In this Chinese population, CU usually affected youth, and CSU was the most common subtype. Autoreactivity and alcohol consumption were the top two triggers for CU, whereas latent infectious and chronic inflammatory diseases were not as common as in previous reports.

ABSTRACT:A new glutathione adduct (M4) was tentatively identified, likely as 2-hydroxy-3-(glutathione-S-yl)-monoclofenac, using liquid chromatography-tandem mass spectrometry analysis of incubations of diclofenac with human liver microsomes. The same conjugate was not detected in incubations with either rat or monkey liver microsomes. Formation of M4 was mediated specifically by CYP2C9 in human liver microsomes, as evidenced by the following observations: 1) cDNA-expressed CYP2C9-catalyzing formation of M4; 2) inhibition of M4 formation by sulfaphenazole, a CYP2C9-selective inhibitor; and 3) strong correlation between the production of M4 and CYP2C9-mediated tolbutamide 4-hydroxylase activities in a panel of human liver microsome samples. Formation of M4 suggests the existence of a new reactive intermediate as diclofenac-2,3-oxide. A tentative pathway states that diclofenac is oxidized to diclofenac-2,3-oxide that reacts with glutathione (GSH) to form a thioether conjugate at the C-3 position, followed by a concomitant loss of chlorine to give rise to M4. Furthermore, a likely mechanism leading to the formation of diclofenac oxides is rationalized: CYP2C9-catalyzed oxidation at the C-3 position of the dichlorophenyl ring to form a cationic -complex that subsequently results in diclofenac-3,4-oxide and diclofenac-2,3-oxide; the former oxide is converted to 4-hydroxy-diclofenac as a major metabolite and can be trapped by GSH to produce 4-hydroxy-3-glutathione-S-yl diclofenac (M2), whereas the latter oxide forms 3-hydroxy-diclofenac and can be trapped by GSH to produce M4. This mechanism is consistent with the structural modeling of the CYP2C9-diclofenac complex, which reveals that both the C-3 and C-4 of the dichlorophenyl ring are proximate to the heme group.

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This study indicates acute urticaria elicits a more prominent Th2 immune response than CSU. There was association between different expression patterns of plasma Th1-, Th2-, Th17- and Th22-related cytokines and serum autoreactivity or allergen sensitivity in CSU. Further studies on the JAK-STAT pathway in the pathogenesis of CSU are warranted.

Background:Foxp3+ regulatory T (Treg) cells and M2 macrophages are associated with increased tumour progression. However, the interaction between Treg cells and M2 macrophages remains unclear.Methods:The expression of FoxP3 and CD163 was detected by immunohistochemistry in 65 cases of laryngeal squamous cell carcinoma (LSCC). In vitro, the generation of activated Treg (aTreg) cells and M2 macrophages by interactions with their precursor cells were analysed by flow cytometry and ELISA. In vivo, the antitumour effects were assessed by combined targeting aTreg cells and M2 macrophages, and intratumoural immunocytes were analysed by flow cytometry.Results:In LSCC tissue, accumulation of aTreg cells and M2 macrophages predicted a poor prognosis and were positively associated with each other. In vitro, aTreg cells were induced from CD4+CD25− T cells by cancer cell-activated M2-like macrophages. Consequently, these aTreg cells skewed the differentiation of monocytes towards an M2-like phenotype, thereby forming a positive-feedback loop. Combined targeting aTreg cells and M2 macrophages led to potent antitumour immunity in vivo.Conclusions:The positive-feedback loop between aTreg cells and M2 macrophages is essential to maintain or promote immunosuppression in the tumour microenvironment and may be a potential therapeutic target to inhibit tumour progression.

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BackgroundT regulatory cells (Tregs) contribute to the progression of head and neck squamous cell carcinoma (HNSCC) by suppressing antitumor immunity. However, little is known regarding the functional heterogeneity of Tregs in HNSCC patients.MethodsUsing multicolor flow cytometry, the frequency of three Treg subsets, separated on the basis of CD45RA and Foxp3, from the peripheral circulation of newly-presenting HNSCC patients (19 oral cavity squamous cell carcinoma, 20 hypopharyngeal squamous cell carcinoma, 18 nasopharyngeal squamous cell carcinoma, 19 oropharyngeal squamous cell carcinoma, and 36 laryngeal squamous cell carcinoma) were assessed with regard to 31 healthy donors and clinicopathological features. Moreover, the functional capacity of each Treg subsets was evaluated based on CD45RA and CD25 expression.ResultsThe frequency of Tregs in the peripheral circulation of HNSCC patients as a whole cohort was higher than in healthy donors (P < 0.0001). However, the frequency of Tregs was similar between patients with oral cavity squamous cell carcinoma and healthy donors (P = 0.269). Further dividing Tregs into three subsets based on Foxp3 and CD45RA expression revealed that the frequency of CD45RA-Foxp3high Tregs and CD45RA-Foxp3lowCD4+ T cells in patients with HNSCC developing from different subsites was higher than in healthy donors (P < 0.0001, P < 0.0001), whereas the frequency of CD45RA+Foxp3low Tregs was lower than in healthy donors (P < 0.0001). Functionally study revealed that CD45RA-CD25+++ Tregs significantly inhibit the proliferation of CD4+CD25- T cells (P < 0.001) and secrete lower levels of cytokines (P < 0.01) compared with CD45RA-CD25++CD4+ T cells. Importantly, the frequency of CD45RA-Foxp3high Tregs positively correlate with tumor stage (P < 0.0001) and nodal status (P < 0.0001).ConclusionsCD45RA-Foxp3high Tregs increase in the peripheral circulation of HNSCC patients, and correlate with tumor stage and nodal status; suggesting a role in tumor progression which may be manipulated by future immunotherapy.

BackgroundChronic spontaneous urticaria (CSU) is a common skin disorder with etiology that is not well understood.MethodsIn this study, we evaluated the prevalence of autologous serum skin test (ASST) and skin prick testing (SPT) to house dust mite (HDM) in 862 CSU cases in China. Clinical features, courses and treatment responses were also recorded.ResultsThe prevalence of positive ASST was 46.3%, and patients aged 30–39 years had the highest positive rate (52.1%). Positive SPT to HDM was seen in 153 patients (17.7%) with the highest positive rate (34.2%) in patients aged 20 or less. Patients with positive ASST had higher urticaria activity scores (UAS) (4.18±0.65 vs. 3.67±0.53) but lower positive rates of HDM (24.6% vs. 37.6%), as compared with those with negative ASST (odds ratio (OR) 1.84, 95% CI 1.38–2.47). Patients could be categorized into four groups based on the results of ASST and SPT to HDM and patients with positive ASST and positive SPT to HDM had the highest disease activity scores, experienced higher frequencies of angioedema, diseases duration, and required higher dosage of loratadine every month, compared with other subgroups (P<0.0001).ConclusionsPatients with CSU showed varied responses of positive ASST and varied sensitivity to HDM, Patients with positive ASST and/or positive SPT had more disease activity compared with patients with negative ASST and/or negative SPT. Further classification can be made based on the result of SPT and ASST.