 enhanced the sensitivity of TMZ;however,overexpression of RAD51AP1 was not sufficient to cause chemotherapy resistance in glioma cells.Furthermore,RAD51AP1 did not impact TMZ sensitivity in GBM cells with high O6-methylguanine-DNA methyltransferase(MGMT)expression.The level of RAD51AP1 expression correlated with the survival rate in MGMT-methylated,but not MGMT-unmethylated TMZ-treated GBM patients.Conclusions:Our results suggest that E2F1 is a key transcription factor in EGFRvIII-positive glioma cells and quickly responds to TMZ treatment.RAD51AP1 was shown to be upregulated by E2F1 for DNA double strand break repair.Targeting RAD51AP1 could facilitate achieving an ideal therapeutic effect in MGMT-methylated GBM cells.

The catalytic effect of the Na and Ca-rich industrial wastes on the thermal ignition of coal combustion

The catalytic effects of four industrial wastes,namely,the soap residue(SR),brine sludge(BS),calcium carbide residue(CCR),and white lime mud(WLM),on coal thermal ignition were investigated.The acidity of palmitate anion associated with Na+in SR was lower than that of chloride anion combined with Na+in BS,which resulted in an improved the combustion of SR.The acidity of OH-anion combined with Ca2+in CCR was lower than that of CO32-anion combined with Ca2+in WLM,resulting in CCR exhibiting a better catalytic effect on coal ignition.The alkaline metal Na had lower initial ionisation energy than the alkaline earth metal Ca.Therefore,the Na-rich SR exhibited higher catalytic activity on coal ignition than Ca-rich CCR.The ignition temperature of coal with 0.5%SR decreased from 544 to 503°C.

Boosting of the enhanced permeability and retention effect with nanocapsules improves the therapeutic effects of cetuximab

Objective:The introduction of therapeutic antibodies(tAbs)into clinical practice has revolutionized tumor treatment strategies,but their tumor therapy efficiency is still far below expectations because of the rapid degradation and limited tumor accumulation of tAbs.Methods:We developed a nanocapsule-based delivery system to induce the self-augmentation of the enhanced permeability and retention(EPR)effect.This system constantly penetrated across the blood-tumor barrier into the tumor while avoiding the attack of tAbs by the immune system.The biodistribution and therapeutic effect were tested with single dose administration of nanocapsule-tAbs in vivo.Results:The accumulation of Nano(cetuximab)within subcutaneous PC9 tumors was gradually enhanced over 6 days after single dose administration,which was contrary to the biodistribution of native cetuximab.Nano(cetuximab)accumulated in tumor tissues via the EPR effect and released cetuximab.The released cetuximab acted on vascular endothelial cells to destroy the blood-tumor barrier and induce self-augmentation of the EPR effect,which in turn contributed to further tumor accumulation of long-circulating Nano(cetuximab).Compared with single dose administration of native cetuximab,Nano(cetuximab)showed an effective tumor suppressive effect for 3 weeks.Conclusions:The nanocapsule-based delivery system efficiently delivered tAbs to tum or tissues and released them to boost the EPR effect,which facilitated further tumor accumulation of the tAbs.This novel self-augmentation of the EPR effect facilitated by the biological characteristics of tAbs and nanotechnology contributed to the improvement of the therapeutic effect of tAbs,and stimulated new ideas for antibody-based tumor therapy.

TGFβ signaling-induced miRNA participates in autophagic regulation by targeting PRAS40 in mesenchymal subtype of glioblastoma

Objective:Mesenchymal subtype of glioblastoma(mesGBM)is a refractory disease condition characterized by therapeutic failure and tumor recurrence.Hyperactive transforming growth factor-β(TGF-β)signaling could be a signature event in mesGBM,which leads to dysregulation of downstream targets and contribute to malignant transformation.In this study we aimed to investigate the hyperactive TGFβsignaling-mediated pathogenesis and possible downstream targets for the development of novel therapeutic interventions for mesGBM.Methods:GBM-BioDP is an online resource for accessing and displaying interactive views of the TCGA GBM data set.Transcriptomic sequencing followed by bioinformatic analysis was performed to identify dysregulated microRNAs.Target prediction by MR-microT and dual luciferase reporter assay were utilized to confirm the predicted target of novel_miR56.CCK-8 assays was used to assesse cell viability.The miRNA manipulation was proceeded by cell transfection and lentivirus delivery.A plasmid expressing GFP-LC3 was introduced to visualize the formation of autophagosomes.Orthotopic GBM model was constructed forin vivo study.Results:TGFβ1 and TGFβreceptor type II(TβRII)were exclusively upregulated in mesGBM(P<0.01).Dysregulated miRNAs were identified after LY2109761(a TβRI/II inhibitor)treatment in a mesGBM-derived cell line,and novel_miR56 was selected as a promising candidate for further functional verification.Novel_miR56 was found to potentially bind to PRAS40 via seed region complementarity in the 3'untranslated region,and we also confirmed that PRAS40 is a direct target of novel_miR56 in glioma cells.In vitro,over expression of novel_miR56 in tumor cells significantly promoted proliferation and inhibited autophagy(P<0.05).The expression levels of P62/SQSTM was significantly increased accompanied by the decrease of BECN1 and LC3B-II/I,which indicated that autophagic activity was reduced after novel_miR56 treatment.In addition,over expression of novel_miR56 also promoted tumor growth and inhibited autophagyin vivo,which is associated with worse prognosis(P<0.05).Conclusions:In summary,we provide novel insight into TGFβsignaling-mediated pathogenesis in mesGBM and TGFβsignaling-induced novel_miR56 may be a novel target for mesGBM management.

Blockage of EGFR/AKT and mevalonate pathways synergize the antitumor effect of temozolomide by reprogramming energy metabolism in glioblastoma

Background Metabolism reprogramming plays a vital role in glioblastoma(GBM)progression and recurrence by producing enough energy for highly proliferating tumor cells.In addition,metabolic reprogramming is crucial for tumor growth and immune-escape mechanisms.Epidermal growth factor receptor(EGFR)amplification and EGFR-vIII mutation are often detected in GBM cells,contributing to the malignant behavior.This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation.Methods Clinical GBM specimens were selected for single-cell RNA sequencing and untargeted metabolomics analysis.A metabolism-associated RTK-fatty acid-gene signature was constructed and verified.MK-2206 and MK-803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism.Energy metabolism in GBM with activated EGFR pathway was monitored.The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide(TMZ)was analyzed by an intracranial tumor model in vivo.Results GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels,supported by the single-cell RNA sequencing and metabolomics of clinical GBM samples.Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production.Mechanistically,the EGFR/AKT pathway upregulated the expressions of acyl-CoA synthetase short-chain family member 3(ACSS3),acyl-CoA synthetase long-chain family member 3(ACSL3),and long-chain fatty acid elongation-related gene ELOVL fatty acid elongase 2(ELOVL2)in an NF-κB-dependent manner.Moreover,inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes,thereby affecting the signal transduction of the EGFR/AKT pathway.Therefore,targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models.Conclusions Our findings not only uncovered the mechanism of metabolic reprogramming in EGFR-activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.

Pyrolytic gas analysis and evaluation from thermal plasma pyrolysis of simulated oil-based drill cuttings

Oil-based drill cuttings(OBDCs)are hazardous wastes generated during shale gas exploration,and the rapid,efficient and safe disposal methods for OBDCs have attracted the attention of many researchers.Plasma pyrolysis technology is widely used in solid waste treatment due to its extremely high temperature and reaction activity.A laboratory-scale thermal plasma pyrolysis system was built to investigate the plasma pyrolysis mechanism of simulated OBDCs.The thermal decomposition characteristics of OBDCs were studied by thermogravimetric-derivative thermo gravimetric-differential scanning calorimetry(TG-DTG-DSC)analysis in the range of 50–1300℃.The thermal decomposition process of OBDCs was divided into the following four stages:evaporation of water and light oil,evaporation and decomposition of heavy oil,carbonate decomposition,and phase change reaction from solid to liquid.The effects of the oil ratio,water content,and water/oil(W/O)ratio of OBDCs on the composition and gas selectivity of pyrolytic gas were investigated.The results show that thermal plasma can crack the mineral oil in the OBDCs into clean gases such as H_(2),CO and C_(2)H_(2),while water can promote the decomposition of the heavy oil molecules and enhance the H_(2)production.The energy consumption model calculation for the pyrolysis and melting of OBDCs shows that the highest energy utilization and the lowest molar energy consumption of H_(2)were achieved at a W/O ratio of 1:4.Based on the thermal plasma pyrolysis system used in this study,the commercial application prospects and economic benefits of the plasma pyrolysis of OBDCs were discussed.

Frequency comparative study of coal-fired fly ash acoustic agglomeration

Particulate pollution is main kind of atmospheric pollution.The fine particles are seriously harmful to human health and environment.Acoustic agglomeration is considered as a promising pretreatment technology for fine particle agglomeration.The mechanisms of acoustic agglomeration are very complex and the agglomeration efficiency is affected by many factors.The most important and controversial factor is frequency.Comparative studies between high-frequency and low-frequency sound source to agglomerate coal- fired fly ash were carried out to investigate the influence of frequency on agglomeration efficiency.Acoustic agglomeration theoretical analysis,experimental particle size distributions （PSDs） and orthogonal design were examined.The results showed that the 20 kHz high-frequency sound source was not suitable to agglomerate coal-fired fly ash.Only within the size ranging from 0.2 to 0.25 μm the particles agglomerated to adhere together,and the agglomerated particles were smaller than 2.5 μm.The application of low-frequency （1000–1800 Hz） sound source was proved as an advisable pretreatment with the highest agglomeration efficiency of 75.3%,and all the number concentrations within the measuring range decreased.Orthogonal design L16 （4） 3 was introduced to determine the optimum frequency and optimize acoustic agglomeration condition.According to the results of orthogonal analysis,frequency was the dominant factor of coal-fired fly ash acoustic agglomeration and the optimum frequency was 1400 Hz.

LES investigation of swirl intensity effect on unconfined turbulent swirling premixed flame

A finite reaction rate model is presented as a closure of large eddy simulation(LES) to numerically study an open premixed methane/air swirling flame. The resultant model is firstly validated by comparing with reported data and then employed to investigate the effect of swirling intensity on flow field, flame characteristics and combustion instability of the swirling flame. Three different swirl numbers are considered. The LES results show that as swirling intensity increases, the vortex entrainment and micro-mixing are enhanced, leading to more lean equivalent ratios at flame front; consequently, higher swirling number causes lower flame temperatures and slower CO oxidization; for all simulated swirl numbers,flame fronts are completely located out of the recirculation zones and anchored at the inner surface of the annular swirling steams; swirl number has a crucial effect on swirling flame extension toward radial and tangential dimensions and then significantly affects streamwise flame length, which is a great influencing factor on combustion instability; vortex-induced disturbance on flame in streamwise plays a critical role in combustion instability.

Effect of particle size and oxygen content on ignition and combustion of aluminum particles

Particle size and oxygen content are two of the key factors that affect the ignition and combustion properties of aluminum particles. In this study, a laser ignition experimental system and flame test system were built to analyze the ignition and combustion characteristics and the flame morphology of aluminum particles. A thermobalance system was used to analyze the thermal oxidation characteristics. In addition, the microstructure of aluminum was analyzed by scanning electron microscopy. It was found that the oxidized products were some of the gas phase products agglomerated. Smaller particle size samples showed better combustion characteristics. The combustion intensity, self-sustaining combustion time and the burn-off rate showed a rising trend with the decrease in the particle size. Increasing the oxygen content in the atmosphere could improve the ignition and combustion characteristics of the samples. Four distinct stages were observed in the process of ignition and combustion. Small particle size samples had a larger flame height and luminance, and the self-sustaining combustion time was much longer.Three distinct stages were observed during the thermal oxidation process. The degree of oxidation for small-sized samples was significantly higher than that for the larger particle size samples.Moreover, it was observed that the higher the oxygen content, the higher the degree of oxidation was.

Ultrasensitive polarization-dependent terahertz modulation in hybrid perovskites plasmoninduced transparency devices

Active control of metamaterial properties with high tunability of both resonant intensity and frequency is essential for advanced terahertz(THz) applications, ranging from spectroscopy and sensing to communications.Among varied metamaterials, plasmon-induced transparency(PIT) has enabled active control with giant sensitivity by embedding semiconducting materials. However, there is still a stringent challenge to achieve dynamic responses in both intensity and frequency modulation. Here, an anisotropic THz active metamaterial device with an ultrasensitive modulation feature is proposed and experimentally studied. A radiative-radiative-coupled PIT system is established, with a frequency shift of 0.26 THz in its sharp transparent windows by polarization rotation. Enabled by high charge-carrier mobility and longer diffusion lengths, we utilize a straightforwardly spincoated MAPbI3 film acting as a photoactive medium to endow the device with high sensitivity and ultrafast speed.When the device is pumped by an ultralow laser fluence, the PIT transmission windows at 0.86 and 1.12 THz demonstrate a significant reduction for two polarizations, respectively, with a full recovery time of 561 ps. In addition, we numerically prove the validity that the investigated resonator structure is sensitive to the optically induced conductivity. The hybrid system not only achieves resonant intensity and frequency modulations simultaneously, but also preserves the all-optical-induced switching merits with high sensitivity and speed, which enriches multifunctional subwavelength metamaterial devices at THz frequencies.

Ultrafast polarization-dependent all-optical switching of germanium-based metaphotonic devices

Metamaterials play an important role in the modulation of amplitude and group delay in the terahertz(THz)regime on account of their optical properties,which are rare in natural materials.Here an ultrafast anisotropic switch of the plasmon-induced transparency(PIT)effect is experimentally and numerically demonstrated by metamaterial devices composed of two pairs of planar split-ring resonators and a pair of closed-ring resonators.By integration with a germanium(Ge)film,a recovery time of 3 ps and a decay constant of 785 fs are realized in the metadevice.Stimulated by the exterior optical pump,the PIT windows at different frequencies are switched off with an excellent property of slow light for vertical and horizontal THz polarizations,realizing an astonishing modulation depth as high as 99.06%.This work provides a new platform for ultrafast anisotropic metadevices tunable for amplitude and group delay.

Downregulation of lncRNA-HOXA11-AS modulates proliferation and stemness in Glioma cells

Background: Glioma stem cells (GSCs) represent a subpopulation of cells within glioma that are characterized by chemotherapy resistance and tumor recurrence. GSCs are therefore important therapeutic target for glioma therapy.Long non-coding RNAs (lncRNAs) have been shown to regulate important functions in cancer. HOXA11-AS is one such lncRNA and has been shown to regulate cell proliferation via promotion of cell cycle progression in glioblastoma (GBM) cells. However, the specific roles of HOXA11-AS in GSCs remain unclear.Methods: Here we investigated the role of HOXA11-AS in driving GSC stemness properties via sphere-forming and protein chip assays.Results: Gain-of-function as well as loss-of-function results showed that the HOXA11-AS maybe a critical modulator in GBM recurrence as demonstrated by cell sphere-forming ability. Furthermore, we showed that induced expression of HOXA11-AS does increase the levels of stemness-related transcription factors (Oct4/Sox17/Sox2) in U87MG cells. In vivo xenograft experiments using the HOXA11-AS knockdown U87MG cells revealed that downregulation of HOXA11-AS could strongly inhibit tumor growth. Furthermore, we found that HOXA11-AS knockdown decreased the expression of cancer stemness markers in vivo.Conclusions: Collectively, these data suggests that HOXA11-AS is involved in GSC stemness and supports its clinical significance as a important therapeutic target in glioma.

Systemic delivery of microRNA for treatment of brain ischemia

Brain ischemia is the second leading cause of death and the third leading cause of disability in the world.Systemic delivery of microRNA,a class of molecules that regulate the expression of cellular proteins associated with angiogenesis,cell growth,proliferation and differentiation,holds great promise for the treatment of brain ischemia.However,their therapeutic efficacy has been hampered by poor delivery efficiency of microRNA.We report herein a platform technology based on microRNA nanocapsules,which enables their effective delivery to the disease sites in the brain.Exemplified by microRNA-21,intravenous injection of the nanocapsules into a rat model of cerebral ischemia could effectively ameliorate the infarct volume,neurological deficit and histopathological severity.

Optically Controlled Extraordinary Terahertz Transmission of Bi2Se3 Film Modulator

Standing on the potential for high-speed modulation and switching in the terahertz (THz) regime, all-optical approaches whose response speeds mainly depend on the lifetime of nonequilibrium free carriers have attracted a tremendous attention. Here, we establish a novel bi-direction THz modulation experiment controlled by femtosecond laser for new functional devices. Specifically, time-resolved transmission measurements are conducted on a series of thin layers Bi2Se3 films fabricated straightforwardly on AI2O3 substrates, with the pump fluence range from 25(iJ/cm2 to 200 |iJ/cm2 per pulse. After photoexcitation, an ultrafast switching of THz wave with a full recovery time of ?1 Ops is observed. For a longer timescale, a photoinduced increase in the transmitted THz amplitude is found in the 8 and 10 quintuple layers (QL) BizSR, which shows a thickness-dependent topological phase transition. Additionally, the broadband modulation effect of the 8 QL Bi2Se3 film is presented at the time delays of 2.2ps and 12.5ps which have a maximum modulation depth of 6.4% and 1.3% under the pump fluence of 200(iJ/cm2, respectively. Furthermore, the absorption of a optical phonon at 1.9 THz shows a time-dependent evolution which is consistent with the cooling of lattice temperature.

Flow behavior of high-temperature flue gas in the heat transfer chamber of a pilot-scale coal-water slurry combustion furnace

The flow characteristics of high-temperature flue gas are important in the heat transfer of coal-water slurry（CWS） combustion furnaces.The flow field of a 250 kg/h vertical-type slag tap cyclone furnace was non-intrusively investigated,using two-dimensional particle-image velocimetry（2D PIV）.The method was verified using traceable fly ash particles in high-temperature flue gas.The flow field of the flue gas was analyzed with a time-averaged method,based on which the effects of excess air ratio and loading were investigated.The flue gas separated by a gas separator maintained good rigidity near the furnace wall,rather than eroding the heating surface.Numerical simulations validated the reliability of PIV under the actual circumstances within the furnace.This study provides guidelines for applying 2D PIV in analyzing flue gas in thermal test boilers.

Temperature insensitive multi-channel light amplification systems on SOI platform

We present a theoretical analysis of a novel multi-channel light amplification photonic system on chip,where the nonlinear Raman amplification phenomenon in the silicon(Si)wire waveguide is considered.Particularly,a compact and temperature insensitive Mach–Zehnder interferometer filter working as demultiplexer is also exploited,allowing for the whole Si photonic system to be free from thermal interference.The propagation of the multi-channel pump and Stokes lights is described by a rigorous theoretical model that incorporates all relevant linear and nonlinear optical effects,including the intrinsic waveguide optical losses,first-and second-order frequency dispersion,self-phase and cross-phase modulation,phase shift and two-photon absorption,free-carriers dynamics,as well as the inter-pulse Raman interaction.Notably,to prevent excessive drift of the transmission window of the demultiplexer caused by ambient temperature variations and high thermo-optical coefficient of Si,an asymmetric waveguide width is adopted in the upper and lower arms of each Mach–Zehnder interferometer lattice cell.A Chebyshev half-band filter is utilized to achieve a flat pass-band transmission,achieving a temperature sensitivity of<1.4 pm=K and over 100 K temperature span.This all-Si amplifier shows a thermally robust behavior,which is desired by future Si-on-insulator(SOI)applications.

Enhancing growth rate of lettuce by mutating lettuce seeds with nuclear irradiation

To improve growth rate of hydroponics lettuce with CO_(2)aeration,lettuce seeds were mutated by nuclear irradiation(c rays from^(137)Cs)and domesticated with high concentration of CO_(2).When lettuce seeds were mutated with 30 Gy dosage,wet weight of lettuce increased by 22.3%(to 52.24 g)on the 30th day and grana volume in the chloroplasts of leaf cells increased by 244%.After the mutant(irradiated by 50 Gy dosage)was domesticated with elevated CO_(2)concentration,wet weight of lettuce increased by 74.6%(to 48.7 g)on the 24th day under 3 vol%CO_(2),compared with wet weight of lettuce under air condition.Results showed that mutagenesis by nuclear irradiation made it possible to improve CO_(2)fixation rate in lettuce in a gene-modified way.