课程文献中心 更多>>

关键词： IKK beta   esophageal squamous cell cancer   CXCL9   t cells   macrophages   IFN gamma   inflammation   early carcinogenesis  

摘要： Esophageal cancer is a major cause of cancer-related death, often preceded with chronic inflammation and injuries. The NF kappa B/IKK beta pathway plays a central role in inflammation, yet its role in early esophageal carcinogenesis remains unclear. This study investigated the role of epithelial IKK beta in early esophageal carcinogenesis. Mice were treated with the carcinogen 4-nitroquinoline-1-oxide (4-NQO) or a vehicle for one month to induce precancerous lesions. Esophagi were harvested and examined through histological, protein, flow cytometry, and RNA analyses. Histological analysis revealed that 4-NQO treatment led to increased inflammation, intraepithelial CD45+ immune cells, and elevated IKK beta phosphorylation levels. Mice with esophageal epithelial-specific Ikk beta deletion (4-NQO/Ikk beta EEC-KO) showed delayed progression to a precancerous state, with reduced immune cell recruitment compared to 4-NQO/controls. Immunophenotyping showed decreased recruitment of T cells, including CD4+, CD8+ and regulatory (Tregs) T cells, and increased recruitment of macrophages in 4-NQO/Ikk beta EEC-KO mice compared with 4-NQO/controls. RNA sequencing data identified 262 differentially expressed genes in 4-NQO/Ikk beta EEC-KO mice, implicating pathways related to inflammation and wound healing. Notably, the chemokine CXCL9, a T cell chemoattractant, was significantly upregulated in 4-NQO control mice, but not in 4-NQO/Ikk beta EEC-KO mice. Further analysis identified IFN gamma as an upstream regulator of Cxcl9 expression, and neutralization of IFN gamma reduced Cxcl9 expression levels in 4-NQO treated mice. Additionally, in vitro studies demonstrated that IFN gamma upregulates Cxcl9 in an NF kappa B dependent manner in esophageal keratinocytes. These findings suggest that epithelial IKK beta regulates the immune microenvironment in early esophageal carcinogenesis through the IFN gamma/CXCL9 axis and influencing T cell recruitment and inflammatory responses. In a mouse

关键词： Anti-IL-23   Biologics   Psoriasis   Psoriatic arthritis   Real-life   Guselkumab  

摘要： IntroductionGuselkumab is a monoclonal antibody targeting the p19 subunit of interleukin (IL)-23, approved for the treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis (PsA). While patients with psoriasis often achieve high clinical response rates (Psoriasis Area and Severity Index [PASI] 90 and PASI 100), the presence of PsA may influence long-term outcomes. We conducted a 260-week, multicenter, retrospective study to compare the effectiveness, safety, and drug survival of guselkumab in patients with and without concomitant *** total of 1765 patients were enrolled, including 352 with a concomitant diagnosis of PsA and 1413 with isolated skin involvement. All patients were treated with guselkumab following the approved dosing schedule for moderate-to-severe plaque psoriasis for at least 1 year. Treatment effectiveness was evaluated in terms of PASI 90, PASI 100, and absolute PASI <= 2 at weeks 16, 28, 52, 104, 156, 204, and 260. Guselkumab drug survival was assessed using the Kaplan-Meier method at the same time points. The safety profile was evaluated by analyzing adverse events recorded in medical charts at each follow-up *** the study period, response rates remained comparable between the two cohorts of patients, with a significant difference at 2 years of follow-up in terms of PASI 90 (80.51% versus 74.02%). Drug survival overall remained stable and similar, with 79.5% (95% confidence interval (CI) 76.9-81.9) of patients without PsA and 78.5% (95% CI 72.9-83.1) of patients with PsA still receiving guselkumab treatment after 5 *** results confirm the long-term effectiveness, persistence, and favorable safety profile of guselkumab in patients with moderate-to-severe psoriasis, regardless of the presence of concomitant PsA.

关键词： aged MSCs   autologous stem cell therapies   CD74   immunogenicity   MHC class II   young microenvironment  

摘要： Older adults are the primary population for cell-based therapies for age-related diseases, but the efficacy of administering autologous mesenchymal stem cells (MSCs) is impaired due to biological aging. In the present study, we cultured aging adipose (AD)-derived MSCs from > 65-year-old donors on extracellular matrix (ECM) synthesized by human amniotic fluid-derived pluripotent stem cells (ECM Plus) versus tissue culture plastic (TCP) and hypothesized that ECM Plus provided an ideal "young" microenvironment for reactivating and preserving early-stage progenitor cells within aging AD-MSCs. To test our hypothesis, we serially sub-cultured aging AD-MSCs on ECM Plus or TCP and characterized the cells both phenotypically and functionally, and then analyzed the cells at the single-cell transcriptomic level for the mechanisms that control cell fate. The results showed that the maintenance of aging AD-MSCs on ECM Plus significantly restored their quantity and quality. The mechanisms responsible for these effects were associated with a remarkable up-regulation of intracellular CD74 when cells were maintained on ECM Plus compared to TCP, which triggered activation of the phosphoinositide-3-kinase (PI3K) pathway as a key modulator of cell survival (anti-apoptosis) and suppression of cellular senescence. Moreover, AD-MSCs maintained on ECM Plus increased their expression of HLA-DR and stimulated T cell activity. These findings challenge the "immune privilege" of allogeneic MSCs as a universal source for MSC-based therapies. The present study leads to a new paradigm for treating age-related diseases: serial administration of rejuvenated autologous MSCs, which may not only replace aged MSCs but also gradually reverse the aged microenvironment.

关键词： Human leukocyte antigen   HLA   Donor-specific antibodies   DSA   Magnetic beads   Eplet   Epitope   Transplantation  

摘要： Sera from patients with previous transplants, transfusions, and pregnancies may contain multiple Human Leukocyte Antigen (HLA)-specific antibodies recognizing various functional epitopes or eplets. The identification and verification of eplets in these high Panel Reactive Antibody (PRA) cases are important for understanding HLA antigenicity and potentially improving transplantation outcomes. For a particular high PRA case, we utilized adsorption and elution techniques using cells and HLA-specific magnetic beads to identify and verify eplets. The resulting eluates confirmed seven established eplet patterns while also uncovering two novel binding patterns against A*01:01 and B*53:01. The isolation of the HLA-specific antibodies allows us to perform competition assays against monoclonal antibodies to confirm the epitope specificity. Using available HLA crystal structures, we proposed that the physicochemical properties of residues 163 and 167 are crucial for the binding of the A*01:01-targeted antibody identified in this study, as well as another A*01:01-targeted antibody previously discovered by Lima et al. [1]. Our studies demonstrate that isolating antibodies and analyzing the physicochemical properties of the eplet will lead to a more comprehensive understanding of HLA immunogenicity.

关键词： IFN-beta   MUC5AC overexpression   EGCG   STAT1   ERK  

摘要： The overexpression of mucin 5AC (MUC5AC) induced by interferon-beta (IFN-(3) plays a critical role in airway mucus hypersecretion and contributes to the mortality associated with coronavirus disease 2019 (COVID-19) patients. Epigallocatechin gallate (EGCG), a polyphenol derived from green tea, has demonstrated potential as a therapeutic agent for the treatment of coronavirus-related diseases. This study aimed to investigate the regulatory effects of EGCG on IFN-(3-induced MUC5AC overexpression and to elucidate its underlying molecular mechanisms. We found that IFN-(3-induced MUC5AC overexpression was associated with the activation of the signal transducer and activator of transcription 1 (STAT1) and extracellular signal-regulated kinase (ERK) signaling pathways. The use of STAT1 or ERK inhibitors significantly attenuated IFN-(3-induced MUC5AC overexpression. EGCG treatment markedly inhibited IFN-(3-induced MUC5AC overexpression and suppressed activation of the STAT1 and ERK signaling pathways. Subsequent research revealed that EGCG binds to Janus kinase 1 (JAK1) and inhibits its kinase activity, leading to reduced phosphorylation of STAT1 and ERK. The use of JAK1 inhibitors reproduced the effects observed with EGCG treatment. Structural analysis indicated that the methyl gallate of the EGCG molecule was crucial for its inhibitory activity. In vivo studies demonstrated that EGCG effectively suppressed IFN-(3-induced mucus hypersecretion and MUC5AC overexpression, along with inhibition of the associated signaling pathways. In conclusion, EGCG inhibits IFN-(3-induced MUC5AC over-expression by suppressing JAK1 kinase activity, thereby blocking activation of the STAT1 and ERK signaling pathways.

关键词： immunopeptidomics   EThcD   HLA ligandome   de novo sequencing   Orbitrap Excedion Pro  

摘要： Gaining a complete and unbiased understanding of the nontryptic peptide repertoire presented by human leukocyte antigen class I (HLA-I) complexes by LC-MS/ MS is indispensable for therapy design for cancer, auto-immunity, and infectious diseases. A serious concern in HLA peptide analysis is that the routinely used collisionbased fragmentation methods [collision-induced dissociation (CID)/higher-energy collision-induced dissociation (HCD)] do not always render sufficiently informative MS2 spectra, whereby gaps in the fragmentation sequence coverage prevent unambiguous assignments. Electrontransfer/higher-energy collision dissociation (EThcD) can be utilized to generate complementary ion series, i.e., b/y ions and c/z ions, resulting in richer, more informative MS2 spectra, thereby filling in the gaps. Here, we present data generated on a novel hybrid orbitrap mass spectrometer, facilitating fast and efficient hybrid fragmentation due to the implementation of EThcD in the ion routing multipole. We hypothesized that this would enable more comprehensive and less error-prone analysis of immunopeptidomes at minimal costs in duty cycle. First, we optimized ETD/EThcD methods using an elastasedigested cell lysate, as this contains peptides of similar length and charge distributions to immunopeptides. Next, we compared HCD and EThcD on immunopeptidomes originating from three cell lines with distinct HLA-I complexes that present peptides with varying physicochemical properties. We demonstrate that the new instrument not only enables efficient and fast ETD reactions but, when combined with collision-based supplemental activation, i.e. EThcD, also consistently increases the sequence coverage and identification of peptide sequences, otherwise missed by using solely HCD. We reveal several of the biochemical properties that make HLA peptides preferably identifiable by EThcD, with internal Arg residues being one of the most dominant determinants. Finally, we demonstrate the power of