Cancer immunotherapies have made much headway during the past decades. Techniques including the immune checkpoint inhibition (ICI) and adoptive cell therapy (ACT) have harvested impressive efficacy ...and provided far-reaching tools for treating cancer patients. However, due to inadequate priming of the immune system, a certain subgroup of patients remains resistant to cancer immunotherapies during or after the treatment. β2-microglobulin (B2M) is an important subunit of major histocompatibility complex (MHC) class I which exerts substantive biological functions in tumorigenesis and immune control. Accumulating evidence has shown that alterations of B2M gene and B2M proteins contribute to poor reaction to cancer immunotherapies by dampening antigen presentation. Here, we discuss the basic biological functions of B2M, its distribution in a spectrum of cancers, and current understanding of its role in ICI, cancer vaccines and chimeric antigen receptor T cell (CAR-T) therapies. Furthermore, we summarize some promising therapeutic strategies to improve the efficacy inhibited by B2M defects.
•B2M loss causes primary and acquired resistance to immune checkpoint inhibition therapy.•B2M gene mutations occur in many cancer types, especially MSI-H cancers.•B2M plays multifaceted role in cancer immune control.•Several immunotherapies are promising approaches to handling B2M-realted resistance.
Styrene-butadiene-styrene copolymer (SBS) and recycled tire rubber are the typical polymers for asphalt modification. The dispersion of crumb tire rubber (CTR) dominates the composite effect of ...rubberized asphalt. And the multiscale of CTR in mixtures always challenges the design and construction of asphalt mixtures. The multiscale dispersion of CTR can be controlled by pre-devulcanization. In this study, lightly devulcanized rubber (LDR) with various dispersive scales in asphalt from microns to dozens of microns, and deeply devulcanized rubber (DDR) with micro-nano scales were prepared and analyzed, respectively. The devulcanized rubber (DR) was further compounded with SBS to prepare composite modified asphalt. The influences of rubber content on the structure and properties of modified asphalt and mixtures were investigated, and the dispersive structure model of asphalt mixture was also established. Furthermore, a high viscoelastic rubberized asphalt was prepared with 4% SBS and 20% DDR in the field plant and paved in a field project, a new first-grade national highway. The results showed that the devulcanization of CTR can help the dispersion of CTR in asphalt by improving the compatibility among CTR, SBS, and asphalt. And the dispersive scale and the content of DR can affect the binder content, high and low temperature performance of asphalt mixtures. The field project showed that the high viscoelastic rubberized asphalt exhibited similar mix design and construction process but better high and low temperature performance compared to SBS modified asphalt.
Display omitted
Interaction between light and magnetism in magneto-optical (MO) nanophotonic devices has been actively studied in the past few years. The recent development of MO all-dielectric resonators and ...metasurfaces has led to the emergence of various novel MO phenomena that were not observed in their bulk counterparts. For example, a large s-polarized transverse MO Kerr effect can be observed at magnetic resonance wavelength, which cannot exist in the bare MO films. We review recent developments in nanophotonic devices based on MO materials and focus on different modes and related MO effects in nanophotonic structures with emphasis on recently discovered new MO phenomena in magnetoplasmonics and all-dielectric nanostructures, such as dark mode, all-dielectric Mie resonance and waveguide mode. Further, we discuss the potential applications of these nanostructures for biological/chemical sensing, magnetic field sensing, and magnetic field-controlled active and nonreciprocal metasurfaces.
Rubber asphalt has always been considered to have the most potential for the disposal of waste tires as sustainable infrastructure. However, the covalently cross-linked tire rubber presents an ...extreme challenge in reusing waste rubbers in roads. Rubberized asphalt with finely dispersed or colloidal structure has been regarded as a potential binder used as road material because of the improved properties in terms of storage stability, easy processing and high content of incorporation. However, the mixing mechanism between the finely dispersed rubber on micro-nano scale with asphalt is still not clear, which restricts its further development as value-added material. Devulcanized rubber (DR) was introduced to improve the compatibility between asphalt and rubber. The basic chemicals of DR and asphalt were introduced based on their structures. Furthermore, the interactions between DR and asphalt were discussed according to the functional elements at different levels, and the concept of DR as “the fifth component” of asphalt was put forward. Finally, high performance, environmental and economic effects and applications of devulcanized-rubber-modified asphalt (DRMA) were discussed. The review is expected to provide a guide for the wide application of DRMA, which is still restricted by poor compatibility and bad stability during processing, storage and recycling.
Proprotein convertase subtilisin/kexin type 9 (PCSK9), the last member of the proprotein convertase family, functions as a classic regulator of low-density lipoprotein (LDL) by interacting with ...low-density lipoprotein receptor (LDLR). Recent studies have shown that PCSK9 can affect the occurrence and development of tumors and can be used as a novel therapeutic target. However, a comprehensive pan-cancer analysis of PCSK9 has yet to be conducted.
The potential oncogenic effects of PCSK9 in 33 types of tumors were explored based on the datasets of The Cancer Genome Atlas (TCGA) dataset. In addition, the immune regulatory role of PCSK9 inhibition was evaluated via in vitro cell coculture and the tumor-bearing mouse model. Finally, the antitumor efficacy of targeted PCSK9 combined with OVA-II vaccines was verified.
Our results indicated that PCSK9 was highly expressed in most tumor types and was significantly correlated with late disease stage and poor prognosis. Additionally, PCSK9 may regulate the tumor immune matrix score, immune cell infiltration, immune checkpoint expression, and major histocompatibility complex expression. Notably, we first found that dendritic cell (DC) infiltration and major histocompatibility complex-II (MHC-II) expression could be upregulated by PCSK9 inhibition and improve CD8
T cell activation in the tumor immune microenvironment, thereby achieving potent tumor control. Combining PCSK9 inhibitors could enhance the efficacies of OVA-II tumor vaccine monotherapy.
Conclusively, our pan-cancer analysis provided a more comprehensive understanding of the oncogenic and immunoregulatory roles of PCSK9 and demonstrated that targeting PCSK9 could increase the efficacy of long peptide vaccines by upregulating DC infiltration and MHC-II expression on the surface of tumor cells. This study reveals the critical oncogenic and immunoregulatory roles of PCSK9 in various tumors and shows the promise of PCSK9 as a potent immunotherapy target.
Metal–organic framework (MOF)‐based drug delivery systems have demonstrated values in oncotherapy. Current research endeavors are centralized on the functionality enrichment of featured MOF materials ...with designed versatility for synergistic multimodal treatments. Here, inspired by the multifarious biological functions including ferroptosis pattern, porphyrins, and cancer cell membrane (CCM) camouflage technique, novel multi‐biomimetic MOF nanocarriers from microfluidics are prepared. The Fe3+, meso‐tetra(4‐carboxyphenyl)porphine and oxaliplatin prodrug are incorporated into one MOF nano‐system (named FeTPt), which is further cloaked by CCM to obtain a “Trojan Horse”‐like vehicle (FeTPt@CCM). Owing to the functionalization with CCM, FeTPt@CCM can target and accumulate at the tumor site via homologous binding. After being internalized by cancer cells, FeTPt@CCM can be activated by a Fenton‐like reaction as well as a redox reaction between Fe3+ and glutathione and hydrogen peroxide to generate hydroxyl radical and oxygen. Thus, the nano‐platform effectively initiates ferroptosis and improves photodynamic therapy performance. Along with the Pt‐drug chemotherapy, the nano‐platform exhibits synergistic multimodal actions for inhibiting cancer cell proliferation in vitro and suppressing tumor growth in vivo. These features indicate that such a versatile biomimetic MOF delivery system from microfluidics has great potential for synergistic cancer treatment.
A “Trojan Horse”‐like system is successfully fabricated from microfluidics for synergistic tumor chemotherapy, ferroptosis, and photodynamic therapy. The designed system demonstrates satisfactory efficiency in killing tumor cells in vitro and suppressing tumor growth in vivo through the combined multimode actions. These studies reveal that the “Trojan Horse”‐like system is a promising synergistic therapy approach for cancer therapy.
Purpose
Sevoflurane is used widely during lung cancer surgery. However, the effect of sevoflurane on the invasion and migration of lung carcinoma cells remains unclear. The aims of this study were to ...explore the role of matrix metalloproteinase (MMP)-2 and MMP-9 in the effect of sevofluane on the invasion and the role of fascin and ezrin on the effect of sevofluane on the migration of human lung adenocarcinoma A549 cells. We also investigated whether sevoflurane regulates the expression of these molecules through the p38 mitogen-activated protein kinase (MAPK) signaling pathway.
Methods
The invasion of cells was evaluated using the Transwell invasion assay, and the migration of cells was determined using the wound healing assay. The expression of MMP-2, MMP-9, ezrin, fascin, and phospho-p38 MAPK in cells was determined by western blotting.
Results
A significant inhibition of cell invasion and migration was found in A549 cells which had been treated with sevoflurane. The data also revealed that sevoflurane could decrease the phosphorylation level of p38 MAPK, which is involved in the downregulation of MMP-2, MMP-9, fascin, and ezrin expression, accompanied by a concomitant inhibition of the invasion and migration of A549 cells. SB203580, a p38 MAPK inhibitor, augmented the downregulation of the expression of these proteins.
Conclusion
The anti-invasion effect of sevoflurane on A549 cells was associated with a downregulation of both MMP-2 and MMP-9 expression, while the anti-migration effect was associated with a downregulation of both fascin and ezrin expression. These effects could occur partly as a result of inactivation of the p38 MAPK signaling pathway.
Abstract MicroRNAs are strongly implicated in cancer but their specific roles and functions in the major cancers have yet to be fully elucidated. In this study, we defined the expression and function ...of miR-137, which we found to be downregulated in glioma samples and glioma cells by qRT-PCR. Ectopic expression of miR-137 in glioma cell lines inhibited proliferation and invasion. Using computational and expression analysis, Cox-2 was identified as a candidate target of miR-137. Reporter assay with 3′UTR of Cox-2 cloned downstream of the luciferase gene showed reduced luciferase activity in the presence of miR-137, providing strong evidence that miR-137 was a direct regulator of Cox-2. Expression analysis further revealed that Cox-2 was elevated in glioma and associated with survival of patients. Furthermore, we observed that Cox-2 knockdown resulted in effects similar to those with miR-137 transfection in glioma cells. In conclusion, our study demonstrates that miR-137 deregulation is common in glioma, and restoration of its function inhibits cell proliferation and invasion, suggesting that miR-137 may act as a tumour suppressor.
Display omitted
Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) resulting in an abrupt deterioration of kidney function. CXC chemokine ligand 16 (CXCL16) ...contributes significantly to the pathogenesis of renal injury. However, the signaling pathway mechanisms of CXCL16 in IRI-induced AKI remains obscured. In this study, we examined the role of the CXCL16/ Rho Associated Coiled-Coil Containing Protein Kinase-1 (ROCK1) signaling pathway in AKI induced by IRI. In vivo, CXCL16 was induced markedly after IRI. Mice treated with anti-CXCL16 antibody displayed less severe renal dysfunction and tubular injury in response to IRI compared with vehicle-treated mice. Inhibition of CXCL16 substantially reduced apoptotic cells and suppresses caspase-3 activation in the kidneys of mice following IRI. Additionally, CXCL16 inhibition profoundly decreased the production of TNF-α, IL-1β and IL-6 in the kidneys of mice post IRI. Furthermore, the level of ROCK1 protein was upregulated in the kidney in response to IRI, an effect that was abolished by CXCL16 inhibitor. Finally, treatment with Y-27632 (a ROCK1 inhibitor) attenuated deterioration of renal function and tubular damage of mice after IRI. Administration of Y-27632 ameliorated apoptosis in the IRI-treated kidneys of mice. In injured HK-2 cells, CXCL16 activated ROCK1 resulting in the upregulation of caspase-3 protein and pro-inflammatory molecules, which was abolished by Y-27632. In summary, our findings demonstrate that CXCL16/ROCK1 signaling pathway may play an important role in the pathogenesis of IRI-induced AKI.
PDF
