VEGFR2 blockade inhibits glioblastoma cell proliferation by enhancing mitochondrial biogenesis.

BACKGROUND: Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor receptor 2 (VEGFR2) inhibition have been investigated as an alternative glioblastoma treatment. However, little is known about the effect of VEGFR2 blockade on glioblastoma cells per se. METHODS: VEGFR2 expression data in glioma patients were retrieved from the public database TCGA. VEGFR2 intervention was implemented by using its selective inhibitor Ki8751 or shRNA. Mitochondrial biogenesis of glioblastoma cells was assessed by immunofluorescence imaging, mass spectrometry, and western blot analysis. RESULTS: VEGFR2 expression was higher in glioma patients with higher malignancy (grade III and IV). VEGFR2 inhibition hampered glioblastoma cell proliferation and induced cell apoptosis. Mass spectrometry and immunofluorescence imaging showed that the anti-glioblastoma effects of VEGFR2 blockade involved mitochondrial biogenesis, as evidenced by the increases of mitochondrial protein expression, mitochondria mass, mitochondrial oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production, all of which play important roles in tumor cell apoptosis, growth inhibition, cell cycle arrest and cell senescence. Furthermore, VEGFR2 inhibition exaggerated mitochondrial biogenesis by decreased phosphorylation of AKT and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which mobilized PGC1α into the nucleus, increased mitochondrial transcription factor A (TFAM) expression, and subsequently enhanced mitochondrial biogenesis. CONCLUSIONS: VEGFR2 blockade inhibits glioblastoma progression via AKT-PGC1α-TFAM-mitochondria biogenesis signaling cascade, suggesting that VEGFR2 intervention might bring additive therapeutic values to anti-glioblastoma therapy.

Cholestasis-induced phenotypic transformation of neutrophils contributes to immune escape of colorectal cancer liver metastasis.

BACKGROUND: Cholestasis is a common yet severe complication that occurs during the advancement of liver metastasis. However, how cholestasis impacts the development, treatment, and tumor microenvironment (TME) of liver metastasis remains to be elucidated. METHODS: Extrahepatic and intrahepatic cholestatic mouse models with liver metastasis were established to detect the differential expression levels of genes, infiltration of immune cells and change in bile acid-associated metabolites by using RNA-Sequencing, flowcytometry, and liquid chromatography and mass spectrometry. Western blot was applied to neutrophils under the stimulation of primary bile acids (BAs) in vitro to study the mechanism of phenotypic alteration. In vitro coculture of BA-treated neutrophils with CD8+ T cells were performed to study the immune-suppressive effect of phenotypic-altered neutrophils. Clinical samples collected from colorectal cancer patients with liver metastasis and cholestasis were applied to RNA-Seq. RESULTS: Compared to non-cholestatic mice, the progression of liver metastasis of cholestatic mice was significantly accelerated, which was associated with increased neutrophil infiltration and T-cell exclusion. Both neutrophils and T cells expressed higher immunosuppressive markers in the cholestatic mouse model, further indicating that an immunosuppressive tumor microenvironment was induced during cholestasis. Although neutrophils deletion via anti-Ly6G antibody partially hindered liver metastasis progression, it reduced the overall survival of mice. Tauro-ß-muricholic acid (Tß-MCA) and Glycocholic acid (GCA), the two most abundant cholestasis-associated primary BAs, remarkably promoted the expression of Arg1 and iNOS on neutrophils via p38 MAPK signaling pathway. In addition, BAs-pretreated neutrophils significantly suppressed the activation and cytotoxic effects of CD8+ T cells, indicating that the immunosuppressive phenotype of neutrophils was directly induced by BAs. Importantly, targeting BA anabolism with Obeticholic acid (OCA) under cholestasis effectively suppressed liver metastasis progression, enhanced the efficacy of immune checkpoint blockade, and prolonged survival of mice. CONCLUSIONS: Our study reveals the TME of cholestasis-associated liver metastasis and proposes a new strategy for such patients by targeting bile acid anabolism.

M1/M4 receptors as potential therapeutic treatments for schizophrenia: A comprehensive study.

Muscarinic acetylcholine receptors (mAChRs) play a significant role in the pathophysiology of schizophrenia. Although activating mAChRs holds potential in addressing the full range of schizophrenia symptoms, clinical application of many non-selective mAChR agonists in cognitive deficits, positive and negative symptoms is hindered by peripheral side effects (gastrointestinal disturbances and cardiovascular effects) and dosage restrictions. Ligands binding to the allosteric sites of mAChRs, particularly the M1 and M4 subtypes, demonstrate activity in improving cognitive function and amelioration of positive and negative symptoms associated with schizophrenia, enhancing our understanding of schizophrenia. The article aims to critically examine current design concepts and clinical advancements in synthesizing and designing small molecules targeting M1/M4, providing theoretical insights and empirical support for future research in this field.

Alcohol reshapes a liver premetastatic niche for cancer by extra- and intrahepatic crosstalk-mediated immune evasion.

Cancer metastatic organotropism is still a mystery. The liver is known to be susceptible to cancer metastasis and alcoholic injury. However, it is unclear whether and how alcohol facilitates liver metastasis and how to intervene. Here, we show that alcohol preferentially promotes liver metastasis in colon-cancer-bearing mice and post-surgery pancreatic cancer patients. The mechanism is that alcohol triggers an extra- and intrahepatic crosstalk to reshape an immunosuppressive liver microenvironment. In detail, alcohol upregulates extrahepatic IL-6 and hepatocellular IL-6 receptor expression, resulting in hepatocyte STAT3 signaling activation and downstream lipocalin-2 (Lcn2) upregulation. Furthermore, LCN2 promotes T cell-exhaustion neutrophil recruitment and cancer cell epithelial plasticity. In contrast, knocking out hepatocellular Stat3 or systemic Il6 in alcohol-treated mice preserves the liver microenvironment and suppresses liver metastasis. This mechanism is reflected in hepatocellular carcinoma patients, in that alcohol-associated signaling elevation in noncancerous liver tissue indicates adverse prognosis. Accordingly, we discover a novel application for BBI608, a small molecular STAT3 inhibitor that can prevent liver metastasis. BBI608 pretreatment protects the liver and suppresses alcohol-triggered premetastatic niche formation. In conclusion, under extra- and intrahepatic crosstalk, the alcoholic injured liver forms a favorable niche for cancer cell metastasis, while BBI608 is a promising anti-metastatic agent targeting such microenvironments.

Enantioselective Total Syntheses of (-)-Caulamidine D and (-)-Isocaulamidine D and Their Absolute Configuration Reassignment.

The first enantioselective total syntheses of (-)-caulamidine D (5) and (-)-isocaulamidine D (6) were accomplished. Their absolute configurations were unambiguously elucidated through X-ray crystallography. The isolated natural samples of both 5 and 6 are determined to be the TFA salts instead of the neutral forms. It took 16 steps (longest linear sequence) to divergently access both 5 and 6 following a unified strategy. The key reactions include (1) development and application of an asymmetric Meerwein-Eschenmoser-Claisen rearrangement to construct the challenging C10, C23 consecutive stereocenters and (2) application of a cascade 6-exo-dig/6-exo-tet amine/nitrile cyclization reaction.

Preclinical evaluation of Mito-LND, a targeting mitochondrial metabolism inhibitor, for glioblastoma treatment.

BACKGROUND: Glioblastoma (GBM) is a brain tumor with the highest level of malignancy and the worst prognosis in the central nervous system. Mitochondrial metabolism plays a vital role in the occurrence and development of cancer, which provides critical substances to support tumor anabolism. Mito-LND is a novel small-molecule inhibitor that can selectively inhibit the energy metabolism of tumor cells. However, the therapeutic effect of Mito-LND on GBM remains unclear. METHODS: The present study evaluated the inhibitory effect of Mito-LND on the growth of GBM cells and elucidated its potential mechanism. RESULTS: The results showed that Mito-LND could inhibit the survival, proliferation and colony formation of GBM cells. Moreover, Mito-LND induced cell cycle arrest and apoptosis. Mechanistically, Mito-LND inhibited the activity of mitochondrial respiratory chain complex I and reduced mitochondrial membrane potential, thus promoting ROS generation. Importantly, Mito-LND could inhibit the malignant proliferation of GBM by blocking the Raf/MEK/ERK signaling pathway. In vivo experiments showed that Mito-LND inhibited the growth of GBM xenografts in mice and significantly prolonged the survival time of tumor-bearing mice. CONCLUSION: Taken together, the current findings support that targeting mitochondrial metabolism may be as a potential and promising strategy for GBM therapy, which will lay the theoretical foundation for further clinical trials on Mito-LND in the future.

Parallel imaging reconstruction using spatial nulling maps.

PURPOSE: To develop a robust parallel imaging reconstruction method using spatial nulling maps (SNMs). METHODS: Parallel reconstruction using null operations (PRUNO) is a k-space reconstruction method where a k-space nulling system is derived using null-subspace bases of the calibration matrix. ESPIRiT reconstruction extends the PRUNO subspace concept by exploiting the linear relationship between signal-subspace bases and spatial coil sensitivity characteristics, yielding a hybrid-domain approach. Yet it requires empirical eigenvalue thresholding to mask the coil sensitivity information and is sensitive to signal- and null-subspace division. In this study, we combine the concepts of null-subspace PRUNO and hybrid-domain ESPIRiT to provide a more robust reconstruction method that extracts null-subspace bases of calibration matrix to calculate image-domain SNMs. Multi-channel images are reconstructed by solving an image-domain nulling system formed by SNMs that contain both coil sensitivity and finite image support information, therefore, circumventing the masking-related procedure. The proposed method was evaluated with multi-channel 2D brain and knee data and compared to ESPIRiT. RESULTS: The proposed hybrid-domain method produced quality reconstruction highly comparable to ESPIRiT with optimal manual masking. It involved no masking-related manual procedure and was tolerant of the actual division of null- and signal-subspace. Spatial regularization could be also readily incorporated to reduce noise amplification as in ESPIRiT. CONCLUSION: We provide an efficient hybrid-domain reconstruction method using multi-channel SNMs that are calculated from coil calibration data. It eliminates the need for coil sensitivity masking and is relatively insensitive to subspace separation, therefore, presenting a robust parallel imaging reconstruction procedure in practice.

Calibrationless reconstruction of uniformly-undersampled multi-channel MR data with deep learning estimated ESPIRiT maps.

PURPOSE: To develop a truly calibrationless reconstruction method that derives An Eigenvalue Approach to Autocalibrating Parallel MRI (ESPIRiT) maps from uniformly-undersampled multi-channel MR data by deep learning. METHODS: ESPIRiT, one commonly used parallel imaging reconstruction technique, forms the images from undersampled MR k-space data using ESPIRiT maps that effectively represents coil sensitivity information. Accurate ESPIRiT map estimation requires quality coil sensitivity calibration or autocalibration data. We present a U-Net based deep learning model to estimate the multi-channel ESPIRiT maps directly from uniformly-undersampled multi-channel multi-slice MR data. The model is trained using fully-sampled multi-slice axial brain datasets from the same MR receiving coil system. To utilize subject-coil geometric parameters available for each dataset, the training imposes a hybrid loss on ESPIRiT maps at the original locations as well as their corresponding locations within the standard reference multi-slice axial stack. The performance of the approach was evaluated using publicly available T1-weighed brain and cardiac data. RESULTS: The proposed model robustly predicted multi-channel ESPIRiT maps from uniformly-undersampled k-space data. They were highly comparable to the reference ESPIRiT maps directly computed from 24 consecutive central k-space lines. Further, they led to excellent ESPIRiT reconstruction performance even at high acceleration, exhibiting a similar level of errors and artifacts to that by using reference ESPIRiT maps. CONCLUSION: A new deep learning approach is developed to estimate ESPIRiT maps directly from uniformly-undersampled MR data. It presents a general strategy for calibrationless parallel imaging reconstruction through learning from the coil and protocol-specific data.

Low-dose imaging denoising with one pair of noisy images.

Low-dose imaging techniques have many important applications in diverse fields, from biological engineering to materials science. Samples can be protected from phototoxicity or radiation-induced damage using low-dose illumination. However, imaging under a low-dose condition is dominated by Poisson noise and additive Gaussian noise, which seriously affects the imaging quality, such as signal-to-noise ratio, contrast, and resolution. In this work, we demonstrate a low-dose imaging denoising method that incorporates the noise statistical model into a deep neural network. One pair of noisy images is used instead of clear target labels and the parameters of the network are optimized by the noise statistical model. The proposed method is evaluated using simulation data of the optical microscope, and scanning transmission electron microscope under different low-dose illumination conditions. In order to capture two noisy measurements of the same information in a dynamic process, we built an optical microscope that is capable of capturing a pair of images with independent and identically distributed noises in one shot. A biological dynamic process under low-dose condition imaging is performed and reconstructed with the proposed method. We experimentally demonstrate that the proposed method is effective on an optical microscope, fluorescence microscope, and scanning transmission electron microscope, and show that the reconstructed images are improved in terms of signal-to-noise ratio and spatial resolution. We believe that the proposed method could be applied to a wide range of low-dose imaging systems from biological to material science.

Adaptive feedback-driven probabilistic shaping for high-order modulation formats in a fiber-THz seamless integration system at 320 GHz.

In this Letter, we propose a novel, to the best of our knowledge, adaptive feedback-driven probabilistic constellation-shaping (FBD-PCS) method based on the robustness evaluation criteria and employ variational autoencoder (VAE)-based equalizers to implement polarization demultiplexing and nonlinear equalization for the recovery of high-order PCS-QAM signals. We experimentally demonstrate the fiber-THz 2 times 2 MIMO system with a net rate of 366.4 Gbit/s using dual-polarization 40 Gbaud PCS-64QAM signal over a 20 km SSMF and 6 m wireless link. Specifically, the feedback mechanism drives the fiber-THz system to solve optimization problems, adaptively matching the optimized distribution of transmitted symbols that maximizes normalized generalized mutual information (NGMI). We also examine six scenarios to explore nonlinear resistances of FBD-PCS symbols and the robustness of VAE-based equalizers. The results demonstrate the superiority of FBD-PCS over the Maxwell-Boltzmann (M-B) distributions in practical nonlinear-dominant systems. Additionally, the FBD-PCS signals can break limitations for ultrahigh rate transmission with the help of advanced equalizers.

Dual blockade of EGFR and PI3K signaling pathways offers a therapeutic strategy for glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is a devastating disease that lacks effective drugs for targeted therapy. Previously, we found that the third-generation epidermal growth factor receptor (EGFR) inhibitor AZD-9291 persistently blocked the activation of the ERK pathway but had no inhibitory effect on the phosphoinositide 3-kinase (PI3K)/Akt pathway. Given that the PI3K inhibitor GDC-0084 is being evaluated in phase I/II clinical trials of GBM treatment, we hypothesized that combined inhibition of the EGFR/ERK and PI3K/Akt pathways may have a synergistic effect in the treatment of GBM. METHODS: The synergistic effects of cotreatment with AZD-9291 and GDC-0084 were validated using cell viability assays in GBM and primary GBM cell lines. Moreover, the underlying inhibitory mechanisms were assessed through colony formation, EdU proliferation, and cell cycle assays, as well as RNA-seq analyses and western blot. The therapeutic effects of the drug combination on tumor growth and survival were investigated in mice bearing tumors using subcutaneously or intracranially injected LN229 xenografts. RESULTS: Combined treatment with AZD-9291 and GDC-0084 synergistically inhibited the proliferation and clonogenic survival, as well as induced cell cycle arrest of GBM cells and primary GBM cells, compared to monotherapy. Moreover, AZD-9291 plus GDC-0084 combination therapy significantly inhibited the growth of subcutaneous tumors and orthotopic brain tumor xenografts, thus prolonging the survival of tumor-bearing mice. More importantly, the combination of AZD-9291 and GDC-0084 simultaneously blocked the activation of the EGFR/MEK/ERK and PI3K/AKT/mTOR signaling pathways, thereby exerting significant antitumor activity. CONCLUSION: Our findings demonstrate that the combined blockade of the EGFR/MEK/ERK and PI3K/AKT/mTOR pathways is more effective against GBM than inhibition of each pathway alone, both in vitro and in vivo. Our results suggest that AZD-9291 combined with GDC-0084 may be considered as a potential treatment strategy in future clinical trials. Video Abstract.

Equivalence theorem for the spectral density of light waves scattered from different types of anisotropic media.

The spectral density equivalence theorem of light waves on scattering from different types of anisotropic media is discussed. The possibility of producing identical spectral density distribution as light waves are scattered by different anisotropic media is also discussed. Moreover, the conditions under which a determinate anisotropic medium and random anisotropic medium may produce identical spectral densities are obtained. It is shown that the complete equivalence theorem in whole space or the partial equivalence theorem in some special planes can be realized under particular conditions.

An Adaptive Sampling Framework for Life Cycle Degradation Monitoring.

Data redundancy and data loss are relevant issues in condition monitoring. Sampling strategies for segment intervals can address these at the source, but do not receive the attention they deserve. Currently, the sampling methods in relevant research lack sufficient adaptability to the condition. In this paper, an adaptive sampling framework of segment intervals is proposed, based on the summary and improvement of existing problems. The framework is implemented to monitor mechanical degradation, and experiments are implemented on simulation data and real datasets. Subsequently, the distributions of the samples collected by different sampling strategies are visually presented through a color map, and five metrics are designed to assess the sampling results. The intuitive and numerical results show the superiority of the proposed method in comparison to existing methods, and the results are closely related to data status and degradation indicators. The smaller the data fluctuation and the more stable the degradation trend, the better the result. Furthermore, the results of the objective physical indicators are obviously better than those of the feature indicators. By addressing existing problems, the proposed framework opens up a new idea of predictive sampling, which significantly improves the degradation monitoring.

Controllable Solid-Phase Fabrication of an Fe2O3/Fe5C2/Fe-N-C Electrocatalyst toward Optimizing the Oxygen Reduction Reaction in Zinc-Air Batteries.

Preparing advanced electrocatalysts via solid-phase reactions encounters the challenge of low controllability for multiconstituent hybridization and microstructure modulation. Herein, a hydrothermal-mimicking solid-phase system is established to fabricate novel Fe2O3/Fe5C2/Fe-N-C composites consisting of Fe2O3/Fe5C2 nanoparticles and Fe,N-doped carbon species with varying morphologies. The evolution mechanism featuring a competitive growth of different carbon sources in a closed hypoxic space is elucidated for a series of Fe2O3/Fe5C2/Fe-N-C composites. The size and dispersity of Fe2O3/Fe5C2 nanoparticles, the graphitization degree of the carbonaceous matrix, and their diverse hybridization states lead to disparate electrocatalytic behaviors for the oxygen reduction reaction (ORR). Among them, microspherical Fe2O3/Fe5C2/Fe-N-C-3 exhibits an optimal ORR performance and the as-assembled zinc-air battery shows all-round superiority to the Pt/C counterpart. This work presents a mild solid-phase fabrication technique for obtaining a variety of nanocomposites with effective control over composition hybridization and microstructural modulation, which is significantly important for the design and optimization of advanced electrocatalysts.

Amino Phenyl Copper Phosphate-Bridged Reactive Phosphaphenanthrene to Intensify Fire Safety of Epoxy Resins.

To improve the compatibility between flame retardant and epoxy resin (EP) matrix, amino phenyl copper phosphate-9, 10-dihydro-9-oxygen-10-phospha-phenanthrene-10-oxide (CuPPA-DOPO) is synthesized through surface grafting, which is blended with EP matrix to prepare EP/CuPPA-DOPO composites. The amorphous structure of CuPPA-DOPO is characterized by X-ray diffraction and Fourier-transform infrared spectroscopy. Scanning electron microscope (SEM) images indicate that the agglomeration of hybrids is improved, resisting the intense intermolecular attractions on account of the acting force between CuPPA and DOPO. The results of thermal analysis show that CuPPA-DOPO can promote the premature decomposition of EP and increase the residual amount of EP composites. It is worth mentioning that EP/6 wt% CuPPA-DOPO composites reach UL-94 V-1 level and limiting oxygen index (LOI) of 32.6%. Meanwhile, their peak heat release rate (PHRR), peak smoke production release (PSPR) and CO2 production (CO2P) are decreased by 52.5%, 26.1% and 41.4%, respectively, compared with those of EP. The inhibition effect of CuPPA-DOPO on the combustion of EP may be due to the release of phosphorus and ammonia free radicals, as well as the catalytic charring ability of metal oxides and phosphorus phases.

[Application of microneedle-assisted percutaneous drug delivery system in treatment of rheumatoid arthritis:a review].

Rheumatoid arthritis(RA) is a chronic degenerative joint disease characterized by inflammation. Due to the complex causes, no specific therapy is available. Non-steroidal anti-inflammatory agents and corticosteroids are often used(long-term, oral/injection) to interfere with related pathways for reducing inflammatory response and delaying the progression of RA, which, however, induce many side effects. Microneedle, an emerging transdermal drug delivery system, is painless and less invasive and improves drug permeability. Thus, it is widely used in the treatment of RA and is expected to be a new strategy in clinical treatment. This paper summarized the application of microneedles in the treatment of RA, providing a reference for the development of new microneedles and the expansion of its clinical application.

[Treatment of rheumatoid arthritis by injection of sinomenine solid lipid nanoparticles under a fluorescence endoscopic laser confocal microscope].

A fluorescence endoscopic laser confocal microscope(FELCM) was used to direct the injection of sinomenine solid lipid nanoparticles(Sin-SLN) into the joint, and the in vitro effectiveness of Sin-SLN in the treatment of rheumatoid arthritis(RA) was evaluated. Sin-SLN was prepared with the emulsion evaporation-low temperature curing method. The Sin-SLN prepared under the optimal conditions showed the encapsulation efficiency of 64.79%±3.12%, the drug loading of 3.84%±0.28%, the average particle size of(215.27±4.21) nm, and the Zeta potential of(-32.67±0.84) mV. Moreover, the Sin-SLN demonstrated good stability after sto-rage for 30 days. The rabbit model of RA was established by the subcutaneous injection of ovalbumin and complete Freund's adjuvant. Five groups were designed, including a control group, a model group, a Sin(1.5 mg·kg~(-1)) group, a Sin-SLN(1.5 mg·kg~(-1)) group, and a dexamethasone(positive drug, 1.0 mg·kg~(-1), ig) group. The control group and the model group only received puncture treatment without drug injection. After drug administration, the local skin temperature and knee joint diameter were monitored every day. The knee joint diameter and the local skin temperature were lower in the drug administration groups than in the model group(P<0.05, P<0.01). FELCM recorded the morphological alterations of the cartilage of knee joint. The Sin-SLN group showed compact tissue structure and smooth surface of the cartilage. Enzyme-linked immunosorbent assay(ELISA) was employed to determine the serum le-vels of interleukin-1(IL-1) and tumor necrosis factor-α(TNF-α). The findings revealed that the Sin-SLN group had lower IL-1 and TNF-α levels than the model group(P<0.05, P<0.01). Hematoxylin-eosin(HE) staining was employed to reveal the pathological changes of the synovial tissue, which were significantly mitigated in the Sin-SLN group. The prepared Sin-SLN had uniform particle size and high stability. Through joint injection administration, a drug reservoir was formed. Sin-SLN effectively alleviate joint swelling and cartilage damage of rabbit, down-regulated the expression of inflammatory cytokines, and inhibited the epithelial proliferation and inflammatory cell infiltration of the synovial tissue, demonstrating the efficacy in treating RA.

Highly Enantio- and Diastereoselective Hydrogenation of Cyclic Tetra-Substituted ß-Enamido Phosphorus Derivatives.

Catalytic asymmetric hydrogenation of enamido phosphorus derivatives is one of the most efficient methods for the construction of chiral amino phosphorus products, among which the congested tetra-substituted substrates remains an unaddressed challenge. In this study, we utilize a commercially available Rh-Josiphos system for the efficient and stereoselective hydrogenation of a wide set of tetra-substituted cyclic ß-enamido phosphonates/phosphine oxides, thus enabling access to chiral ß-amino phosphorus compounds featuring two vicinal stereocenters. This protocol was broadly applicable to different ring systems possessing various phosphonate/phosphine oxide groups and further applied in the preparation of amino-phosphine ligands. DFT mechanistic explorations indicate that the C=C migratory insertion into RhIII -H bond could be the rate- and stereo-determining step. The origins of stereoselectivity are revealed through distortion/interaction analysis, which is primarily regulated by distinguished dispersion interactions and steric repulsions.

Modulating Coordination of Iron Atom Clusters on N,P,S Triply-Doped Hollow Carbon Support towards Enhanced Electrocatalytic Oxygen Reduction.

Constructing atom-clusters (ACs) with in situ modulation of coordination environment and simultaneously hollowing carbon support are critical yet challenging for improving electrocatalytic efficiency of atomically dispersed catalysts (ADCs). Herein, a general diffusion-controlled strategy based on spatial confining and Kirkendall effect is proposed to construct metallic ACs in N,P,S triply-doped hollow carbon matrix (MACs /NPS-HC, M=Mn, Fe, Co, Ni, Cu). Thereinto, FeACs /NPS-HC with the best catalytic activity for oxygen reduction reaction (ORR) is thoroughly investigated. Unlike the benchmark sample of symmetrical N-surrounded iron single-atoms in N-doped carbon (FeSAs /N-C), FeACs /NPS-HC comprises bi-/tri-atomic Fe centers with engineered S/N coordination. Theoretical calculation reveals that proper Fe gathering and coordination modulation could mildly delocalize the electron distribution and optimize the free energy pathways of ORR. In addition, the triple doping and hollow structure of carbon matrix could further regulate the local environment and allow sufficient exposure of active sites, resulting in more enhanced ORR kinetics on FeACs /NPS-HC. The zinc-air battery assembled with FeACs /NPS-HC as cathodic catalyst exhibits all-round superiority to Pt/C and most Fe-based ADCs. This work provides an exemplary method for establishing atomic-cluster catalysts with engineered S-dominated coordination and hollowed carbon matrix, which paves a new avenue for the fabrication and optimization of advanced ADCs.

Targeting HNRNPU to overcome cisplatin resistance in bladder cancer.

PURPOSE: The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. EXPERIMENTAL DESIGN: The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity. RESULTS: Significant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1). CONCLUSIONS: Our study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.