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关键词： Biobanking   Cytokine storage   Psychiatric patients   Biomarker   Cytokine stability-inflammation  

摘要： Cytokines are increasingly incorporated in psychiatric research. While biobanking provides advantages for different study designs, long-term storage could degrade cytokine quality and introduce bias. To date, reports on cytokine stability are based on small sample sizes (n < 20) and do not address long-term (4+ years) storage effects. This article reports two studies evaluating IL-6 and TNF-alpha measurements in human plasma samples biobanked for long periods. In the first study, with samples stored between 5and 139 months (11.6 years), IL-6 concentrations were not significantly correlated with storage length in all available baseline data of the Signature Biobank (n[IL-6] = 1206, n[TNF-alpha] = 1223). TNF-alpha correlated negatively with storage length (r =-0.217;p < 0.001) indicating a decrease of concentrations with longer storage. In the second study, IL-6 and TNF-alpha concentrations were measured twice in the same plasma samples of 50 psychiatric participants from the Signature Biobank stored between analyses from 32 to 45 months. We assessed if storage effects differed between analytes. In IL-6, we observe a relatively good stability in samples stored up to 6 years. For TNF-alpha, we observed only a moderate stability of measurements (rTNF-alpha = 0.59;rIL-6 = 0.71) with linear decrease over time. As a potential solution, a corrective equation extracted from Study 1 was applied to TNF-alpha in the Study 2 sample;however, this did not improve correlation coefficients but might be useful in other settings. Integrating samples' age in statistical analyses and/or more systematic quality controls could mitigate degradation process.

关键词： Acute myeloid leukemia   FLT3   FLT3 ligand   TIM-3   HIF-1 alpha   TNF-alpha  

摘要： BackgroundAcute Myeloid Leukemia (AML) pathogenesis is driven by the dysregulation of various cell signaling pathways, including the FMS-Like Tyrosine Kinase 3 (FLT3) pathway and its ligand (FLT3L). These pathways play a critical role in promoting cell survival, proliferation, and resistance to apoptosis, contributing to leukemogenesis. In this study, we investigated the effects of FLT3L on the expression of key genes associated with immune regulation, hypoxia, and inflammation-TIM-3, HIF-1 alpha, and TNF-alpha-in the THP-1 cell line, a well-established model for AML ***-1 cells were cultured under standard conditions and treated with varying concentrations of FLT3L, alongside PMA as a positive control. Quantitative RT-PCR was employed to measure the expression levels of TIM-3, HIF-1 alpha, and TNF-alpha genes after 48 h of *** findings demonstrated that specific concentrations of FLT3L significantly upregulated the expression of TIM-3, HIF-1 alpha, and TNF-alpha in THP-1 cells. This suggests that FLT3L not only influences cell proliferation and survival but also modulates pathways related to immune evasion, hypoxia adaptation, and inflammatory responses, which are hallmarks of leukemia *** results highlight the pivotal role of FLT3L in regulating the expression of genes associated with AML pathogenesis, particularly those involved in hypoxia (HIF-1 alpha), immune checkpoint regulation (TIM-3), and inflammation (TNF-alpha). The findings underscore the potential of targeting the FLT3 pathway as a therapeutic strategy in AML. Further studies are warranted to elucidate the underlying molecular mechanisms and explore their clinical implications for improving patient outcomes.

关键词： Mercuric chloride   Cytotoxicity   Gene expression   Oxidative stress   Inflammation   Pyroptosis   Pyroptosis  

摘要： An in vitro model using human peripheral blood mononuclear cells (PBMCs) was established to investigate the cytotoxic, oxidative and inflammatory effects and changes in purinergic system parameters caused by mercuric chloride (HgCl2). Cells were exposed to concentrations of HgCl2 (0.05, 0.5, 5, and 50 mu M) for 24, 48 and 72 h. Cell viability was measured by trypan blue and MTT assays, and IC50;apoptosis and cell death were assessed by flow cytometry. Oxidative stress was evaluated by reactive species (RS) generation, determination of Mercury (ICP-MS), Nitric Oxide (NO), and lipid peroxidation. Increased levels of HgCl2 induced RS generation, NO, lipid peroxidation, apoptosis, and altered the cell cycle, reducing DNA synthesis and cell division of PBMCs. Flow cytometry confirmed decreased viability and increased late apoptosis. HgCl2 accumulation in PBMCs was confirmed by ICP-MS. HgCl2 altered purinergic system components, inhibiting NTPDase and increasing ADA activity. At 5 mu M, it increased gene expression of purinergic receptors and both anti-inflammatory (IL-10) and pro-inflammatory markers (IL-1 beta, IL-6, TNF-alpha, NLRP3, CASP-1, NF-kappa B). Overexpression of the P2X7/NLRP3/CASP-1/IL-1 beta axis triggered cell death by pyroptosis. These findings provide compelling evidence HgCl2 induces cytotoxic and inflammatory effects in PBMCs.

关键词： APML   Cryptic PML::RARA fusion   HLA-DR  

摘要： We report the case of a 42-year-old female presented with cytopenia and abnormal promyelocytes on blood film. The promyelocytes were HLA-DR positive by flow cytometry. The rapid FISH for PML::RARA was negative. Myeloid NGS identified PML::RARA fusion, which was confirmed by molecular karyotyping and PCR. She was treated with ATRA and ATO to complete molecular remission. This case highlighted the importance of using rapid RNA sequencing to identify cryptic fusion and rare fusions and combining morphologic, immunophenotypic, cytogenetic and molecular analyses to ensure correct diagnosis and optimal management.

关键词： Collagen   Fish swim bladder   Macrophage polarization   Small diameter vascular graft  

摘要： Collagen is a structural protein that plays a critical role in tissue regeneration and is widely utilized in biomedical applications. Recent studies have demonstrated that collagen can modulate macrophage polarization;however, most studies have focused on mammalian collagen such as type I collagen derived from bovine and pig sources. In this study, we performed a comprehensive investigation of the role of collagen derived from aquatic sources, specifically fish swim bladder-derived collagen (SCC), in modulating macrophage inflammation using in vitro and in vivo experiments. First, collagen-coated and collagen-incorporated electrospun poly(epsilon-caprolactone) (PCL) films were prepared. RNA-Seq analysis showed that SCC could promote M0 and M1 phenotype macrophage transition into M2 through the activation of TNF-alpha/NF-kappa B and the downstream signaling pathways. Subcutaneous implantation and artery replacement were also performed. Moreover, SCC prolonged coagulation and synergistically reduces the risk of stenosis. Finally, mouse carotid artery replacement demonstrated that the SCCmodified vascular graft exhibited higher patency in combination with rapid endothelialization and reduced inflammatory responses in vivo. Taken together, we provide strong evidence that fish swim bladder-derived collagen has the capability to modulate macrophage polarization and shows great potential for tissue remodeling and regeneration.

关键词： IL-33   Endometriosis   Pain   Macrophages   Inflammation  

摘要： Endometriosis, a persistent inflammatory disease, is associated with pelvic or abdominal pain. The immune system and sensory nervous system show a synergistic effect on regulation of pain. In particular, Interleukin-33 (IL-33) is released as a danger signal and drives key hallmarks of severe endometriosis. To explore the mechanistic involvement of IL-33 in pain associated with endometriosis, both an in vivo murine endometriosis model and in vitro experiments with RAW 264.7 cells and dorsal root ganglion (DRG) neurons were utilized. In vivo, we demonstrated that IL-33 significantly exacerbated endometriosis and induced hyperalgesia in mice. By interacting with the ST2 receptor in macrophages, IL-33 enhanced the release of tumor necrosis factor alpha (TNF-alpha) and Interleukin 1 beta (IL-1 beta). This process set off an inflammatory cascade, which further facilitated macrophages recruitment and neurogenesis in ectopic lesions. As an ion channel expressed by nociceptors, transient receptor potential vanilloid 1 (TRPV1) expression was significantly increased in DRG in the presence of IL-33. In vitro, we confirmed that IL-33 elevated the release of TNF-alpha in macrophages. Ultimately, macrophage-derived TNF-alpha increased TRPV1 protein level in DRG neuronal cells through the TNFR1/p38 MAPK signaling pathway. Overall, these results revealed an inductive role of IL-33 in pain associated with endometriosis, and highlighted the interaction between macrophages and sensory neurons.

关键词： IL-6   Post-transplantation cyclophosphamide   Anti-thymocyte globulin   GVHD   Hematopoietic stem cell transplantation  

摘要： BackgroundPost-transplantation cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are common prophylactic strategies for graft-versus-host disease (GVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Interleukin (IL)-6 is a surrogate marker for cytokine release syndrome (CRS) and acute GVHD. MethodThe clinical outcomes and complications of haplo-HSCT with PTCy plus ATG versus PTCy monotherapy were compared according to serum IL-6 levels at Chungnam National University Hospital (Daejeon, South Korea) from January 2019 to February 2023. ResultsForty patients who underwent haplo-HSCT were analyzed. A significant difference in IL-6 levels was observed between the PTCy plus ATG and PTCy alone groups (7.47 +/- 10.55 vs. 117.65 +/- 127.67;p = 0.003). More patients in the PTCy plus ATG group had a CRS grade of 0 than in the PTCy alone group (p < 0.001). Serum IL-6 levels were associated with grades II-IV acute GVHD (r = 0.547, p < 0.001). The cumulative incidence (CI) of grades II-IV acute GVHD was significantly higher in the PTCy alone group (67.9% vs. 4.8%;p < 0.001). No significant difference in the CI for chronic GVHD was detected between the PTCy plus ATG and PTCy alone groups (72.1% vs. 82.0%;p = 0.730). The CI of 1-year non-relapse mortality was significantly higher in the PTCy alone group than in the PTCy plus ATG group (42.2% vs. 15.9%;p = 0.022). The 1-year overall survival (OS) was significantly better in the PTCy plus ATG group (75.9% vs. 35.3%;p = 0.011). The 1-year GVHD-free, relapse-free survival rate was 29.4% in the PTCy alone group and 54.0% in the PTCy plus ATG group (p = 0.038). ConclusionSerum IL-6 levels were higher in the PTCy alone group than in the PTCy plus ATG group. The addition of ATG before stem cell infusion affected IL-6 levels and reduced the incidences of CRS and grade II-IV acute GVHD in haplo-HSCT patients. This study suggests that PTCy plus ATG as GVHD prophylaxis in haplo-HSCT is beneficial in terms o

关键词： Oplegnathus punctatus   TARBP2   RGNNV   Viral replication   Type I interferon response  

摘要： Trans-Activation-Responsive RNA-Binding Protein (TARBP), a dsRNA-binding protein family member, serves as a hub for regulating gene expression and influencing diverse biological processes. While current research primarily focuses on its cytoplasmic interactions with factors like Dicer, protein kinase RNA-activated (PKR), and PKR activator (PACT), its role in teleost antiviral immunity remains less explored. In this study, we cloned and characterized an ortholog of TARBP2 from spotted knifejaw (Oplegnathus punctatus), designated OpTARBP2. Its open reading frame (ORF) spans 1038 bp, encoding a 345-amino acid protein with a predicted molecular weight of 37.1 kDa. Sequence analysis revealed that OpTARBP2 possesses three conserved dsRNA-binding domains and shares 96.81 % sequence homology with giant grouper (Epinephelus lanceolatus) TARBP2. Expression profiling indicated widespread OpTARBP2 distribution across tissues, with highest levels in the liver and intestine. Fluorescence microscopy confirmed its cytoplasmic localization. Functionally, overexpression of OpTARBP2 in grouper spleen (GS) cells reduced the transcription of pro-inflammatory cytokines and interferon-related genes, and thereby promoting replication of the red-spotted grouper nervous necrosis virus (RGNNV). Furthermore, OpTARBP2 significantly inhibited E. coioides Melanoma differentiation-associated gene 5 (MDA5), Mitochondrial anti viral signaling protein (MAVS), and TANK-Binding Kinase 1 (TBK1)-induced luciferase activity driven by the Interferon-stimulated response elements (ISRE) and NF-kappa B promoters. Collectively, these results demonstrate that OpTARBP2 enhanced viral replication by negatively regulating type I interferon responses, laying a foundation for understanding the antiviral immune role of TARBP2 in teleosts.

关键词： Cancer   SMAC memetic (IAP antagonist)   T cell   chimeric antigen receptor (CAR) cell therapy   dendritic cell (DC)   inhibitor of apoptosis proteins (IAPs)   macrophage   tumor necrosis factor-α (TNFα)  

摘要： Chimeric antigen receptor (CAR)-T cells are effective in treating blood cancers but not solid cancers and can cause severe side effects, including cytokine release syndrome (CRS). One strategy to enhance the efficacy of CAR-T cells while avoiding CRS in cancer treatment is to deliver a single tumoricidal factor. TNFα is well known for triggering apoptosis signaling; however, it alone is not effective in treating cancers because it significantly increases the levels of inhibitor of apoptosis proteins (IAPs), a family of E3 ubiquitin ligases that block caspase-induced apoptosis. Thus, localized delivery of TNFα by targeting the tumors using the adoptive cells combined with an IAP antagonist, which degrades IAP proteins, could lead to improved outcomes in cancer treatment. This article reviews TNFα-induced apoptosis signaling pathway, outlines the principles for designing CAR-T cells, CAR-macrophages and CAR-dendritic cells expressing TNFα, used alone or in combination with IAP antagonists, and discusses the potential contraindications of IAP antagonists with several clinical used drugs for cancer treatment.