Background Estrogen/estrogen receptor signaling influences the tumor microenvironment and affects the efficacy of immunotherapy in some tumors, including melanoma. This study aimed to construct an estrogen response-related gene signature for predicting response to immunotherapy in melanoma. Methods RNA sequencing data of 4 immunotherapy-treated melanoma datasets and TCGA melanoma was obtained from open access repository. Differential expression analysis and pathway analysis were performed between immunotherapy responders and non-responders. Using dataset GSE91061 as the training group, a multivariate logistic regression model was built from estrogen response-related differential expression genes to predict the response to immunotherapy. The other 3 datasets of immunotherapy-treated melanoma were used as the validation group. The correlation was also examined between the prediction score from the model and immune cell infiltration estimated by xCell in the immunotherapy-treated and TCGA melanoma cases. Results “Hallmark Estrogen Response Late” was significantly downregulated in immunotherapy responders. 11 estrogen response-related genes were significantly differentially expressed between immunotherapy responders and non-responders, and were included in the multivariate logistic regression model. The AUC was 0.888 in the training group and 0.654–0.720 in the validation group. A higher 11-gene signature score was significantly correlated to increased infiltration of CD8+ T cells (rho=0.32, p=0.02). TCGA melanoma with a high signature score showed a significantly higher proportion of immune-enriched/fibrotic and immune-enriched/non-fibrotic microenvironment subtypes (p<0.001)–subtypes with better response to immunotherapy–and significantly better progression-free interval (p=0.021). Conclusion In this study, we identified and verified an 11-gene signature that could predict response to immunotherapy in melanoma and was correlated with tumor-infiltrating lymphocytes. Our study suggests targeting estrogen-related pathways may serve as a combination strategy for immunotherapy in melanoma.
Neurotrophin receptor-interacting MAGE homolog (NRAGE) has been considered as a tumor suppressor. In the previous study, we established human esophageal carcinoma resistance cell line TE13R120 and found the difference of NRAGE expression between TE13 and TE13R120 cells by gene microarray. Herein, we further discuss the possible molecular mechanism of NRAGE on participating the radiation sensitivity of esophageal carcinoma cells.We used colony formation assay to measure the surviving fraction and relevant radiobiological parameters. NRAGE expression was estimated by immunofluorescence and Western blot. Tumor growth factor-β (TGF-β) was used for inducing epithelial-mesenchymal transition (EMT) in TE13 cells to detect the relationship between NRAGE and EMT; the capacity of cell migration was also assessed by wound healing assay.TE13R120 cells were showed significantly radioresistance compared with TE13. The D0, Dq, and N value of TE13R120 were all higher than those of TE13 (2.499, 1.991, and 2.219 vs. 2.242, 0.854, and 1.645), as well as SF2 (0.734 vs. 0.538). Results of immunofluorescences showed that NRAGE was mainly expressed in the nucleus of TE13R120 cells, but in TE13 cells, it was mainly in cytoplasm. In addition, EMT phenotype was observed in TE13R120 cells and TGF-β-induced EMT in TE13 cells, E-cadherin expression was decreased, but vimentin was upregulated. Furthermore, TE13 cells have a rising tendency in NRAGE nucleus expression after treatment with TGF-β. Results of wound healing assay showed that the cell migration of TE13R120 and TGF-β-induced EMT in TE13 cells were remarkably enhanced.Our results indicate that NRAGE subcellular localization is related to radiation resistance of esophageal carcinoma cell and EMT may be involved in NRAGE subcellular location.
Abstract Background Individuals residing in underdeveloped rural settings may have a higher prevalence of chronic non-communicable diseases (NCDs), lower level of health-related quality of life (HRQoL), and distinct lifestyles. However, this triadic association remains inadequately studied and understood, particularly regarding the role played by health lifestyle. Yunnan province, as a typical underdeveloped region in China, is also witnessing population aging, with NCDs emerging as primary factors influencing both health status and HRQoL among middle-aged and older adults. This study aims to examine the relationship between the number of NCDs and HRQoL while exploring the potential moderating effect of health lifestyle among middle-aged and older adults residing in resource-limited areas. Methods This cross-sectional study was conducted in Yunnan province from July to December 2022. Spearman’s correlation test and Pearson’s correlation test were employed to examine the pairwise correlations among the number of NCDs, HRQoL, and health lifestyle. Hierarchical linear regression analysis was performed to explore the relationship between the number of NCDs and HRQoL, as well as investigate the potential moderating effect of health lifestyle on this relationship. Results Out of the total 2,704 participants, 57.91% presented with at least one NCD. The mean score for health lifestyle and health utility value were calculated as 11.109 and 0.944 respectively. A significant negative association was observed between the number of NCDs and health utility value, while a positive correlation was found between the number of NCDs and health lifestyle score. Health lifestyle exerted a moderating effect on the relationship between the number of NCDs and HRQoL ( β = 0.006, P < 0.001), which was also observed for specific health-related behaviors such as sleep duration ( β = 0.013, P < 0.001), physical examination attendance ( β = 0.006, P < 0.05) and physical activity ( β = 0.013, P < 0.001). Conclusions The study highlights that a healthy lifestyle exerts a crucial role in moderating the association between the number of NCDs and HRQoL. Considering the high prevalence of NCDs and substantial decline in HRQoL among middle-aged and older adults, recognizing the potential influence of a healthy lifestyle as a moderator in this relationship could be pivotal for developing effective interventions for this population, even within resource-constrained rural settings.
Redox homeostasis contributing to the maintenance of normal cellular physiological states. On the contrary, off-kilter redox as a resolution member in the production of cardiovascular disease, rheumatoid arthritis, and even cancer. To date, a few reports have focused on ratiometric sustainable assays for ClO - and GSH cycling due to the headache of transient reactivity, ultra-low concentrations and short lifetimes. However, methods for the design of ratiometric fluorescent probes also need to be further expanded. In this paper, we present a novel approach to the construction of ratiometric fluorescent probes via controlled modification of polysiloxane backbones. We aimed at the controlled assembly of a biocompatible, more pliable and stable “Si-O-Si” bridging framework, “red gene” perylenetetracarboxylic anhydride and “green gene” molecular sensors, successfully constructing a dual-excitation, dual-emission ratiometric fluorescent probe ( PBN-1 ) with favorable biosafety properties, excellent photostability and promising sensitivity. PBN-1 sustainability dynamically tracked ClO - /GSH oxidation fluctuations in HepG2 cells and zebrafish. Notably, PBN-1 distinguished dramatically the fluctuations of ClO - /GSH in zebrafish at different growth and developmental periods. We expect that PBN-1 could provide an effective method for the design of future ratiometric fluorescent probes and expand the application of polysiloxanes in bioimaging.
Metastasis is the primary cause of death in patients with breast cancer. Although VEGF-A, C and D are considered to be prime factors in lymph node metastasis in breast cancer, the published studies have conflicting conclusions.To resolve this conflict, we conducted a meta-analysis of 37 studies (n = 5,001 patients) evaluating the correlation between VEGF-A, C and D immunohistochemical expression and lymph node metastasis (LNM). The meta-analysis included 22 studies of VEGF-A, 17 of VEGF-C, and 6 of VEGF-D. The relationships between VEGF-A, C and D and clinicopathological parameters were also examined.The results showed a significant association between VEGF-A or VEGF-C overexpression and LNM (risk ratio [RR] = 1.28 [95% CI 1.04-1.58], p = 0.02; and RR = 1.36 [95% CI 1.07-1.72], p = 0.01, respectively). Subgroup evaluation showed a significant association between VEGF-A, C and D overexpression and LNM when analyses were limited to Asian patients (RR = 1.78 [95% CI 1.28-2.46], p = 0.0005; RR = 1.38 [95% CI 1.04-1.84], p = 0.03, and RR = 2.62 [95% CI 1.35-5.09], p = 0.004, respectively). VEGF-A overexpression was significantly associated with lymph vessel invasion (RR = 1.86 [95% CI 1.33-2.60], p = 0.0003). Overexpression of VEGF-C or VEGF-D was significantly associated with HER-2 positivity (RR = 1.30 [95% CI 1.06-1.59], p = 0.01; and RR = 1.75 [95% CI 1.01-3.03], p = 0.05, respectively).With some limitations, our meta-analysis indicated that VEGF-A and C could predict LNM in patients with breast cancer, particularly Asian patients.
Hyperlipidemia (HLP) is a complex pathological condition results from lipid metabolism disorder, which is closely related to obesity, atherosclerosis and steatohepatitis. Emodin (EM), a natural anthraquinone, exhibits prominent hypolipidemic effects. However, its exact mechanism is still unclear. In this study, we successfully established hyperlipidemic zebrafish model induced by 4 % high-cholesterol diet (HCD) for 10 days and explored the anti-hyperlipidemic roles and underlying mechanisms of EM. The results indicated that EM attenuated the mortality and body mass index (BMI) of zebrafish with HLP, and ameliorated abnormal lipid levels involved in TC, TG, LDL-C and HDL-C levels. Besides, EM effectively reduced lipid accumulation in blood vessels and liver, alleviated hepatic histological damage, and inhibited vascular neutrophil inflammation. Finally, the mRNA expression of molecules related to lipid metabolism were studied by using real-time quantitative polymerase chain reaction (RT-qPCR) to investigated the underlying mechanism. Further results found that treatment with EM up-regulated AMPKα, LDLR, ABCA1 and ABCG1, and down-regulated SREBP-2, PCSK9 and HMGCR expression. In conclusion, EM showed a prominent mitigative effect on lipid metabolism disorder in zebrafish larvae with HCD-stimulated HLP, which was associated with the enhancement of LDL-C uptake and reverse cholesterol transport, and inhibition of cholesterol synthesis.
Triple-negative breast cancer (TNBC) is a significant cause of patient morbidity. The exactly pathobiological features of this condition has yet to be completely elucidated.Breast cancer data obtained from The Cancer Genome Atlas (TCGA) database were evaluated for lncRNA SNHG6 expression. Normal human breast epithelial cell line (MCF-10A) and other breast cancer cell lines (BT-549, MDA-MB-231, Hs 578t, ZR-75-30, SK-BR-3, MCF-7) were also assessed for lncRNA SNHG6 expressions. Cellular proliferative ability was evaluated with colony formation and CCK-8 assays. The ability of cells to migrate was scrutinized with the wound healing and Boyden chamber cell migration assays. qRT-PCR enabled for detection of lncRNA SNHG6, miR-125b-5p and BMPR1B mRNA expressions. Protein BMPR1B expressions were further assessed using Western Blotting. Direct binding sites between transcripts were determined using dual-luciferase reporter assays. We also constructed a xenograft mouse model to further dissect the vivo implications of lncRNA SNHG6. Ki-67 and c-Caspase-3 expressions were detected using immunohistochemistry staining.Breast cancer cell lines demonstrated higher lncRNA SNHG6 expressions, particularly TNBC cell lines, in contrast to normal breast epithelial cell lines. This finding coincided with those noted on analysis of TCGA breast cancer data. lncRNA SNHG6 knockdown inhibited TNBC cell proliferation, migration, while promoted cell apoptosis. Furthermore, suppressed lncRNA SNHG6 expressions resulted in lower tumor weights and volumes in a xenograft mouse model, as evidenced by Ki-67 and c-Caspase-3 expression profiles in tumor tissues. miR-125b-5p and lncRNA SNHG6/BMPR1B both possessed direct binding sites for each other which was validated utilizing a dual-luciferase reporter assay. Decreasing lncRNA SNHG6 expression in TNBC cells upregulated miR-125b-5p expression. Another side, inhibiting miR-125b-5p upregulated BMPR1B expression in these cells. Moreover, knocking down lncRNA SNHG6 downregulated BMPR1B expression in TNBC cells, and the finding was rescued in cells which were exposed to miR-125b-5p inhibitor. Downregulating miR-125b-5p mitigated the effect of suppressing lncRNA SNHG6 on TNBC cell proliferation, migration, and apoptosis.Downregulation of lncRNA SNHG6 could inhibit TNBC cell proliferative, migratory capabilities and promote apoptosis capability, likely through modulation of the miR-125b-5p/BMPR1B axis. This axis may be targeted in formulating new therapies for TNBC.
An increasing number of studies have suggested that traumatic brain injury (TBI) is associated with some neurodegenerative diseases, including Alzheimer's disease (AD). Various aspects of the mechanism of TBI-induced AD have been elucidated. However, there are also studies opposing the view that TBI is one of the causes of AD. In the present study, we demonstrated that TBI exacerbated the disruption of hippocampal-dependent learning and memory, worsened the reductions in neuronal cell density and synapse formation, and aggravated the deposition of Aβ plaques in the hippocampi of APP/PS1 mice. We also found that TBI rapidly activated microglia in the central nervous system (CNS) and that this effect lasted for at least for 3 weeks. Furthermore, TBI boosted Aβ-related microglia-mediated neuroinflammation in the hippocampi of APP/PS1 mice and the transformation of microglia toward the proinflammatory phenotype. Therefore, our experiments suggest that TBI accelerates the onset of cognitive dysfunction and Alzheimer-like pathology in the APP/PS1 mouse model, at least partly by altering microglial reactions and polarization.
Abstract Background Leiomyosarcoma (LMS) is one of the most common soft tissue sarcomas. LMS is prone to distant metastasis (DM), and patients with DM have a poor prognosis. Aim In this study, we investigated the risk factors of DM in LMS patients and the prognostic factors of LMS patients with DM. Methods and results LMS patients diagnosed between 2010 and 2016 were extracted from the Surveillance, Epidemiology, and End Result (SEER) database. Patients were randomly divided into the training set and validation set. Univariate and multivariate logistic regression analyses were performed, and a nomogram was established. The area under the curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the nomogram. Based on the nomogram, a web‐based nomogram is established. The univariate and multivariate Cox regression analyses were used to assess the prognostic risk factors of LMS patients with DM. Eventually, 2184 patients diagnosed with LMS were enrolled, randomly divided into the training set (n = 1532, 70.14%) and validation set (n = 652, 29.86%). Race, primary site, grade, T stage, and tumor size were correlated with DM incidence in LMS patients. The AUC of the nomogram is 0.715 in training and 0.713 in the validation set. The calibration curve and DCA results showed that the nomogram performed well in predicting the DM risk. A web‐based nomogram was established to predict DM's risk in LMS patients ( https://wenn23.shinyapps.io/riskoflmsdm/ ). Epithelioid LMS, in uterus, older age, giant tumor, multiple organ metastasis, without surgery, and chemotherapy had a poor prognosis. Conclusions The established web‐based nomogram ( https://wenn23.shinyapps.io/riskoflmsdm/ ) is an accurate and personalized tool to predict the risks of LMS developing DM. Advanced age, larger tumor, multiple organ metastasis, epithelioid type, uterine LMS, no surgery, and no chemotherapy were associated with poor prognosis in LMS patients with DM.
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