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关键词： Cancer   Biotechnology   Drug discovery   Gene therapy   Immunology   Therapeutics  

关键词： chronic nonbacterial osteomyelitis   CNO   autoinflammatory   autoinflammatory bone disorder   chronic recurrent multifocal osteomyelitis   CRMO   DMARD   disease-modifying anti-rheumatic drug   CARRA   Childhood Arthritis and Rheumatology Research Alliance   CNO   Chronic nonbacterial osteomyelitis   CRMO   Chronic recurrent multifocal osteomyelitis   IBD   Inflammatory bowel disease   IL   Interleukin   MRI   Magnetic resonance imaging   NSAID   Non-steroidal anti-inflammatory drug   PPP   Palmoplantar pustulosis   SAPHO   Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis   TNFi   Tumor necrosis factor-inhibitor   WB-MRI   Whole-body MRI  

摘要： Disciplines that may be involved in the diagnosis and management of children with chronic nonbacterial osteomyelitis Discipline Relation to CNO Primary evaluation and management practitioners General pediatrician, family physician May be first poi...

关键词： bone fracture healing   otubain 2   TNF-receptor associated factor 3   fracture callus   ubiquitin  

摘要： Increased incidence of traumatic fracture markedly effects the quality of life of patients. Using a rat model of femur fracture, the present study aimed to investigate the effects of otubain 2 (OTUB2), a deubiquitinating enzyme, on bone fracture healing. Bone marrow mesenchymal stem cells (BMSCs) were harvested from the marrow cavity of rat femurs and tibiae and subsequently subjected to osteogenic differentiation in vitro. Results of the present study revealed that lentivirus-mediated OTUB2 overexpression accelerated rat bone fracture healing, potentiated fracture callus formation and cartilaginous ossification and regulated the expression of proteins associated with bone remodeling. In addition, OTUB2 overexpression facilitated the osteogenic differentiation and mineralization of BMSCs and promoted the expression of TNF-receptor associated factor 3 (TRAF3) both in vivo and in vitro. Co-immunoprecipitation analysis was used to verify the physical interaction between OTUB2 and TRAF3 and further results demonstrated that OTUB2 reduced the ubiquitination of TRAF3. The results of the present study also demonstrated that TRAF3 knockdown repressed the OTUB2-induced osteogenic differentiation and mineralization of BMSCs. Collectively, these results demonstrated that OTUB2 may stabilize TRAF3 to accelerate bone fracture healing.

关键词： Idiopathic pulmonary hypertension   Non-classical monocytes   HLA-DPA1   scRNA-seq   Mendelian randomization  

摘要： Aberrant immune and inflammatory responses are critical in idiopathic pulmonary arterial hypertension (IPAH). Thus, investigating immune-related therapeutic targets of IPAH is imperative. By integrating single-cell RNA sequencing (scRNA-seq), genome-wide association studies (GWAS), expression quantitative trait loci (eQTL), and single-cell eQTL (sc-eQTL) data, we identified a non-classical monocyte (NCM)-specific gene that was causally linked to PAH. NCM were classified into three subgroups based on HLA-DPA1 expression: negative, low, and high expression groups. We analyzed intercellular communication, molecular mechanisms, biological processes and assessed the metabolic activity of three subgroups. Additionally, we obtained bulk RNA-seq from lung tissue and Peripheral blood mononuclear cells (PBMCs) transcriptional profiles of IPAH patients to explore HLA-DPA1's functions. We demonstrated that IPAH patients had higher proportions of monocytes and NCM in peripheral blood compared to healthy controls. rs13203715 was causally associated with PAH and downregulated HLADPA1 expression in NCM. Differentially expressed genes in three subpopulations were enriched in immune and inflammatory responses. Additionally, HLA-DPA1 expression correlated with immune and inflammatory disruptions in IPAH. In conclusion,HLA-DPA1 exhibited significant downregulation and loss in the NCM of IPAH patients, which was closely associated with disease exacerbation by promoting immune dysregulation and vascular remodeling.

关键词： human epidermal growth factor receptor 2-positive breast cancer   pyrotinib   cytokine   interferon-gamma   clinical efficacy   adverse events  

摘要： Pyrotinib has been extensively utilized in the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC), yet few reliable markers for predicting pyrotinib efficacy in these patients have been identified. Therefore, the present study aimed to explore the predictive clinical factors for treating patients with HER2-positive ABC with pyrotinib. To this aim, a prospective observational study was conducted on the prognostic potential of serum cytokines in a cohort of 58 patients with HER2-positive cancer receiving pyrotinib treatment, enrolled from January 2020 to December 2022. Patients were treated with oral pyrotinib (400 mg/day, 30 min after eating) combined with capecitabine (1,000 mg/m2 twice daily on days 1-14 of a 21-day cycle) or vinorelbine soft capsules (40 mg/day, 3 times weekly). Peripheral blood was collected from these patients before and 4 weeks after the initial administration of pyrotinib. Plasma cytokine levels (IL-6, IL-8, IL-10, IL-17 and IFN-gamma) were measured via multiple microsphere flow cytometry luminescence. Univariate analysis revealed that patients who received pyrotinib as second-line therapy had an improved progression-free survival (PFS) time compared with those who received it as third- or later-line therapy [median PFS (mPFS), 17.0 vs. 9.5 months;P=0.016]. Furthermore, patients with increased plasma IL-8 levels had a poorer PFS time than those with decreased levels (mPFS, 9.4 vs, 14.0 months;P=0.021). Patients with increased plasma IFN-gamma levels had a longer PFS time than those with decreased levels (mPFS, 13.0 vs. 11.0 months;P=0.010). Multivariate Cox regression analysis revealed that pyrotinib application beyond third-line therapy and decreased plasma IFN-gamma levels were independent risk factors for PFS (P=0.025 and P=0.033, respectively). In conclusion, early application of pyrotinib may improve the PFS time of patients with HER2-positive ABC who are resistant to trastuzum

关键词： Single-cycle rVHSV   Interferon-gamma   Olive flounder   Vaccine efficacy  

摘要： Single-cycle viruses generated by the deletion of gene(s) essential for viral replication in the genome can be a way to enhance the safety of attenuated virus-based vaccines because single-cycle viruses can infect cells only once and cannot produce infective viral particles. In the present study, not only to guarantee safety as a prophylactic vaccine but also to enhance the protective efficacy, a single-cycle viral hemorrhagic septicemia virus (VHSV) lacking the G gene and containing olive flounder (Paralichthys olivaceus) interferon-gamma (IFN gamma) ORF between N and P genes of the viral genome (rVHSV-A-IFN gamma-Delta G) was rescued using reverse genetic technology, and its protective potential was evaluated through the immunization of olive flounder. In the challenge experiment, the cumulative mortality in the control group reached 80%, while groups of fish immunized with various doses of rVHSV-A-IFN gamma-Delta G (ranging from 1 x 103 to 1 x 105 pfu/fish) showed no mortalities. In contrast, fish immunized with various doses of rVHSV-Delta G exhibited 0-20% mortality in a dose-dependent manner. Serum ELISA analysis revealed that groups receiving the highest doses of rVHSV-Delta G and rVHSV-A-IFN gamma-Delta G showed significantly elevated titers compared to the control group. Although no statistically significant differences in ELISA titers were observed among groups immunized with lower doses of recombinant VHSVs, particularly at 1 x 103 pfu/fish, and the control group, the markedly higher protection compared to the control group suggests that these single-cycle viruses possess a limited capacity to induce antibody responses, yet are capable of conferring protective immunity against VHSV independently of humoral mechanisms. Moreover, the complete protection achieved with low-dose immunization of rVHSV-A-IFN gamma-Delta G indicates its strong potential as a highly effective prophylactic vaccine candidate.

关键词： Trogocytosis   CD8+CD45RC low   Regulatory T cells   Plasmacytoid dendritic cells   Immune tolerance  

摘要： Objective: Donor-specific suppression by MHC-II+CD8+CD45RClow/-regulatory T cells (Tregs) was observed in our prior study, here we endeavor to investigate the mechanism underlying generation of the MHCII+CD8+CD45RClow/-Tregs. Methods: The presence of MHC-II+CD8+CD45RClow/-Tregs within tolerated grafts was confirmed using a multicolor immunofluorescence technique in spontaneous tolerant rat liver transplant model. We aimed to elucidate the generation mechanism of MHC-II+CD8+CD45RClow/-Tregs by purifying naive CD8+CD45RClow/-Tregs and plasmacytoid dendritic cells (pDCs) from recipients and co-culturing them to induce trogocytosis. Initially, we examined the immunophenotype and cytokine secretion of MHC-II+CD8+CD45RClow/-Treg using flow cytometry. Trogocytosis of peptide-MHC class II complexes was visualized using a confocal microscope. Subsequently, we analyzed the donor-specific inhibitory effect of MHC-II+CD8+CD45RClow/-Tregs using CFSE-based lymphocyte proliferation analysis. Finally, we explored the possible transfer mechanisms of MHC class II using IFN-gamma stimulation and 1-MT to block indoleamine-(2,3)-dioxygenase (IDO). Results: In the spontaneously tolerant rat liver transplants, MHC-II+CD8+CD45RClow/-Tregs and IL-10 expression were upregulated. Our in vitro study revealed that trogocytosis occurring between naive CD8+CD45RClow/-Tregs and pDCs could induce MHC-II+CD8+CD45RClow/-Tregs. The semi-direct pathway represents the primary mode of Trogocytosis-mediated transfer of MHC-II molecules from pDCs to CD8+CD45RClow/-Tregs. The MHCII+CD8+CD45RClow/-Tregs exhibited high secretion of IL-10 and IFN-gamma. Co-culturing with MHCII+CD8+CD45RClow/-Tregs significantly suppressed the proliferation of CD4+CD25-effector T cells. Moreover, this inhibitory effect was donor-specific and could be overcome in the presence of third-party antigen-presenting cells. Our data also suggested that blocking the IFN-gamma/IDO signaling pathway could inhibit the generation of trogocyt