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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.

摘要： The cytogenetic risk category retains a pivotal role in the prediction of prognosis in acute myeloid leukemia (AML) patients undergoing hematopoietic stem cell transplantation (HSCT), however, its impact on secondary AML (sAML) is less established. We assessed whether the ELN 2022 cytogenetic risk score predicts outcomes in sAML patients in remission undergoing HSCT from HLA-matched donors performed between 2010 and 2022. Among 1119 patients, 829 had intermediate and 284 had adverse cytogenetics (6 with favorable risk were excluded). Engraftment rates was 72.4% vs. 99.5%. Acute graft-versus-host disease (GVHD) incidence did not differ, but 2-years all grades and extensive chronic GVHD were higher in the intermediate vs. adverse cytogenetics risk groups, hazard ratio (HR) = 0.72;p = 0.034 and HR = 0.58;p = 0.027, respectively. Two-year non-relapse mortality (NRM) was similar. All other HSCT outcomes were inferior in the adverse risk vs. intermediate-risk patients: The HR for 2-year relapse incidence (RI) was 2.48 (95% CI 1.95-3.15, p < 0.001). The HRs for 2-year leukemia-free survival (LFS), overall survival (OS), and GVHD-free/relapse-free survival (GRFS) were 1.62 (95% CI 1.34-1.95, p < 0.001), 1.59 (95% CI 1.3-1.93, p < 0.001) and 1.38 (95% CI 1.15-1.65, p < 0.001), respectively. We conclude that cytogenetic risk score predicts HSCT outcomes in sAML patients.

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].

摘要： Drug effects are difficult to investigate in detail in vivo. However, a mechanistic understanding of drug action is clearly beneficial for both pharmaceutical development as well as for optimization of treatment designs. We here established a quantitative systems pharmacology (QSP) mouse model which simultaneously describes whole-body pharmacokinetics of murine IFN-α as well as the cellular pharmacodynamic effect through the antiviral response biomarker Mx2. To this end, a dynamic model of intracellular IFN-α signalling in the JAK/STAT pathway was combined with a whole-body physiologically-based pharmacokinetic model of IFN-α in mice. The pharmacodynamic behaviour of the resulting mouse IFN-α QSP model was first compared to a cellular model of the JAK/STAT pathway to compare in vitro and in vivo drug effects and to identify functional differences. It was found that the in vitro drug effect in the cellular model overestimates the in vivo response in mice at least by a factor of two which is partly due to the missing drug clearance in vitro. Also, the drug responses in the in vitro model were time delayed. Interspecies analyses in murine and a previously published human QSP model of IFN-α next show a similar dynamic behavior. However, our models demonstrate eight to 16-fold stronger response levels in mice than in humans due to more efficient interferon binding. Our analysis supports a mechanistic analysis of both upstream pharmacokinetic as well as downstream pharmacodynamic drug effects through the combination of physiological knowledge and quantitative computational models. The study hence shows potential applications for QSP modelling in terms of study planning, for example by choosing physiologically relevant in vitro concentrations. Also, the QSP model allows inter-species comparisons of the effect strength in specific functional readouts, which in humans are otherwise not possible due to the limited sampling possibilities. We expect QSP modelling to play an inc

关键词： HLA‐B*46:107   nanopore sequencing   novel allele  

摘要： HLA-B*46:107 differs from HLA-B*46:01:01:01 by one nucleotide substitution at codon 83 in exon 2.

关键词： HLA‐C*05:312   HLA   novel allele   sequencing‐based typing  

摘要： HLA-C*05:312 differs from HLA-C*05:01:01:01 by one nucleotide substitution in codon 308 in exon 5.

关键词： M2 macrophage   alternatively activated macrophage   dendritic epidermal T cell   intraepithelial lymphocyte   wound repair  

摘要： Murine epidermal γδ T cells, known as dendritic epidermal T cells (DETCs), play critical roles in cutaneous wound healing by secreting chemokines, cytokines and growth factors. Although DETCs predominantly produce IL-13 early after activation, the specific role of DETC-derived IL-13 in wound repair remains unknown. Here, we show that periwound DETCs are the primary source of IL-13 at early wound sites (4 h after full-thickness skin wounding). The delayed wound closure in DETC-deficient Tcrd mice was restored by the local application of IL-13 immediately after wounding. Previous studies have demonstrated that macrophages infiltrating the wound granulation tissue undergo a phenotypic shift from iNOS-positive, proinflammatory type to arginase-1-positive, anti-inflammatory type during the late inflammatory phase (3-5 days post injury). At 24 h post wounding, however, most macrophages infiltrating the periwound hypodermis expressed arginase-1. In Tcrd mice, both the number of macrophages in the periwound hypodermis and their arginase-1 expression were significantly reduced. Local IL-13 administration restored arginase-1 expression in the hypodermal macrophages without altering their overall number in Tcrd mice. These results indicate that IL-13 rapidly produced by DETCs upon skin injury plays a critical role in wound healing by inducing arginase-1-positive macrophages in the periwound hypodermis during the early inflammatory phase.

摘要： HLA-G*01:64 differs from HLA-G*01:04:01 by one nonsynonymous nucleotide substitution in codon 107 in exon 2.

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.