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BACKGROUND: Health problems associated with shift work and night shift work are gaining increasing public attention. OBJECTIVE: To investigate the association between night shift work and the hazard of mortality. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 283,579 individuals with paid employment or self-employment aged 37-73 years were included from the UK Biobank with a median follow-up period of 14.0 years. MAIN MEASURES: Participants were divided into day workers and shift workers, including the frequency of night shifts, to evaluate the association between baseline work schedules and all-cause and cause-specific mortality using the Cox proportional hazards model. Additionally, 75,760 participants with work histories were assessed for the association between average frequency and cumulative years of exposure to night shift work and all-cause and cause-specific mortality. KEY RESULTS: Compared with that of day workers, the adjusted hazard of all-cause mortality was increased by 12.0% (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.07-1.18) in shift workers, particularly in those with no or rare night shifts (approximately 16.1%; HR, 1.16; 95% CI, 1.08-1.25) and those with irregular night shifts (approximately 9.2%; HR, 1.09; 95% CI, 1.00-1.19). Moreover, a non-linear relationship was identified between cumulative night shift years and all-cause and cause-specific mortality. Only individuals who worked night shifts for 20-30 years exhibited a substantially increased hazard of all-cause (HR, 1.52; 95% CI, 1.15-2.00) and cardiovascular disease (CVD; HR, 2.08; 95% CI, 1.16-3.71) mortality. CONCLUSIONS: Shift workers, particularly those with rare or irregular night shifts, exhibited an increased hazard of mortality. Additionally, participants who worked night shifts for 20-30 years exhibited a substantially increased hazard of all-cause and CVD mortality.
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The inflammatory response plays a crucial role in determining the prognosis and therapeutic response of skin cutaneous melanoma (SKCM). However, the molecular subtypes based on the inflammatory response and their clinical significance in SKCM have not been extensively studied. Clustering analyses to identify inflammation subtypes of SKCM based on the expression levels of inflammation response gene. We identified three subtypes: Inflammation_H, Inflammation_M, and Inflammation_L, which offer a more nuanced understanding of the complex relationship between inflammation and SKCM. The Inflammation_H subtype is associated with the most favourable prognosis, and is characterised by high levels of immune infiltrates and PD-L1 expression, low levels of stemness, high differentiation, and high genomic stability. In contrast, the Inflammation_L subtype has the least favourable prognosis, with the lowest levels of immune infiltrates and PD-L1 expression, high levels of stemness, low differentiation, and low genomic stability. In addition, the Inf-score, which is a linear risk scoring model based on the expression levels of inflammatory response genes, can be a useful tool for clinicians to assess SKCM prognosis and guide therapeutic decisions. This scoring model shows promise for clinical use in predicting patient outcomes and helps clinicians tailor treatments for individual patients. In conclusion, these findings represent a significant contribution to our understanding of the molecular subtypes of SKCM based on the levels of inflammatory response genes and their potential clinical significance. However, further studies are necessary to validate these findings and explore the underlying mechanisms of different subtypes.
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Psoriasis is a highly prevalent chronic disease associated with a substantial social and economic burden. Oxeiptosis is a programmed cell death that occurs when cells are in a state of high oxidative stress, which has a potent anti-inflammatory effect. However, there is still no research on oxeiptosis in psoriasis, and the agonists or antagonists of oxeiptosis remain an unclear field. Here, we found that oxeiptosis of keratinocytes was inhibited in psoriasis lesions. KEAP1, as the upstream molecular component of oxeiptosis, is highly expressed in psoriasis lesions. Knockdown of KEAP1 in HaCaT cells caused oxeiptosis in the condition of M5 cocktail stimulation. Next, we found that the cell-permeable derivative of itaconate, 4-octylitaconate (OI) promoted oxeiptosis of keratinocytes by inhibiting KEAP1 and then activating PGAM5 which are two upstream molecular components of oxeiptosis. At the same time, OI can reduce the expression of inflammatory cytokines induced by M5 cocktail stimulation in vitro. Similarly, we found that OI can alleviate IMQ-induced psoriatic lesions in mice and downregulate the levels of inflammatory cytokines in psoriatic lesions. In summary, our findings suggest that oxeiptosis of keratinocytes was inhibited in psoriasis and OI can significantly inhibit inflammation and alleviate psoriasis as an agonist of oxeiptosis, indicating that oxeiptosis may be involved in regulating the progression of psoriasis, which may provide new therapeutic targets for psoriasis treatment.
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Factor 2 Relacionado con NF-E2 , Psoriasis , Humanos , Animales , Ratones , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Psoriasis/inducido químicamente , Inflamación/tratamiento farmacológico , Queratinocitos , Citocinas/metabolismoRESUMEN
Introduction: Psoriasis is a chronic inflammatory disease of the skin. A few studies have shown that psoriasis is an immune-mediated disease in which multiple immune cells play crucial roles. However, the association between circulating immune cells and psoriasis remains elusive. Methods: To explore the role of circulating immune cells in psoriasis, 361,322 individuals from the UK Biobank (UKB) and 3,971 patients with psoriasis from China were included to investigate the association between white blood cells and psoriasis via an observational study. Genome-wide association studies (GWAS) and Mendelian randomization (MR) were used to evaluate the causal relationship between circulating leukocytes and psoriasis. Results: The risk of psoriasis increased with high levels of monocytes, neutrophils, and eosinophils (relative risks and 95% confidence intervals, respectively: 1.430 (1.291-1.584) for monocytes, 1.527 (1.379-1.692) for neutrophils, and 1.417 (1.294-1.551) for eosinophils). Upon further MR analysis, eosinophils showed a definite causal relationship with psoriasis (odds ratio of inverse-variance weighted: 1.386, 95% confidence intervals: 1.092-1.759) and a positive correlation with the psoriasis area and severity index (PASI) score (P = 6.6 × 10-5). The roles of the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) in psoriasis were also assessed. More than 20,000 genetic variations associated with NLR, PLR, and LMR were discovered in a GWAS analysis using the UKB data. Following adjustment for covariates in the observational study, NLR and PLR were shown to be risk factors for psoriasis, whereas LMR was a protective factor. MR results indicated that there was no causal relationship between these three indicators and psoriasis; however, NLR, PLR, and LMR correlated with the PASI score (NLR: rho = 0.244, P = 2.1 × 10-21; PLR: rho = 0.113, P = 1.4 × 10-5; LMR: rho = -0.242, P = 3.5×10-21). Discussion: Our findings revealed an important association between circulating leukocytes and psoriasis, which is instructive for the clinical practice of psoriasis treatment.
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Estudio de Asociación del Genoma Completo , Psoriasis , Humanos , Leucocitos , Psoriasis/genética , Monocitos , CausalidadRESUMEN
Immune checkpoints blockades have shown promising clinical effects in various malignancies, but the overall response rate is low. Here, the immune features are comprehensively characterized in >10 000 cancer patients from The Cancer Genome Atlas and significantly positive correlations are observed between targets of Sunitinib and inhibitory immune checkpoints and suppressive immune cells. It is further confirmed that Sunitinib treatment increases the antitumor immunity in a phase III trial. Mechanistically, it is discovered that Sunitinib regulates the stability of tumor PD-L1 via p62, that p62 can bind to PD-L1 and specifically promote its translocation into autophagic lysosome for degradation. Preclinically, Sunitinib shows a synergistic antitumor effect with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody (mAb) in melanoma and nonsmall cell lung cancer (NSCLC) immune competent mice by promoting the tumor-infiltrating lymphocytes activity. Clinically, a higher PD-L1 level but a lower p62 level in the tumor region of responders as compared to those of nonresponders among anti-PD-1-treated NSCLC patients is observed. Taken together, by utilizing rigorous computational analysis, functional characterization in vitro and in vivo, and neoadjuvent clinical trial, a novel molecular mechanism is revealed regarding the regulation of PD-L1 via p62, thus providing a novel therapeutic strategy by the combination treatment of CTLA-4 with Sunitinib.
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BACKGROUND: Immune checkpoint blockade (ICB) therapy has demonstrated considerable clinical benefit in several malignancies, but has shown favorable response in only a small proportion of cancer patients. Recent studies have shown that matrix metalloproteinases (MMPs) are highly associated with the microenvironment of tumors and immune cells. However, it is unknown whether MMPs are involved in immunotherapy. METHODS: Here, we used integrative analysis to explore the expression landscape of the MMP family and its association with immune features across multiple cancer types. We used T cell cytotoxicity-mediated tumor killing assay to determine the co-cultured T cell activity of SB-3CT, an MMP2/9 inhibitor. We then used in vitro assays to examine the regulating roles of SB-3CT on PD-L1. We further characterized the efficacy of SB-3CT, in combination with anti-PD-1 and/or anti-CTLA4 treatment in mouse models with melanoma and lung cancer. RESULTS: Our computational analysis demonstrated a strong association between MMP2/9 and immune features. We demonstrated that inhibition of MMP2/9 by SB-3CT significantly reduced the tumor burden and improved survival time by promoting anti-tumor immunity. Mechanistically, we showed that SB-3CT treatment significantly diminished both mRNA and protein levels of PD-L1 in cancer cells. Pre-clinically, SB-3CT treatment enhanced the therapeutic efficacy of PD-1 or CTLA-4 blockade in the treatment of both primary and metastatic tumors. CONCLUSIONS: Our study unraveled novel molecular mechanisms regarding the regulation of tumor PD-L1 and provided a novel combination therapeutic strategy of SB-3CT and ICB therapy to enhance the efficacy of immunotherapy.
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Antígeno B7-H1/genética , Compuestos Heterocíclicos con 1 Anillo/farmacología , Vigilancia Inmunológica/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Sulfonas/farmacología , Animales , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Linfocitos/inmunología , Linfocitos/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Melanoma Experimental , Ratones , Microambiente TumoralRESUMEN
Here, we show that tumor ADORA1 deletion suppresses cell growth in human melanoma cell lines in vitro and tumor development in vivo in immune-deficient xenografts. However, this deletion induces the upregulation of PD-L1 levels, which inactivates cocultured T cells in vitro, compromises anti-tumor immunity in vivo, and reduces anti-tumor efficacy in an immune-competent mouse model. Functionally, PD-1 mAb treatment enhances the efficacy of ADORA1-deficient or ADORA1 antagonist-treated melanoma and NSCLC immune-competent mouse models. Mechanistically, we identify ATF3 as the factor transcriptionally upregulating PD-L1 expression. Tumor ATF3 deletion improves the effect of ADORA1 antagonist treatment of melanoma and NSCLC xenografts. We observe higher ADORA1, lower ATF3, and lower PD-L1 expression levels in tumor tissues from nonresponders among PD-1 mAb-treated NSCLC patients.