Brain Metastasis from EGFR-Mutated Non-Small Cell Lung Cancer: Secretion of IL11 from Astrocytes Up-Regulates PDL1 and Promotes Immune Escape.

Patients who have non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations are more prone to brain metastasis (BM) and poor prognosis. Previous studies showed that the tumor microenvironment of BM in these patients is immunosuppressed, as indicated by reduced T-cell abundance and activity, although the mechanism of this immunosuppression requires further study. This study shows that reactive astrocytes play a critical role in promoting the immune escape of BM from EGFR-mutated NSCLC by increasing the apoptosis of CD8+ T lymphocytes. The increased secretion of interleukin 11(IL11) by astrocytes promotes the expression of PDL1 in BM, and this is responsible for the increased apoptosis of T lymphocytes. IL11 functions as a ligand of EGFR, and this binding activates EGFR and downstream signaling to increase the expression of PDL1, culminating in the immune escape of tumor cells. IL11 also promotes immune escape by binding to its intrinsic receptor (IL11Rα/glycoprotein 130 [gp130]). Additional in vivo studies show that the targeted inhibition of gp130 and EGFR suppresses the growth of BM and prolongs the survival time of mice. These results suggest a novel therapeutic strategy for treatment of NSCLC patients with EGFR mutations.

Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET.

BACKGROUND: Brain metastasis (BM) is common among cases of advanced non-small cell lung cancer (NSCLC) and is the leading cause of death for these patients. Mesothelin (MSLN), a tumor-associated antigen expressed in many solid tumors, has been reported to be involved in the progression of multiple tumors. However, its potential involvement in BM of NSCLC and the underlying mechanism remain unknown. METHODS: The expression of MSLN was validated in clinical tissue and serum samples using immunohistochemistry and enzyme-linked immunosorbent assay. The ability of NSCLC cells to penetrate the blood-brain barrier (BBB) was examined using an in vitro Transwell model and an ex vivo multi-organ microfluidic bionic chip. Immunofluorescence staining and western blotting were used to detect the disruption of tight junctions. In vivo BBB leakiness assay was performed to assess the barrier integrity. MET expression and activation was detected by western blotting. The therapeutic efficacy of drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) on BM was evaluated in animal studies. RESULTS: MSLN expression was significantly elevated in both serum and tumor tissue samples from NSCLC patients with BM and correlated with a poor clinical prognosis. MSLN significantly enhanced the brain metastatic abilities of NSCLC cells, especially BBB extravasation. Mechanistically, MSLN facilitated the expression and activation of MET through the c-Jun N-terminal kinase (JNK) signaling pathway, which allowed tumor cells to disrupt tight junctions and the integrity of the BBB and thereby penetrate the barrier. Drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) effectively blocked the development of BM and prolonged the survival of mice. CONCLUSIONS: Our results demonstrate that MSLN plays a critical role in BM of NSCLC by modulating the JNK/MET signaling network and thus, provides a potential novel therapeutic target for preventing BM in NSCLC patients.

Microzone-Acidification-Driven Degradation Mechanism of the NiFe-Based Anode in Seawater Electrolysis.

The anode stability is critical for efficient and reliable seawater electrolyzers. Herein, a NiFe-based film catalyst was prepared by anodic oxidation to serve as a model electrode, which exhibited a satisfactory oxygen evolution performance in simulated alkaline seawater (1 M KOH + 0.5 M NaCl) with an overpotential of 348 mV at 100 mA cm-2 and a long-term stability of over 100 h. After that, the effects of the current density and bulk pH of the electrolyte on its stability were evaluated. It was found that the electrode stability was sensitive to electrolysis conditions, failing at 20 mA cm-2 in 0.1 M KOH + 0.5 M NaCl but over 500 mA cm-2 in 0.5 M KOH + 0.5 M NaCl. The electrode dissolved, and some precipitates immediately formed at the region very close to the electrode surface during the electrolysis. This can be ascribed to the pH difference between the electrode/electrolyte interface and the bulk electrolyte under anodic polarization. In other words, the microzone acidification accelerates the corrosion of the electrode by Cl-, thus affecting the electrode stability. The operational performances of the electrode under different electrolysis conditions were classified to further analyze the degradation behavior, which resulted in three regions corresponding to the stable oxygen evolution, violent dissolution-precipitation, and complete passivation processes, respectively. Thereby increasing the bulk pH could alleviate the microzone acidification and improve the stability of the anode at high current densities. Overall, this study provides new insights into understanding the degradation mechanism of NiFe-based catalysts and offers electrolyte engineering strategies for the application of anodes.

Targeting of endothelial cells in brain tumours.

BACKGROUND: Aggressive brain tumours, whether primary gliomas or secondary metastases, are characterised by hypervascularisation and are fatal. Recent research has emphasised the crucial involvement of endothelial cells (ECs) in all brain tumour genesis and development events, with various patterns and underlying mechanisms identified. MAIN BODY: Here, we highlight recent advances in knowledge about the contributions of ECs to brain tumour development, providing a comprehensive summary including descriptions of interactions between ECs and tumour cells, the heterogeneity of ECs and new models for research on ECs in brain malignancies. We also discuss prospects for EC targeting in novel therapeutic approaches. CONCLUSION: Interventions targeting ECs, as an adjunct to other therapies (e.g. immunotherapies, molecular-targeted therapies), have shown promising clinical efficacy due to the high degree of vascularisation in brain tumours. Developing precise strategies to target tumour-associated vessels based on the heterogeneity of ECs is expected to improve anti-vascular efficacy.

Warburg effect enhanced by AKR1B10 promotes acquired resistance to pemetrexed in lung cancer-derived brain metastasis.

BACKGROUND: Resistance to pemetrexed (PEM), a rare chemotherapeutic agent that can efficiently cross the blood-brain barrier, limits the therapeutic efficacy for patients with lung cancer brain metastasis (BM). Aldo-keto reductase family 1 B10 (AKR1B10) was recently found to be elevated in lung cancer BM. The link between AKR1B10 and BM-acquired PEM is unknown. METHODS: PEM drug-sensitivity was assessed in the preclinical BM model of PC9 lung adenocarcinoma cells and the BM cells with or without AKR1B10 interference in vitro and in vivo. Metabolic reprogramming of BM attributed to AKR1B10 was identified by chromatography-mass spectrometry (GC-MS) metabolomics, and the mechanism of how AKR1B10 mediates PEM chemoresistance via a way of modified metabolism was revealed by RNA sequencing as well as further molecular biology experimental approaches. RESULTS: The lung cancer brain metastatic subpopulation cells (PC9-BrM3) exhibited significant resistance to PEM and silencing AKR1B10 in PC9-BrM3 increased the PEM sensitivity in vitro and in vivo. Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle. CONCLUSIONS: Our finding demonstrates that AKR1B10/glycolysis/H4K12la/CCNB1 promotes acquired PEM chemoresistance in lung cancer BM, providing novel strategies to sensitize PEM response in the treatment of lung cancer patients suffering from BM.

StemP: A Fast and Deterministic Stem-Graph Approach for RNA Secondary Structure Prediction.

We propose a new deterministic methodology to predict the secondary structure of RNA sequences. What information of stem is important for structure prediction, and is it enough ? The proposed simple deterministic algorithm uses minimum stem length, Stem-Loop score, and co-existence of stems, to give good structure predictions for short RNA and tRNA sequences. The main idea is to consider all possible stem with certain stem loop energy and strength to predict RNA secondary structure. We use graph notation, where stems are represented as vertexes, and co-existence between stems as edges. This full Stem-graph presents all possible folding structure, and we pick sub-graph(s) which give the best matching energy for structure prediction. Stem-Loop score adds structure information and speeds up the computation. The proposed method can predict secondary structure even with pseudo knots. One of the strengths of this approach is the simplicity and flexibility of the algorithm, and it gives a deterministic answer. Numerical experiments are done on various sequences from Protein Data Bank and the Gutell Lab using a laptop and results take only a few seconds.

3D Bioprinting for Tumor Metastasis Research.

Tumor metastasis is a multiple cascade process where tumor cells disseminate from the primary site to distant organs and subsequently adapt to the foreign microenvironment. Simulating the physiology of tumor metastatic events in a realistic and three-dimensional (3D) manner is a challenge for in vitro modeling. 3D bioprinting strategies, which can generate well-customized and bionic structures, enable the exploration of dynamic tumor metastasis process in a species-homologous, high-throughput and reproducible way. In this review, we summarize the recent application of 3D bioprinting in constructing in vitro tumor metastatic models and discuss its advantages and current limitations. Further perspectives on how to harness the potential of accessible 3D bioprinting strategies to better model tumor metastasis and guide anti-cancer therapies are also provided.

Biphase Co@C core-shell catalysts for efficient Fenton-like catalysis.

Despite the vital roles of Co nanoparticles catalytic oxidation in the Fenton-like system for eliminating pollutants, contributions of Co phases are typically overlooked. Herein, a biphase Co@C core-shell catalyst was synthesized by the electrochemical co-reduction of CaCO3 and Co3O4 in molten carbonate. Unlike the traditional pyrolysis method that is performed over 700 °C, the electrolysis was deployed at 450 °C, at which biphase structures, i.e., face-centered cubic (FCC) and hexagonal close-packed (HCP) structures, can be obtained. The biphase Co@C shows excellent catalytic oxidation performance of diethyl phthalate (DEP) with a high turnover frequency value (TOF, 28.14 min-1) and low catalyst dosage (4 mg L-1). Furthermore, density functional theory (DFT) calculations confirm that the synergistic catalytic effect of biphase Co@C is the enhancement for the breaking of the peroxide O-O bond and the charge transfer from catalysts to PMS molecule for the activation. Moreover, the results of radicals quenching experiments and electron paramagnetic resonance (EPR) tests confirm that SO4•-, •OH, O2•-, and 1O2 co-degrade DEP. Remarkably, 100% removals of three model contaminants, including DEP, sulfamethoxazole (SMX) and 2,4-dichlorophen (2,4-DCP), were achieved, either in pure water or actual river water. This paper provides an electrochemical pathway to leverage the phase of catalysts and thereby mediate their catalytic capability for remediating refractory organic contaminants.

A highly sensitive octopus-like azobenzene fluorescent probe for determination of abamectin B1 in apples.

The development of detecting residual level of abamectin B1 in apples is of great importance to public health. Herein, we synthesized a octopus-like azobenzene fluorescent probe 1,3,5-tris (5'-[(E)-(p-phenoxyazo) diazenyl)] benzene-1,3-dicarboxylic acid) benzene (TPB) for preliminary detection of abamectin B1 in apples. The TPB molecule has been characterized by ultraviolet-visible absorption spectrometry, 1H-nuclear magnetic resonance, fourier-transform infrared (FT-IR), electrospray ionization mass spectroscopy (ESI-MS) and fluorescent spectra. A proper determination condition was optimized, with limit of detection and limit of quantification of 1.3 µg L-1 and 4.4 µg L-1, respectively. The mechanism of this probe to identify abamectin B1 was illustrated in terms of undergoing aromatic nucleophilic substitution, by comparing fluorescence changes, FT-IR and ESI-MS. Furthermore, a facile quantitative detection of the residual abamectin B1 in apples was achieved. Good reproducibility was present based on relative standard deviation of 2.2%. Six carboxyl recognition sites, three azo groups and unique fluorescence signal towards abamectin B1 of this fluorescent probe demonstrated reasonable sensitivity, specificity and selectivity. The results indicate that the octopus-like azobenzene fluorescent probe can be expected to be reliable for evaluating abamectin B1 in agricultural foods.