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关键词： MHC-II peptide binding   Supervised contrastive learning   Binding affinity prediction   Binding core identification   Interpretability analysis  

摘要： Accurate prediction of major histocompatibility complex (MHC)-peptide binding affinity can improve our understanding of cellular immune responses and guide personalized immunotherapies. Nevertheless, the existing deep learning-based approaches for predicting MHC-II peptide interactions fall short of satisfactory performance and offer restricted model interpretability. In this study, we propose a novel deep neural network, termed ConBoTNet, to address the above issues by introducing the designed supervised contrastive learning and bottleneck transformer extractors. Specifically, the supervised contrastive learning pre-training enhances the model's representative and generalizable capabilities on MHC-II peptides by pulling positive pairs closer and pushing negative pairs further in the feature space, while the bottleneck transformer module focuses on MHC-II peptide interactions to precisely identify binding cores and anchor positions in an unsupervised manner. Extensive experiments on benchmark datasets under 5-fold cross-validation, leave-one-molecule-out validation, independent testing, T-cell epitope identification, and binding core prediction settings highlighted the superiority of our proposed ConBoTNet over current state-of-the-art methods. Data distribution analysis in the latent feature space demonstrated that supervised contrastive learning can aggregate MHC-II-peptide samples with similar affinity labels and learn common features of similar affinity. Additionally, we interpreted the trained neural network by associating the attention weights with peptides and innovatively find both well-established and potential peptide motifs. This work not only introduces an innovative tool for accurately predicting MHCpeptide affinity, but also provides new insights into a new paradigm for modeling essential biological interactions, advancing data-driven discovery in biomedicine.

关键词： Interleukin 11   PTGS2   PGE2   Granulosa cell   Cattle  

摘要： Ovulation is a highly organized and multifaceted series of events, which parallels with inflammatory processes. Prostaglandins (PGs) have been shown to play an important role in the modulation of ovulation. Our previous study revealed that Interleukin 11 (IL-11) signaling is critical in regulating steroidogenesis in bovine granulosa cells (GCs). However, the precise roles of IL-11 in the regulation of PGs remain unclear. In the present study, we investigated the effects and underlying molecular mechanisms of IL-11 on the production of PGs in primary bovine GCs. At LH-induced levels, we observed that 10 ng/mL IL-11 significantly increased prostaglandin E2 (PGE2) production via upregulating the expression of prostaglandin-endoperoxide synthase 2 (PTGS2), while IL11 treatment did not affect the production of prostaglandin F2 alpha (PGF2 alpha). Furthermore, 10 ng/mL IL-11 treatment activated the phosphorylation of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3), which was accompanied by STAT3 nuclear translocation. Additionally, these effects were inhibited by the addition of the STAT3-specific inhibitor C188-9. Specifically, C188-9 treatment blocked the IL-11-induced STAT3 nuclear translocation, downregulated the mRNA and protein expression levels of PTGS2, and ultimately led to a reduction in PGE2 production induced by 10 ng/mL IL-11. Our findings elucidate the cellular and molecular mechanisms by which IL-11 regulates PGE2 expression through the JAK1/STAT3 signaling pathway in bovine GCs in the presence of LH, contributing to a better understanding of the ovulatory process.

关键词： Immunology   Immunotherapy   NKT cells   Oncology  

摘要： Pancreatic ductal adenocarcinoma cancer (PDAC) continues to pose a significant health burden, with a 5-year survival rate of only 10%. Prostate stem cell antigen (PSCA) is highly expressed on the surface of tumor cells of most PDAC patients, with minimum expression in most normal tissues. Here, we generated cryopreserved, off-the-shelf, allogeneic PSCA chimeric antigen receptor (CAR) invariant NKT (iNKT) cells using human peripheral blood mononuclear cells as a cell source. In multiple in vitro and in vivo PDAC models, freshly manufactured PSCA CAR_sIL-15 iNKT cells and frozen-thawed, off-the-shelf PSCA CAR_sIL-15 iNKT cells demonstrate comparable efficacies, and both show remarkable suppression of PSCA-positive and gemcitabine-resistant PDAC. Importantly, off-the-shelf cryopreserved PSCA CAR_sIL-15 iNKT cells show equivalent efficacy when compared with PSCA CAR T cells using the same PSCA CAR and in the same PDAC model;however, PSCA CAR_sIL-15 iNKT cells do not appear to induce systemic toxicity or graft-versus-host disease, thus allowing for multiple infusions to control recurrent disease. Collectively, our study suggests that PSCA CAR_sIL-15 iNKT cells merit clinical investigation for PDAC patients exhibiting positive PSCA expression. The therapy could be given as a single agent or in combination with established therapeutic modalities for PDAC. © 2025, Dai et al.

关键词： dengue   HLA   dengue fever (DF)   dengue haemorrhagic fever   serotype   climate change  

摘要： Dengue, a viral infection transmitted by Aedes mosquitoes, is an emerging global health threat exacerbated by climate change. Rising temperatures and altered precipitation patterns create favourable conditions for vector proliferation and extended transmission periods, increasing the risk of dengue in endemic regions and facilitating its spread to non-endemic areas. Understanding the interplay between critical genetic factors and dengue susceptibility is crucial for developing effective public health strategies. The Human Leukocyte Antigen (HLA) genes encode proteins essential for an effective immune response against pathogens, and their genetic variations influence susceptibility to severe dengue. In this study, we conducted a comprehensive meta-analysis of HLA alleles associated with dengue infection and dengue severity. We analysed 19 case-control studies on dengue infections in populations worldwide to infer HLA associations with various pathological forms of dengue and to examine differences across different populations. Our findings indicate that HLA-A*02 increases susceptibility to dengue fever (DF), while HLA-A*03 increases the risk of Dengue Haemorrhagic Fever (DHF), with these increased susceptibilities primarily observed in Southeast Asian populations. Additionally, HLA-A*24 is associated with DHF and all symptomatic dengue infections (DEN), contributing to dengue risk in both Southeast Asia and the Caribbean. Conversely, HLA-A*33 and HLA-B*44 show a protective effect against DHF but show significant regional heterogeneity, highlighting divergent, population-specific susceptibility profiles. This study underscores the importance of population-specific genetic risk assessments for dengue infection and emphasizes the need for targeted medical interventions and improved predictive models to mitigate dengue's impact, especially as climate change accelerates disease spread.

关键词： OSCC   periodontitis   oral cancer   oral medicine   Lichen Planus   leukoplakia   N plus   lymph node metastases  

摘要： Background Immune cells play a major role in the development and progression of inflammatory and malignant diseases of the oral mucosa. There is growing evidence that immune cells contribute to oral cancer progression and metastases. Inflammatory carcinogenesis is believed to be relevant for oral Lichen Planus as well as for oral Leukoplakia. In addition, there is growing evidence that periodontitis might also be linked to oral cancer development. Yet there is no analysis available comparing the immune cell composition in these different inflammatory and malignant neoplastic diseases. A better understanding of similarities and differences of the diseases could eventually also pave the way for the use of immunotherapy in non-malignant *** In the current pilot study, a tissue microarray (TMA) was created of a total of 29 patients with periodontitis (PD, n=4), oral Leukoplakia (OL, n=4), oral Lichen Planus (OLP, n=4), oral squamous cell cancer without lymphatic metastases (OSCC N0, n=5), or with lymphatic metastases (OSCC N+, n=4), OSCC biopsies prior to and resection specimens after anti-PD1 immunotherapy (IT) (each n=3) as well as healthy control gingiva (n=5). In each patient two tissue samples were analyzed. The TMA was stained with a 4X multiplex immunofluorescent staining for IL-23R, CD68, CD11c, and CD163. Samples were digitalized and an AI-based cell counting was performed. Statistical analysis was performed using the Mann-Whitney U *** IL-23R expression, macrophage infiltration as well as M2 polarization in OL and OLP were significantly higher compared to controls. OLP showed a significantly higher M2 infiltration and polarization than OL. PD showed a trend for increased macrophage infiltration compared to controls without significance. N+ OSCC showed a significantly increased macrophage infiltration compared to N0 cases. In response to anti-PD1 IT, CD11c and CD163 infiltration was significantly increased. Most IL-23R positive cells co-ex

摘要： The interleukin-36 (IL-36) family comprises of three pro-inflammatory receptor agonists (IL-36 alpha, IL-36 beta and IL-36 gamma), two anti-inflammatory receptor antagonists (IL-36RA and IL-38) along with the IL-36 receptor (IL-36R). Part of the IL-1 cytokine superfamily, the IL-36 family was discovered in the early 2000s due to the homology of its member sequences to the IL-1 cytokines. As pro- and anti-inflammatory cytokines, respectively, IL-36 alpha, IL-36 beta, IL-36 gamma and IL-38 aid in maintaining homoeostasis by reciprocally regulating the body's response to damage and disease through IL-36R-associated signalling. With the significant roles of IL-36 alpha, IL-36 beta and IL-36 gamma in regulating the immune response realised, interest has grown in investigating their roles in cancer. While initial studies indicated solely tumour-suppressing roles, more recent work has identified tumour-promoting roles in cancer, suggesting a more complex dual functionality of the IL-36 cytokines. The activity of IL-38 in cancer is similarly complex, with the receptor antagonist displaying distinct tumour-suppressive roles, particularly in colorectal cancer (CRC), in addition to broad tumour-promoting roles in various other malignancies. This review provides a comprehensive overview of the IL-36 and IL-38 cytokines, their activation and IL-36R signalling, the physiological functions of these cytokines, and their activity in cancer.

关键词： Ovarian tumors   IL-35   Serum biomarkers   Cancer  

摘要： IL-35 is known to enhance tumor progression by promoting angiogenesis, increasing cancer cell proliferation, and facilitating immune suppression. Elevated levels of IL-35 have been correlated with the severity of malignancy and clinical stage in various cancers. The aim of this study was to investigate the relationship between serum IL-35 levels and the presence and clinicopathological features of primary benign and malignant ovarian tumors. This case-control study consisted of 60 women diagnosed with primary benign and malignant ovarian tumors and 60 age-matched healthy controls. The demographic and clinicopathological data were also collected. The serum level of IL-35 was evaluated using an ELISA kit, and the results were analyzed using SPSS software. The patients had a mean age of 47.93 +/- 14.52 which was similar to that of the controls (53.43 +/- 11.69) (P = 0.519). The mean serum level of IL-35 was 7.01 +/- 0.843 pg/ml in the control group and 7.24 +/- 0.811 pg/ml in the patient group (P = 0.213). There was no significant difference in serum IL-35 levels between the tumor types (P = 0.991). There was also no significant association between serum IL-35 levels and disease stage (P = 0.559), grade (P = 0.635), lymph node involvement (P = 0.091), or tumor size (P = 0.564). No significant difference in serum IL-35 levels was observed between the patient and control groups, nor was there a significant association between IL-35 levels and tumor characteristics (stage, grade, size, lymph node involvement. However, further studies with more cases at different stages of the disease are necessary.

关键词： Low-carbohydrate diet   Interleukin-6   TNF-alpha   Carbohydrate restriction   Inflammation   Meta-analysis  

摘要： Background Low-carbohydrate diets (LCDs) have been associated with inflammation while there is still conflicting evidence regarding the effects of this type of diet on inflammatory markers and the clinical benefit of them remains uncertain. So, we aimed to ascertain the effects of LCDs on serum concentrations of tumor necrosis factor alpha (TNF-alpha) and interleukin- 6 (IL- 6) by performing a systematic review and meta-analysis of randomized clinical trials (RCTs). Methods The online databases PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Web of Science, and Scopus were comprehensively searched up to February 2024, to find pertinent RCTs. Pooled weighted mean difference (WMD) with 95% confidence intervals (CIs) were calculated using the random-effects model. Results This meta-analysis of 33 studies assessed a total of 2106 adults irrespective of their health status. Compared with control group, participants on LCDs experienced a decline in IL- 6 levels (WMD: - 0.31 pg/mL;95% CI: - 0.49 to - 0.12;P = 0.001). However, no significant effect was revealed for TNF-alpha (WMD: - 0.02 pg/mL;95% CI: - 0.08 to - 0.03;P = 0.449). Stratification analyses indicated that beneficial effects of LCDs on inflammatory cytokines (WMD: - 0.28 pg/mL;95% CI: - 0.47 to - 0.10;P = 0.003, WMD: - 0.26 pg/mL;95% CI: - 0.48 to - 0.03;P = 0.027, for TNF-alpha and IL- 6, respectively) were stronger when carbohydrate intake was < 10%. The results of Meta-regression analyses suggested that baseline level of both markers remained as a strong predictor of the effect size (P = 0.038 and P = 0.001 for TNF-alpha and IL- 6, respectively). Conclusion Adherence to LCDs appeared to be effective at improving inflammatory cytokines particularly, when carbohydrate intake was restricted to less than 10% of total energy. Nevertheless, further rigorously designed clinical trials considering factors such as race and genetic, the sources and quality of dietary carbohydrates, protein, an

关键词： IL1RAP   Acute myeloid leukemia   Surfaceome   Immunotherapy   Cancer   Single cell  

摘要： BackgroundSurface antigens of potential clinical significance remain under-characterized in AML. The European Leukemia Network classifies normal karyotype AML (NK-AML) mutated for NPM1 (NPM1c) as a distinct entity associated with favorable outcomes if not associated with FLT3-ITD mutation. A subset of NPM1c NK-AML shows additional mutations in 2 genes: FLT3 (FLT3-ITD) and DNMT3 A. These leukemias, also referred to as NK triple mutated AML (NKt-AML), are particularly difficult to eradicate with current treatment options. Therefore, novel therapies are necessary that use proteins specifically expressed at the *** order to identify surface antigens for immunotherapy in NKt-AML, an extensive multi-omic analysis was conducted on primary AML samples. Surface proteome enrichment was performed on 100 primary AML samples, twelve of which were NKt-AML. Transcriptome analysis was carried out on the 691 primary AML samples, and single-cell RNA sequencing was conducted on 23 primary AML ***, using multi-omics data from the Leucegene collection, we identify IL1RAP as a promising antigen for this AML subgroup. We demonstrate that IL1RAP is expressed at the surface of primitive AML cells reminiscent of leukemic stem cells in NKt-AML primary human AML specimens, while showing relatively low expression levels in normal bone marrow HSCs. Furthermore, results indicate that elevated IL1RAP expression associates with poor overall and relapse-free survival in the Leucegene cohort of AML patients and predicts nonresponse to hematopoietic stem cell transplantation. Finally, we show that IL1RAP protein is internalized following exposure to specific antibodies, suggesting that IL1RAP represents an interesting target for antibody-drug conjugate development in ***1RAP exhibits preferential expression within NKt-AML, correlating with diminished overall survival rates and diminished responsiveness to hematopoietic stem cell transplantation. Moreov

摘要： T cell immunoglobulin and ITIM domain (TIGIT) is one of the most important immune checkpoints expressed on lymphocytes, and poliovirus receptor (PVR, also CD155) serves as the most crucial ligand for TIGIT, harboring an important function in cancer cells and influencing the tumor microenvironment (TME). While it's well-established that TIGIT blockade could reverse immunosuppression, the question of whether direct inhibition of PVR yields comparable results remains to be fully elucidated. This study investigated the role of PVR within the TME on the LLC, CT26 and MC38 tumor models and found that direct blockade of PVR on tumor cells could trigger T cell activation, enhance the production of immunostimulatory cytokine IFN-gamma, and drive the differentiation of intratumoral myeloid-derived suppressor cells (MDSCs) into pro-inflammatory macrophages through the IFN-gamma-p-STAT1-IRF8 axis. Furthermore, this study found that the anti-PVR nanobody monotherapy reduced tumor volume in the CT26 and MC38 tumor models. Combination of anti-PVR nanobody and anti-PD-1 antibody was effective in the LLC, CT26 and MC38 tumor models and had acceptable toxicity. These findings collectively suggest that PVR exhibits considerable promise as a therapeutic target in the development of immunotherapies aimed at augmenting the anti-tumor immune response.