BackgroundThe majority of anti-programmed cell-death 1 (PD-1) monoclonal antibodies (mAbs) use S228P mutation IgG4 as the structural basis to avoid the activation of immune cells or complement. ...However, little attention has been paid to the Fc–Fc interactions between IgG4 and other IgG Fc fragments that could result in adverse effects. Fc-null IgG1 framework is a potential safer alternative to avoid the undesirable Fc–Fc interactions and Fc receptor binding derived effects observed with IgG4. This study provides a comprehensive evaluation of anti-PD-1 mAbs of these two frameworks.MethodsTrastuzumab and rituximab (both IgG1), wildtype IgG1 and IgG4 were immobilized on nitrocellulose membranes, coated to microplates and biosensor chips, and bound to tumor cells as targets for Fc–Fc interactions. Wildtype IgG1 and IgG4, anti-PD-1 mAb nivolumab (IgG4 S228P), penpulimab (Fc-null IgG1), and tislelizumab (Fc-null IgG4 S228P-R409K) were assessed for their binding reactions to the immobilized IgG proteins and quantitative kinetic data were obtained. To evaluate the effects of the two anti-PD-1 mAbs on immune responses mediated by trastuzumab and rituximab in the context of combination therapy, we employed classic immune models for antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement dependent cytotoxicity. Tumor-bearing mouse models, both wildtype and humanized, were used for in vivo investigation. Furthermore, we also examined the effects of IgG1 and IgG4 on diverse immune cell populationsResultsExperiments demonstrated that wildtype IgG4 and nivolumab bound to immobilized IgG through Fc–Fc interactions, diminishing antibody-dependent cell-mediated cytotoxicity and phagocytosis reactions. Quantitative analysis of kinetic parameters suggests that nivolumab and wildtype IgG4 exhibit comparable binding affinities to immobilized IgG1 in both non-denatured and denatured states. IgG4 exerted inhibitory effects on various immune cell types. Wildtype IgG4 and nivolumab both promoted tumor growth in wildtype mouse models. Conversely, wildtype IgG1, penpulimab, and tislelizumab did not show similar adverse effects.ConclusionsFc-null IgG1 represents a safer choice for anti-PD-1 immunotherapies by avoiding both the adverse Fc–Fc interactions and Fc-related immune inhibitory effects of IgG4. Fc-null IgG4 S228P-R409K and Fc-null IgG1 displayed similar structural properties and benefits. This study contributes to the understanding of immunotherapy resistance and the advancement of safer immune therapies for cancer.
Competitive endogenous messenger RNAs (ceRNAs) affect other RNAs transcription through competitively binding common microRNAs (miRNAs). In this study we identified long non-coding RNA (lncRNA) MALAT1 ...can function as a ceRNA of cell division cycle 42 (cdc42) 3′UTR in inducing migration and invasion of breast cancer cells via miR-1. We found that miR-1 bound both MALAT1 and cdc42 3′UTR directly. Further study showed that MALAT1 induced migration and invasion of breast cancer cells while reduced the level of cdc42. Our results suggest that MALAT1 regulated migration and invasion of breast cancer cells via affecting cdc42 through binding miR-1 competitively.
•Verifying MALAT1 does promote migration and invasion of breast cancer cells.•MiR-1 plays an important role in MALAT1 and cdc42 regulating network.•MALAT1 competitively binds miR-1 with cdc42 to promote migration and invasion of breast cancer cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
With the promotion of low-carbon travel, pedestrian network plays an important role in many location-based applications, such as pedestrian navigation and refined traffic management. Due to the lack ...of systematic data acquisition mechanics, the accuracies and detail levels of pedestrian network data are hardly capable of satisfying the demands of such transportation applications. Presently, various mobile phone apps recorded and stored users' movement trajectories, which provide a valuable data source for pedestrian network construction. Hence, this article proposes a crowdsourcing-based system for generating pedestrian network that encompasses three key components of crowdsourced walking trajectory data filtering, pedestrian network construction and evaluation of pedestrian network. Self-collected data and open platform data were used to evaluate the proposed system. Experimental results demonstrate that the proposed method can accurately and completely extract pedestrian network. Moreover, the pedestrian network can be updated in a timely manner by the proposed method. The data collection application and the collected data are available to the public.
The gastric bacterial pathogen
Helicobacter pylori
persistently colonizes the gastric mucosa of humans and plays a critical role in the development of gastritis, peptic ulceration and gastric ...adenocarcinoma. Consequently, the eradication of
H. pylori
might contribute to the prevention of
H. pylori
-associated gastric diseases. In this study, a multi-epitope vaccine CTB-UE (CUE) was displayed on the surface of non-genetically modified
Lactococcus lactis
particles (GEM) to enhance immunogenicity. This particulate vaccine CUE-GEM induced serum and mucosal specific antibody responses against native
H. pylori
urease and provided potent protection to eliminate
H. pylori
colonization and relieve gastritis in an
H. pylori
-infected BALB/c mouse model. The immuno-protective mechanisms are highly associated with CD4
+
Th cell-mediated and humoral immunity, especially local immunity. There might be two main aspects of this association. One aspect is related to the suppression of urease activity by promotion of the production of specific mucosal neutralizing antibody. The other aspect is correlated with alleviating gastritis by regulating the gastric pro-inflammatory cytokine profile, especially IFN-γ and IL-17. These results demonstrated that conjugating antigen vaccines with GEM particles could lead to promising oral therapeutic vaccine formulations against
H. pylori
infection.
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CEKLJ, DOBA, EMUNI, FZAB, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
CXCR4 is the most common chemokine receptor expressed on tumor cells, and it is closely correlated with cancer cell stemness. This study was carried out to explore whether CXCR4 could function as a ...competitive endogenous RNA to promote metastasis, proliferation and survival in MCF-7 breast cancer cells. We validated that CXCR4, together with TRAF6 and EGFR, was directly targeted by miR-146a in MCF-7 cells. Overexpression of CXCR4 3′UTR inhibited the activity of miR-146a, thus elevating the expression of CXCR4, TRAF6 and EGFR. These oncoproteins further activated NF-κB pathway and promoted the proliferation, migration, invasion and anti-apoptotic activity of MCF-7 cells. Collectively, our study provided new insights into the function of CXCR4 in breast cancer: it promotes tumor progression as both a protein-coding gene and a non-coding RNA, complicating the mechanism by which oncogenes promote tumor progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
CXCR4 is the most common chemokine receptor expressed on tumor cells, and it is closely correlated with cancer cell stemness. This study was carried out to explore whether CXCR4 could function as a ...competitive endogenous RNA to promote metastasis, proliferation and survival in MCF-7 breast cancer cells. We validated that CXCR4, together with TRAF6 and EGFR, was directly targeted by miR-146a in MCF-7 cells. Overexpression of CXCR4 3'UTR inhibited the activity of miR-146a, thus elevating the expression of CXCR4, TRAF6 and EGFR. These oncoproteins further activated NF-κB pathway and promoted the proliferation, migration, invasion and anti-apoptotic activity of MCF-7 cells. Collectively, our study provided new insights into the function of CXCR4 in breast cancer: it promotes tumor progression as both a protein-coding gene and a non-coding RNA, complicating the mechanism by which oncogenes promote tumor progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Silver plating can be divided into replacement plating and electroplating.In order to compare the corrosion resistance and galvanic corrosion behavior of coatings prepared by these two methods，the ...corrosion resistance and galvanic corrosion behaviors of the ZHL-02 replacement plating and ZHL-02 electroplating coatings in cyanide-free silver plating process using 5，5-dimethylamide as the main complexing agent were analyzed by scanning electron microscopy，XRD，electrochemical workstation，Tafel curve and galvanic corrosion methods.Results showed that the replacement coating had better crystallization and more complete coverage，and its resistance to galvanic corrosion was slightly better than that of the electroplating coating under the same thickness.With the prolongation of replacement silver plating time，the self-corrosion rate of the coating gradually decreased.However，the replacement plating took a long time，and it was difficult to obtain a thickness of more than 1 μm，which limited its application to a certai
The myosin light chain kinase (MLCK) pathway controls intestinal epithelial barrier permeability by regulating the tight junction. 1,25-dihydroxyvitamin D (1,25(OH)2D3)-vitamin D receptor (VDR) ...signaling protects the epithelial barrier, but the molecular mechanism is incompletely understood.
MLCK activation and barrier permeability were studied using monolayers of HCT116, Caco-2, and SW480 cells treated with tissue necrosis factor α with or without 1,25(OH)2D3. The MLCK pathway was analyzed in normal and inflamed colonic biopsies from patients with ulcerative colitis. Colonic mucosal barrier permeability and MLCK activation were also investigated using trinitrobenzene sulfonic acid-induced colitis models in vitamin D analog paricalcitol-treated wild-type mice and mice carrying VDR deletion in colonic epithelial cells.
Tissue necrosis factor α increased cell monolayer permeability and induced long isoform of MLCK expression and myosin II regulatory light chain (MLC) phosphorylation, and 1,25(OH)2D3 blocked tissue necrosis factor α-induced increases in monolayer permeability and MLCK-MLC pathway activation by a VDR-dependent fashion. 1,25(OH)2D3 directly suppressed long MLCK expression by attenuating NF-κB activation, and chromatin immunoprecipitation assays confirmed that 1,25(OH)2D3 disrupted p65 binding to 3 κB sites in long MLCK gene promoter. In human ulcerative colitis biopsies, VDR reduction was associated with increases in long MLCK expression and MLC phosphorylation. In trinitrobenzene sulfonic acid colitis models, paricalcitol ameliorated colitis, attenuated the increase in mucosal barrier permeability, and inhibited long MLCK induction and MLC phosphorylation. In contrast, mice with colonic epithelial VDR deletion exhibited more robust increases in mucosal barrier permeability and MLCK activation compared with wild-type mice.
These data demonstrate that 1,25(OH)2D3-VDR signaling preserves the mucosal barrier integrity by abrogating MLCK-dependent tight junction dysregulation during colonic inflammation.
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