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关键词： Sonic vibration   interelukin-10   macrophages   lipopolysaccharide   colitis  

摘要： Sonic vibration (SV), or vibroacoustic therapy, is applied to enhance local and systemic blood circulation and alleviate pain using low-frequency sine wave vibrations. However, there is limited scientific data on the mechanisms through which the benefits are achieved. In this study, we investigated the impact of SV on inflammatory responses by assessing cytokine secretion in both in vivo and in vitro models. After inducing inflammatory responses in mice and macrophages, we studied cytokine expression and the symptoms of inflammatory diseases in response to three frequencies (14, 45, or 90 Hz) of SV stimulation at 0.5 m/s2 of amplitude. The results showed that SV at 90 Hz significantly increased interelukin-10 (IL-10) secretion in mice who were administered lipopolysaccharides (LPS) and increased the expression of IL-10 transcripts in peritoneal exudate cells and macrophages. Furthermore, SV at 90 Hz improved LPS-induced lethality and alleviated symptoms in a colitis model. In conclusion, this study scientifically proves the anti-inflammatory effects of vibration therapy through its ability to increase IL-10 expression.

关键词： Biologics   psoriasis   psoriasis treatment   tildrakizumab  

摘要： PurposeTildrakizumab is a selective inhibitor of IL-23 approved for the treatment of moderate-to-severe plaque psoriasis in two dosages. We conducted a 16-week multicenter retrospective study to compare the effectiveness and safety of tildrakizumab 200 mg versus tildrakizumab 100 mg in patients with a high disease burden or high body *** and methodsOur retrospective study included 134 patients treated with tildrakizumab 200 mg and 364 patients treated with tildrakizumab 100 mg from 28 Italian Dermatology Units affected by moderate-to-severe plaque psoriasis. The patients had a body weight above 90 kg or a high disease burden (Psoriasis Area and Severity Index [PASI] >= 16 or the involvement of difficult-to-treat areas). We evaluated the effectiveness of tildrakizumab at the week-16 visit in terms of PASI90, PASI100 and absolute PASI <= *** 16 weeks of treatment with tildrakizumab 200 mg, PASI90 was reached by 57.5% of patients and PASI100 by 39.6% of patients. At the same time point, 34.3% and 24.2% of patients treated with tildrakizumab 100 mg achieved PASI90 and PASI100, *** data suggest that tildrakizumab 200 mg has better effectiveness than tildrakizumab 100 mg in patients with a body weight >= 90 kg and a high disease burden.

关键词： Risankizumab   guselkumab   tildrakizumab   IL-23   hidradenitis suppurativa   vitiligo   alopecia   lichen planus  

摘要： BackgroundWhile IL-23 inhibitors, which include guselkumab, tildrakizumab, and risankizumab, are currently FDA-approved solely for the treatment of psoriasis, several other inflammatory skin conditions have been associated with elevated IL-23 levels. The purpose of this review is to summarize and interpret the literature surrounding the off-label uses of IL-23 inhibitors in dermatologic *** conducted searches on PubMed and *** for clinical trials, observational studies, case series, and case reports assessing use of the three IL-23 inhibitors for non-psoriatic dermatologic *** exhibiting promising response to treatment with IL-23 inhibitors include hidradenitis suppurativa, lichen planus, pityriasis rubra pilaris, pyoderma gangrenosum, dissecting cellulitis of the scalp, congenital ichthyosiform erythroderma, lichen planus pemphigoides, acrofacial vitiligo, lichen planopilaris, frontal fibrosing alopecia, lupus erythematosus tumidus, and Stewart-Treves *** literature suggests that IL-23 inhibitors may be effective in treating these conditions due to shared pathophysiologic pathways with psoriasis. Although these results are promising, further research through large-scale, randomized clinical trials is needed to further evaluate the efficacy and safety of IL-23 inhibitors in treating these off-label conditions.

关键词： Hepatocellular carcinoma   sorafenib   gut microbiota   IFN-gamma(+)CD8(+) T cell   ferroptosis  

摘要： The gut microbiota plays an important role in the development and treatment of hepatocellular carcinoma (HCC). However, the implication of specific gut microbiota in targeted sorafenib therapy for advanced HCC and the microbiota mode of action, remain to be elucidated. Here, we confirmed that four bacterial genera, Lachnoclostridium, Lachnospira, Enterobacter and Enterococcus, are associated with the therapeutic efficacy of Sorafenib, and that Enterobacter faecium (Efm) plays a crucial role in modulating the sorafenib activity. The effective colonization by Emf induced the IL-12 and IFN-gamma production and an increased proportion of IFN-gamma(+)CD8(+) T cells in the tumor microenvironment. Finally, exopolysaccharides (EPS) from Efm were the primary inducer to prompt IFN-gamma(+)CD8(+) T cells to secrete IFN-gamma, which together with sorafenib instigated ferroptosis in HCC cells. Collectively, these results indicate that Efm is a promising probiotics that enhances the efficacy of sorafenib treatment in advanced HCC.

关键词： Antibody   antibody engineering   bispecific   cancer   CRS   cytokine release syndrome   major histocompatibility complex   MHC   T cell engager   TCE  

摘要： T cell engagers (TCEs) are becoming an integral class of biological therapeutic owing to their highly potent ability to eradicate cancer cells. Nevertheless, the widespread utility of classical CD3-targeted TCEs has been limited by narrow therapeutic index (TI) linked to systemic CD4+ T cell activation and aberrant cytokine release. One attractive approach to circumvent the systemic activation of pan CD3+ T cells and reduce the risk of cytokine release syndrome is to redirect specific subsets of T cells. A promising strategy is the use of peptide-major histocompatibility class I bispecific antibodies (pMHC-IgGs), which have emerged as an intriguing modality of TCE, based on their ability to selectively redirect highly reactive viral-specific effector memory cytotoxic CD8+ T cells to eliminate cancer cells. However, the relatively low frequency of these effector memory cells in human peripheral blood mononuclear cells (PBMCs) may hamper their redirection as effector cells for clinical applications. To mitigate this potential limitation, we report here the generation of a pMHC-IgG derivative known as guided-pMHC-staging (GPS) carrying a covalent fusion of a monovalent interleukin-2 (IL-2) mutein (H16A, F42A). Using an anti-epidermal growth factor receptor (EGFR) arm as a proof-of-concept, tumor-associated antigen paired with a single-chain HLA-A *02:01/CMVpp65 pMHC fusion moiety, we demonstrate in vitro that the IL-2-armored GPS modality robustly expands CMVpp65-specific CD8+ effector memory T cells and induces potent cytotoxic activity against target cancer cells. Similar to GPS, IL-2-armored GPS molecules induce modulated T cell activation and reduced cytokine release profile compared to an analogous CD3-targeted TCE. In vivo we show that IL-2-armored GPS, but not the corresponding GPS, effectively expands grafted CMVpp65 CD8+ T cells from unstimulated human PBMCs in an NSG mouse model. Lastly, we demonstrate that the IL-2-armored GPS modality exhibits a favorable d

关键词： HLA   transgenic   animal model   neuroinflammation   Multiple sclerosis  

摘要： It is known that certain human leukocyte antigen (HLA) genes are associated with autoimmune central nervous system (CNS) diseases, such as multiple sclerosis (MS), but their exact role in disease susceptibility and etiopathogenesis remains unclear. The best studied HLA-associated autoimmune CNS disease is MS, and thus will be the primary focus of this review. Other HLA-associated autoimmune CNS diseases, such as autoimmune encephalitis and neuromyelitis optica will be discussed. The lack of animal models to accurately capture the complex human autoimmune response remains a major challenge. HLA transgenic (tg) mice provide researchers with powerful tools to investigate the underlying mechanisms promoting susceptibility and progression of HLA-associated autoimmune CNS diseases, as well as for elucidating the myelin epitopes potentially targeted by T cells in autoimmune disease patients. We will discuss the potential role(s) of autoimmune disease-associated HLA alleles in autoimmune CNS diseases and highlight information provided by studies using HLA tg mice to investigate the underlying pathological mechanisms and opportunities to use these models for development of novel therapies.

关键词： Anti-TNF   Inflammatory bowel disease   Persistence   Ustekinumab   Vedolizumab  

摘要： BACKGROUND/AIMS:The increasing use of biologic therapies for moderate to severe inflammatory bowel disease (IBD) highlights the importance of optimal treatment sequencing, particularly after vedolizumab (VDZ) exposure. Studies comparing the effectiveness of ustekinumab (UST) and antitumor necrosis factor (anti-TNF) agents post-VDZ are limited. METHODS:This retrospective study analyzed VDZ-experienced IBD patients treated with UST or anti-TNF (adalimumab and infliximab) from May 2019 to January 2024. We conducted a comparative analysis of the 52-week treatment persistence between UST and anti-TNF therapies, while also identifying independent predictors that influence 52-week persistence. RESULTS:The study included 110 participants, with 40 diagnosed with ulcerative colitis (UC) and 70 with Crohn's disease (CD). Demographics were comparable across treatment groups. The primary discontinuation reason for VDZ was secondary non-response. Kaplan-Meier analysis revealed that UST demonstrated superior 52-week persistence in overall IBD, CD and UC patients, compared to anti-TNF. Cox regression analysis also showed UST's superiority in overall IBD (HR: 0.15, 95% CI: 0.05-0.45, p < 0.001), CD (HR: 0.09, 95% CI: 0.01-0.68, p = 0.02), and UC (HR: 0.28, 95% CI: 0.08-0.996, p = 0.049). The independent predictors for 52-week treatment persistence are Crohn's disease (Odds Ratio: 7.151, 95% CI: 1.763-28.995, p = 0.006) and UST treatment (Odds Ratio: 7.912, 95% CI: 1.789-34.992, p = 0.006). Notably, UST required more frequent dosing adjustments than anti-TNF, although both treatments exhibited comparable safety profiles. CONCLUSIONS:UST demonstrated superior 52-week treatment persistence in IBD patients previously treated with VDZ compared to anti-TNF agents, albeit with a need for more frequent dose adjustments.

关键词： Drug-induced severe cutaneous adverse reactions   acute generalized exanthematous pustulosis   Steven-Johnson syndrom   toxic epidermal necrolysis   TNF-alpha inhibitors  

摘要： Background: Severe cutaneous adverse reactions (SCARs) including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and its related diseases, and toxic epidermal necrolysis (TEN) are of great concern due to their high mortality rates. While systemic corticosteroids have been widely used to treat SCARs, their efficacy has been debated due to the increased risk of infection. In recent years, tumor necrosis factor (TNF)-alpha inhibitors have emerged as a new therapeutic ***: This study aimed to report the clinical outcomes of different types of SCARs treated with TNF-alpha ***: Since 2020, our department has treated 4 SCAR patients, aged 20-54 years, with 1 diagnosed with AGEP and 3 with TEN. All patients received TNF-alpha inhibitor therapy, including etanercept and ***: All 4 patients achieved successful outcomes, with rapid recovery of skin lesions and mucosal involvement, and no subsequent complications. Notably, one patient improved after initial corticosteroid and intravenous immunoglobulin treatment ***: The pathogenesis of SCARs involves T cell-mediated keratinocyte apoptosis, in which TNF-alpha plays a crucial role. TNF-alpha inhibitors, by downregulating the TNF-alpha signaling pathway, have demonstrated potential in the treatment of SCARs. However, large-scale clinical trials supporting their efficacy are still lacking, and their use remains limited, requiring a careful balance of treatment risks and benefits.

关键词： Candida tropicalis   inflammatory bowel disease   vitamin B3   IL-17A   IL-22   mucosal immunity   epithelial barrier function   epithelial cell proliferation  

摘要： Candida tropicalis-a prevalent gut commensal fungus in healthy individuals - contributes to intestinal health and disease. However, how commensal C. tropicalis influences intestinal homeostasis and barrier function is poorly understood. Here, we demonstrated that the reference strain of C. tropicalis (MYA-3404) ameliorated intestinal inflammation in murine models of chemically induced colitis and bacterial infection. Intestinal colonization of C. tropicalis robustly upregulated the expression of IL-17A and IL-22 to increase barrier function and promote proliferation of intestinal epithelial cells in the mouse colon. Metabolomics analysis of fecal samples from mice colonized with C. tropicalis revealed alterations in vitamin B3 metabolism, promoting conversion of nicotinamide to nicotinic acid. Although nicotinamide worsened colitis, treatment with nicotinic acid alleviated disease symptoms and enhanced epithelial proliferation and Th17 cell differentiation. Oral gavage of C. tropicalis mitigated nicotinamide-induced intestinal dysfunction in experimental colitis. Blockade of nicotinic acid production with nicotinamidase inhibitors lowered the protective effects against colitis in mice treated with C. tropicalis. Notably, a clinical C. tropicalis strain isolated from patients with candidemia lacked the protective effects against murine colitis observed with the reference strain. Together, our results highlight a novel role for C. tropicalis in resolving intestinal inflammation through the modulation of vitamin B3 metabolism.

关键词： Chemotherapy   immunotherapy   myeloid-derived suppressor cells   neutrophils   pancreatic cancer   TNFR2   tumor necrosis factor  

摘要： Pancreatic cancer is characterized by extreme therapeutic resistance. In pancreatic cancers harboring high-risk genomes, we describe that cancer cell-neutrophil signaling circuitry provokes neutrophil-derived transmembrane (tm)TNF-TNFR2 interactions that dictate inflammatory polarization in cancer-associated fibroblasts and T-cell dysfunction - two hallmarks of therapeutic resistance. Targeting tmTNF-TNFR2 signaling may sensitize pancreatic cancer to chemo +/- immunotherapy.