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Tumor-specific neoantigens can be highly immunogenic, but their identification for each patient and the production of personalized cancer vaccines can be time-consuming and prohibitively expensive. In contrast, tumor-associated antigens are widely expressed and suitable as an off the shelf immunotherapy. Here, we developed a PLGA-based nanoparticle vaccine that contains both the immunogenic cancer germline antigen NY-ESO-1 and an α-GalCer analog IMM60, as a novel iNKT cell agonist and dendritic cell transactivator. Three peptide sequences (85–111, 117–143, and 157–165) derived from immunodominant regions of NY-ESO-1 were selected. These peptides have a wide HLA coverage and were efficiently processed and presented by dendritic cells via various HLA subtypes. Co-delivery of IMM60 enhanced CD4 and CD8 T cell responses and antibody levels against NY-ESO-1 in vivo . Moreover, the nanoparticles have negligible systemic toxicity in high doses, and they could be produced according to GMP guidelines. Together, we demonstrated the feasibility of producing a PLGA-based nanovaccine containing immunogenic peptides and an iNKT cell agonist, that is activating DCs to induce antigen-specific T cell responses.

Objectives This study aimed to investigate the anti‐PD‐1 inhibitor pembrolizumab as a potential agent for use in non‐muscle‐invasive bladder cancer (NMIBC) by conducting a Phase 1 safety run‐in study to assess the safety and tolerability of intravesical pembrolizumab after transurethral resection of the bladder tumour (TURBT). Patients and methods Eligible patients had recurrent NMIBC for which adjuvant treatment post TURBT was a reasonable treatment option, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–1 and adequate end‐organ function. Pembrolizumab was administered by intravesical instillation once weekly for a total of six doses. Intra‐patient dose escalation was performed in three paired patient cohorts with doses starting at 50 mg and increasing through 100 mg to a maximum of 200 mg. Adverse events (AEs) were assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.03 with dose limiting toxicity (DLT) defined as a clinically significant, drug‐related, Grade 4 haematological or Grade 3 or higher non‐haematological toxicity occurring within 7 days of administration of the first treatment at a given dose for that patient. Results Six patients were treated with no DLTs seen during dose escalation. Drug‐related AEs were of low grade and included dysuria and fatigue. All patients completed six doses of treatment as planned. Pharmacokinetic and pharmacodynamic assays did not detect any pembrolizumab in the serum following repeated intravesical administration, and no changes in peripheral immune cell populations were observed. Conclusions Administration of intravesical pembrolizumab was well tolerated and did not raise any safety concerns in patients with NMIBC following TURBT. There was no evidence of systemic absorption or systemic immune effects following intravesical administration. Further studies are required to assess whether intravesical administration has anti‐tumour activity.

NOD2 and TLR2 recognize components of bacterial cell wall peptidoglycan and direct defense against enteric pathogens. CD8 T cells are important for immunity to such pathogens but how NOD2 and TLR2 induce antigen specific CD8 T cell responses is unknown. Here, we define how these pattern recognition receptors (PRRs) signal in primary dendritic cells (DCs) to influence MHC class I antigen presentation. We show NOD2 and TLR2 phosphorylate PI31 via TBK1 following activation in DCs. PI31 interacts with TBK1 and Sec16A at endoplasmic reticulum exit sites (ERES), which positively regulates MHC class I peptide loading and immunoproteasome stability. Following NOD2 and TLR2 stimulation, depletion of PI31 or inhibition of TBK1 activity impairs DC cross-presentation and CD8 T cell activation. DCs from Crohn's patients expressing polymorphisms show dysregulated cross-presentation and CD8 T cell responses. Our findings reveal unidentified mechanisms that underlie CD8 T cell responses to bacteria in health and in Crohn's.

Due to the customized design of high-speed bus protocols used by different aircraft designs, there are many kinds of high-speed bus protocols for flight test. Currently, one test system can only collect data on one kind of bus protocol, which puts great pressure on the allocation of test resources. In this paper, the reconfigurable testing technology of multi-type high-speed buses is studied concerning the architecture requirement of a software-defined system. Firstly, the universal heterogeneous platform of the high-speed bus test system is designed, the data communication model between heterogeneous processors is established, and the hardware platform and software system are decoupled. Then, the protocol domain mapping model is established to realize the unification of different protocol data parsing algorithms. The parallel retrieval technology with addressable content is designed to realize the independent retrieval of data and meet the requirements of synchronous collection. Finally, the experimental verification shows that the technology can realize the rapid reconfiguration of equipment functions, enhance the interchangeability of test equipment, and ensure the effectiveness of flight test mission scheduling.

Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103 + T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61 + tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies. CD103 + T cells are associated with control over tumors but how this is mediated is unclear. Here the authors show that CD61 colocalizes and functionally combines with CD103 in the T cell synaptic response to promote antitumor T cell responses.

Semaphorin-3A (SEMA3A) functions as a chemorepulsive signal during development and can affect T cells by altering their filamentous actin (F-actin) cytoskeleton. The exact extent of these effects on tumour-specific T cells are not completely understood. Here we demonstrate that Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 are upregulated on stimulated CD8 T cells, allowing tumour-derived SEMA3A to inhibit T cell migration and assembly of the immunological synapse. Deletion of NRP1 in both CD4 and CD8 T cells enhance CD8 T-cell infiltration into tumours and restricted tumour growth in animal models. Conversely, over-expression of SEMA3A inhibit CD8 T-cell infiltration. We further show that SEMA3A affects CD8 T cell F-actin, leading to inhibition of immune synapse formation and motility. Examining a clear cell renal cell carcinoma patient cohort, we find that SEMA3A expression is associated with reduced survival, and that T-cells appear trapped in SEMA3A rich regions. Our study establishes SEMA3A as an inhibitor of effector CD8 T cell tumour infiltration, suggesting that blocking NRP1 could improve T cell function in tumours.

Semaphorin-3A (SEMA3A) functions as a chemorepulsive signal during development and can affect T cells by altering their filamentous actin (F-actin) cytoskeleton. The exact extent of these effects on tumour-specific T cells are not completely understood. Here we demonstrate that Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 are upregulated on stimulated CD8 + T cells, allowing tumour-derived SEMA3A to inhibit T cell migration and assembly of the immunological synapse. Deletion of NRP1 in both CD4 + and CD8 + T cells enhance CD8 + T-cell infiltration into tumours and restricted tumour growth in animal models. Conversely, over-expression of SEMA3A inhibit CD8 + T-cell infiltration. We further show that SEMA3A affects CD8 + T cell F-actin, leading to inhibition of immune synapse formation and motility. Examining a clear cell renal cell carcinoma patient cohort, we find that SEMA3A expression is associated with reduced survival, and that T-cells appear trapped in SEMA3A rich regions. Our study establishes SEMA3A as an inhibitor of effector CD8 + T cell tumour infiltration, suggesting that blocking NRP1 could improve T cell function in tumours. Interactions between Semaphorin-3A (SEMA3A) and Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 have been shown to affect T cell development. Here the authors investigate how these interactions affect CD8 + T cells in tumour immunity, showing that NRP-1, Plexin-A1 and Plexin-A4 are upregulated on T cells allowing tumour derived SEMA3A to inhibit CD8 + T cell migration and function.

Background: Cataract is the leading cause of blindness worldwide. In order to achieve large-scale cataract screening and remarkable performance, several studies have applied artificial intelligence (AI) to cataract detection based on fundus images. However, the fundus images they used are original from normal optical circumstances, which is less impractical due to the existence of poor-quality fundus images for inappropriate optical conditions in actual scenarios. Furthermore, these poor-quality images are easily mistaken as cataracts because both show fuzzy imaging characteristics, which may decline the performance of cataract detection. Therefore, we aimed to develop and validate an antiinterference AI model for rapid and efficient diagnosis based on fundus images. Materials and Methods: The datasets (including both cataract and noncataract labels) were derived from the Chinese PLA general hospital. The antiinterference AI model consisted of two AI submodules, a quality recognition model for cataract labeling and a convolutional neural networks-based model for cataract classification. The quality recognition model was performed to distinguish poor-quality images from normal-quality images and further generate the pseudo labels related to image quality for noncataract. Through this, the original binary-class label (cataract and noncataract) was adjusted to three categories (cataract, noncataract with normal-quality images, and noncataract with poor-quality images), which could be used to guide the model to distinguish cataract from suspected cataract fundus images. In the cataract classification stage, the convolutional-neural-network-based model was proposed to classify cataracts based on the label of the previous stage. The performance of the model was internally validated and externally tested in real-world settings, and the evaluation indicators included area under the receiver operating curve (AUC), accuracy (ACC), sensitivity (SEN), and specificity (SPE). Results: In the internal and external validation, the antiinterference AI model showed robust performance in cataract diagnosis (three classifications with AUCs >91%, ACCs >84%, SENs >71%, and SPEs >89%). Compared with the model that was trained on the binary-class label, the antiinterference cataract model improved its performance by 10%. Conclusion: We proposed an efficient antiinterference AI model for cataract diagnosis, which could achieve accurate cataract screening even with the interference of poor-quality images and help the government formulate a more accurate aid policy.

The present study aims to investigate the association of transforming growth factor-β2 (TGF-β2) and matrix metalloproteinases (MMPs), MMP-2 and MMP-3, and tissue inhibitors of matrix metalloproteinases (TIMPs), TIMP-1, TIMP-2 and TIMP-3 in the aqueous humor of patients with high myopia or cataracts. The levels of TGF-β2 and MMPs/TIMPs were measured with the Luminex xMAP Technology using commercially available Milliplex xMAP kits. The association between TGF-β2 and MMPs/TIMPs levels was analyzed using the Spearmans correlation test. The levels of TGF-β2 were identified to be positively correlated with the levels of TIMP-1 and TIMP-3 (TIMP-1: r=0.334; P=0.007; TIMP-3: r=0.309; P=0.012). The levels of MMP-2, MMP-3 and TIMP-2 did not significantly correlate with TGF-β2 levels (P>0.05). A positive correlation was identified between TGF-β2 and TIMPs in the aqueous humor of human eyes with elongated axial length. It appears that TGF-β2 stimulates the expression of TIMPs as a compensatory reaction to the development of high myopia.