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关键词： nuclear PD-L1   transcription   IFNγ   immune checkpoint blockade   cancer immunotherapy   ovarian cancer   RNA polymerase II   tumor immunology  

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-y (IFNy), a pleiotropic cytokine produced in response to chemotherapy or immune checkpoint blockade. We have recently shown that IFNy 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 IFNy-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 IFNy-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.

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

摘要： BackgroundLymphomas 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-alpha (TNF-alpha) *** PresentationA 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 *** 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-alpha 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： Biomarkers  

摘要： To investigate the relationship between early-stage (48-72 h after onset) serum levels of migration inhibitory factor (MIF), monocyte chemoattractant protein 1 (MCP-1), and interleukin 6 (IL-6) in severe acute pancreatitis (SAP) patients and late-stage (after four weeks) pancreatic pseudocyst (PPC) development. 121 SAP patients from Zhoukou Central Hospital (September 2022-June 2024) had their clinical data collected and serum biomarker levels measured via ELISA. After a four-week follow-up, they were grouped as PPC (n = 33) and non-PPC (n = 88). Univariate and multivariate stepwise logistic regression analyzed associations between biomarkers and PPC formation, and receiver operating characteristic (ROC) curves evaluated predictive accuracy. Serum MIF, MCP-1, and IL-6 levels were higher in PPC patients (P < 0.05). Multivariate analysis, adjusting for multiple factors, showed that higher MIF (adjusted OR = 1.480, 95% CI: 1.235-1.775, P < 0.001) and MCP-1 (adjusted OR = 1.070, 95% CI: 1.005-1.140, P = 0.035) predicted PPC. Alcohol-related pancreatitis also increased PPC odds (OR = 1.600, 95% CI: 1.100-2.320, P = 0.013). ROC analysis revealed different predictive values for each biomarker. Early-stage elevated serum MIF and MCP-1 are positively linked to PPC in SAP patients, suggesting predictive potential. Serum IL-6 is not associated with PPC and may not be a reliable predictor.

关键词： Natural killer cell   Cancer immunotherapy   IL-2   IL-15   Cytokine  

摘要： NK cell adoptive cell therapy (ACT) has emerged as a promising strategy for cancer immunotherapy, offering advantages in scalability, accessibility, efficacy, and safety. Ex vivo activation and expansion protocols, incorporating feeder cells and cytokine cocktails, have enabled the production of highly functional NK cells in clinically relevant quantities. Advances in NK cell engineering, including CRISPR-mediated gene editing and chimeric Ag receptor technologies, have further enhanced cytotoxicity, persistence, and tumor targeting. Cytokine support post-adoptive transfer, particularly with IL-2 and IL-15, remains critical for promoting NK cell survival, proliferation, and anti-tumor activity despite persistent challenges such as regulatory T cell expansion and cytokine-related toxicities. This review explores the evolving roles of IL-2 and IL-15 in NK cell-based ACT, evaluating their potential and limitations, and highlights strategies to optimize these cytokines for effective cancer immunotherapy.

摘要： Interleukin 17 (IL-17) is a proinflammatory cytokine that is commonly dysregulated in autoimmune diseases. Biologics targeting IL-17 (ixekizumab, secukinumab, brodalumab, bimekizumab) have been approved to treat conditions including psoriasis, psoriatic arthritis, and ankylosing spondylitis. Although inflammatory bowel disease (IBD) is characterized by dysregulated IL-17 signaling, IL-17 inhibitors have not shown benefit for IBD patients and are paradoxically associated with new-onset colitis. Here, we searched our biopsy archives and consult material to identify patients on IL-17 inhibitors with new-onset GI symptoms. Our final cohort included 5 patients, and most presented with new-onset bloody diarrhea that began from a few days to more than a year after IL-17 inhibitor initiation. Endoscopic impressions were similar to those in IBD, and histologic features included acute colitis, erosion/ulceration, crypt distortion, Paneth cell metaplasia, epithelial apoptosis, lamina propria lymphoplasmacytosis, and granulomas. Of 4 patients with follow-up, all received clinical diagnoses of IBD. IL-17 inhibitors were discontinued, and patients additionally required IBD therapeutic regimens for symptom resolution. Follow-up biopsies were available for 3 patients (maintained on IBD regimens) and showed normal mucosa;another patient developed a fistula. We conclude that patients on IL-17 inhibitors with new-onset colitis have a clinical and histologic spectrum that overlaps with IBD, primary immunodeficiencies, and other immunomodulatory therapies. The requirement of IBD biologics to achieve and maintain clinical/histologic remission in our cohort suggests that this process is more than a self-limited drug reaction. Future studies of expanded cohorts are required to determine whether IL-17 inhibitors unmask IBD in predisposed individuals or cause de novo IBD.