Long noncoding RNA (lncRNA) have critical roles in various pathophysiological processes, and are frequently dysregulated in many diseases, particularly in cancer. The lncRNA glypican 3 antisense ...transcript 1 (GPC3‐AS1) has been reported to be a potential biomarker for hepatocellular carcinoma (HCC) screening. However, the exact biological functions of GPC3‐AS1 in HCC, and its roles and regulation mechanisms regarding GPC3 are still unknown. In this study, we observed a significant upregulation of GPC3‐AS1 in HCC. Increased expression of GPC3‐AS1 was associated with α‐fetoprotein, tumor size, microvascular invasion, encapsulation, Barcelona Clinic Liver Cancer stage, and worse prognosis of HCC patients. Furthermore, we found that GPC3‐AS1 physically associated with P300/CBP‐associated factor and recruited it to the GPC3 gene body region, consequently inducing an increase in euchromatic histone marks and activating GPC3 transcription. GPC3‐AS1 expression was strongly correlated with GPC3 in HCC tissues. Gain‐of‐function and loss‐of‐function analyses showed that GPC3‐AS1 overexpression enhanced HCC cell proliferation and migration in vitro and xenograft tumor growth in vivo. GPC3‐AS1 knockdown inhibited HCC cell proliferation and migration. Moreover, the effects of GPC3‐AS1 on HCC cell proliferation and migration were dependent on the upregulation of GPC3. Collectively, our studies indicate that GPC3‐AS1 significantly promotes HCC progression via epigenetically activating GPC3, and identifies GPC3‐AS1 as a potential therapeutic target for HCC.
The long noncoding RNA GPC3‐AS1 is significantly upregulated in hepatocellular carcinoma (HCC) and indicates poor prognosis of HCC patients. GPC3‐AS1 physically associates with P300/CBP‐associated factor (PCAF) and recruits it to the GPC3 gene body region, consequently inducing an increase in euchromatic histone marks and activating GPC3 transcription. GPC3‐AS1 overexpression enhances HCC cell proliferation and migration in vitro and xenograft tumour growth in vivo.
The methyltransferase like 3 （METTL3）-containing methyltransferase complex catalyzes the N6-methyladenosine （m6A） formation, a novel epitranscriptomic marker; however, the nature of this complex ...remains largely unknown. Here we report two new components of the human m6A methyltransferase complex, Wilms＇ tumor 1-associating protein （WTAP） and methyltransferase like 14 （METTL14）. WTAP interacts with METTL3 and METTL14, and is required for their localization into nuclear speckles enriched with pre-mRNA processing factors and for catalytic ac- tivity of the m6A methyltransferase in vivo. The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif. In the absence of WTAP, the RNA-binding capability of METTL3 is strongly reduced, suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets. Furthermore, transcriptomic analyses in combination with photoactivatable-ribonucleoside-en- hanced crosslinking and immunoprecipitation （PAR-CLIP） illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing. Morpholino-mediated knockdown targeting WTAP and/or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis. These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism.
Autonomous driving has so far received numerous attention from academia and industry. However, the inevitable occlusion is a great menace to safety and reliable driving. Existing works have primarily ...focused on improving the perception ability of a single autonomous vehicle (AV), but the safety problem brought by occlusions remains unanswered. In this paper, we propose a multi-tier perception task offloading framework with a collaborative computing approach, where an AV is able to achieve a comprehensive perception of the concerned region-of-interest (RoI) by leveraging collaborative computation with nearby AVs and road side units (RSUs). Besides, the collaborative computation provides offloading service for computationally intensive tasks so as to reduce processing delay. Specifically, we formulate a joint problem of perception task assignment, offloading and resource allocation, by fully considering the AV's mobility, task dependency, and delay requirement. The collaborative offloading is modeled as a mixed-integer nonlinear programming (MINLP) problem. We design a two-layer binary intelligent firefly (TL-BIFA) algorithm to solve MINLP, with the goal of minimizing execution delay. The proposed TL-BIFA synthesizes the advantages of heuristic methods and deterministic methods. Through extensive simulations, the proposed collaborative offloading approach and the TL-BIFA show superiority in enhancing the autonomous driving system's safety, efficiency and resource utilization.
Being conductive and flexible, 2D transition metal nitrides and carbides (MXenes) can serve in Li–S batteries as sulfur hosts to increase the conductivity and alleviate the volume expansion. However, ...the surface functional groups, such as OH and F, weaken the ability of bare MXenes in the chemisorption of polysulfides. Besides, they create numerous hydrogen bonds which make MXenes liable to restack, resulting in substantial loss of active area and, thus, inaccessibility of ions and electrolyte. Herein, a facile, one‐step strategy is developed for the growth of TiO2 quantum dots (QDs) on ultrathin MXene (Ti3C2Tx) nanosheets by cetyltrimethylammonium bromide‐assisted solvothermal synthesis. These QDs act as spacers to isolate the MXene nanosheets from restacking, and preserve their 2D geometry which guarantees larger electrode–electrolyte contact area and higher sulfur loading. The stronger adsorption energy of polysulfides with TiO2 (than with Ti3C2Tx), as proven by density functional theory calculations, is essential for better on‐site polysulfide retention. The ultrathin nature and protected conductivity ensure rapid ion and electron diffusion, and the excellent flexibility maintains high mechanical integrity. In result, the TiO2 QDs@MXene/S cathode exhibits significantly improved long‐term cyclability and rate capability, disclosing a new opportunity toward fast and stable Li–S batteries.
TiO2 quantum dots (QDs) are grown on ultrathin MXene nanosheets by a facile, one‐step strategy through cetyltrimethylammonium bromide‐assisted solvothermal synthesis, resulting in TiO2 QDs@MXene nanohybrids that serve as a high‐performance sulfur host toward fast and stable Li–S batteries.
Cancer immunotherapy: Pros, cons and beyond Tan, Shuzhen; Li, Dongpei; Zhu, Xiao
Biomedicine & pharmacotherapy,
April 2020, 2020-Apr, 2020-04-00, 20200401, 2020-04-01, Letnik:
124
Journal Article
Recenzirano
Odprti dostop
•Tumor immunotherapy mainly includes ICIs, cellular immunotherapy, exosome immunotherapy, and other novel therapies.•The therapeutic effect of immunotherapy is affected by immune microenvironment, ...intestinal bacteria and TMB.•Drug resistance and adverse reactions are challenges in the development of immunotherapy.•The future direction of immunotherapy is mainly to reduce side effects and improve the targeting of therapy.
Cancer immunotherapy is an innovative treatment for tumors today. In various experiments and clinical studies, it has been found that immunotherapy does have incomparable advantages over traditional anti-tumor therapy, which can prolong progression-free survival (PFS) and overall survival (OS). However, immunotherapy has obvious complexity and uncertainty. Immunotherapy may also cause severe adverse reactions due to an overactive immune system. More effective and fewer adverse reactions immunological checkpoints are still under further exploration. This review gives an overview of recent developments in immunotherapy and indicates a new direction of tumor treatment through analyzing the pros and cons of immunotherapy coupled with keeping a close watch on the development trend of the immunotherapy future.
The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain ...obscure. Here we identify PKCβII as a critical contributor of ferroptosis through independent genome-wide CRISPR-Cas9 and kinase inhibitor library screening. Our results show that PKCβII senses the initial lipid peroxides and amplifies lipid peroxidation linked to ferroptosis through phosphorylation and activation of ACSL4. Lipidomics analysis shows that activated ACSL4 catalyses polyunsaturated fatty acid-containing lipid biosynthesis and promotes the accumulation of lipid peroxidation products, leading to ferroptosis. Attenuation of the PKCβII-ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKCβII as a sensor of lipid peroxidation, and the lipid peroxidation-PKCβII-ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment.
Metal‐organic cages (MOCs) are supramolecular coordination complexes that have internal cavities for hosting guest molecules and exhibiting various properties. However, the functions of MOCs are ...limited by the choice of the building blocks. Post‐synthetic modification (PSM) is a technique that can introduce new functional groups and replace existing ones on the MOCs without changing their geometry. Among many PSM methods, covalent PSM is a promising approach to modify MOCs with tailored structures and functions. Covalent PSM can be applied to either the internal cavity or the external surface of the MOCs, depending on the functionality expected to be customized. However, there are still some challenges and limitations in the field of covalent PSM of MOCs, such as the balance between the stability of MOCs and the harshness of organic reactions involved in covalent PSMs. This concept article introduces the organic reaction types involved in covalent PSM of MOCs, their new applications after modification, and summarizes and provides an outlook of this research field.
Covalent post‐synthetic modification (PSM) is a powerful research paradigm capable of constructing metal‐organic cages (MOCs) with customized structures and properties. A variety of efficient organic reactions have been developed for the functionalization of MOCs, and these new products have shown potential applications in multiple fields.
Mammalian target of rapamycin (mTOR) regulates cell proliferation, autophagy, and apoptosis by participating in multiple signaling pathways in the body. Studies have shown that the mTOR signaling ...pathway is also associated with cancer, arthritis, insulin resistance, osteoporosis, and other diseases. The mTOR signaling pathway, which is often activated in tumors, not only regulates gene transcription and protein synthesis to regulate cell proliferation and immune cell differentiation but also plays an important role in tumor metabolism. Therefore, the mTOR signaling pathway is a hot target in anti-tumor therapy research. In recent years, a variety of newly discovered mTOR inhibitors have entered clinical studies, and a variety of drugs have been proven to have high activity in combination with mTOR inhibitors. The purpose of this review is to introduce the role of mTOR signaling pathway on apoptosis, autophagy, growth, and metabolism of tumor cells, and to introduce the research progress of mTOR inhibitors in the tumor field.
Being conductive and flexible, MXenes, including transition metal carbides and nitrides, are expected to compete with, or even outperform graphene as 2D substrates serving in versatile applications. ...On the other hand, the extraordinary electrochemical activities of MXenes make them promising candidates as electrode materials in rechargeable batteries and supercapacitors, or as electrocatalysts in water splitting. However, MXenes are inclined to self‐restack due to hydrogen bonding or van der Waals interactions, which may lead to substantial loss of electroactive area as well as inaccessibility of ions and electrolytes. In this sense, hybridizing 2D MXenes and low‐dimensional inorganic nanostructures in elaborately designed architectures is of utmost significance, and provides a chance to integrate their unique properties in a complementary way. As such, this review is dedicated to highlighting recent progress in this regime, putting emphasis on the methods, structural and functional synergies, and energy‐related applications. Moreover, the present challenges and the future development directions are also discussed in depth.
Hybridizing 2D MXenes and low‐dimensional inorganic nanostructures in elaborately designed architectures is of utmost significance, and provides a chance to integrate their unique properties in a complementary way. This review highlights recent progress in this regime, putting emphasis on the methods, structural and functional synergies, and energy‐related applications. Moreover, the present challenges and the future development directions are also discussed.
Background
Trimethylamine‐N‐oxide (TMAO) has recently been identified as a novel and independent risk factor for promoting atherosclerosis through inducing vascular inflammation. However, the exact ...mechanism is currently unclear. Studies have established a central role of nucleotide‐binding oligomerization domain–like receptor family pyrin domain–containing 3 (NLRP3) inflammasome in the pathogenesis of vascular inflammation. Here, we examined the potential role of the NLRP3 inflammasome in TMAO‐induced vascular inflammation in vitro and in vivo and the underlying mechanisms.
Methods and Results
Experiments using liquid chromatography‐tandem mass spectrometry, Western blot, and fluorescent probes showed that TMAO‐induced inflammation in human umbilical vein endothelial cells (HUVECs) and aortas from ApoE−/− mice. Moreover, TMAO promoted NLRP3 and activated caspase‐1 p20 expression and caspase‐1 activity in vitro and in vivo. Notably, a caspase‐1 inhibitor (YVAD), an NLRP3 inhibitor (MCC950), as well as NLRP3 short interfering RNA attenuated TMAO‐induced activation of the NLRP3 inflammasome, subsequently leading to suppression of inflammation in HUVECs. TMAO additionally stimulated reactive oxygen species (ROS) generation, in particular, mitochondrial ROS, while inhibiting manganese superoxide dismutase 2 (SOD2) activation and sirtuin 3 (SIRT3) expression in HUVECs and aortas from ApoE−/− mice. TMAO‐induced endothelial NLRP3 inflammasome activation was ameliorated by the mitochondrial ROS scavenger Mito‐TEMPO, or SIRT3 overexpression in HUVECs. Conversely, TMAO failed to further inhibit SOD2 and activate the NLRP3 inflammasome or induce inflammation in SIRT3 short interfering RNA–treated HUVECs and aortas from SIRT3−/− mice.
Conclusions
TMAO promoted vascular inflammation by activating the NLRP3 inflammasome, and the NLRP3 inflammasome activation in part was mediated through inhibition of the SIRT3‐SOD2–mitochondrial ROS signaling pathway.
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