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Asthma is the chronic pulmonary inflammatory response that could lead to respiratory failure when allergic reactions exacerbate. It is featured by type 2 immunity with eosinophilic inflammation, mucus, and IgE production, and Th2 cytokine secretion upon repeated challenge of allergens. The symptom severity of asthma displays an apparent circadian rhythm with aggravated airway resistance in the early morning in patients. Bmal1 is the core regulator of the circadian clock, while the regulatory role of Bmal1 in asthma remains unclear. Here, we investigate whether the myeloid Bmal1 is involved in the pathogenesis of house dust mite (HDM)–induced lung allergy. We found that knockdown of Bmal1 in macrophages suppressed the time-of-day variance of the eosinophil infiltration in the alveolar spaces in chronic asthmatic mice. This was accompanied by decreased bronchial mucus production, collagen deposition, and HDM-specific IgE production. However, the suppression effects of myeloid Bmal1 deletion did not alter the allergic responses in short-term exposure to HDM. The transcriptome profile of alveolar macrophages (AMs) showed that Bmal1-deficient AMs have enhanced phagocytosis and reduced production of allergy-mediating prostanoids thromboxane A2 and prostaglandin F2α synthesis. The attenuated thromboxane A2 and prostaglandin F2α may lead to less induction of the eosinophil chemokine Ccl11 expression in bronchial epithelial cells. In summary, our study demonstrates that Bmal1 ablation in macrophages attenuates eosinophilic inflammation in HDM-induced chronic lung allergy, which involves enhanced phagocytosis and reduced prostanoid secretion. [ABSTRACT FROM AUTHOR]

Background: To identify patients at low risk of synchronous bone metastasis who should not receive bone scans when initially diagnosed with nasopharyngeal carcinoma (NPC). Methods: In total, 6652 patients were enrolled in the training cohort and 1919 patients in the multicenter external validation cohort. Logistic regression analyses were performed to assess independent predictors of synchronous bone metastasis for the nomogram model. Results: After risk stratification, 46.3% (3081/6652) patients were separated into the low‐risk group with an incidence of 0.71% for synchronous bone metastasis. The odds ratio of the intermediate and high‐risk groups was 5.61 and 23.82 times that of the low‐risk group, respectively. For patients with high EBV DNA, we recommend routine screening for N2‐3 female patients, but that all male subgroups are screened. Conclusions: Bone scans should not be routine. Patients in the low‐risk group should not be screened, which would avoid excessive radiation and economize iatrical resource. [ABSTRACT FROM AUTHOR]

Background: To develop a common follow‐up strategy for appropriate imaging examination at an appropriate time for nasopharyngeal carcinoma (NPC). Methods: Independent prognostic factors were identified by Cox regression analysis, and a nomogram model was developed. Random survival forest (RSF) model was constructed to depict probability of disease failure during a 5‐year follow‐up and establish a reasonable risk‐based follow‐up strategy. Results: The nomogram model finally categorized the patients into three risk groups. RSF model demonstrated distribution trends for local and regional recurrences, bone metastasis, liver metastasis, and lung metastasis of NPC. Adequate imaging at follow‐up should be considered between 10 and 21 months for patients at moderate‐risk of recurrence or metastasis and 7–36 months for those at high‐risk. Conclusions: The temporal distribution of incidence rates of recurrence or metastasis varied among different risk groups. We recommend implementing a focused and targeted imaging surveillance intervention at appropriate times to improve its efficiency and reduce costs. [ABSTRACT FROM AUTHOR]

Aims In addition to its involvement of inflammatory responses, limited information is available on the phenotype and behaviour of vascular macrophages during hypertensive vascular remodelling. Here, we aim at studying the contribution of BMAL1 to the pro-fibrotic macrophage phenotype in the vasculature during hypertension, which leads to enhanced vascular remodelling and promoted blood pressure increase. Methods and results Wild type Bmal1f/f and myeloid cell selective Bmal1 knockout Bmal1f/f; LysMCre/+ mice were infused with AngII for 4 weeks to induce hypertension. AngII-induced blood pressure increase, vascular media thickness and vascular dysfunction were enhanced in Bmal1f/f; LysMCre/+ mice, accompanied with a pro-fibrotic M2 phenotype of the vascular macrophages. Bmal1f/f; LysMCre/+ mice also have more up-regulations of MMP9 and MMP13 expression in the vascular wall, accompanied by enhanced collagen deposition after AngII infusion. Loss of Bmal1 in bone marrow-derived macrophages enhanced STAT6 activation induced by IL4, and the subsequent MMP13 up-regulation and activity. In macrophages, loss of Bmal1 enhanced the phosphorylation and nuclear translocation of STAT6 triggered by IL4, through possibly a direct interaction between BMAL1 and STAT6. To further determine whether IL4-induced signalling in macrophage contributes to enhanced vascular remodelling in hypertensive mice, we showed that deletion of myeloid IL4Rα in Il4raf/f; LysMCre/+ mice attenuated blood pressure increase and hypertensive vascular remodelling after AngII infusion. Conclusions Our results suggested a tonic effect of BMAL1 deletion on hypertensive vascular remodelling. BMAL1 might inhibit IL4-STAT6 signalling in macrophages through the interaction with STAT6 to reduce STAT6 activation and target gene transcription, especially MMP9 and MMP13, contributing to vascular remodelling. [ABSTRACT FROM AUTHOR]

Atherosclerosis is initiated by endothelial cell dysfunction and vascular inflammation under the condition of hyperlipidemia. Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+)-dependent mitochondrial deacetylase, which plays a key role in maintaining normal mitochondrial function. The present study tested whether endothelial-selective SIRT3 deletion accelerates vascular inflammation and oxidative stress, and assessed the protective effect of NAD+ to alleviate these changes in endothelial cells and in mouse models of atherosclerosis. We found that the selective deletion of SIRT3 in endothelial cells further impaired endothelium-dependent vasodilatation in the aorta treated with IL-1β, which was accompanied by upregulation of vascular inflammation markers and mitochondrial superoxide overproduction. Excepting the dysfunction of endothelium-dependent vasodilatation, such effects could be attenuated by treatment with NAD+. In human umbilical vein endothelial cells, SIRT3 silencing potentiated the induction of inflammatory factors by IL-1β, including VCAM-1, ICAM-1, and MCP1, and the impairment of mitochondrial respiration, both of which were alleviated by NAD+ treatment. In ApoE-deficient mice fed with a high-cholesterol diet, supplementation with nicotinamide riboside, the NAD+ precursor, reduced plaque formation, improved vascular function, and diminished vascular inflammation. Our results support the SIRT3-dependent and -independent of NAD+ to improve endothelial function in atherosclerosis. [ABSTRACT FROM AUTHOR]

Ppardδ, one of the lipid‐activated nuclear receptor expressed in many cell types to activate gene transcription, also regulates cellular functions other than lipid metabolism. The mechanism regulating the function of antigen‐presenting cells during the development of atherosclerosis is not fully understood. Here we aimed to study the involvement of PPARδ in CD11c+ cells in atherosclerosis. We used the Cre‐loxP approach to make conditional deletion of Ppard in CD11c+ cells in mice on Apoe–/– background, which were fed with high cholesterol diet to develop atherosclerosis. Ppard deficiency in CD11c+ cells attenuated atherosclerotic plaque formation and infiltration of myeloid‐derived dendritic cells (DCs) and T lymphocytes. Reduced lesion was accompanied by reduced activation of dendritic cells, and also a reduction of activation and differentiation of T cells to Th1 cells. In addition, DC migration to lymph node was also attenuated with Ppard deletion. In bone marrow‐derived DCs, Ppard deficiency reduced palmitic acid‐induced upregulation of co‐stimulatory molecules and pro‐inflammatory cytokine IL12 and TNFα. Our results indicated PPARδ activation by fatty acid resulted in the activation of myeloid DCs and subsequent polarization of T lymphocytes, which contributed to atherosclerosis in Apoe–/– mice. These findings also reveal the potential regulatory role of PPARδ in antigen presentation to orchestrate the immune responses during atherosclerosis. [ABSTRACT FROM AUTHOR]