ABSTRACT
BACKGROUND: Growth arrest-specific 6 (GAS6) is a vitamin K-dependent protein related to inflammation, fibrosis, as well as platelet function. Genetic ablation of GAS6 in mice protects against cardiac hypertrophy and dysfunction. Nonetheless, the association between plasma GAS6 levels and acute heart failure (AHF) patients is still unknown. METHODS: We measured plasma GAS6 concentrations in 1039 patients with AHF who were enrolled in the DRAGON-HF trial (NCT03727828). Mean follow-up of the study was 889 days. The primary endpoint is all-cause death. RESULTS: In total, there were 195 primary endpoints of all-cause death and 135 secondary endpoints of cardiovascular death during the mean follow-up duration of 889 days. The higher levels of GAS6 were associated with higher rates of all-cause and cardiovascular death (P < 0.05). Baseline plasma GAS6 levels were still strongly correlated with clinical outcomes in different models after adjustment for clinical factors and N-terminal pro-brain natriuretic peptide (NT-proBNP, P < 0.05). GAS6 could further distinguish the risks of clinical outcomes based on NT-proBNP measurement. CONCLUSION: Elevated plasma GAS6 levels were associated with an increased risk of all-cause and cardiovascular death in patients with AHF. Trial registration NCT03727828 (DRAGON-HF trial) clinicaltrials.gov.
Subject(s)
Heart Failure , Intercellular Signaling Peptides and Proteins , Biomarkers , Heart Failure/diagnosis , Natriuretic Peptide, Brain , Peptide Fragments , Prognosis , Stroke Volume , Humans , Intercellular Signaling Peptides and Proteins/bloodABSTRACT
BACKGROUND AND OBJECTIVES: Lymph node metastasis is a key factor in predicting and determining the prognosis of patients with colorectal cancer (CRC). Sodium channels are highly expressed in a variety of tumors and are closely related to tumor development, metastasis, and invasion. We investigated the relationship between the expressions of different subtypes of Nav channels and lymph node metastasis of CRC. METHODS: Real-time PCR (RT-qPCR) was carried out to measure the expressions of different sodium channel subtypes, chemokine receptors (CCR2, CCR4, CCR7), and lymphocyte infiltration-related biomarkers (CD3e, CD8a, IL-2RA) in CRC tissues from 97 patients. The expressions of Nav1.5 and Nav1.6 in surgically isolated lymph nodes were detected by immunohistochemistry. Correlation analysis between expressions of different genes and lymph node metastasis was performed by two-tailed t test. RESULTS: Nav1.1 and Nav1.6 were highly expressed in CRC tissues and positively correlated with CRC lymph node metastasis. Nav1.6 was also highly expressed in metastatic lymph nodes. Further analysis showed that the high expression of Nav1.6 was closely related to the one of CCR2\CCR4 in tumor lymph node metastasis. CONCLUSIONS: These results suggested that Nav1.6 might be a novel marker for CRC lymph node metastasis.
Subject(s)
Colorectal Neoplasms/pathology , NAV1.6 Voltage-Gated Sodium Channel/analysis , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/metabolism , Female , Humans , Lymphatic Metastasis , Lymphocytes, Tumor-Infiltrating/pathology , Male , Middle Aged , Receptors, CCR2/analysis , Receptors, CCR4/analysisABSTRACT
BACKGROUND AND AIMS: There is an association between cancer and increased ribosome biogenesis. At present, the RPL7L1 (60S Ribosomal Protein L7-Like 1) were less reported by literature search. Study reports that RPL7L1 is associated with mouse embryonic and skeletal muscle. The study of RPL7L1 on tumors has not been reported. METHODS: Our team downloaded the pan-cancer dataset that is uniformly normalized from the UCSC database (N=19131). Our study examined the relationship between RPL7L1 expression level and clinical prognosis with methylation, anti-tumour immunity, functional states, MSI, TMB, DNSss, LOH and chemotherapeutic responses in 43 cancer types and subtypes. RESULTS AND CONCLUSIONS: RPL7L1 was overexpressed in nine tumor types. Gene mutation, tumor microenvironment and methylation modification of RPL7L1 plays a key role in patient prognosis. And the high expression of RPL7L1 was associated with TMB, MSI, LOH especially LIHC and HNSC. We experimentally verified that genes can promote the proliferation and migration of tumor cells. Our study suggested that RPL7L1 biomarker can be used for treating cancer, detecting it, and predicting its prognosis.
ABSTRACT
BACKGROUND: Although diabetes mellitus (DM) is regarded as a risk factor of colorectal cancer (CRC), the impacts of pre-existing DM on CRC without drug intervention remain unknown. The purpose of this study was to investigate and analyze the effects of diabetes mellitus (DM) on colorectal cancer (CRC). And, to further explore the influencing factors and the mechanisms of DM affects CRC progression. METHODS: In this study, we investigated the effects of DM on CRC progression in a streptozotocin-induced DM mice model. Furthermore, we evaluated the change of T cells levels using flow cytometry and indirect immunofluorescence. We assessed the alternation of gut microbiome and the transcriptional response using 16s rRNA sequencing and RNA-seq. RESULTS: Results showed that the mice survival time was significantly decreased in CRC complicated with DM group (DM-CRC), compared with only tumor bearing mice (CRC group). Furthermore, we found that DM could affect the immune response by changing the infiltration of CD4+ T cells, CD8+ T cells and mucosal-associated invariant T cell (MAIT) in the CRC progression. In addition, DM could induce gut microbiome dysbiosis and change the transcriptional response in CRC complicated with DM. CONCLUSION: For the first time, the effects of DM on CRC were systematically characterized in a mice model. Our findings highlight the effects of pre-existing DM on CRC, and these findings should facilitate further studies in exploring and developing potentially targeted therapy for CRC in diabetic patients. Our results suggest that the effects induced by DM should be considered in the treatment for CRC complicated with DM patients.
Subject(s)
Colorectal Neoplasms , Diabetes Mellitus , Animals , Mice , CD8-Positive T-Lymphocytes/pathology , RNA, Ribosomal, 16S/genetics , Colorectal Neoplasms/pathology , Risk FactorsABSTRACT
Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation. Colorectal cancer (CRC) cells evade ferroptosis despite their requirement of substantial iron and reactive oxygen species (ROS) to sustain active metabolism and extensive proliferation. However, the underlying mechanism is unclear. Herein, we report the role of lymphoid-specific helicase (LSH), a chromatin-remodeling protein, in suppressing erastin-induced ferroptosis in CRC cells. We demonstrate that erastin treatment leads to dose- and time-dependent downregulation of LSH in CRC cells, and depletion of LSH increases cell sensitivity to ferroptosis. Mechanistically, LSH interacts with and is stabilized by ubiquitin-specific protease 11 (USP11) via deubiquitination; this interaction was disrupted by erastin treatment, resulting in increased ubiquitination and LSH degradation. Moreover, we identified cytochrome P450 family 24 subfamily A member 1 (CYP24A1) as a transcriptional target of LSH. LSH binds to the CYP24A1 promoter, promoting nucleosome eviction and reducing H3K27me3 occupancy, thus leading to transcription of CYP24A1. This cascade inhibits excessive intracellular Ca2+ influx, thereby reducing lipid peroxidation and ultimately conferring resistance to ferroptosis. Importantly, aberrant expression of USP11, LSH, and CYP24A1 is observed in CRC tissues and correlates with poor patient prognosis. Taken together, our study demonstrates the crucial role of the USP11/LSH/CYP24A1 signaling axis in inhibiting ferroptosis in CRC, highlighting its potential as a therapeutic target in CRC treatment.
Subject(s)
Colorectal Neoplasms , Ferroptosis , Humans , Cell Line, Tumor , Colorectal Neoplasms/genetics , Epigenesis, Genetic , Ferroptosis/genetics , Iron/metabolism , Reactive Oxygen Species/metabolism , Thiolester Hydrolases/metabolism , Vitamin D3 24-Hydroxylase/metabolismABSTRACT
Hyponatremia is a risk factor associated with poor prognosis in patients with heart failure (HF) with reduced ejection fraction. However, whether hyponatremia has a similar role in patients with HF with preserved ejection fraction (HFpEF) has remained controversial. Therefore, the present study aimed to investigate the clinical characteristics and 24-month prognostic profile of a cohort of patients with HFpEF in China. From a registered observational cohort study on 1,027 subjects with HF, 496 patients with HFpEF were included. The association between baseline hyponatremia on admission and 24-month adverse outcomes (including all-cause mortality, re-hospitalization for HF and stroke) was analyzed using logistic regression with the Cox proportional hazards model. Of the 496 patients with HFpEF with a mean age of 72.8 years and proportion of males of 53.0%, 71 patients were diagnosed with hyponatremia. Furthermore, 29 patients (5.8%) were lost to follow-up. The hyponatremia group had lower blood pressure and serum hemoglobin, higher N-terminal pro B-type natriuretic peptide (NT-proBNP) and D-dimer, more patients with a history of atrial fibrillation and a higher proportion of spironolactone and loop diuretic use. According to a multivariate regression analysis, New York Heart Association functional classes III-IV and a serum NT-proBNP level above the median were risk factors for hyponatremia, while higher systolic blood pressure and ß-blocker use were protective factors against hyponatremia. In the Kaplan-Meier analysis, hyponatremia was associated with all-causes of mortality, re-hospitalization for HF and a poor prognosis for patients suffering from strokes (log-rank P<0.05 for all 3 endpoints). On multivariate logistic regression analysis with the Cox proportional hazard model, hyponatremia was an independent predictor of three adverse outcomes [all-cause mortality: Hazard ratio (HR)=1.54, 95% CI=1.07-2.91, P=0.034; re-hospitalization for heart failure: HR=1.28, 95% CI=1.16-2.47, P=0.013; stroke: HR=1.78, 95% CI=1.04-2.89, P=0.016]. Collectively, the present results suggested that hyponatremia on admission was significantly associated with all-cause mortality, re-hospitalization and stroke within 24 months in a cohort of hospitalized patients with HFpEF in China. Thus, hyponatremia should be carefully monitored and frequently adjusted in patients with HFpEF (NCT04062500).