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关键词： Cardiotoxicity   Post-transplant cyclophosphamide   Graft-versus host disease   North Japan hematology study group  

摘要： IntroductionPost-transplant cyclophosphamide (PTCy)-based prophylaxis for graft-versus-host disease (GVHD) is widely used in HLA-haploidentical hematopoietic cell transplantation (haplo-HCT). One of the major drawbacks of PTCy is the risk of rare but potentially lethal cardiotoxicity, which prompted the development of regimens with reduced doses of *** retrospectively compared the incidence of early cardiotoxicity with standard-dose of PTCy (cyclophosphamide 50 mg/kg/day for 2 days, PTCy100) versus reduced-dose (40 mg/kg/day for 2 days, PTCy80). In total, 179 patients underwent PTCy-based haplo-HCT, including PTCy100 (n = 111) and PTCy80 (n = 68).ResultsThe PTCy80 group included significantly more elderly patients, patients who received reduced-intensity conditioning, and patients with a history of HCT than the PTCy100 group. Nine eligible patients (5.0%) experienced severe cardiotoxicity. The incidence of severe cardiotoxicity did not differ significant between PTCy80 and PTCy100 (4.4% vs. 5.4%;p = 1). The incidence of fatal cardiotoxicity was lower with PTCy80, but the small size may have prevented the difference from reaching statistical *** the cyclophosphamide dose in PTCy-based GVHD prophylaxis may lower the risk of fatal cardiotoxicity without significantly altering the overall incidence of severe cardiotoxicity.

关键词： ischemic stroke   interleukin 6   biomarker  

摘要： The pathophysiology of a stroke is a complex process involving oxidative stress and inflammation. As a result of the actions of reactive oxygen species (ROS), not only does vascular damage occur, but the brain tissue is also damaged. It is a dynamic process, induced by a cellular-molecular immune response, focused on the development of an immediate reaction. During ischemia, inflammatory mediators are released, among which IL-6 plays a particularly important role in the acute phase of a stroke. Recently, a lot of attention has been devoted to this pleiotropic pro-inflammatory cytokine, which enhances the migration of leukocytes and is controlled by chemokines and the expression of adhesion handlers. The impact of IL-6 on the severity of neurological treatment and on patient prognosis in AIS is of interest to many researchers. More and more data indicate that it may be a reliable prognostic factor in strokes.

关键词： Palmoplantar psoriasis   IL 23   IL 17   drug survival   switch  

摘要： BackgroundThe aim of this study is to confront the effectiveness of anti-IL 17 versus anti-IL 23 mAb in treating palmoplantar psoriasis by comparing the incidence of patients that required a therapy switch to another mAb class. Furthermore, we calculated the mean time intercurrent the beginning therapy with mAbs and the necessity to switch class due to *** design and methodsWe enrolled 116 patients with moderate to severe palmoplantar psoriasis. Patients with the pustular variant were excluded from this study. We performed statistical analysis to calculate the incidence of therapy switch in anti-IL 17 and anti-IL 23 mAb *** results of both univariate and multivariate statistical analysis demonstrated that patients in therapy with anti-IL 23 mAb have a lower incidence of therapy switch compared to patients in therapy with anti-IL 17 drugs. The median switch time is 105 months. No other significant factors predictive of therapy switch were *** real-life evidence confirms the reduced necessity of therapy switch in patients with palmoplantar psoriasis treated with anti-IL 23 antibodies, compared to those treated with IL 17 inhibitors.

摘要： The Interleukin-36 (IL-36) cytokine family have emerged as important players in mounting an inflammatory response at epithelial barriers and tailoring appropriate adaptive immune responses. As members of the Interleukin-1 superfamily, IL-36 cytokines lack a signal peptide for conventional secretion and require extracellular proteolysis to generate bioactive cytokines. Although the IL-36 family plays an important role in the pathogenesis of plaque and pustular psoriasis, little is known about the release mechanisms of these cytokines from keratinocytes and the physiological stimuli involved. Nucleic acid released from damaged or dying keratinocytes initiates early inflammatory signals that result in the breaking of tolerance associated with psoriasis pathogenesis onset. Cathelicidin peptide, LL37 binds to DNA or double-stranded RNA (dsRNA) and activates a type I Interferon responses in plasmacytoid dendritic cells and keratinocytes. Here, we demonstrate that LL37 binds to dsRNA and induces IL-36 gamma release from human primary keratinocytes. LL37/dsRNA complexes activate RIG-I-like Receptor signalling, resulting in Caspase-3 and Gasdermin E (GSDME) cleavage. Subsequent GSDME pore formation facilitates IL-36 gamma release. This response is magnified by priming with psoriasis-associated cytokines, IL-17A and IFN gamma. IL-36 gamma release in this manner is largely independent of cell death in primary keratinocytes and lacked extracellular proteolysis of IL-36 gamma. Conversely, transfection of keratinocytes directly with dsRNA synthetic analogue, Poly(I:C) induces NLRP1 inflammasome activation, which facilitates IL-36 gamma expression and release in a GSDMD-dependent manner. Inflammasome-associated cell death also enables extracellular processing of IL-36 gamma by the release of keratinocyte-derived proteases. These data highlight the distinct responses triggered by dsRNA sensors in keratinocytes. Depending on the inflammatory context and magnitude of the exogenous th

关键词： Peptide   Interleukin-17 receptor   Autoimmunity   Inflammation   Targeted therapy  

摘要： Interleukin-17 receptor A (IL17RA) is a critical mediator of pro-inflammatory cytokine signaling and a key immune checkpoint in autoimmune diseases. While monoclonal antibodies targeting IL17RA have demonstrated clinical efficacy, their high costs, complexity in production, and lack of oral bioavailability present significant limitations. In response to these challenges, we developed AL-8(0), a novel peptide specifically designed to inhibit the IL17A-IL17RA signaling pathway. AL-8(0) was synthesized with high purity and systematically evaluated for its binding affinity and anti-inflammatory activity. Biophysical and cellular assays confirmed the peptide's strong affinity for IL17RA and its ability to inhibit inflammatory cytokine production in IL17RA-expressing monocyte-macrophages and keratinocytes. Moreover, its anti-inflammatory effects were com-parable to IL17RA-targeting monoclonal antibodies and were dependent on IL17RA expression, as demonstrated by experiments using IL17RA-deficient cells. These results underscore AL-8(0)'s potential as a targeted therapeutic for autoimmune diseases, offering a peptide-based alternative with lower antigenicity, improved scalability, and potential for oral administration. This study lays the groundwork for further development of AL-8(0) and similar peptides as innovative treatments for inflammatory disorders driven by the IL17A-IL17RA pathway.

关键词： HIV   inflammation   IL-32   cardiovascular diseases   arterial calcification   atherosclerosis   osteoclasts   osteoblasts   osteoprotegerin   TGF-beta  

摘要： People with HIV (PWH) have an increased risk of developing cardiovascular disease (CVD). Our recent data demonstrated that the multi-isoform proinflammatory cytokine IL-32 is upregulated in PWH and is associated with arterial stiffness and subclinical atherosclerosis. However, the mechanisms by which IL-32 contributes to the pathogenesis of these diseases remain unclear. Here, we show that while the less expressed IL-32 alpha isoform induces the differentiation of human classical monocytes into the calcium-resorbing osteoclast cells, the dominantly expressed isoforms IL-32 beta and IL-32 gamma suppress this function through the inhibition of TGF-beta and induce the differentiation of monocytes into the calcium-depositing osteocalcin+ osteoblasts. These results aligned with the increase in plasma levels of osteoprotegerin, a biomarker of vascular calcification, and its association with the presence of coronary artery subclinical atherosclerosis and calcium score in PWH. These findings support a novel role for the proinflammatory cytokine IL-32 in the pathophysiology of CVD by increasing vascular calcification in PWH.

关键词： Darier disease   IL‐17   acitretin   biologic therapy   brodalumab   case series  

关键词： psoriasis   UVB phototherapy   HLA-class I expression   melanocyte immunogenicity   HLA-C*06:02  

摘要： UVB phototherapy effectively treats psoriasis. Although it suppresses both innate and adaptive immunity, it remains unclear why UVB irradiation is primarily effective for T-cell-mediated but not inflammatory skin diseases of other etiologies. Using a V alpha 3S1/V beta 13S1 T-cell receptor (TCR) from a lesional psoriatic CD8(+) T-cell clone, we recently demonstrated that in psoriasis, the major psoriasis risk allele HLA-C*06:02 mediates an autoimmune response of CD8(+) T-cells against melanocytes by presenting a melanocyte autoantigen. We now investigate the effect of UVB irradiation on melanocyte immunogenicity using the psoriatic V alpha 3S1/V beta 13S1 TCR in a reporter assay. The immunogenicity of melanocytes for the V alpha 3S1/V beta 13S1 TCR depended on the up-regulation of HLA-C expression by IFN-gamma. UVB irradiation reduced the stimulatory capacity of IFN-gamma-conditioned melanocytes for the V alpha 3S1/V beta 13S1 TCR by suppressing key IFN-gamma-induced MHC-class I transcriptional regulators (STAT1, IRF1, NLRC5), the HLA-C-specific transcription factor Oct1, and by inducing miR-148a, which specifically inhibits HLA-C expression. This resulted in the suppression of the IFN-gamma-induced expression of HLA-class I molecules and, in particular, an almost complete loss of HLA-C expression. We conclude that suppression of the inflammatory increase in HLA-class I expression and antigen-presentation may contribute to the efficacy of UVB phototherapy in T-cell-mediated skin diseases. The pronounced downregulation of HLA-C on melanocytes could render psoriasis, as HLA-C-associated disease, particularly susceptible to this effect.

关键词： Superficial dermatomycosis   Severity   Interleukin-1 beta   Toll-like receptor 4   Interleukin-6   Tumor necrosis factor-alpha  

摘要： Objective This study explored the correlation between interleukin-1 receptor/Toll-like receptor (IL-1R/TLRs)-mediated inflammatory signaling pathways and the severity of superficial dermatomycosis. Methods From May 2020 to August 2022, 76 patients with superficial dermatomycosis (infected group) and 52 patients without infection (non-infected group) were enrolled. The indicators related to IL-1R/TLRs pathway were analyzed, and the diagnostic value of the combined detection of each index for superficial dermatomycosis and disease severity was analyzed. The correlation between each index and the severity of infection was analyzed. Results IL-1 beta, TLR4, IL-6, and TNF-alpha in the infected group were higher than those in the non-infected group (P < 0.05). The AUC of IL-1R/TLRs combined detection in the group diagnosed with a superficial dermatomycosis was higher than that of each single detection (P < 0.05). IL-1 beta, TLR4, IL-6, and TNF-alpha in the severe group were higher than those in the mild group (P < 0.05). IL-1 beta, TLR4, IL-6, and TNF-alpha were positively correlated with the degree of infection (P < 0.05). The AUC of IL-1R/TLRs combined detection was higher than that of each single test (P < 0.05). IL-1 beta >= 2.87 ng/L, TLR4 >= 3.12 ng/L, IL-6 >= 4.58 ng/L, TNF-alpha >= 70.53 ng/L were the influencing factors of severe superficial dermatomycosis (P < 0.05). Conclusion IL-1R/TLRs pathway is related to the severity of superficial dermatomycosis, and the collective identification of each indicator provides diagnostic insight into infection severity.