课程文献中心 更多>>

关键词： Single-cell RNA sequencing   Late-stage triple-negative breast cancer   IL2RG   CD8(+) T cells   Nanoparticles   Cytotoxicity   Glycolysis  

摘要： Background: The manipulation of CD8+ T cell functions through genetic modifications presents a novel approach to cancer immunotherapy. This study aimed to explore the effects of IL2RG-overexpressing CD8(+) T cells and assess the efficacy of delivering IL2RG mRNA via nanoparticles (NPs) to the tumor microenvironment in triple-negative breast cancer (TNBC). Methods: Single-cell RNA sequencing (scRNA-seq) was conducted on tissue from early and late-stage TNBC, followed by a meta-analysis of six breast cancer arrays from the GEO database to identify candidate genes. CRISPR/Cas9 was employed for gene knockout and overexpression in CD8+ T cells, which were then analyzed using flow cytometry, ELISA, immunofluorescence, and metabolic assays. A 3D cancer cell spheroid model was used for co-culture experiments. Lipid-coated calcium-phosphate (LCP)@IL2RG NPs were synthesized and injected into TNBC mouse models. Results: IL2RG was identified as significantly associated with late-stage TNBC. Overexpression of IL2RG in CD8+ T cells led to increased cell activation, cytotoxicity, and glycolysis, while knockout reduced these effects. Overexpressing IL2RG in CD8+ T cells co-cultured with 3D cancer spheroids resulted in enhanced apoptosis and reduced cancer cell invasion. Injection of LCP@IL2RG NPs into TNBC mouse models significantly mitigated tumor growth. Conclusions: Overexpressing IL2RG in CD8+ T cells enhances tumor immunotherapy. Delivering IL2RG mRNA via NPs further amplifies this effect, offering a promising strategy for the treatment of late-stage TNBC.

关键词： allogeneic hematopoietic cell transplant   GvHD   non-relapse mortality   post-transplant cyclophosphamide  

摘要： Objective: This retrospective single center study aims to describe changes in the severity and organ-specific distribution of GvHD, by comparing the outcomes of 3 distinct GvHD prophylaxis approaches. Methods: Between January 2012 and June 2022, 226 patients underwent allogeneic hematopoietic stem cell transplantation from HLA-matched or 1-allele mismatched related or unrelated donors. Fifty-eight (26%) received prophylaxis with calcineurin inhibitor in combination with mycophenolate mofetil or a short course of methotrexate (Cohort-1), 87 (38%) tacrolimus plus sirolimus (Cohort-2), and 81 (36%) post-transplant cyclophosphamide (PTCy) plus tacrolimus (Cohort-3). Results: The incidence of grade II-IV aGvHD was 69% vs. 41.4% vs. 27.2%;p < .01. The most significant reduction with PTCy was observed in both stage 3-4 skin and lower gastrointestinal (GI) involvement (p < .01). The incidence of moderate-to-severe cGvHD at 12 months was 34.5% vs. 34.5% vs. 6.2%;p < .01. Moderate-to-severe skin and GI cGvHD was less common after PTCy (p < .01). The 1-year GvHD-free/relapse-free survival was higher with PTCy (p < .01). Conclusions: Our study indicates that PTCy-based GvHD prophylaxis reduces the frequency and severity of both acute and chronic GvHD, with a notable decrease in severe GI and cutaneous manifestations. The higher GRFS may result in lower GvHD-related mortality, leading to an improved quality of life among survivors.

关键词： Asthma   capsaicin   functional dyspepsia   interleukin-33   neuronal dysfunction  

摘要： Background: Neuronal dysfunction is implicated in the pathophysiology of asthma and functional dyspepsia (FD). However, the relationship between these diseases remains unclear. Objective: This study aimed to clarify the clinical implications of comorbid FD in asthma and to explore the unified pathway between asthma and FD by focusing on airway neuronal dysfunction. Methods: Clinical indices and biomarkers, including capsaicin cough sensitivity (C-CS), were compared between patients with asthma with and without FD. C-CS was determined on the basis of capsaicin concentration that induced at least 2 coughs (C2) or 5 coughs (C5). Additionally, the associations of airway inflammation with airway innervation and gastrointestinal motility were evaluated in mouse models of type 2 airway inflammation. Results: Patients with asthma with FD had worse asthma control and cough severity and lower C2 and C5 thresholds than those without FD. The severity of FD symptoms was negatively correlated with C2 and C5 thresholds. FD and poor asthma control were predictors of heightened C-CS (defined as C5 <= 2.44 mu mol) in asthma. A mouse model of papain-induced airway inflammation developed airway hyperinnervation and gastrointestinal dysmotility, and both pathologies were ameliorated by an anti-IL-33 antibody. Moreover, papain-induced gastrointestinal dysmotility was mitigated by silencing the airway sensory neurons using QX-314, a sodium channel blocker. Furthermore, sputum IL-33 levels were significantly elevated in patients with asthma with FD or heightened C-CS compared to their counterparts. Conclusion: FD is significantly associated with airway neuronal dysfunction in asthma. IL-33-mediated airway neuronal dysfunction may contribute to the interaction between asthma and FD.

关键词： Prion   IL-3   IL-3R   JAK2-STAT5   PI3K   AKT   mTOR  

摘要： Interleukin 3 (IL-3) plays an important role in hematopoiesis and immune regulation, brain IL-3/IL-3R signaling has been shown to involve in the physiological and pathological processes of a variety of neurodegenerative diseases, but its role in prion diseases is rarely described. Here, the changes of IL-3/IL-3R and its downstream signaling pathways in a scrapie-infected cell line and in the brains of several scrapie-infected rodent models were evaluated by various methods. Markedly decreased IL-3R & alpha;were observed in the brains of scrapie-infected rodents at terminal stage and in the prion-infected cell model, which showed increased in the brain samples collected at early and middle stage of infection. The IL-3 levels were almost unchanged in the brains of scrapie-infected mice and in the prion-infected cell line. Morphological assays identified close co-localization of the increased IL-3R & alpha;signals with NeuN- and Iba1-positive cells, whereas co-localization of IL-3 signals with NeuN- and GFAP-positive cells in the scrapie-infected brain tissues. Some downstream components of IL-3/IL-3R pathways, including JAK2-STAT5 and PI3K/AKT/mTOR pathways, were downregulated in the brains of scrapie-infected rodents at terminal stage and in the prion-infected cells. Stimulation of recombinant IL-3 on the cultured cells showed prion that the prion-infected cells displayed markedly more reluctant responses of JAK2-STAT5 and PI3K/AKT/mTOR pathways than the normal partner cells. These data suggest that although prion infection or PrPSc accumulation in brain tissues does not affect IL-3 expression, it significantly downregulates IL-3R levels, thereby inhibiting the downstream pathways of IL-3/IL-3R and blocking the neuroregulatory and neuroprotective activities of IL-3.

关键词： sIL6RA   SMOC1   Alzheimer's disease   Inflammation   Mild cognitive impairment   Disease progression   Dementia  

摘要： Despite the central role attributed to neuroinflammation in the etiology and pathobiology of Alzheimer's disease (AD), the direct link between levels of inflammatory mediators in blood and cerebrospinal fluid (CSF) compartments, as well as their potential implications for AD diagnosis and progression, remains inconclusive. Moreover, there is debate on whether inflammation has a protective or detrimental effect on disease onset and progression. Indeed, distinct immunological mechanisms may govern protective and damaging effects at early and late stages, respectively. This study aims to (i) identify inflammatory mediators demonstrating robust correlations between peripheral and central nervous system (CNS) compartments by means of plasma and CSF analysis, respectively, and (ii) assess their potential significance in the context of AD and disease progression from mild cognitive impairment (MCI) to dementia. To achieve this, we have examined the inflammatory profile of a well-defined subcohort comprising 485 individuals from the Ace Alzheimer Center Barcelona (ACE). Employing a hierarchical clustering approach, we thoroughly evaluated the intercompartmental correlations of 63 distinct inflammation mediators, quantified in paired CSF and plasma samples, using advanced SOMAscan technology. Of the array of mediators investigated, only six mediators (CRP, IL1RAP, ILRL1, IL6RA, PDGFRB, and YKL-40) exhibited robust correlations between the central and peripheral compartments (proximity scores <400). To strengthen the validity of our findings, these identified mediators were subsequently validated in a second subcohort of individuals from ACE (n = 873). The observed plasma correlations across the entire cohort consistently have a Spearman rho value above 0.51 (n = 1,360, p < 1.77E-93). Of the high CSF-plasma correlated proteins, only soluble IL6RA (sIL6RA) displayed a statistically significant association with the conversion from MCI to dementia. This association remained robu

关键词： Interleukin-6   Inflammation   Cardiovascular outcomes   Risk prediction   Hs-CRP   Atherosclerosis  

摘要： Purpose of ReviewThe objective of this narrative review is to summarize data from recently published prospective observational studies that analyze the association between circulating interleukin-6 (IL-6) levels and cardiovascular clinical or imaging *** FindingsHigher levels of IL-6 are associated with a higher risk of cardiovascular death, major adverse cardiovascular events, myocardial infarction, stroke, peripheral artery disease, and heart failure. Imaging studies have also shown an association between IL-6 and carotid intima-media thickness progression, carotid plaque progression, severity, and vulnerability. These observations have been consistent across a wide range of study populations and after adjusting for traditional and emerging risk factors including high-sensitivity C-reactive *** epidemiologic evidence supports IL-6 as a central mediator of cardiovascular risk along with human genetic studies and mechanistic experiments. Ongoing clinical studies are testing the therapeutic hypothesis of IL-6 inhibition in patients with atherosclerotic cardiovascular disease or heart failure.

关键词： Systemic lupus erythematosus   Autoantibodies   Interferon signature   NETosis   Patient stratification  

摘要： Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a variety of disease symptoms and an unpredictable clinical course. To improve treatment outcome, stratification based on immunological manifestations commonly seen in patients with SLE such as autoantibodies, type I interferon (IFN) signature and neutrophil extracellular trap (NET) release may help. It is assumed that there is an association between these immunological phenomena, since NET release induces IFN production and IFN induces autoantibody formation via B-cell activation. Here we studied the association between autoantibodies, the IFN signature, NET release, and clinical manifestations in patients with SLE. Methods: We performed principal component analysis (PCA) and hierarchical clustering of 57 SLE-related autoantibodies in 25 patients with SLE. We correlated each autoantibody to the IFN signature and NET inducing capacity. Results: We observed two distinct clusters: one cluster contained mostly patients with a high IFN signature. Patients in this cluster often present with cutaneous lupus, and have higher anti-dsDNA concentrations. Another cluster contained a mix of patients with a high and low IFN signature. Patients with high and low NET inducing capacity were equally distributed between the clusters. Variance between the clusters is mainly driven by antibodies against histones, RibP2, RibP0, EphB2, RibP1, PCNA, dsDNA, and nucleosome. In addition, we found a trend towards increased concentrations of autoantibodies against EphB2, RibP1, and RNP70 in patients with an IFN signature. We found a negative correlation of NET inducing capacity with anti-FcER (r = -0.530;p = 0.007) and anti-PmScl100 (r = -0.445;p = 0.03). Conclusion: We identified a subgroup of patients with an IFN signature that express increased concentrations of antibodies against DNA and RNA-binding proteins, which can be useful for further patient stratification and a more targeted therapy. We did not

关键词： association   Chinese population   promoter region   T2DM   TNF-alpha   variants  

摘要： Type 2 diabetes (T2DM) is characterised by insulin resistance and a relative shortage of insulin secretion. Tumour necrosis factor-alpha (TNF-alpha) plays an important role in insulin resistance by impairing insulin signal transduction. The variants of the TNF-alpha promoter region are considered to influence its transcription and are associated with the TNF-alpha level. Therefore, it is worth detecting the association of the variants in the TNF-alpha gene with the development of T2DM. The aim of this study was to investigate the association of five variants (rs1799964, rs1800630, rs1799724, rs1800629 and rs361525) in the TNF-alpha gene promoter region with T2DM in a Chinese Han population. A total of 713 subjects with T2DM and 751 nondiabetic subjects were genotyped using the TaqMan method. The associations of the five variants with the development of T2DM were evaluated. The associations of the five variant genotypes with metabolic traits in nondiabetic subjects were analysed. Our data showed that the A allele of rs1800629 could increase the risk of developing T2DM (p = .002, OR = 1.563;95% CI: 1.18-2.08). According to inheritance mode analysis, compared with the G/G genotype, the G/A+2A/A genotype of rs1800629 showed a risk effect on T2DM in the log-additive mode (p = .002, OR = 1.56;95% CI: 1.17-2.07). The haplotypes analysis identified that the rs1799724-rs1800629CA was associated with high risk of the development of T2DM (p = .002, OR = 1.559, 95% CI: 1.173-2.072). Conversely, the rs1799724-rs1800629CG was a protective haplotype of T2DM (p = .001, OR = 0.732, 95% CI: 0.607-0.884). Moreover, compared with the rs1799964 (T/T+C/T) genotype, the rs1799964 C/C genotype was associated with higher glycosylated haemoglobin (HbA1c) levels in nondiabetic subjects (p = .017). Our results revealed that the rs1800629 in the TNF-alpha gene promoter region was associated with T2DM in a Chinese Han population.

关键词： BMSCs   chondrogenesis   embryonic bone development   IL-4/IL-4R alpha  

摘要： Interleukin-4 (IL-4)/IL-4 receptor alpha (IL-4R alpha) signalling pathways play important roles in the complex process of bone formation and bone remodelling. However, whether IL-4/IL-4R alpha participates in skeletogenesis during embryonic development is not completely understood. We used the anti-IL-4R alpha monoclonal antibody (anti-IL-4R alpha mAb) as a powerful investigational tool to evaluate the potential roles of IL-4/IL-4R alpha in the chondrogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs) in vitro. Simultaneously, we explored the effect of IL-4/IL-4R alpha on bone ossification during rat embryo-fetal development. In this study, we found that, compared to the control group, IL-4 can significantly promote the chondrogenic differentiation of BMSCs. Furthermore, following exposure to anti-IL-4R alpha mAb in pregnant rats, unexpected phenomena were observed in fetal bone development, including non-ossification of the fetal sternum, an incomplete ossification centre in long bones and a reduced number of ossification points in digit (toe) bones. To further investigate the underlying mechanism of the phenotype, we studied the rat sternum as the target organ, starting from different time points of sternum development in the embryonic stage. The results indicated that the retardation mainly occurred in the middle and late stages of embryonic development. This retardation was characterized by the inhibition of the differentiation process of mesenchymal stem cells into chondrocytes, resulting in reduced angiogenesis near the ossification centre, failure of osteoblasts to invade the centre of the cartilage body with the blood vessels and delayed formation of the primary ossification centre (POC). Overall, our study demonstrated the significant function of IL-4/IL-4R alpha in chondrogenic differentiation of BMSCs and bone ossification during embryo-fetal development.

关键词： Air quality   Car pollution   Exhaust and non-exhaust emissions   Tire and road wear particles (TRWP)   Combined toxicity   Co-exposure  

摘要： Road traffic is a major contributor to air pollution and consequently negatively affects human health. Car pollution originates both from exhaust emissions (EE) and non-exhaust emissions (NEE, such as tire and brake wear particles, erosion of road surfaces and resuspension of road dust). While the toxicity of EE and NEE has been characterized separately, their combined effects are poorly documented. However, we are constantly exposed to a mixture of pollutants and their interactions should not be neglected as they may significantly impact their toxicological profile resulting in additive, synergistic or antagonistic effects. To fill this gap, we investigated in vitro the combined toxicity of exhaust gases and benzo[a]pyrene (representative of EE) and tire particles (representative of NEE). Macrophages from the RAW264.7 cell line were exposed for 24 h to tire particles (TP) of variable size (6-113 mu m), alone or in combination with exhaust gases (CO2, CO, NO, NO2) and benzo[a]pyrene (B [a]P) as an archetype of polycyclic aromatic hydrocarbon (PAH). The cell response was assessed in terms of cytotoxicity, proinflammatory response and oxidative stress. TP, gases and B[a]P, alone or in combination triggered neither cytotoxicity nor oxidative stress. On the contrary, a proinflammatory response was elicited with two different profiles depending on the size of the TP: TNF-alpha production was either slightly (with the finest TP) or strongly (with coarse TP) increased in the presence of gases and B[a]P, suggesting that the effects of TP, gases and B[a]P were either additive or synergistic, depending on TP size.