The regulation of Tfh cell differentiation by ß-hydroxybutyrylation modification of transcription factor Bcl6.

Transcriptional repressor B cell lymphoma 6 (Bcl6) is a major transcription factor involved in Tfh cell differentiation and germinal center response, which is regulated by a variety of biological processes. However, the functional impact of post-translational modifications, particularly lysine ß-hydroxybutyrylation (Kbhb), on Bcl6 remains elusive. In this study, we revealed that Bcl6 is modified by Kbhb to affect Tfh cell differentiation, resulting in the decrease of cell population and cytokine IL-21. Furthermore, the modification sites are identified from enzymatic reactions to be lysine residues at positions 376, 377, and 379 by mass spectrometry, which is confirmed by site-directed mutagenesis and functional analyses. Collectively, our present study provides evidence on the Kbhb modification of Bcl6 and also generates new insights into the regulation of Tfh cell differentiation, which is a starting point for a thorough understanding of the functional involvement of Kbhb modification in the differentiations of Tfh and other T cells.

Prediction models for deep vein thrombosis after knee/hip arthroplasty: A systematic review and network meta-analysis.

Deep vein thrombosis (DVT) is one of the common complications after joint replacement, which seriously affects the quality of life of patients. We systematically searched nine databases, a total of eleven studies on prediction models to predict DVT after knee/hip arthroplasty were included, eight prediction models for DVT after knee/hip arthroplasty were chosen and compared. The results of network meta-analysis showed the XGBoost model (SUCRA 100.0%), LASSO (SUCRA 84.8%), ANN (SUCRA 72.1%), SVM (SUCRA 53.0%), ensemble model (SUCRA 40.8%), RF (SUCRA 25.6%), LR (SUCRA 21.8%), GBT (SUCRA 1.1%), and best prediction performance is XGB (SUCRA 100%). Results show that the XGBoost model has the best predictive performance. Our study provides suggestions and directions for future research on the DVT prediction model. In the future, well-designed studies are still needed to validate this model.

Broadening anticancer spectrum by preprocessing and treatment of T- lymphocytes expressed FcγRI and monoclonal antibodies for refractory cancers.

Background: Chimeric antigen receptor T (CAR-T) cell therapies have achieved remarkable success in the treatment of hematological tumors. However, given the distinct features of solid tumors, particularly heterogeneity, metabolic aggressiveness, and fewer immune cells in tumor microenvironment (TME), the practical utility of CAR-T cells for solid tumors remains as a challenging issue. Meanwhile, although anti-PD-1 monoclonal antibody (mAb) has shown clinical efficacy, most mAbs also show limited clinical benefits for solid tumors due mainly to the issues associated with the lack of immune cells in TME. Thus, the infiltration of targeted immunological active cells into TME could generate synergistic efficacy for mAbs. Methods: We present a combinational strategy for solid tumor treatment, which combines armored-T cells to express Fc-gamma receptor I (FcγRI) fragment on the surfaces for targeting various tumors with therapeutically useful mAbs. Choosing CD20 and HER-2 as the targets, we characterized the in vitro and in vivo efficacy and latent mechanism of the combination drug by using flow cytometry, ELISA and other methods. Results: The combination and preprocessing of armored T-cells with corresponding antibody of Rituximab and Pertuzumab exerted profound anti-tumor effects, which is demonstrated to be mediated by synergistically produced antibody-dependent cellular cytotoxicity (ADCC) effects. Meanwhile, mAb was able to carry armored-T cell by preprocessing for the infiltration to TME in cell derived xenograft (CDX) model. Conclusions: This combination strategy showed a significant increase of safety profiles from the reduction of antibody doses. More importantly, the present strategy could be a versatile tool for a broad spectrum of cancer treatment, with a simple pairing of engineered T cells and a conventional antibody.

Modulation of immune-responses by DSF/Cu enhances the anti-tumor effects of DTX for metastasis breast cancer.

Metastasis has been one of the most important causes of death from breast cancer, and chemotherapy remains the major option for metastatic breast cancer. However, drug resistance and higher toxicity from chemotherapy have been an obstacle for clinical practice, and the combination of chemotherapy with immunotherapy has emerged as a promising treatment strategy. Here, we describe a therapy based on the combination of disulfiram (DSF) and Cu2+ with widely used cytotoxic docetaxel (DTX). DSF/Cu-induced immunogenic cell death promoted the release of type I interferon and human monocyte-induced dendritic cell maturation, which established a foundation for the combination with chemotherapy. Consequently, the combination of DSF/Cu and DTX resulted in significantly more potent anti-tumor effects in 4T1-bearing mice than in single therapy. The present study has shed new light on combining DSF/Cu-induced immune responses with traditional chemotherapeutic agents to achieve greater benefits for patients with metastasis.

Mesenchymal stem cells prevent H7N9 virus infection via rejuvenating immune environment to inhibit immune-overactivity.

BACKGROUND: Influenza is a clinically important infectious disease with a high fatality rate, which always results in severe pneumonia. Mesenchymal stem cells (MSCs) exhibit promising therapeutic effects on severe viral pneumonia, but whether MSCs prevent virus infection and contribute to the prevention of influenza remains unknown. METHODS: ICR mice were pretreated with human umbilical cord (hUC) MSCs and then infected with the influenza H7N9 virus. Weight, survival days, and lung index of mice were recorded. Serum antibody against influenza H7N9 virus was detected according to the hemagglutination inhibition method. Before and after virus infection, T cell and B cell subtypes in the peripheral blood of mice were evaluated by flow cytometry. Cytokines in the supernatants of MSCs, innate immune cells, and mouse broncho alveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assay (ELISA) or Luminex Assay. RESULTS: Pretreatment with MSCs protected mice against influenza H7N9 virus infection. Weight loss, survival rate, and structural and functional damage to the lungs of infected mice were significantly improved. Mechanistically, MSCs modulated T lymphocyte response in virus-infected mice and inhibited the cGAS/STING pathway. Importantly, the protective effect of MSCs was mediated by cell-to-cell communications and attenuation of cytokine storm caused by immune overactivation.

Comparative effectiveness of different exercise interventions for elderly patients with hip fracture: A systematic review and Bayesian network meta-analysis protocol of randomized controlled trials.

BACKGROUND: Exercise intervention (EI) is a promising and economical way for elderly patients with hip fracture, but the evidence regarding effective EIs remains fragmented and controversial, and it is unclear which type of exercise is optimal. The purpose of this Bayesian network meta-analysis (NMA) is to compare and rank the efficacy of various EIs in elderly patients with hip fracture. MATERIALS AND METHODS: A comprehensive literature search was performed using a systematic approach across various databases including Medline (via PubMed), CINAHL, CNKI, Web of Science, Wan Fang, Embase, VIP, Cochrane Central Register of Controlled Trials and CBM databases. The search encompasses all available records from the inception of each database until December 2022. The Inclusion literature comprises randomized controlled trials that incorporate at least one EI for elderly patients with hip fracture. We will assess the risk of bias of the studies in accordance with the Cochrane Handbook for Systematic Reviews of Interventions, and assess each evidence of outcome quality in accordance with the Grading of Recommendations Assessment, Development and Evaluation framework. The NMA will be performed by STATA 15.0 software and OpenBUGS version 3.2.3. The identification of publication bias will be accomplished through the utilization of a funnel plot. We will rank the EIs effects according to the cumulative ranking probability curve (surface under the cumulative ranking area, SUCRA). The primary outcomes will be hip function in elderly patients, and the secondary outcomes will be activities of daily living, walking capacity and balance ability of elderly patients. TRIAL REGISTRATION: PROSPERO registration number: CRD4202022340737.