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关键词： 白细胞介素1β   白细胞介素6   人牙髓干细胞   牙髓炎   增殖   成骨分化  

摘要： 目的 探讨白细胞介素1β（IL-1β）和白细胞介素6（IL-6）对体外培养的人牙髓干细胞（hDPSCs）增殖和分化的影响。方法 体外分离培养hDPSCs，设置对照组（0 ng/mL IL-1β）和IL-1β组（0.1,1,10,100 ng/mL IL-1β）；同理设置对照组（0 ng/mL IL-6）和IL-6组（0.1,1,10,100 ng/mL IL-6）。培养24,48,72 h时，应用细胞计数试剂盒-8（CCK-8）检测hDPSCs增殖活性；培养7,14,21 d时，应用5-溴-4氯-3-吲哚-磷酸盐（BCIP）/氯化硝基四氮唑蓝（NBT）碱性磷酸酯酶（ALP）显色试剂盒和茜素红（AR）显色试剂盒分别检测hDPSCs ALP染色、ALP活性、AR染色变化和钙结节定量。结果 CCK-8结果显示，不同浓度IL-1β组培养48 h细胞增殖活性均小于对照组（P<0.05）,72 h时仅100 ng/mL IL-1β组增殖活性小于对照组（P<0.05）。成骨诱导第14,21天时，与对照组比较，1,10,100 ng/mL IL-1β组肉眼观ALP和AR染色变浅，ALP活性和钙结节OD450降低（P<0.05）。CCK-8结果显示，不同浓度IL-6组在48 h时细胞增殖活性均小于对照组（P<0.05）,72 h时仅100 ng/mL IL-6组增殖活性小于对照组（P<0.05）。成骨诱导第21天，与对照组相比，肉眼观100 ng/mL IL-6组ALP染色较浅，ALP活性降低（P<0.05）,0.1,1,10 ng/mL IL-6组在成骨诱导第7,14,21天，ALP染色、AR染色、ALP活性和钙结节OD450均无明显变化。结论 IL-1β和IL-6对hDPSCs增殖活性的影响均取决于其浓度和作用时间。高浓度的IL-1β抑制hDPSCs的成骨分化；IL-6对hDPSCs的成骨分化无明显影响。

摘要： The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) poses a major challenge in hemophilia A (HA) treatment. The formation of FVIII inhibitors is a CD4+ T-cell dependent mechanism which includes antigen presenting cells (APCs), B- and T-helper lymphocytes. APCs present FVIII derived peptides on major histocompatibility complex class II (MHC-II) to CD4+ Tcells. We previously established a mass spectrometry based approach to delineate the FVIII repertoire presented on HLA-DR and HLA-DQ. In this study, specific attention was directed towards the identification of FVIII peptides presented on HLA-DP. A data-set of naturally processed FVIII peptides was generated by incubating human FVIII with immature monocytes-derived dendritic cells (moDCs) from HLA-typed healthy donors. Using this method, we identified 176 to 1352 different HLA-DP presented peptides per donor, including 26 different FVIII derived peptides. The most frequently presented peptides derived from the A3, and C2 domains of FVIII. Comparison of the FVIII repertoire presented on HLA-DP with that presented on HLA-DR revealed considerable overlap but also suggested preferential presentation of specific peptides on either HLA-DR or HLA-DP. Fourteen FVIII peptides presented on HLA-DP were synthesized and evaluated for their binding ability to the commonly expressed HLA-DP4 molecule which is highly prevalent in the Caucasian population. Peptide binding studies showed that 7 of 14 peptides competed with a reference peptide to HLADP4. Interestingly, an A3 domain derived peptide bound with high affinity to HLA-DP4 positioning this peptide as a prime candidate for the development of novel peptide-based tolerogenic strategies for FVIII inhibitors.

关键词： MicroRNA-122   TNF-alpha   Acute liver failure   Children   Steroid   Biomarker  

摘要： BackgroundAcute liver failure (ALF) is a rare illness marked by rapid deterioration of liver function, leading to high morbidity and mortality rates, particularly in children. While steroids have been observed to correlate with improved survival, evidence supporting their efficacy in ALF children remains limited. miR-122, a liver-specific microRNA, plays a pivotal role in liver pathology, with its expression significantly altered in various liver diseases. Thus, it is considered a potential biomarker for disease progression, aids in prognosis, and identifies therapeutic targets. Our study aims to assess the expression of miR-122 in 24 children with ALF, both before and after steroid therapy, alongside its relationship with tumor necrosis factor-alpha (TNF-alpha), to better understand its potential role in treatment response and disease outcomes. miR-122 levels were determined using quantitative real-time RT-PCR (qRT-PCR), while TNF-alpha levels were assessed using enzyme-linked immunosorbent assay (ELISA) in patient *** ALF children who survived after steroid treatment, miR-122 was markedly decreased compared to both pre-treatment levels (p = 0.003) and levels in deceased patients (p = 0.01). In addition, TNF-alpha levels significantly increased in surviving patients compared to pre-treatment levels (p = 0.008) and levels in deceased children (p = 0.028). A negative correlation was observed between TNF-alpha and miR-122 following steroids (r=-0.46, p = 0.04). miR-122 demonstrated 72% sensitivity and 67% specificity in distinguishing survivors and non-survivors, as indicated by its receiver-operated characteristic curve. A positive correlation was found between miR-122 before steroid therapy and both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) before (r = 0.641, p = 0.002 and r = 0.512, p = 0.02, respectively) and after (r = 0.492, p = 0.03 and r = 0.652, p = 0.003, respectively) steroids *** data implies that lo

关键词： Severe aplastic anemia   Haploidentical   HSCT   Nomogram   Prognostic scoring system  

摘要： In recent years, great progress has been made in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) treatment for hematological malignant diseases because of the advent of novel conditioning regimens, optimized graft manipulation, improved graft-versus-host disease (GVHD) prophylaxis, and advances in supportive care. Recent studies have shown very favorable outcomes in severe aplastic anemia (SAA) patients, with comparable outcomes to those of patients receiving immune suppressive therapy (IST) and allogeneic HSCT from a matched sibling donor (MSD) or matched unrelated donor (MUD). However, most of the previous studies relied on single-center data analyses, and the conditioning regimen, GVHD prophylaxis and supportive care used were relatively singular. We do not know whether there are differences in the survival of SAA patients after haplo-HSCT and MSD-HSCT under conditions involving different transplant centers, conditioning regimens and GVHD prophylaxis. This is a disease-specific, multicenter and retrospective study. We retrospectively studied 156 consecutive patients with SAA who underwent haplo-HSCT or MSD-HSCT at four transplant centers in China. The 5-year overall survival (OS) rate was 87.5% in the haplo-HSCT group and 89.7% in the MSD-HSCT group. The time to hematopoietic reconstitution, incidence of graft versus host disease, and infection and graft failure rates were not significantly different between the groups. Haplo-HSCT achieved outcomes comparable to those of MSD-HSCT for SAA patients. According to the nomogram score, we developed a SAA prognostic scoring system. Haplo-HSCT should be considered an effective alternative for patients with SAA without a matched sibling donor. The SAA transplant-specific prognostic scoring system proposed in this study can conveniently predict the OS for SAA patients following MSD-HSCT or haplo-HSCT.

关键词： IgE   IL-10   IP-10   monocyte   SHIP-1  

摘要： IgE-mediated stimulation of monocytes regulates multiple cellular functions including cellular maturation, cytokine release, antiviral responses, and T-cell differentiation. Expression of the high-affinity IgE receptor, Fc epsilon RI, is closely linked to serum IgE levels and atopic disease. The signaling molecules regulating Fc epsilon RI effector functions have been well studied in mast cells and basophils;however, less is known about the signaling and regulatory mechanisms in monocytes. This study sought to identify regulators of IgE-mediated cytokine release in human monocytes. SHIP-1 was identified as a negative regulator of IgE-induced IL-10 production. It was also determined that IgE-mediated stimulation and SHIP-1 inhibition decreased antiviral IP-10 production after liposomal poly(I:C) stimulation, indicating differential regulation by SHIP-1 in IgE-driven and antiviral response pathways. SHIP-1 and NF-kappa B were activated following IgE-mediated stimulation of monocytes, and NF-kappa B activation was related to both SHIP-1 and Fc epsilon RI alpha cellular expression levels. To our knowledge, this is the first study to identify a role for SHIP-1 in regulating IgE-mediated and antiviral responses in human monocytes. Given the importance of monocytes in inflammation and immune responses, a better understanding of the signaling and regulatory mechanisms downstream of the Fc epsilon RI receptor could lead to new therapeutic targets in allergic disease.

关键词： arthritis, psoriatic   patient reported outcome measures   fatigue  

摘要： Objectives To prospectively evaluate the effect of guselkumab through 48 weeks across various clinical outcomes in subgroups of patients with psoriatic arthritis (PsA) and inadequate response to tumour necrosis factor inhibitors (TNFi-IR) from the phase 3b COSMOS trial. Subgroups were defined by baseline demographics, disease characteristics and prior/ongoing *** Patients with active PsA (tender joint count (TJC) and swollen joint count (SJC) both >= 3) and TNFi-IR were randomised 2:1 to receive guselkumab 100 mg at week 0, week 4, then every 8 weeks through week 44 or to placebo with cross-over to guselkumab 100 mg at week 16 (early escape) or week 24 (planned). Guselkumab effect on joints (American College of Rheumatology (ACR) 20/50/70, enthesitis, dactylitis), skin (Psoriasis Area and Severity Index 90/100, Investigator's Global Assessment 0/1), patient-reported outcomes (PROs) (Functional Assessment of Chronic Illness Therapy-Fatigue, Health Assessment Questionnaire-Disability Index) and composite outcome measures (PsA Disease Activity Score low disease activity, minimal disease activity) were evaluated by baseline patient age, sex, body mass index, SJC, TJC, PsA duration, %body surface area, C reactive protein, pain Visual Analogue Scale, number of prior TNFi and discontinuation reason, and conventional synthetic disease-modifying antirheumatic drug status. Results are descriptive *** Baseline characteristics were similar between guselkumab (n=189) and placebo (n=96) groups. The benefit of guselkumab over placebo in achieving ACR 20 (primary endpoint;50% vs 28%) and ACR 50 (23% vs 8%) response at week 24 was observed within all subgroups. Furthermore, response rates in the guselkumab group increased between week 24 and week 48 within almost all subgroups. Similar response patterns at week 24 and through week 48 were observed across various clinical *** Guselkumab every 8 weeks led to consistent improvements through week

关键词： exercise   genetic variant   interleukin-6   metabolism   skeletal muscle  

摘要： Interleukin-6 (IL-6) is produced and secreted by skeletal muscle cells during exercise and plays an important role in mediating metabolic responses to exercise. The promoter region of the IL-6 gene contains a common genetic variant (-174 G/C, rs1800795) which may alter responses to exercise training. To isolate the impact of this gene variant on exercise-induced IL-6 expression and skeletal muscle transcription responses following exercise we generated knock-in mice with a GG or variant CC genotype for the murine homolog of rs1800795. The overall gross metabolic phenotype of resting mice was similar between genotypes; however, following acute treadmill running the variant CC genotype was associated with a greater increase in skeletal muscle IL-6 mRNA and circulating IL-6. Furthermore, we observed that mice with the variant CC genotype exhibited sex-specific differences in skeletal muscle master metabolism regulatory genes, and had greater increases in genes controlling mitochondrial biogenesis in skeletal muscle post-exercise. However, there was no effect of genotype on exercise-induced skeletal muscle glycogen depletion, circulating free fatty acids, blood glucose and lactate production, or exercise-responsive gene expression in subcutaneous fat. These findings suggest that the IL-6 promoter variant -174 G/C may result in enhanced skeletal muscle adaptations in response to exercise training, and could mean that individuals with the 'C' allele may more readily gain improvements in metabolic health in response to exercise training.

关键词： bimekizumab   biologics   Il-17 inhibitors   intraclass switch   psoriasis  

关键词： NK cell   CAR-NK cell   cord blood   progenitor cell   adoptive cell therapy  

摘要： Cord blood (CB)-derived chimeric antigen receptor (CAR)-natural killer (NK) cells targeting CD19 have been shown to be effective against B cell malignancies. While human CD56+ NK cells can be expanded in vitro, NK cells can also be differentiated from hematopoietic progenitor cells. It is still unclear whether CAR-NK cells originate from mature NK cells or NK progenitor cells in CB. Here, we determined that CAR-NK cells were predominantly derived from CD56- NK progenitor cells. We fi rst found that substantial numbers of CD19 CAR-NK cells were produced from CD56- CB mononuclear cells after in vitro culture for 2 weeks. Single-cell RNA sequencing analysis of CD56-CD3-CD14-CD19- CB mononuclear cells revealed that these cells could be subdivided into three subpopulations based on the expression of CD34 and human leukocyte antigen (HLA)-DR. NK cells originated primarily from CD34-HLA- DR- cells. In addition, among the CD34-HLA-DR- cells, only CD7+ cells could differentiate into NK cells. These results indicate that CD56-CD7+CD34-HLA-DR- lineage marker (Lin)- cells are the major origin of human CB-derived CAR-NK cells, indicating the importance of developing methods to enhance the quality and quantity of NK cells produced from these NK progenitor cells.

摘要： Ulcerative colitis (UC) is a chronic inflammatory bowel disease with an unknown etiology and is difficult to treat. Studies have shown that some helminths and their associated products have therapeutic potential in controlling or preventing inflammatory diseases. This study is to investigate the mitigation effects of Hymenolepis nana antigens (HnAg) on the UC model. HnAg significantly improved the disease activity index, colon length, and colonic pathological damage in mice with dextran sulfate sodium (DSS)-induced colitis. HnAg intervention could protect the number of goblet cells and enhance the expression of tight junction proteins and mucins, thereby improving intestinal barrier integrity. HnAg attenuated small intestinal organoid damage and stimulated intestinal stem cells proliferation in a DSS-induced mouse organoid inflammation model. The protective mechanism of HnAg might be related to the activation of the aryl hydrocarbon receptor (AhR)/IL-22 signaling pathway, which regulates intestinal barrier function and promotes the proliferation and differentiation of intestinal stem cells. In conclusion, HnAg has a therapeutic effect on UC mice. Our study provides a new approach for alleviating UC by Hymenolepis nana and its associated products.