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关键词： Transcription  

摘要： Immunotherapies blocking cell surface signaling of the immune checkpoint PD-L1 have shown great promise in several cancers, but the results have been disappointing in ovarian cancer (OC). One of the main underlying mechanisms likely consists of the cell-intrinsic intracellular functions of PD-L1, which are incompletely understood. The expression of PD-L1 in OC cells is induced by interferon-γ (IFNγ), a pleiotropic cytokine produced in response to chemotherapy or immune checkpoint blockade. We have recently shown that IFNγ induces expression of the proto-oncogene Bcl3, the proangiogenic chemokine interleukin-8 (IL-8)–CXCL8, and the transcription factor STAT1, resulting in increased OC cell proliferation and migration. Here, we report that IFNγ-induced expression of PD-L1 results in PD-L1 recruitment to IL-8, Bcl3, and STAT1 promoters. The occupancy of PD-L1 at IL-8, Bcl3, and STAT1 promoters is associated with increased histone acetylation and RNA polymerase II recruitment to these promoters. Suppression of IFNγ-induced PD-L1 decreases the expression of IL-8, Bcl3, and PD-L1 and increases apoptosis in OC cells. Together, these findings demonstrate that PD-L1 promotes transcription of IL-8, Bcl3, and STAT1, thus providing a novel function of PD-L1 in cancer cells, and suggesting that the increased IL-8, Bcl3, and STAT1 expression mediated by PD-L1 might contribute to the limited effectiveness of cancer immunotherapies targeting the surface expression of PD-L1 in OC. © 2025 The Authors

关键词： Crohn disease   anti‐TNF therapy   classic Hodgkin lymphoma   iatrogenic disease   inflammatory bowel disease  

摘要： Background:Lymphomas present a significant challenge in the field of gastrointestinal diseases, often being mistaken for other gastrointestinal tumors or inflammatory bowel disease conditions, causing clinical confusion. Early diagnosis plays a pivotal role in effective treatment. This case highlights the importance of recognizing lymphoproliferative disorders as a rare association of anti-tumor necrosis factor-α (TNF-α) therapy. Case Presentation:A 41-year-old man with a 15-year history of Crohn disease on long-term therapy with adalimumab underwent a right hemicolectomy due to a semi-circumferential lesion at the ileocecal valve causing near complete obstruction and severe anemia (Hgb 6.4 g/dL). Previous biopsies of the mass showed an Epstein Barr Virus-positive (EBV+) classic Hodgkin lymphoma (CHL) in Crohn disease. At resection, the lymphoma showed transmural involvement of the ileum and regional lymph nodes. Conclusion:Primary intestinal CHL comprises less than 5% of gastrointestinal lymphomas; CHL arising in the context of Crohn disease is even more rare. Most lymphomas associated with inflammatory bowel disease and/or immunosuppression are non-Hodgkin type. In this case, the long-term treatment with anti-TNF-α and EBV positivity suggested an iatrogenic immunodeficiency-associated lymphoma, an emerging group of lymphoproliferative disorders associated with the increased use of immunosuppressants.

关键词： HLA-B*18:05:01:03   HLA genotyping   Illumina   next-generation sequencing   novel allele  

摘要： The HLA-B*18:05:01:03 allele differs from HLA-B*18:05:01:02 by a single-nucleotide substitution in Intron 5.

关键词： breast cancer   IFN-gamma-inducible lysosomal thiol reductase   MYC   OICR-9429   WDR5  

摘要： BackgroundBreast cancer has become a severe threat to human health, making it imperative to identify effective drugs and therapeutic *** molecular biology experiments, such as western blot analysis, cytologic effect, co-immunoprecipitation, and immunofluorescence assays, as well as a nude mouse xenograft tumor model, were used to comprehensively analyze the impact of gamma-interferon-inducible lysosomal thiol reductase (GILT) on the malignant phenotype of breast cancer cells. This work was performed to examine GILT expression levels and explore the potential mechanism in breast *** protein expression levels were significantly lower in breast cancer cells than in normal breast epithelial cells. Overexpressing GILT inhibited breast cancer cell proliferation and migration and slowed tumor growth. GILT inhibited the interaction between the MYC and WDR5 transcription complex and played a tumor-suppressive role. The MYC/WDR5 transcription complex inhibitor OICR-9429 could synergize with GILT to inhibit breast cancer cell *** study reveals a potential mechanism by which GILT can slow breast cancer growth, as well as identifying the possible clinical application value of small molecule inhibitor OICR-9429. These data collectively provide novel treatment strategies for breast cancer therapy.

关键词： Human dermal fibroblasts   Methylnissolin-3-O-R-D -glucopyranoside   Tumor necrosis factor-alpha   Methylnissolin   Skin-aging  

摘要： Methylnissolin-3-O-R-D-glucopyranoside (MNG) and methylnissolin (MN) are pterocarpan derivatives that are found in plants, such as Astragalus membranaceus. There are limited existing studies on the potential health benefits of MNG, and currently there is no evidence to suggest that MNG has any impact on skin-aging. Tumor necrosis factor-alpha (TNF-alpha) plays a significant role in skin aging by promoting chronic inflammation, damaging skin cells, and impairing the skin's natural repair mechanisms. Targeting TNF-alpha or its downstream signaling pathways may be a promising strategy for preventing or reversing skin-aging. We tested the effect of MNG and MN on skin-aging by inducing cell inflammation and oxidative stress with TNF-alpha in HDFs. MNG and MN significantly reduced the TNF-alpha-induced secretion of matrix metalloproteinase-1 (MMP-1). However, MNG has more beneficial compound for oral administration than MN in pharmacokinetics analysis. The mechanism underlying the anti-skin-aging effect of MNG is related to the suppression of TNF-alpha-induced reactive oxygen species (ROS) generation and mitogen-activated protein kinase (MAPKs) phosphorylation. Our results suggest that MNG is a potential candidate for preventing skin-aging induced by TNF-alpha.

摘要： Activating mutations in STAT6 are common in Follicular Lymphoma (FL) and transformed FL and various other B cell lymphomas. Here, we report RNA-seq based gene expression data on normal human lymph node derived B lymphocytes (NBC;N = 6), and primary human FL WT (N = 11) or mutant (N = 4) for STAT6 before and after ex vivo stimulation with IL4. We found that STAT6 mutants result in broad based augmentation of IL4-induced gene expression. Unexpectedly, in FL with WT STAT6 we measured reduced baseline and IL4-induced gene expression levels when compared with NBC lymphocytes or FL with STAT6 mutations. We tracked the attenuated IL4/JAK/STAT6 response to co-existing CREBBP mutations and experimentally verified that intact CREBBP is required for the induction of many IL4-induced genes. One of the IL4-induced genes here identified is RRAGD, a small G-protein involved in lysosomal mTOR activation. We show that IL4 treatment induced RRAGD expression, that RRAGD is required for mTOR activation in lymphoma cells and that IL4-enhanced BCR signaling induced mTOR activation. The IL4 and BCR-induced mTOR activation was reduced by CREBBP mutants and augmented by mutant STAT6, establishing a link between STAT6 mutations and mTOR regulated pro-growth pathways in lymphoma.

关键词： HLA‐C*03:595   NGS   new allele  

摘要： The novel HLA-C*03:595 allele was identified in an individual from the Sichuan province of China.

关键词： PLEK2   PDAC   Migration   Invasion   MMP1  

摘要： Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis primarily due to metastasis. Accumulating evidence suggests that PLEK2 acts as an oncogene in various tumors. This study aimed to investigate the effects of PLEK2 on PDAC. Expression analysis of PLEK2 was conducted using qRT-PCR, Western blot, and immunohistochemistry in PDAC. Wound healing and transwell assays were performed to evaluate the impact of PLEK2 on cell migration and invasion. A xenograft tumor model was employed to assess the in vivo proliferation of PLEK2. Additionally, the downstream pathway of PLEK2 was analyzed through RNA-seq and confirmed by Western blot analysis. The results demonstrated the upregulation of PLEK2 expression in tumor specimens. High PLEK2 expression was significantly associated with poor overall survival and advanced TNM stages. Correlation analyses revealed positive correlations between PLEK2 and TGF-beta, EGFR, and MMP1. Wound healing and transwell assays demonstrated that PLEK2 promoted PDAC cell migration and invasion, potentially through the activation of the epithelial-to-mesenchymal transition process. The in vivo experiment further confirmed that PLEK2 knockdown suppressed tumor growth. RNA-seq analysis revealed PLEK2's regulation of MMP1 and activation of p-ERK and p-STAT3, which were verified by Western blot analysis. Overall, the present study suggests that PLEK2 may play a tumor-promoting role in PDAC. These findings provide valuable insights into the molecular mechanisms of pancreatic cancer and highlight the potential of PLEK2 as a therapeutic target.