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摘要： Sonelokimab is a novel humanized Nanobody (∼40 kDa) with high affinity to IL-17A and IL-17F, designed to penetrate difficult-to-reach tissues and directly target inflammation. The Phase 2 MIRA trial in patients with moderate-to-severe HS met the p...

关键词： Dysgeusia   Taste disorders   Tumor Necrosis Factor-alpha   Antineoplastic agents, Neoplasms  

摘要： Objectives: The aim of this study is to evaluate the role of TNF-alpha by investigating salivary levels and their influence on Dysgeusia in patients undergoing chemotherapy for breast tumors. Design: Clinicopathological and sociodemographic data, taste test results and subjective taste analysis, salivary flow, quality of life, ECOG performance status, body mass index (BMI), body surface area and other side effects were recorded. The saliva obtained was stored at-80 degrees C after addition of the protease inhibitor (Sigma;P2714-1BTLL), salivary TNF-alpha was measured using the TNF-alpha ELISA kit for human (ELH-TNFa-5, RayBio (R)) following the manufacturer's recommendation. The data was analyzed using Kolmogorov-Smirnov, Mann-Whitney, Spearman and Wilcoxon chi-square/Fisher's exact tests with all analyses adopted a 95 % confidence level in the SPSS for Windows software.
Results: The group without dysgeusia (WD) had a longer chemotherapy time than the group with dysgeusia (D) (p <0.001) and a higher frequency of toxicity during CT than the D group (p = 0.012), the mean BMI increased slightly from 28.16 +/- 5.34-28.30 +/- 5.39 (p = 0.016), an increase which only occurred in the WD patients (p = 0.030) and not in the D patients (p = 0.106). There was a correlation with taste parameters, with an inversion between salivary TNF-alpha levels and the taste test (p = 0.033, r =-0.288). In the control group, salivary TNF-alpha concentration was directly correlated with VAS scale scores (p = 0.044, r = 0.266).
Conclusions: The increase in salivary TNF alpha had a direct impact on gustatory tests, and the development of dysgeusia has a negative impact on the quality of life of patients undergoing antineoplastic treatment.

关键词： CD8(+) T cells   high-mobility group protein B1   programmed cell death ligand 1  

摘要： T cells are the most important cytotoxic cells involved in antitumor immune responses. After recognizing the major histocompatibility complex (MHC)-peptide complex, cytokines including interferon-gamma (IFN-gamma) are released to kill tumor cells. However, IFN-gamma can also induce tumor cells to express PD-L1. This molecule can bind to PD-1 on the surface of T cells to exert inhibitory functions. In response to stimuli, like chemoradiotherapy or immunotherapy, tumor cells release damage-associated molecular patterns, including high-mobility group protein B1 (HMGB1). Our previous studies revealed that HMGB1 can increase the antitumor activity of T cells and enhance the secretion of cytokines, including IFN-gamma. However, the effect of HMGB1 on PD-L1 expression in non-small cell lung cancer remains unclear. Here, we examined the expression of HMGB1 and PD-L1 in tumor tissue slices of patients with non-small cell lung cancer with high expression of IFN-gamma and observed that they exhibited a negative correlation, which was also verified by our analysis in The Cancer Genome Atlas. In vitro experiments demonstrated that HMGB1 could bind to RAGE (receptor for advanced glycation end products) and inhibit IFN-gamma induction of PD-L1 by inhibiting the JAK1/STAT3 pathway. In vitro and in vivo experiments indicated that HMGB1 enhanced the antitumor effects of chimeric antigen receptor T cells and inhibited tumor growth. These results showed that HMGB1 inhibited IFN-gamma-induced PD-L1 expression, thereby enhancing the antitumor effects of T cells, and confirmed the role of HMGB1 as a prognostic indicator for lung cancer treated with chimeric antigen receptor T cells.

关键词： CD8 + T cells   Lupus   IL7 receptor   Neutrophils  

摘要： Background This study aims to interrogate the implications of CD8(+) T cells in lupus by examining CD8(+) T cell heterogeneity and assessing the significance of this heterogeneity in promoting inflammation and tissue damage. Methods Our own and publicly available RNA-seq and microarray data from the peripheral blood and kidney tissues of patients with lupus were analysed. Imaging Mass Cytometry (IMC) analysis of immune cells was conducted in lupus and normal kidney tissues. The effects of CD8(+) T cell subsets on neutrophils were evaluated ex vivo. Findings Our scRNA-seq analysis showed an accumulation of effector memory (EM) CD8(+) T cell subsets that expressed low levels of the IL7 receptor gene (IL7R(low)) but high levels of effector molecule genes, including GZMB, GZMK, PRF1, and GNLY, in the peripheral blood and kidneys of patients with lupus. CD8(+) T cell infiltrations and cytotoxic molecule expression in lupus kidney tissues were associated with treatment outcomes, as determined by IMC. The gene signatures of IL7R(low) CD8(+) T cell subsets correlated with type I IFN gene signature in the peripheral blood of paediatric and adult patients with lupus. IL7R(low) EM CD8(+) T cells induced neutrophil extracellular trap (NET), a key inflammatory pathway in lupus pathogenesis, dependently of TNF-alpha and IFN-gamma. Interpretation Our study provides insights into lupus pathogenesis by demonstrating the clinical and biological implications of cytotoxic and inflammatory IL7R(low) EM CD8(+) T cell accumulation in lupus. This raises the prospect of therapeutic targets aimed at such CD8(+) T cells.

关键词： Adipose tissue-derived stem cells   Allergic rhinitis   Regulatory T cells   T helper 17 cells   Interleukin-2  

摘要： Introduction: The aim of the study was to investigate how adipose-derived mesenchymal stem cells regulate the balance between regulatory T (Treg) cells and Th17 cells through the IL-2/JAK-3/STAT-5 signaling pathway in a rat model of allergic rhinitis (AR). Methods: Adipose-derived stem cells (ADSCs) were used to treat an ovalbumin (OVA)-induced AR rat model. The pathological changes and nasal symptoms were observed by HE staining and scanning electron microscopy. The concentrations of OVA-sIgE, IL-10, and IL-17 in serum were measured by enzyme-linked immunosorbent assay (ELISA). The mRNA expressions of JAK-3, STAT-5, forkhead box P3 (Foxp3), and retinoic acid-associated orphan receptor gamma t (ROR gamma t) in nasal mucosa were detected by reverse transcription-polymerase chain reaction (RT-PCR). The expression of IL-2, JAK-3, and STAT-5 proteins in nasal mucosa was detected by Western blotting, and the expression patterns of these proteins were analyzed. Results: ADSCs significantly reduced nasal symptoms and histological abnormalities by significantly reducing the levels of OVA-sIgE, IL-17 and increasing IL-10 levels. The expressions of IL-2, JAK-3, STAT-5, Foxp3, and ROR gamma t in the nasal mucosa of AR rats were abnormal, but ADSCs treatment significantly restored this change. Conclusion: ADSC can control the development of Treg/Th17 cells by the IL-2/JAK-3/STAT-5 signaling pathway and reduce OVA-induced allergic inflammation.

关键词： Resveratrol   Acute lung injury   Excessive autophagy/mitophagy   TNF/NF-kappa B/JNK pathway   DNMT2/TRDMT1  

摘要： Acute lung injury (ALI) is a hypoxic respiratory insufficiency disease characterized by oxidative damage, inflammatory response, and autophagic cell death. Resveratrol (Res) modulates the autophagy activation and excessive autophagy inhibition to counteract oxidative stress, yet the latter mechanism has been vague. Herein, effects and regulatory mechanisms of Res on lung injury, inflammation, and autophagy/mitophagy were explored in lipopolysaccharide (LPS)-stimulated rats and RAW264.7 cells. Transcriptome data exhibited that, Res influenced oxidative stress, inflammation, apoptosis, necroptosis, proliferation, and migration probably through TNF/NF-kB-mediated phagosome and lysosome formations in ALI rats. In subsequent assays, Res significantly reversed the LPS-induced lung injury and mitochondrial dysfunction via activating the SIRT1/PGC-1 alpha pathway. Also, Res reduced LPS-triggered inflammatory cytokines through restraining the TNF/NF-kappa B/JNK pathway. Importantly, Res attenuated excessive LC3/ATG5/p62-mediated autophagy and PINK1/Parkin-adjusted mitophagy, decreasing the autophagic flux by inactivating the NF-kappa B pathway. Thus, Res augmented antioxidative and anti-inflammatory effects most likely through ameliorating the excessive autophagy/mitophagy via two converging pathways (SIRT1/PGC-1 alpha and TNF/NF-kappa B/JNK). Notably, Res down-regulated the DNMT2/ TRDMT1 expression and probably adopted a similar binding pattern with plant flavonoids to block this enzyme. Altogether, these findings will provide a novel mechanism and therapeutic strategy for ALI or related lung diseases by Res-modulated autophagy/mitophagy inactivation and DNMT2/TRDMT1 inhibition.

摘要： Introduction: This post hoc analysis of lutikizumab in HS phase 2 trial evaluates the effect of the IL 1α/1β antagonist lutikizumab on draining tunnels (dTs) in patients with moderate-to-severe HS who have failed anti-TNF therapy. Methods: Adult p...