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关键词： airway   epithelium   paediatrics   TSLP   viral bronchiolitis   virus  

摘要： Thymic stromal lymphopoietin (TSLP) is a primarily epithelial-derived cytokine that drives type 2 allergic immune responses. Early life viral respiratory infections elicit high TSLP production, which leads to the development of type 2 inflammation and airway hyperreactivity. The goal of this study was to examine in vivo and in vitro the human airway epithelial responses leading to high TSLP production during viral respiratory infections in early infancy. A total of 129 infants (<1-24 m, median age 10 m) with severe viral respiratory infections were enrolled for in vivo (n = 113), and in vitro studies (n = 16). Infants were classified as 'high TSLP' or 'low TSLP' for values above or below the 50th percentile. High versus low TSLP groups were compared in terms of type I-III IFN responses and production of chemokines promoting antiviral (CXCL10), neutrophilic (CXCL1, CXCL5, CXCL8), and type 2 responses (CCL11, CCL17, CCL22). Human infant airway epithelial cell (AEC) cultures were used to define the transcriptomic (RNAseq) profile leading to high versus low TSLP responses in vitro in the absence (baseline) or presence (stimulated) of a viral mimic (poly I:C). Infants in the high TSLP group had greater in vivo type III IFN airway production (median type III IFN in high TSLP 183.2 pg/mL vs. 63.4 pg/mL in low TSLP group, p = 0.007) and increased in vitro type I-III IFN AEC responses after stimulation with a viral mimic (poly I:C). At baseline, our RNAseq data showed that infants in the high TSLP group had significant upregulation of IFN signature genes (e.g., IFIT2, IFI6, MX1) and pro-inflammatory chemokine genes before stimulation. Infants in the high TSLP group also showed a baseline AEC pro-inflammatory state characterized by increased production of all the chemokines assayed (e.g., CXCL10, CXCL8). High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity and increased baseline AEC production of pro-inflam

关键词： Maternal high-fat diet   Kiss1 gene   Methylation   Ten-eleven translocation methylcytosine   dioxygenase 2   Interleukin-6  

摘要： Maternal high-fat diet (HFD) is known to impair the reproductive function of female offspring, but the underlying epigenetic mechanisms of this developmental programming remain unclear. In this study, female rats were fed either a control diet (CD;10 % kcal from fat) or an HFD (60 % kcal from fat) prior to and during gestation and lactation. After weaning, female offspring were randomly assigned to continue on either a CD or HFD, resulting in four groups: C/C, C/HF, HF/C, and HF/HF. Maternal HFD significantly reduced primordial follicle numbers, increased follicular atresia and granulosa cell apoptosis, and disrupted sex hormone levels in female offspring at 3 months of age. Female offspring from HFD-fed dams exhibited reduced Kiss1 gene expression and increased promoter methylation in both the ovaries and hypothalami. Additionally, the IL-6/STAT3 pathway was activated, and the expression of Ten-eleven translocation methylcytosine dioxygenase 2 (TET2), a key regulator of DNA demethylation, was downregulated. Post-weaning exposure to a normal diet partially attenuated these effects by 6 months of age. Furthermore, in vitro experiments demonstrated that IL-6/STAT3 signaling downregulated the expression of TET2 and Kisspeptin. Overall, our study demonstrates that maternal HFD consumption reduces TET2 expression in the ovaries and hypothalami of female offspring via the IL-6/STAT3 pathway, leading to Kiss1 promoter hypermethylation and a subsequent decrease in Kisspeptin levels. These findings highlight a potential epigenetic mechanism linking maternal diet to long-term reproductive toxicity in female offspring.

关键词： Interleukin-17   Cardiovascular diseases   Inflammation   Immunotherapy  

摘要： Interleukin-17 (IL-17), a pleiotropic cytokine produced by Th17 cells and innate immune cells, plays a pivotal role in cardiovascular diseases (CVDs) by bridging innate and adaptive immunity. Preclinical studies highlight its pro-inflammatory effects in atherosclerosis, myocardial infarction, hypertension, myocarditis, and heart failure, driving endothelial dysfunction, immune cell infiltration, oxidative stress, and tissue remodeling. Elevated IL-17 levels correlate with vulnerable plaque burden, adverse cardiac events, hypertension severity, and arrhythmogenesis. Paradoxically, IL-17 may stabilize plaques in specific contexts, underscoring its dual roles. Clinical data link IL-17 isoforms (e.g., IL-17A, IL-17E) to coronary artery disease progression and psychological comorbidities. While IL-17-targeted therapies (e.g., monoclonal antibodies) show promise in preclinical models, clinical outcomes remain heterogeneous, with controversies regarding cardiac adverse events (e.g.,coronary artery disease, pericarditis and atrial fibrillation) in autoimmune populations. Mechanistic insights emphasize IL-17's interactions with lipid metabolism, thrombotic pathways, and immune cross-talk. However, conflicting evidence on its protective versus detrimental effects necessitates further translational research. This review underscores the need for rigorous clinical trials to validate IL-17 modulation strategies in CVDs, balancing therapeutic benefits against potential adverse effects.

关键词： Visceral Leishmaniasis   L. donovani   Hypoalbuminemia   Albumin   CEBP-beta   IL-10  

摘要： Visceral leishmaniasis, caused by Leishmania donovani is characterized by clinicopathological features like hepatomegaly with loss of liver function, etc. Albumin is an essential parameter of liver function, performing various tasks like maintaining osmotic balance in blood vessels, preventing tissue fluid leakage, carrier properties, etc. Human VL patients and Leishmania donovani-infected hamsters (ExVL) were tested for their albumin levels. IL-10 derived from Leishmania donovani-infected monocytes and recombinant IL-10 were tested on HepG2 cells for CEBP-(3 and albumin expression with IL-10 blocking and JAK1/STAT3 inhibition. CEBP-(3 binding onto the albumin promoter and its silencing were performed to confirm its role in albumin expression. Low albumin, i. e., hypoalbuminemia, was found in visceral leishmaniasis and ExVL. Its levels were inversely associated with parasitic load and hepatic IL-10 in both models. When treated with Leishmania donovani-driven IL-10 from the infected monocytes and recombinant IL-10, there was a significant decrease in albumin expression from HepG2 cells in a JAK1/STAT3-dependent manner. To further explore the molecular mechanism behind hypoalbuminemia in Visceral leishmaniasis, CEBP-(3, a transcription factor having three isoforms (LAP1, LAP2, and LIP), was shown to increase upon recombinant IL-10 treatment and bind to the D site of the albumin promoter using Chromatin immunoprecipitation PCR. shRNA silencing results confirm CEBP-(3-mediated decrease in albumin levels. Our findings showed that increased hepatic IL-10 upon Leishmania donovani infection reduces albumin levels in a JAK1/STAT3 and CEBP-(3-dependent manner.

关键词： Interferon alpha-2b (IFN alpha 2b), Immunotherapy, JAK-STAT pathway, PEGylation   Probody technology   Dendritic cell vaccines  

摘要： Interferon alpha-2b (IFN alpha 2b) has been a pivotal drug in cancer immunotherapy since its FDA approval in the 1980s, demonstrating both direct and indirect anticancer benefits. It directly triggers cell cycle arrest and death via Bax/Bcl-2 regulation and inhibits angiogenesis, primarily mediated by the JAK-STAT system, which activates over 300 interferon-stimulated genes (ISGs). IFN alpha 2b indirectly increases immune surveillance by augmenting natural killer (NK) cell cytotoxicity, facilitating dendritic cell (DC) maturation, and bolstering T-cell activation, while concurrently inhibiting regulatory T cells (Tregs) and immunosuppressive cytokines such as TGF-(3. Clinically, IFN alpha 2b has shown effectiveness in melanoma, renal cell carcinoma (RCC), and hematologic malignancies. In stage III melanoma, high-dose IFN alpha 2b enhances relapse-free survival, decreasing recurrence by 28 %. RCC exhibits a response to IFN alpha 2b in conjunction with interleukin-2, attaining an 18 % objective response rate, but chronic myelogenous leukemia (CML) demonstrates a 76 % survival rate at 36 months. Combination therapy, particularly those incorporating immune checkpoint inhibitors such as pembrolizumab, have enhanced results in advanced melanoma, with objective response rates of 60 %. Innovations like pegylation (prolonging half-life to 48-72 h) and Probody technology (Pb-IFN alpha 2b) enhance safety and tumor specificity. Nonetheless, obstacles persist, including as dose-limiting toxicities, resistance associated with JAK-STAT dysregulation, and immunosuppressive tumor microenvironments. Innovative approaches like as dendritic cell-based vaccinations, biomarker-driven patient stratification, and sophisticated delivery methods seek to surmount these obstacles. As precision oncology advances, IFN alpha 2b continues to be an essential therapeutic agent, connecting its historical significance with future-oriented immunotherapy.

关键词： CLL   IL-9   STAT3   miR-155   miR-21  

摘要： Following the publication of the above article, an interested reader drew to the authors' attention that, in Fig. 1A on p. 3067, the western blots shown for the STAT3 data in the upper right‑hand gels (for the N3, N4, and C5‑C8 experiments) were strikingly similar to the GAPDH data shown in the lower right‑hand gels (for the C14‑C16 and N6‑N8 experiments). Furthermore, in Fig. 2A on p. 3068, the phosphorylated (p‑)STAT western blots had apparently already appeared in a paper published by the same research group in the journal . After inspecting their original data, the authors realized that the data of interest in Figs. 1 and 2 had inadvertently been chosen incorrectly. The revised and corrected versions of Figs. 1 and 2, now showing replacement data for the upper and lower right‑hand gels in Fig. 1A and the upper three left‑hand panels in Fig. 2A, are shown on the next two pages. Note that the errors made with the assembly of the data in these figures did not affect the overall conclusions reported in the paper. The authors apologize to the Editor of and to the readership for any inconvenience caused. [Oncology Reports 39: 3064‑3072, 2018; DOI: 10.3892/or.2018.6367].

关键词： HLA‐DRB1   NGS   novel allele  

摘要： Three novel HLA-DRB1 alleles were identified during routine next generation sequencing.

关键词： Allergic contact dermatitis   ECM   Lumican   Biglycan   Lymph node   CD4+T cell   Fibroblastic reticular cells   Decorin  

摘要： Allergic contact dermatitis (ACD) is a delayed-type IV hypersensitivity response driven by innate and adaptive immune cells. While specific immune regulations of these cell types are amply elucidated, their regulations by extracellular matrix (ECM) components and T cell mediated adaptive immunity in ACD remains unclear. Lumican and biglycan are ECM proteoglycans abundant in the dermis and lymph node, known to regulate innate immune myeloid cells, but have not been investigated in lymphoid cell regulations in ACD. By immunohistology we localized lumican and biglycan in skin biopsies of psoriatic patients. Using wild type (WT), lumican and biglycan knockout mice, we investigated CD4+T cell infiltration, activation and proliferation in the skin and draining lymph node (dLN) of contact hypersensitivity (CHS)-challenged mice by immunohistochemistry and flow cytometry. We used the OT-II adoptive transfer model to test antigen specific CD4+T cell activation. We assessed interactions of the proteoglycans with LFA-1 on T cells by confocal microscopy. Compared to WTs, the knockouts showed severe ear inflammation, with increased CD4+T cells infiltration in the dermis. CHSchallenged knockout mice dLN showed increased T-bet, STAT1 and -STAT4 signaling, indicating enhanced Th1 commitment and proliferation. We found that WT lymph node fibroblastic reticular cells (FRCs) secrete lumican, biglycan and decorin, a related proteoglycan, while none are expressed by naive or activated T cells. Lumican and biglycan interact with LFA-1 on T cell surfaces, and in vitro all three proteoglycans suppress CD4+T cell activation. Secreted by dLN FRCs, lumican, biglycan, and possibly decorin interact with LFA-1 on CD4+T cells to restrict their activation and reduce dermatitis severity.

关键词： Osteosarcoma   Cannabidiol   NF-kappa B   CCL5   Tumor metastasis  

摘要： Background: Osteosarcoma remains a therapeutic challenge due to its aggressive behavior and high metastatic potential, necessitating exploration of novel treatment modalities. Cannabidiol (CBD), a non-psychoactive phytocannabinoid with emerging anticancer properties, has shown promise in preclinical cancer models. However, its mechanisms of action in osteosarcoma remain incompletely understood. This study systematically investigates the antitumor effects of CBD on osteosarcoma and elucidates its molecular targets within the TNF-alpha/NF-kappa B/CCL5 signaling axis. Methods: The effective concentration of CBD was determined using the CCK-8 assay. Functional assays (EdU proliferation, Transwell migration/invasion, and scratch wound healing) evaluated its impact on osteosarcoma cell malignancy. A mouse xenograft model assessed in vivo efficacy. Network pharmacology and RNA-seq identified key pathways, which were validated via ELISA, qRT-PCR, and western blot. Molecular interactions were confirmed through CETSA, SPR, ITC, and molecular docking analyses targeting p65 (NF-kappa B subunit). Results: CBD potently suppressed osteosarcoma cell proliferation, migration, and invasion while inhibiting xenograft tumor growth in vivo. Mechanistically, CBD disrupted the TNF-alpha/NF-kappa B/CCL5 axis by directly binding p65, thereby attenuating NF-kappa B-mediated transcriptional activation of CCL5. Notably, CBD abrogated a p65-CCL5 positive feedback loop that perpetuates inflammatory signaling, a novel finding linking CBD's effects to inflammatory cascade disruption in osteosarcoma. Conclusion: This study provides the first evidence that CBD inhibits osteosarcoma progression by targeting the TNF-alpha/NF-kappa B/CCL5 axis, disrupting a coordinated inflammatory-proliferative cascade. These findings position CBD as a promising therapeutic candidate for osteosarcoma, warranting further clinical investigation.

关键词： HLA‐B   HLA‐C   NGS   novel allele   synonymous mutation  

摘要： The sequences of HLA-B*07:62:02 and HLA-C*07:02:165 alleles are reported.