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The dynamic changes of RNA N6-methyladenosine (m 6 A) during cancer progression participate in various cellular processes. However, less is known about a possible direct connection between upstream regulator and m 6 A modification, and therefore affects oncogenic progression. Here, we have identified that a key enzyme in N4-acetylcytidine (ac4C) acetylation NAT10 is highly expressed in human osteosarcoma tissues, and its knockdown enhanced m 6 A contents and significantly suppressed osteosarcoma cell growth, migration and invasion. Further results revealed that NAT10 silence inhibits mRNA stability and translation of m 6 A reader protein YTHDC1, and displayed an increase in glucose uptake, a decrease in lactate production and pyruvate content. YTHDC1 recognizes differential m 6 A sites on key enzymes of glycolysis phosphofructokinase (PFKM) and lactate dehydrogenase A (LDHA) mRNAs, which suppress glycolysis pathway by increasing mRNA stability of them in an m 6 A methylation-dependent manner. YTHDC1 partially abrogated the inhibitory effect caused by NAT10 knockdown in tumor models in vivo, lentiviral overexpression of YTHDC1 partially restored the reduced stability of YTHDC1 caused by lentiviral depleting NAT10 at the cellular level. Altogether, we found ac4C driven RNA m 6 A modification can positively regulate the glycolysis of cancer cells and reveals a previously unrecognized signaling axis of NAT10/ac4C-YTHDC1/m 6 A-LDHA/PFKM in osteosarcoma. 6WoSibQBSZGZLQEcMB75Lw Video Abstract

Cancer patients have a higher risk of all types of cardiovascular diseases (CVDs). Cardiologists are encountering a growing number of cancer patients with CVDs, and an increasing number of cancer patients undergoing percutaneous coronary intervention (PCI). The mechanistic link between cancer and CVDs remains elusive. Here, the meta‐analysis shows the increased incidence ratio of all‐cause mortality and cardiovascular (CV) mortality in patients undergoing PCI with cancer compared with non‐cancer. We experimentally demonstrated that cancer aggravated mitochondrial dysfunction and myocardial ischemia/reperfusion (I/R) injury in two models of lung cancer in mice. Plasma extracellular vesicles (EVs) derived from cancer mice exacerbated cardiac I/R injury in vivo and in vitro, while inhibition of tumor EVs secretion by lipid‐coated polyacrylic acid/calcium phosphate nanoparticles delivered a neutral sphingomyelinase inhibitor (GW4869) showed the opposite results. Lung‐specific miR‐485‐3p sponges mediated by Adeno‐associated virus 6 suppress cardiac damage and mitochondrial dysfunction in CC10‐KRASG12D mice post‐I/R. Mechanistically, PPARGC1A/PGC‐1α is post‐transcriptionally repressed by miR‐485‐3p in cardiomyocytes, leading to the inhibition of mitochondrial complex I subunits and ATP synthesis. Taken together, our findings reveal for the first time that cancer can aggravate cardiac injury and mitochondrial dysfunction by releasing miR‐485‐3p‐enriched extracellular vesicles derived from cancer cells. This study reveals a novel mechanistic connection between cancer and ischemia/reperfusion (I/R)‐induced cardiac injury. The meta‐analysis demonstrates significantly higher incidence ratios of both all‐cause mortality and cardiovascular mortality in cancer patients undergoing percutaneous coronary intervention (PCI) compared to non‐cancer patients. The findings suggest that cancer exacerbates cardiac injury and mitochondrial dysfunction through the release of miR‐485‐3p‐enriched extracellular vesicles originating from lung cancer cells. The graphical is created using Scidraw and BioRender.

The dynamic changes of RNA N6-methyladenosine (m A) during cancer progression participate in various cellular processes. However, less is known about a possible direct connection between upstream regulator and m A modification, and therefore affects oncogenic progression. Here, we have identified that a key enzyme in N4-acetylcytidine (ac4C) acetylation NAT10 is highly expressed in human osteosarcoma tissues, and its knockdown enhanced m A contents and significantly suppressed osteosarcoma cell growth, migration and invasion. Further results revealed that NAT10 silence inhibits mRNA stability and translation of m A reader protein YTHDC1, and displayed an increase in glucose uptake, a decrease in lactate production and pyruvate content. YTHDC1 recognizes differential m A sites on key enzymes of glycolysis phosphofructokinase (PFKM) and lactate dehydrogenase A (LDHA) mRNAs, which suppress glycolysis pathway by increasing mRNA stability of them in an m A methylation-dependent manner. YTHDC1 partially abrogated the inhibitory effect caused by NAT10 knockdown in tumor models in vivo, lentiviral overexpression of YTHDC1 partially restored the reduced stability of YTHDC1 caused by lentiviral depleting NAT10 at the cellular level. Altogether, we found ac4C driven RNA m A modification can positively regulate the glycolysis of cancer cells and reveals a previously unrecognized signaling axis of NAT10/ac4C-YTHDC1/m A-LDHA/PFKM in osteosarcoma. Video Abstract.

Background: Phototherapies based on sunlight, infrared, ultraviolet, visible, and laser-based treatments present advantages like high curative effects, small invasion, and negligible adverse reactions in cancer treatment. We aimed to explore the potential therapeutic effects of blue light emitting diode (LED) in human hepatoma cells and decipher the underlying cellular and molecular mechanisms. Methods: Wound healing and transwell assays were employed to probe the inhibition of the invasion and migration of hepatocellular carcinoma cells in the presence of blue LED. The sphere-forming test was used to evaluate the effect of LED blue light irradiation on cancer stem cell properties. Immunofluorescence and western blotting were used to detect the changes in γ-H2AX. The Cell Counting Kit-8 assay, 5-ethynyl-2′-deoxyuridine staining, and colony formation assay were used to detect the combined effect of blue LED and sorafenib on cell proliferation inhibition. Results: We demonstrated that the irradiation of blue LED light in hepatoma cells could lead to cell proliferation reduction along with the increase of cell apoptosis. Simultaneously, blue LED irradiation also markedly suppressed the migration and invasion ability of human hepatoma cells. Sphere formation analysis further revealed the decreased cancer stemness of hepatoma cells upon blue LED irradiation. Mechanistically, blue LED irradiation significantly promoted the expression of the phosphorylation of the core histone protein H2AX (γ-H2AX), a sensitive molecular marker of DNA damage. In addition, we found that the combined treatment of blue LED irradiation and sorafenib increased cancer cell sensitivity to sorafenib. Conclusion: Collectively, we demonstrated that blue LED irradiation exhibited anti-tumor effects on liver cancer cells by inducing DNA damage and could enhance chemosensitivity of cancer cells, which represents a potential approach for human hepatoma treatment.

Selenium (Se) is an appealing alternative cathode material for secondary battery systems that recently attracted research interests in the electrochemical energy storage field due to its high theoretical specific capacity and good electronic conductivity. However, despite the relevant capacity contents reported in the literature, Se-based cathodes generally show poor rate capability behavior. To circumvent this issue, we propose a series of selenium@carbon (Se@C) composite positive electrode active materials capable of delivering a four-electron redox reaction when placed in contact with an aqueous copper-ion electrolyte solution (i.e., 0.5 M CuSO 4 ) and copper or zinc foils as negative electrodes. The lab-scale Zn | |Se@C cell delivers a discharge voltage of about 1.2 V at 0.5 A g −1 and an initial discharge capacity of 1263 mAh g Se −1 . Interestingly, when a specific charging current of 6 A g −1 is applied, the Zn | |Se@C cell delivers a stable discharge capacity of around 900 mAh g Se −1 independently from the discharge rate. Via physicochemical characterizations and first-principle calculations, we demonstrate that battery performance is strongly associated with the reversible structural changes occurring at the Se-based cathode. Aqueous battery Se-based cathodes are based on a two-electron transfer electrochemical reaction and generally show inadequate rate capability behaviour. Here, the authors propose a four-electron Se chemistry with copper ions as charge carriers to enable fast-charging battery cycling.

•Non-invasive mALPS-index was closely related to the classical detected glymphatic clearance function, providing an alternative method in researches on glymphatic system.•WMHs, lacunas, microbleeds and EPVS in basal ganglia were related to glymphatic clearance function.•Glymphatic clearance function was related to cognitive function in CSVD patients. Few studies have focused on the connection between glymphatic dysfunction and cerebral small vessel disease (CSVD), partially due to the lack of non-invasive methods to measure glymphatic function. We established modified index for diffusion tensor image analysis along the perivascular space (mALPS-index), which was calculated on diffusion tensor image (DTI), compared it with the classical detection of glymphatic clearance function calculated on Glymphatic MRI after intrathecal administration of gadolinium (study 1), and analyzed the relationship between CSVD imaging markers and mALPS-index in CSVD patients from the CIRCLE study (ClinicalTrials.gov ID: NCT03542734) (study 2). Among 39 patients included in study 1, mALPS-index were significantly related to glymphatic clearance function calculated on Glymphatic MRI ( r  = -0.772~-0.844, p < 0.001). A total of 330 CSVD patients were included in study 2. Severer periventricular and deep white matter hyperintensities (β = -0.332, p < 0.001; β = -0.293, p < 0.001), number of lacunas (β = -0.215, p < 0.001), number of microbleeds (β = -0.152, p = 0.005), and severer enlarged perivascular spaces in basal ganglia (β = -0.223, p < 0.001) were related to mALPS-index. Our results indicated that non-invasive mALPS-index might represent glymphatic clearance function, which could be applied in clinic in future. Glymphatic clearance function might play a role in the development of CSVD.

Developing biomimetic nanoparticles without loss of the integrity of proteins remains a major challenge in cancer chemotherapy. Here, we develop a biocompatible tumor-cell-exocytosed exosome-biomimetic porous silicon nanoparticles (PSiNPs) as drug carrier for targeted cancer chemotherapy. Exosome-sheathed doxorubicin-loaded PSiNPs (DOX@E-PSiNPs), generated by exocytosis of the endocytosed DOX-loaded PSiNPs from tumor cells, exhibit enhanced tumor accumulation, extravasation from blood vessels and penetration into deep tumor parenchyma following intravenous administration. In addition, DOX@E-PSiNPs, regardless of their origin, possess significant cellular uptake and cytotoxicity in both bulk cancer cells and cancer stem cells (CSCs). These properties endow DOX@E-PSiNPs with great in vivo enrichment in total tumor cells and side population cells with features of CSCs, resulting in anticancer activity and CSCs reduction in subcutaneous, orthotopic and metastatic tumor models. These results provide a proof-of-concept for the use of exosome-biomimetic nanoparticles exocytosed from tumor cells as a promising drug carrier for efficient cancer chemotherapy. The generation of biomimetic nanoparticles that retain the integrity of proteins has been a challenge. Here, the authors generate biomimetic nanoparticles that are exocytosed from tumour cells and show their therapeutic potential in targeting tumours and cancer stem cells in multiple mouse models.

Genetically engineered T cells expressing a chimeric antigen receptor (CAR) are rapidly emerging a promising new treatment for haematological and non-haematological malignancies. CAR-T therapy can induce rapid and durable clinical responses but is associated with unique acute toxicities. Moreover, CAR-T cells are vulnerable to immunosuppressive mechanisms. Here, we report that CAR-T cells release extracellular vesicles, mostly in the form of exosomes that carry CAR on their surface. The CAR-containing exosomes express a high level of cytotoxic molecules and inhibit tumour growth. Compared with CAR-T cells, CAR exosomes do not express Programmed cell Death protein 1 (PD1), and their antitumour effect cannot be weakened by recombinant PD-L1 treatment. In a preclinical in vivo model of cytokine release syndrome, the administration of CAR exosomes is relatively safe compared with CAR-T therapy. This study supports the use of exosomes as biomimetic nanovesicles that may be useful in future therapeutic approaches against tumours. Genetically engineered T cells expressing a chimeric antigen receptor (CAR-T cells) are a promising new treatment for cancer, but are associated with unique toxicities. Here, the authors test CAR-T-cell-derived exosomes as a surrogate for CAR-T cells and show that they can elicit a potent antitumour immune response in preclinical models of breast cancer with reduced signs of cytokine release syndrome compared with CAR-T therapy.

Structural health monitoring technology can assess the status and integrity of structures in real time by advanced sensors, evaluate the remaining life of structure, and make the maintenance decisions on the structures. Piezoelectric materials, which can yield electrical output in response to mechanical strain/stress, are at the heart of structural health monitoring. Here, we present an overview of the recent progress in piezoelectric materials and sensors for structural health monitoring. The article commences with a brief introduction of the fundamental physical science of piezoelectric effect. Emphases are placed on the piezoelectric materials engineered by various strategies and the applications of piezoelectric sensors for structural health monitoring. Finally, challenges along with opportunities for future research and development of high-performance piezoelectric materials and sensors for structural health monitoring are highlighted.

Increasing evidence has indicated that long noncoding RNAs (lncRNAs) play important roles in human diseases, including cancer; however, only a few of them have been experimentally validated and functionally annotated. Here, we identify a novel lncRNA that we term HITT (HIF-1α inhibitor at translation level). HITT is commonly decreased in multiple human cancers. Decreased HITT is associated with advanced stages of colon cancer. Restoration of the expression of HITT in cancer cells inhibits angiogenesis and tumor growth in vivo in an HIF-1α-dependent manner. Further study reveals that HITT inhibits HIF-1α expression, mainly by interfering with its translation. Mechanically, HITT titrates away YB-1 from the 5′-UTR of HIF-1α mRNA via a high-stringency YB-1-binding motif. The reverse correlation between HITT and HIF-1α expression is further validated in human colon cancer tissues. Moreover, HITT is one of the most altered lncRNAs upon the hypoxic switch and HITT downregulation is required for hypoxia-induced HIF-1α expression. We further demonstrate that HITT and HIF-1α form an autoregulatory feedback loop where HIF-1α destabilizes HITT by inducing MiR-205, which directly targets HITT for degradation. Together, these results expand our understanding of the cancer-associated functions of lncRNAs, highlighting the HITT –HIF-1α axis as constituting an additional layer of regulation of angiogenesis and tumor growth, with potential implications for therapeutic targeting.