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Epstein‐Barr virus (EBV) is associated with various malignancies and infects >90% of the global population. EBV latent proteins are expressed in numerous EBV‐associated cancers and contribute to carcinogenesis, making them critical therapeutic targets for these cancers. Thus, this study aims to develop mRNA‐based therapeutic vaccines that express the T‐cell‐epitope‐rich domain of truncated latent proteins of EBV, including truncatedlatent membrane protein 2A (Trunc‐LMP2A), truncated EBV nuclear antigen 1 (Trunc‐EBNA1), and Trunc‐EBNA3A. The vaccines effectively activate both cellular and humoral immunity in mice and show promising results in suppressing tumor progression and improving survival time in tumor‐bearing mice. Furthermore, it is observed that the truncated forms of the antigens, Trunc‐LMP2A, Trunc‐EBNA1, and Trunc‐EBNA3A, are more effective than full‐length antigens in activating antigen‐specific immune responses. In summary, the findings demonstrate the effectiveness of mRNA‐based therapeutic vaccines targeting the T‐cell‐epitope‐rich domain of EBV latent proteins and providing new treatment options for EBV‐associated cancers. mRNA‐based vaccines expressing truncated Epstein‐Barr virus (EBV) latent protein domains effectively elicit cellular and humoral immunity, inhibit tumor progression, and improve the survival of tumor‐bearing mice. Truncated antigens show superior immune activation compared to full‐length antigens, offering promising therapeutic options for EBV‐related malignancies.

SARS-CoV-2 variants have evolved a variety of critical mutations, leading to antigenicity changes and immune escape. The recent emerging SARS-CoV-2 Omicron variant attracted global attention due to its significant resistance to current antibody therapies and vaccines. Here, we profiled the mutations of Omicron and other various circulating SARS-CoV-2 variants in parallel by computational interface analysis and in vitro experimental assays. We identified critical mutations that lead to antigenicity changes and diminished neutralization efficiency of a panel of 14 antibodies due to diverse molecular mechanisms influencing the antigen-antibody interaction. Our study identified that Omicron exhibited extraordinary potency in immune escape compared to the other variants of concern, and explores the application of computational interface analysis in SARS-CoV-2 mutation surveillance and demonstrates its potential for the early identification of concerning variants, providing preliminary guidance for neutralizing antibody therapy.

Background Peptide-based therapeutics for melanoma have received increasing attention in medical research. However, the local delivery of such therapeutics poses unique challenges. Cell-penetrating peptides (CPPs) with the ability to selectively enter cancer cells, with sufficient stability and increased endosomal escape mechanisms, can provide a new and improved delivery strategy for therapeutic agents for treating cancer. Methods We developed a new combination strategy for the synthesis of penetrating peptides functionalized with targeting of integrin α6. The linear peptide S5 was multimerized with 4 copies in linear sequential order spaced by GSG between each copy to yield the 4S5 peptide. The multimerized 4S5 peptide coupled with an intracellular delivery peptide (N) and endosomal escape peptide (G) was separated by a GGS spacer. This optimized peptide was called 4S5NG. The 4S5NG, EGFP or PE24 peptide-protein conjugates were purified via a C-terminal His-tag. The uptake efficacy, intracellular distribution and integrin α6-targeting ability of these 4S5NG peptides were systematically characterized via IncuCyte, flow cytometry and in vivo imaging using 4S5NG-Cy5 or 4S5NG-EGFP. Moreover, 4S5NG-incorporated Pseudomonas aeruginosa (PE24) exotoxin A generated therapeutic peptides. The antitumor efficacy and underlying mechanism were studied in cell lines and a mouse model. In addition, the effect of 4S5NG-PE24 on antitumor immunity of a healthy immune system was investigated via a mouse model. Results Images of living cells and mice indicated that 4S5NG accumulated at tumor sites in vitro and in vivo and was much more effective than the S5 and 4S5 peptides. 4S5NG-PE24 induced cell pyroptosis in integrin α6-expressing melanoma through the caspase 3/gasdermin E (GSDME) signaling pathway in the absence of histological alterations in other organs. 4S5NG-PE24 also promoted the response rate of programmed cell death protein-1 (PD-1) checkpoint blockade to increase antitumor efficacy. Conclusions Collectively, these results highlight the potential use of 4S5NG to deliver the toxin PE24 to selectively eliminate integrin α6 + cells in melanoma, which may represent a novel treatment approach for melanoma patients.

ObjectiveOptical molecular imaging technology that indiscriminately detects intracranial glioblastoma (GBM) can help neurosurgeons effectively remove tumor masses. Transferrin receptor 1 (TfR 1) is a diagnostic and therapeutic target in GBM. A TfR 1-targeted peptide, CRTIGPSVC (CRT), was shown to cross the blood brain barrier (BBB) and accumulate at high levels in GBM tissues. In this study, we synthesized a TfR 1-targeted near-infrared fluorescent (NIRF) probe, Cy5-CRT, for identifying the GBM tissue margin in mouse models.MethodsWe initially confirmed the overexpression of TfR 1 in GBM and the tumor-specific homing ability of Cy5-CRT in subcutaneous and orthotopic GBM mouse models. We then examined the feasibility of Cy5-CRT for identifying the tumor margin in orthotopic GBM xenografts. Finally, we compared Cy5-CRT with the clinically used fluorescein sodium in identifying tumor margins.ResultsCy5-CRT specifically accumulated in GBM tissues and detected the tumor burden with exceptional contrast in mice with orthotopic GBM, enabling fluorescence-guided GBM resection under NIRF live imaging conditions. Importantly, Cy5-CRT recognized the GBM tissue margin more clearly than fluorescein sodium.ConclusionsThe TfR 1-targeted optical probe Cy5-CRT specifically differentiates tumor tissues from the surrounding normal brain with high sensitivity, indicating its potential application for the precise surgical removal of GBM.

KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting “undruggable” proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.

In order to meet the requirement of grooved rail geometric parameter detection, based on the previous research of the project team, this paper combines the principle of inertial measurement and laser triangulation, a comprehensive algorithm to develop a grooved rail detection system for detecting the longitudinal and alignment irregularity. The system is composed of geometric parameter detecting vehicle and upper computer software. Firstly, the outline data of grooved rail are measured by 2D laser sensors, and the motion data of the vehicle are measured by inertial sensors. Then, this paper presents an inertial measurement - laser triangulation comprehensive algorithm and the laser triangulation is used to process the outline data and calculate the gauge of grooved rail. The error of laser triangulation and the attitude angle of vehicle are corrected through inertial measurement method. Finally, the longitudinal irregularity and alignment irregularity are calculated through numerical integration method in the upper computer. The stability and accuracy of the system are verified by designing experiments. The results show that the repeating precision of the irregularity is less than 0.5mm while the detection accuracy is within ±0.7mm.

Lymph node metastasis (N classification) is one of the most important prognostic factors of nasopharyngeal carcinoma (NPC), and nerve involvement is associated with the transition of the N category in NPC patients. Although the nervous system has been reported to participate in many types of cancer progression, its functions in NPC progression remains unknown. Through analysis of gene profiling data, we demonstrate an enrichment of genes associated with neuronal development and differentiation in NPC tissues and cell lines. Among these genes, Nogo receptor 3 (NgR3), which was originally identified in the nervous system and plays a role in nerve development and regeneration, was inappropriately overexpressed in NPC cells and tissues. Immunohistochemical analysis demonstrated that the overexpression of NgR3 was correlated with poor prognosis in NPC patients. Overexpression of NgR3 promoted, and knocking down NgR3 inhibited, NPC cell migration and invasion in vitro and metastasis in vivo. The ability of NgR3 to promote cell migration was triggered by the downregulation of E-cadherin and enhanced cytoskeletal rearrangement and cell polarity, which were correlated with the activation of focal adhesion kinase (FAK). Collectively, NgR3 is a novel indicator of poor outcomes in NPC patients and plays an important role in driving the progression of NPC. These results suggest a potential link between the nervous system and NPC progression.Key messagesGenes involved in the neuronal biological process are enriched in nasopharyngeal carcinoma.Overexpression of NgR3 correlates with poor prognosis of nasopharyngeal carcinoma.NgR3 promotes NPC cell migration by downregulating E-cadherin.NgR3 promotes NPC cell polarity and enhances the formation of NPC cell pseudopodia by activating FAK/Src pathway.

Epstein–Barr virus (EBV) is implicated as an aetiological factor in B lymphomas and nasopharyngeal carcinoma. The mechanisms of cell-free EBV infection of nasopharyngeal epithelial cells remain elusive. EBV glycoprotein B (gB) is the critical fusion protein for infection of both B and epithelial cells, and determines EBV susceptibility of non-B cells. Here we show that neuropilin 1 (NRP1) directly interacts with EBV gB 23–431 . Either knockdown of NRP1 or pretreatment of EBV with soluble NRP1 suppresses EBV infection. Upregulation of NRP1 by overexpression or EGF treatment enhances EBV infection. However, NRP2, the homologue of NRP1, impairs EBV infection. EBV enters nasopharyngeal epithelial cells through NRP1-facilitated internalization and fusion, and through macropinocytosis and lipid raft-dependent endocytosis. NRP1 partially mediates EBV-activated EGFR/RAS/ERK signalling, and NRP1-dependent receptor tyrosine kinase (RTK) signalling promotes EBV infection. Taken together, NRP1 is identified as an EBV entry factor that cooperatively activates RTK signalling, which subsequently promotes EBV infection in nasopharyngeal epithelial cells. Epstein–Barr virus (EBV) is involved in the development of some cancers including nasopharyngeal carcinoma. Here, the authors show that a direct interaction between the viral protein gB and a host protein, neuropilin 1, is required for EBV infection of nasopharyngeal epithelial cells.

Acupuncture is widely used to relieve shoulder pain. A survey was conducted in order to recognize hotspots and frontiers of acupuncture for shoulder pain from the year 2000-2022. The Web of Science Core Collection was used to collect literature related to acupuncture therapy for shoulder pain, which spanned January 2000 to August 2022. The number of publications yearly, countries/institutions, journals, and keywords was analyzed and visualized in shoulder pain with acupuncture therapy by CiteSpace v.5.7.R5. We totally analyzed 214 articles that met the inclusion criteria. The overall trend of publication volume continues to increase. The most productive authors in the field were César Fernández las Peñas and José L Arias-Buría, and the most influential author was Green S. Kyung Hee University and the People's Republic of China had the highest volume of publications, respectively. The most influential journal is Pain with high citation and impact factor. The hot keywords were \"acupuncture\", \"shoulder pain\", \"dry needling\", \"randomized trial\", and \"injection\". The research frontier in acupuncture for treating chronic shoulder pain was mainly \"mechanism\". Over the last 22 years, the findings of this bibliometric analysis have provided research trends and frontiers in clinical research on acupuncture therapy for patients with shoulder pain, which identifying hot topics and exploring new directions for the future may be helpful to researchers. Studying mechanisms underlying acupuncture therapy for shoulder pain remains a focus of future research.

A high-speed data exchange network based on multimode fiber and RapidIO technology is widely used in existing projects. It consists of a fiber switch and a high-speed interface module. The fiber switch is used as the data exchange core to complete protocol conversion. The high-speed interface module is connected to the universal device node and is responsible for access conversion of the RapidIO bus between the optical network. The hardware design utilizes the commercial shelf architecture, the software design adopts a multi-buffer and multi-thread data exchange method to increase the entire network bandwidth from 300MB/s to 800MB/S.