Dendritic cells (DCs) play a central role in the regulation of the balance between CD8 T cell immunity vs. tolerance to tumor antigens. Cross-priming, a process which DCs activate CD8 T cells by ...cross-presenting exogenous antigens, plays a critical role in generating anti-tumor CD8 T cell immunity. However, there are compelling evidences now that the tumor microenvironment (TME)-mediated suppression and modulation of tumor-infiltrated DCs (TIDCs) impair their function in initiating potent anti-tumor immunity and even promote tumor progression. Thus, DC-mediated cross-presentation of tumor antigens in tumor-bearing hosts often induces T cell tolerance instead of immunity. As tumor-induced immunosuppression remains one of the major hurdles for cancer immunotherapy, understanding how DCs regulate anti-tumor CD8 T cell immunity in particular within TME has been under intensive investigation. Recent reports on the Batf3-dependent type 1 conventional DCs (cDC1s) in anti-tumor immunity have greatly advanced our understanding on the interplay of DCs and CD8 T cells in the TME, highlighted by the critical role of CD103
cDC1s in the cross-priming of tumor antigen-specific CD8 T cells. In this review, we will discuss recent advances in anti-tumor CD8 T cell cross-priming by CD103
cDC1s in TME, and share perspective on future directions including therapeutic applications and memory CD8 T cell responses.
Significant progress has been made in single image super-resolution (SISR) based on deep convolutional neural networks (CNNs). The attention mechanism can capture important features well, and the ...feedback mechanism can realize the fine-tuning of the output to the input. However, they have not been reasonably applied in the existing deep learning-based SISR methods. Additionally, the results of the existing methods still have serious artifacts and edge blurring. To address these issues, we proposed an Edge-enhanced with Feedback Attention Network for image super-resolution (EFANSR), which comprises three parts. The first part is an SR reconstruction network, which adaptively learns the features of different inputs by integrating channel attention and spatial attention blocks to achieve full utilization of the features. We also introduced feedback mechanism to feed high-level information back to the input and fine-tune the input in the dense spatial and channel attention block. The second part is the edge enhancement network, which obtains a sharp edge through adaptive edge enhancement processing on the output of the first SR network. The final part merges the outputs of the first two parts to obtain the final edge-enhanced SR image. Experimental results show that our method achieves performance comparable to the state-of-the-art methods with lower complexity.
As the initiators of adaptive immune responses, DCs play a central role in regulating the balance between CD8 T cell immunity versus tolerance to tumor antigens. Exploiting their function to ...potentiate host anti-tumor immunity, DC-based vaccines have been one of most promising and widely used cancer immunotherapies. However, DC-based cancer vaccines have not achieved the promised success in clinical trials, with one of the major obstacles being tumor-mediated immunosuppression. A recent discovery on the critical role of type 1 conventional DCs (cDC1s) play in cross-priming tumor-specific CD8 T cells and determining the anti-tumor efficacy of cancer immunotherapies, however, has highlighted the need to further develop and refine DC-based vaccines either as monotherapies or in combination with other therapies. DC-derived exosomes (DCexos) have been heralded as a promising alternative to DC-based vaccines, as DCexos are more resistance to tumor-mediated suppression and DCexo vaccines have exhibited better anti-tumor efficacy in pre-clinical animal models. However, DCexo vaccines have only achieved limited clinical efficacy and failed to induce tumor-specific T cell responses in clinical trials. The lack of clinical efficacy might be partly due to the fact that all current clinical trials used peptide-loaded DCexos from monocyte-derived DCs. In this review, we will focus on the perspective of expanding current DCexo research to move DCexo cancer vaccines forward clinically to realize their potential in cancer immunotherapy.
As the sentinels of the immune system, dendritic cells (DCs) play a critical role in initiating and regulating antigen-specific immune responses. Cross-priming, a process that DCs activate CD8 T ...cells by cross-presenting exogenous antigens onto their MHCI (Major Histocompatibility Complex class I), plays a critical role in mediating CD8 T cell immunity as well as tolerance. Current DC vaccines have remained largely unsuccessful despite their ability to potentiate both effector and memory CD8 T cell responses. There are two major hurdles for the success of DC-based vaccines: tumor-mediated immunosuppression and the functional limitation of the commonly used monocyte-derived dendritic cells (MoDCs). Due to their resistance to tumor-mediated suppression as inert vesicles, DC-derived exosomes (DCexos) have garnered much interest as cell-free therapeutic agents. However, current DCexo clinical trials have shown limited clinical benefits and failed to generate antigen-specific T cell responses. Another exciting development is the use of naturally circulating DCs instead of in vitro cultured DCs, as clinical trials with both human blood cDC2s (type 2 conventional DCs) and plasmacytoid DCs (pDCs) have shown promising results. pDC vaccines were particularly encouraging, especially in light of promising data from a recent clinical trial using a human pDC cell line, despite pDCs being considered tolerogenic and playing a suppressive role in tumors. However, how pDCs generate anti-tumor CD8 T cell immunity remains poorly understood, thus hindering their clinical advance. Using a pDC-targeted vaccine model, we have recently reported that while pDC-targeted vaccines led to strong cross-priming and durable CD8 T cell immunity, cross-presenting pDCs required cDCs to achieve cross-priming in vivo by transferring antigens to cDCs. Antigen transfer from pDCs to bystander cDCs was mediated by pDC-derived exosomes (pDCexos), which similarly required cDCs for cross-priming of antigen-specific CD8 T cells. pDCexos thus represent a new addition in our arsenal of DC-based cancer vaccines that would potentially combine the advantage of pDCs and DCexos.
Background
Postoperative cognitive dysfunction (POCD) is a poorly understood disorder, very common even after total hip arthroplasty (THA). It is widely considered that inflammation response play a ...role in the pathogenesis of POCD.
Aims
The aim of the present study was to investigate whether inflammation cytokine concentrations could serve as biomarkers for POCD in patients undergoing THA.
Methods
A systematic search of databases was conducted to retrieve publications measuring circulating inflammatory markers of patients with and without POCD after THA. Inflammatory markers identified in more than two studies were pooled. The standardized mean difference (SMD) and the 95% confidence interval (95% CI) were calculated for each outcome. Fail-safe N statistics was calculated to estimate possible publication bias.
Results
The pooled incidence rate of POCD after THA by combining 11 cohort studies was 31%. A total of five inflammatory markers, CRP, S-100B, IL-1β, IL-6 and TNF-α, were assessed. Significantly higher pre-operative CRP (
P
= 0.012) and S-100B (
P
< 0.0001) as well as post-operative CPR (
P
= 0.005) and IL-6 (
P
< 0.0001) at 6 h were found in POCD compared with non-POCD patients undergoing THA. Fail-safe N statistics revealed that these results are robust.
Discussion
The current evidence suggests that some of the inflammatory markers, including CRP, S-100B, and IL-6, were correlated with the occurrence of POCD after THA.
Conclusion
Monitor of inflammatory markers might help early diagnosis of POCD after THA and development of preventive strategies.
Despite largely disappointing clinical trials of dendritic cell (DC)-based vaccines, recent studies have shown that DC-mediated cross-priming plays a critical role in generating anti-tumor CD8 T cell ...immunity and regulating anti-tumor efficacy of immunotherapies. These new findings thus support further development and refinement of DC-based vaccines as mono-immunotherapy or combinational immunotherapies. One exciting development is recent clinical studies with naturally circulating DCs including plasmacytoid DCs (pDCs). pDC vaccines were particularly intriguing, as pDCs are generally presumed to play a negative role in regulating T cell responses in tumors. Similarly, DC-derived exosomes (DCexos) have been heralded as cell-free therapeutic cancer vaccines that are potentially superior to DC vaccines in overcoming tumor-mediated immunosuppression, although DCexo clinical trials have not led to expected clinical outcomes. Using a pDC-targeted vaccine model, we have recently reported that pDCs required type 1 conventional DCs (cDC1s) for optimal cross-priming by transferring antigens through pDC-derived exosomes (pDCexos), which also cross-prime CD8 T cells in a bystander cDC-dependent manner. Thus, pDCexos could combine the advantages of both cDC1s and pDCs as cancer vaccines to achieve better anti-tumor efficacy. In this review, we will focus on the pDC-based cancer vaccines and discuss potential clinical application of pDCexos in cancer immunotherapy.
Recent studies have demonstrated that β-catenin in DCs serves as a key mediator in promoting both CD4⁺ and CD8⁺ T-cell tolerance, although how β-catenin exerts its functions remains incompletely ...understood. Here we report that activation of β-catenin in DCs inhibits cross-priming of CD8⁺ T cells by up-regulating mTOR-dependent IL-10, suggesting blocking β-catenin/mTOR/IL-10 signaling as a viable approach to augment CD8⁺ T-cell immunity. However, vaccination of DC–β-catenin−/−(CD11c-specific deletion of β-catenin) mice surprisingly failed to protect them against tumor challenge. Further studies revealed that DC–β-catenin−/−mice were deficient in generating CD8⁺ T-cell immunity despite normal clonal expansion, likely due to impaired IL-10 production by β-catenin−/−DCs. Deletion of β-catenin in DCs or blocking IL-10 after clonal expansion similarly led to reduced CD8⁺ T cells, suggesting that β-catenin in DCs plays a positive role in CD8⁺ T-cell maintenance postclonal expansion through IL-10. Thus, our study has not only identified mTOR/IL-10 as a previously unidentified mechanism for β-catenin–dependent inhibition of cross-priming, but also uncovered an unexpected positive role that β-catenin plays in maintenance of CD8⁺ T cells. Despite β-catenin’s opposite functions in regulating CD8⁺ T-cell responses, selectively blocking β-catenin with a pharmacological inhibitor during priming phase augmented DC vaccine-induced CD8⁺ T-cell immunity and improved antitumor efficacy, suggesting manipulating β-catenin signaling as a feasible therapeutic strategy to improve DC vaccine efficacy.
We prepared the core-shell lipid-polymer nanoparticles (LPNs) as the carriers of brinzolamide (Brz-LPNs) and investigated the potential of enhancing sustained drug release, corneal permeation and ...intraocular pressure (IOP) reduction of Brz-LPNs.
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Nowadays, tremendous researches have been focused on the core-shell lipid-polymer nanoparticles (LPNs) due to the advantages of both liposomes and polymer nanoparticles. In this work, LPNs were applied to encapsulate brinzolamide (Brz-LPNs) for achieving sustained drug release, improving drug corneal permeation and enhancing drug topical therapeutic effect. The structure of Brz-LPNs was composed of poly(lactic-co-glycolic) acid (PLGA) nanocore which encapsulated Brz (Brz-NPs) and lipid shell around the core. Brz-LPNs were prepared by a modified thin-film dispersion method. With the parameters optimization of Brz-LPNs, optimal Brz-LPNs showed an average particle size of 151.23 ± 1.64 nm with a high encapsulation efficiency (EE) of 86.7% ± 2.28%. The core-shell structure of Brz-LPNs were confirmed by transmission electronic microscopy (TEM). Fourier transformed infrared spectra (FTIR) analysis proved that Brz was successfully entrapped into Brz-LPNs. Brz-LPNs exhibited obvious sustained release of Brz, compared with AZOPT® and Brz-LPs. Furthermore, the corneal accumulative permeability of Brz-LPNs significantly increased compared to the commercial available formulation (AZOPT®) in vitro. Moreover, Brz-LPNs (1 mg/mL Brz) showed a more sustained and effective intraocular pressure (IOP) reduction than Brz-LPs (1 mg/mL) and AZOPT® (10 mg/mL Brz) in vivo. In conclusion, Brz-LPNs, as promising ocular drug delivery systems, are well worth developing in the future for glaucoma treatment.
The elucidation of species diversity and distribution is critical within the fields of evolution, genetics, and conservation. The genus Sibynophis contains rare snakes that have historically received ...little attention. In this study, we conducted comprehensive sampling and use both mitochondrial and nuclear genetic markers to explore Sibynophis species diversity within China. Our findings revealed that S. c. miyiensis should be considered synonymous with S. c. grahami, and S. c. grahami should be gave a specific rank as S. grahami. In addition, we discovered S. triangularis was new to China and Myanmar. Based on the specimens and molecular phylogeny results, we redefined the species distribution boundaries of each Chinese species.
This study first explored the species diversity of Chinese species of the genus Sibynophis using both mitchondiral and nuclear gene data. The results indicated that S. c. miyiensis is a synonym of S. c. grahami, and S. c. grahami should be gave a specific rank as S. grahami. Sibynophis triangularis was uncovered to be new to China and Myanmar. The species distribution boundaries of each Chinese species were redefined.
The budding of endoplasmic reticulum (ER)-derived vesicles is dependent on the COPII coat complex. Coat assembly is initiated when Sar1-GTP recruits the cargo adaptor complex, Sec23/Sec24, by binding ...to its GTPase-activating protein (GAP) Sec23 (ref. 2). This leads to the capture of transmembrane cargo by Sec24 (refs 3, 4) before the coat is polymerized by the Sec13/Sec31 complex. The initial interaction of a vesicle with its target membrane is mediated by tethers. We report here that in yeast and mammalian cells the tethering complex TRAPPI (ref. 7) binds to the coat subunit Sec23. This event requires the Bet3 subunit. In vitro studies demonstrate that the interaction between Sec23 and Bet3 targets TRAPPI to COPII vesicles to mediate vesicle tethering. We propose that the binding of TRAPPI to Sec23 marks a coated vesicle for fusion with another COPII vesicle or the Golgi apparatus. An implication of these findings is that the intracellular destination of a transport vesicle may be determined in part by its coat and its associated cargo.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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