课程文献中心 更多>>

关键词： IBC   HER2   ScRNA   TME   Immunosuppression   PTN   TNF  

摘要： BackgroundInflammatory breast cancer (IBC), of which HER2 + is the predominant subtype, is extremely aggressive and difficult to treat. Previous studies have suggested that targeting the tumour microenvironment (TME) may provide new directions for IBC diagnosis and *** this study, we used single-cell transcriptome technology (scRNA-seq) to investigate the molecular features of the TME of HER2 + IBC patients and performed a comprehensive and detailed comparison of the cellular components and molecular phenotypes of the TME between IBC patients and noninflammatory breast cancer (nIBC) patients to elucidate the cell types that are specifically enriched in the TME of IBC patients, as well as the molecular features that are responsible for the preferential remodelling of the cellular functional state in the *** total of 15,832 cells, including epithelial cells, endothelial cells, stromal cells, T cells, B cells, antibody secreting cells (ASCs) and myeloid cells, were obtained from tumour tissues from 3 HER2 + IBC patients for scRNA analysis. By comparing the TME with that of HER2 + nIBC patients in a public database, we found that the TME of HER2 + IBC patients had a greater level of lymphocyte infiltration than that of nIBC patients did, and an especially significant enrichment of ASCs (mainly plasmablasts or plasma cells). In the TME of HER2 + IBC patients, tumour-infiltrating T cells exhibited a dual molecular phenotype of high activation and high exhaustion, with tumour-infiltrating B cells preferring the extrafollicular developmental pathway, and tumour-infiltrating myeloid and mesenchymal cells exhibiting a greater immunosuppressive status. By performing a cellular interaction analysis, we revealed that PTN molecules were significantly overexpressed in HER2 + IBC tumour cells and that the cellular interactions mediated by these molecules were strongly correlated with the functional polarisation of the cellular components in the TME. We obse

关键词： AIDS/HIV   Immunotherapy   Infectious disease   NK cells  

摘要： BACKGROUND. NK cell function is impaired in people with HIV (PWH), hindering their potential to reduce the lymphoid tissue (LT) reservoir. The IL-15 superagonist N-803 has been shown to enhance NK and T cell function and thus may reduce viral reservoirs. METHODS. To determine the impact of N-803 on LTs, we conducted a clinical trial where 10 PWH on effective antiretroviral therapy (ART) were given 3 subcutaneous 6 mcg/kg doses of N-803. We obtained PBMCs and lymph node (LN) and gut biopsies at baseline and after the last N-803 dose. RESULTS. We found a nonstatistically significant approximately 0.50 median log reduction in the frequency of viral RNA+ (vRNA+) and vDNA+ cells/gin the 6 participants with baseline and posttreatment LN biopsies. In the ileum, we observed reductions ofvRNA+ cells in 8/10 participants and vDNA+ cells in all participants. We also found significant inverse correlations between NK cell proliferation and the frequency of vRNA+ cells and between NKG2A expression on NK cells and the frequency of vRNA+ cells. CONCLUSION. Our findings suggest N-803 may reduce the HIV reservoir in LTs of PWH on ART, an effect likely mediated by enhanced NK cell function. Controlled studies assessing the impact of NK cell therapy on HIV LTs are needed. TRIAL REGISTRATION. *** NCT04808908.

摘要： BACKGROUND:HGSOC is the leading cause of death among all gynaecological malignancies. We recently identified that genomically unstable cancers that display high levels of chromosomal instability, including HGSOC, rely on a cGAS/STING/IL-6R autocrine loop for survival. Here, we determined the prevalence of IL-6R expression in HGSOC samples to identify patients that could potentially benefit from treatment inhibiting IL-6R. METHODS:Immunohistochemical staining of IL-6R and STING in a well-characterized cohort of advanced-stage HGSOC patients (N = 268) was digitally quantified. After excluding patients with less than two cores or an "unknown" alive status, the resulting data of 230 patients was correlated with overall survival, and relevant histopathological, clinical, genetic, and therapeutic variables were assessed. RESULTS:The majority of patient cores were positive for IL-6R and STING, where the staining intensity for IL-6R was more varied, while STING had a more consistent expression. We found that IL-6R expression is associated with improved survival. Multivariate analyses also identified that IL-6R, BRCA1/BRCA2 mutation, primary treatment, and surgical outcome are strong independent prognostic factors of overall survival. CONCLUSIONS:Our findings suggest that ~37% of HGSOC patients might benefit from treatment targeting IL-6R. The high prevalence and underlying molecular data warrant further investigation in a clinical trial.

关键词： prostate cancer   tumor immune microenvironment   CD8+T cell   regulatory T cells   CXCL12/CXCR4 axis   IL-2/STAT5 signaling  

摘要： Background Prostate cancer (PCa) is characterized by high incidence and recurrence rates, presenting as an immune 'cold' tumor that exhibits a poor response to immunotherapy. The mechanisms underlying immune suppression and evasion within the tumor microenvironment (TME) of PCa remain inadequately *** A comprehensive analysis of the immune environment in PCa was conducted using combined single-cell and spatial transcriptomic approaches, encompassing samples from healthy tissue, adjacent normal tissue, and localized tumors. Cell abundance and polarization state analyses were performed to identify pivotal cellular populations. Spatial deconvolution techniques were employed to elucidate cell composition within its spatial context. Additionally, cell niche and spatial colocalization analyses were conducted to evaluate potential cellular interactions. Immune response enrichment analysis was utilized to assess cellular response states. In vivo and in vitro experiments were conducted to validate *** Data indicated a prevalent immunosuppressive state among CD8 T cells, accompanied by variations in cell abundance. Macrophages emerged as key regulators in recruiting CD8+ effector T cells and regulatory T cells (Tregs) into the TME, mediated by the CXCL12/CXCR4 axis. A spatial proximity relationship was established between CD8+ effector T cells and Tregs, suggesting Tregs directly influence CD8+ T cell function. Immune cell state analysis revealed interleukin-2 (IL-2) as a critical cytokine in reshaping the immune microenvironment, with Tregs competitively depleting IL-2 and mediating IL-2/STAT5 signaling to induce CD8+ effector T cell exhaustion. Treatment with CXCR4 inhibitor and IL-2 demonstrated significant antitumor effects and reversed immune dysfunction in both in vivo and in vitro experiments, with combined treatment exhibiting superior *** These findings elucidate the role of macrophages in mediating the CXCL12/CXCR4 axis

关键词： Sjogren's disease   salivary gland   spatial transcriptome   interleukin-14 alpha transgenic   RNAseq   sialadenitis  

摘要： Sjogren's disease (SjD) is a systemic autoimmune disorder primarily affecting the exocrine glands and characterized by dry mouth and dry eye, the presence of anti-SSA and/or anti-SSB autoantibodies in blood serum, and chronic lymphocytic infiltration of salivary and lacrimal glands (i.e., sialadenitis and dacryoadenitis, respectively). In addition to reduced quality of life, SjD patients experience severe oral health complications and are at increased risk of developing B cell lymphoma. Because current SjD treatments primarily focus on oral and ocular symptom management, identifying initiating factors and mechanisms of disease progression may offer new therapeutic insights for SjD. The interleukin-14 alpha transgenic (IL-14 alpha TG) mouse model of SjD recapitulates many aspects of human SjD, including progressive sialadenitis, loss of salivary gland function, and development of B cell lymphoma. We utilized immunofluorescence, flow cytometry, bulk RNA sequencing and spatial transcriptomic analyses to identify immune cell subpopulations and differentially expressed genes (DEGs) in submandibular glands of IL-14 alpha TG Sjogren's-like mice and age-matched C57BL/6 mouse controls. We further compared the gene ontology of DEGs in IL-14 alpha TG mice to DEGs identified in minor salivary gland biopsies from SjD patients and healthy volunteers. Results demonstrated significantly increased sialadenitis in IL-14 alpha TG compared to C57BL/6 mice that correlated with an increased proportion of marginal zone B cells infiltrating the submandibular gland. Whole transcriptome analyses showed substantial overlap in enriched DEG ontology between IL-14 alpha TG mouse submandibular gland and SjD patient minor salivary gland, compared to C57BL/6 mice and healthy human volunteer controls, respectively. Lastly, we spatially resolved DEG expression and localization within IL-14 alpha TG salivary glands, marking the first publication of a spatial transcriptomic dataset from submandibular g

关键词： IBS   inflammatory bowel disease   anti-TNF alpha   originators   biosimilars  

摘要： The review by Zeng et al. (2024) provides a timely synthesis of clinical and economic implications of TNFα biosimilars in inflammatory bowel disease (IBD). While the article addresses critical aspects of biosimilar adoption, several methodological and contextual limitations warrant clarification to enhance its academic rigor and relevance. This commentary highlights key concerns, proposes actionable revisions, and underscores the importance of addressing these gaps to solidify the article's utility for clinicians and *** review cites cost-saving data from 2017 U.S. biologics expenditures (Kappelman et al., 2008), which fails to reflect recent market dynamics. Furthermore, the review's overall assessment of the evidence landscape appears inadequately updated. Consider the systematic review by Martelli & Peyrin-Biroulet (2019), which synthesized the state of knowledge up to 2016. Martelli et al. concluded that while infliximab biosimilars showed promise in IBD, significant knowledge gaps regarding long-term safety, interchangeability, and real-world effectiveness in complex populations persisted, necessitating large post-marketing studies. A 2024 review has the responsibility to critically evaluate how these gaps identified in 2019 have been addressed by subsequent evidence (e.g., Schreiber et al., 2021;Kennedy et al., 2019 on long-term safety; NOR-SWITCH extension on interchangeability; IQVIA 2023 on market penetration and cost savings). Failing to incorporate and discuss these key post-2019 developments -particularly immunogenicity monitoring strategies validated in prospective cohorts (Kennedy et al., 2019) significantly diminishes the review's currency and utility for understanding the current biosimilar landscape in *** authors heavily rely on rheumatoid arthritis (RA) studies (e.g., VOLTAIRE-CD) to support biosimilar efficacy, while IBD-specific long-term safety data remain underrepresented. For instance, CT-P13's safety profile in IBD cohorts b

关键词： IL-3   TNF-alpha   Osteoblastogenesis   Alkaline phosphatase   Osteocalcin   NF-kappa B/beta-CATENIN  

摘要： BackgroundIn inflammatory bone loss disorders, such as rheumatoid arthritis and post-menopausal osteoporosis, TNF-alpha is an important effector cytokine that promotes osteoclastogenesis and inhibits osteoblastogenesis. Currently, clinical interventions primarily include anti-osteoclastic agents to prevent bone loss, however, anabolic agents are scarce and there's an utmost need. Previously, IL- 3 has been shown to enhance osteogenic differentiation of human bone marrow-derived mesenchymal stem cells in vitro. However, its role remains unclear in inflammatory pathologies, where TNF-alpha negatively impacts osteoblast differentiation. This study aims to investigate IL- 3's impact on osteogenic differentiation process under the negative influence of *** pre-osteoblasts were isolated from BALB/c mice pups and in vitro osteoblast differentiation was performed as per established protocols. TNF-alpha was used as a negative regulator of osteoblast differentiation and the effect of IL- 3 on this differentiation was studied by assessing matrix mineralization using Alizarin red S staining. Osteoblast differentiation markers, including, alkaline phosphatase and osteocalcin were evaluated using qPCR. ALP activity was measured using the pNPP colorimetric assay. Furthermore, Western blotting was employed to deduce the mechanism(s) of IL- 3 action on TNF-alpha-induced-inhibition of osteoblast *** red S staining revealed that IL- 3 priming protects pre-osteoblasts from TNF-alpha-induced-inhibition of osteoblast differentiation and that this protective effect is irreversible. Mechanistically, IL- 3 pretreatment suppresses TNF- alpha-induced activation of NF-kappa B/SMURF1 axis thus preventing beta-CATENIN degradation, which drives osteogenic gene *** mouse pre-osteoblasts with IL- 3 prevents TNF-alpha-induced of osteoblast differentiation in vitro, and, thus, could be a novel candidate in the treatment of i

关键词： 非洲猪瘟病毒   p30蛋白   免疫原性   单克隆抗体  

摘要： 本研究将非洲猪瘟病毒p30蛋白截短为8个两端重叠肽段，通过大肠杆菌表达系统进行表达，利用4种不同类型样品系统分析p30蛋白的免疫原性。结果显示：p30蛋白免疫小鼠血清和单克隆抗体制备过程中阳性孔培养上清能够与101-130aa、126-155aa和176-195aa肽段发生反应；非洲猪瘟临床阳性猪血清仅能与101-130aa肽段发生反应；3株单克隆抗体抗原表位均位于126-155aa肽段。研究发现，p30蛋白免疫小鼠和非洲猪瘟感染猪对p30蛋白的免疫应答存在明显差异，但二者均能对101-130aa肽段产生较强的免疫反应；在筛选抗原表位时，利用单克隆抗体制备过程中阳性细胞孔培养上清比单克隆抗体更全面。本研究为非洲猪瘟抗体检测试剂盒和亚单位疫苗研发提供了思路。

摘要： INTRODUCTION:Ulcerative colitis (UC) increases the risk of colorectal cancer (CRC). Although 5-aminosalicylic acid (5‑ASA) have long been regarded as chemopreventive, it remains unclear whether 5-ASA therapy still confers this benefit when used concomitantly with tumour necrosis factor (TNF) inhibitors. METHODS:We performed a retrospective cohort study using the nationwide Japanese Medical Data Vision database. Patients with UC who initiated TNF inhibitors were followed from the first TNF-inhibitor prescription until CRC diagnosis or disenrollment. Concomitant 5-ASA use was defined as prescription within 90 days before or after TNF initiation. Cumulative incidence was compared with Kaplan-Meier curves and the log-rank test; hazard ratios (HRs) were estimated with multivariable Cox regression and inverse probability-of-treatment weighting (IPTW), adjusting for age, sex, primary sclerosing cholangitis (PSC), diabetes, obesity, immunomodulator use, type of TNF agent and prior advanced-therapy exposure. RESULTS:Among 9,919 eligible patients, 8,387 (84.6%) received concomitant 5-ASA. During follow-up (median 3.14 years), 161 CRC events occurred: crude incidence 3.67/1,000 person-years (with 5-ASA use) versus 4.58/1,000 person-years (without 5-ASA use) (P = 0.42). Concomitant 5-ASA was not associated with CRC risk (adjusted HR 1.25, 95% CI 0.76-2.04; IPTW-adjusted HR 1.28, 95% CI 0.78-2.11). Independent risk factors were older age, male sex and PSC. CONCLUSIONS:We found no measurable chemopreventive benefit of concomitant 5-ASA in UC patients receiving TNF inhibitors during this treatment phase. Accordingly, 5-ASA need not be prioritized for colorectal-cancer prevention at this stage. Longer observation is required to clarify any benefit beyond the early years of TNF inhibitors.