MiR-6511b-5p suppresses metastasis of pMMR colorectal cancer through methylation of CD44 by directly targeting BRG1

Purpose: Distal metastases are a major cause of poor prognosis in colorectal cancer patients. Approximately 95% of metastatic colorectal cancers are defined as DNA mismatch repair proficient (pMMR). Our previous study found that miR-6511b-5p was downregulated in pMMR colorectal cancer. However, the mechanism of miR-6511b-5p in pMMR colorectal cancer metastases remain unclear.MethodsWe first used quantitative real-time PCR to evaluate the role of miR-6511b-5p in colorectal cancer. Second, we conducted invasion assays and wound healing assays to investigate the role of miR-6511b-5p and CD44 in colorectal cancer cells metastases. Third, luciferase reporter assay, in situ hybridization (ISH), and immunohistochemistry assays were performed to study the relationship between miR-6511b-5p and BRG1. Finally, real-time quantitative PCR, immunohistochemistry, and chromatin immunoprecipitation (ChIP) assays were performed to analyze the relationship between BRG1 and CD44 in colorectal cancer.ResultsWe found that lower expression of miR-6511b-5p appeared more often in pMMR colorectal cancer patients compared with dMMR (mismatch repair deficient) cases, and was positively correlated with metastases. In vitro, overexpression of miR-6511b-5p inhibited metastasis by decreasing CD44 expression via directly targeting BRG1 in colorectal cancer. Furthermore, BRG1 knockdown decreased the expression of CD44 by promoting CD44 methylation in colorectal cancer cells.ConclusionOur data suggest that miR-6511b-5p may act as a promising biomarker and treatment target for pMMR colorectal cancer, particularly in metastatic patients. Mechanistically, miR-6511b-5p suppresses invasion and migration of colorectal cancer cells through methylation of CD44 via directly targeting BRG1. (AU)

MiR-6511b-5p suppresses metastasis of pMMR colorectal cancer through methylation of CD44 by directly targeting BRG1.

PURPOSE: Distal metastases are a major cause of poor prognosis in colorectal cancer patients. Approximately 95% of metastatic colorectal cancers are defined as DNA mismatch repair proficient (pMMR). Our previous study found that miR-6511b-5p was downregulated in pMMR colorectal cancer. However, the mechanism of miR-6511b-5p in pMMR colorectal cancer metastases remain unclear. METHODS: We first used quantitative real-time PCR to evaluate the role of miR-6511b-5p in colorectal cancer. Second, we conducted invasion assays and wound healing assays to investigate the role of miR-6511b-5p and CD44 in colorectal cancer cells metastases. Third, luciferase reporter assay, in situ hybridization (ISH), and immunohistochemistry assays were performed to study the relationship between miR-6511b-5p and BRG1. Finally, real-time quantitative PCR, immunohistochemistry, and chromatin immunoprecipitation (ChIP) assays were performed to analyze the relationship between BRG1 and CD44 in colorectal cancer. RESULTS: We found that lower expression of miR-6511b-5p appeared more often in pMMR colorectal cancer patients compared with dMMR (mismatch repair deficient) cases, and was positively correlated with metastases. In vitro, overexpression of miR-6511b-5p inhibited metastasis by decreasing CD44 expression via directly targeting BRG1 in colorectal cancer. Furthermore, BRG1 knockdown decreased the expression of CD44 by promoting CD44 methylation in colorectal cancer cells. CONCLUSION: Our data suggest that miR-6511b-5p may act as a promising biomarker and treatment target for pMMR colorectal cancer, particularly in metastatic patients. Mechanistically, miR-6511b-5p suppresses invasion and migration of colorectal cancer cells through methylation of CD44 via directly targeting BRG1.

[Diagnostic accuracy of muscle ultrasound and plasma monocyte chemoattractant protein-1 for ICU-acquired weakness in patients with sepsis].

OBJECTIVE: To explore the diagnostic accuracy of muscle ultrasound and plasma monocyte chemoattractant protein-1 (MCP-1) for ICU-acquired weakness (ICU-AW) in patients with sepsis. METHODS: A prospective observational study was conducted. Patients with sepsis admitted to the intensive care unit (ICU) of Henan Provincial People's Hospital from April 2021 to October 2021 were enrolled. The demographic data were collected. The enrolled patients were evaluated with Medical Research Council (MRC) score every day until discharged from ICU. During this period, patients with total MRC score < 48 (for two consecutive times and a time interval of 24 hours) were divided into ICU-AW group, those with total MRC score ≥ 48 were served as non-ICU-AW group. On the 1st, 4th and 7th day following admission into ICU, ultrasound was used to measure the muscle linear thickness of the rectus femoris (RF-MLT), the cross sectional area of the rectus femoris (RF-CSA) and the muscle linear thickness of the vastus intermedius muscle (VI-MLT). And meanwhile, the plasmas samples of patients were collected to measure MCP-1 concentration by enzyme-linked immunosorbent assay (ELISA). The difference of each index was compared between the ICU-AW group and the non-ICU-AW group. The risk factors of ICU-AW in patients with sepsis were analyzed by binary Logistic regression. Besides, receiver operator characteristic curve (ROC curve) was plotted, the diagnostic value of ultrasound parameters and plasma MCP-1 level for ICU-AW in patients with sepsis was analyzed. RESULTS: A total of 99 septic patients were enrolled, with 68 patients in the ICU-AW group and 31 patients in the non-ICU-AW group. Compared with the patients in the ICU-AW group, the patients in the non-ICU-AW group tended to be older, and had higher sequential organ failure assessment (SOFA) score, higher acute physiology and chronic health evaluation II (APACHE II) score, higher rates of septic shock, higher blood lactic acid and lower Glasgow coma score (GCS). Binary Logistic regression analysis showed that APACHE II score and septic shock were the risk factors of ICU-AW for septic patients [odds ratio (OR) and 95% confidence interval (95%CI) were 1.310 (1.138-1.509) and 0.232 (0.072-0.746), respectively, both P < 0.05]. The RF-MLT, RF-CSA and VI-MLT on the 1st, 4th and 7th ICU day was falling over time. Compared with the patients in the ICU-AW group, the patients in the non-ICU-AW group had smaller RF-MLT on the 7th day [cm: 0.32 (0.22, 0.47) vs. 0.45 (0.34, 0.63), P < 0.05] and higher 7-day RF-CSA atrophy rate [25.85% (10.37%, 34.28%) vs. 11.65% (2.28%, 22.41%), P < 0.05]. According to ROC curve analysis, 7-day RF-MLT had diagnostic value for ICU-AW of septic patients. Area under ROC curve (AUC) was 0.688 (95%CI was 0.526-0.849); when the cut-off value was 0.41 cm, the sensitivity and the specificity were 66.7% and 68.4%. The levels of plasma MCP-1 in the ICU-AW group were significantly higher than those in the non-ICU-AW group on the 1st, 4th and 7th day. ROC curve analysis showed that the plasma MCP-1 levels on the 1st, 4th and 7th day played a significant role to diagnose ICU-AW for septic patients, the AUC and 95%CI were 0.732 (0.629-0.836), 0.865 (0.777-0.953), 0.891 (0.795-0.986), respectively. When the cut-off values were 206.3, 410.9, 239.5 ng/L, the sensitivity was 87.1%, 64.0%, 82.4%, and the specificity was 54.4%, 96.1%, 86.2%, respectively. CONCLUSIONS: The muscle mass parameters on the 7th day of bedside ultrasound and plasma MCP-1 levels had certain diagnostic values for ICU-AW in patients with sepsis.

[Characteristics and control measures of 2019 novel coronavirus Delta variant of concern].

2019 novel coronavirus (2019-nCoV) Delta variant of concern (VOC) is one of the variants of 2019-nCoV, which has the characteristics of strong transmission, high pathogenicity, and rapid progression. 2019-nCoV Delta VOC has caused a global pandemic. Understanding the characteristics of 2019-nCoV Delta VOC and implementing targeted control measures are important aspects of controlling the pandemic. In this paper, the characteristics and control measures of 2019-nCoV Delta VOC were reviewed.

[Risk factors and their predictive value for intensive care unit acquired weakness in patients with sepsis].

OBJECTIVE: To explore the risk factors of intensive care unit acquired weakness (ICUAW) in patients with sepsis, and to evaluate the predictive value of each risk factor for ICUAW. METHODS: A case control study was conducted, 60 septic patients admitted to the intensive care unit (ICU) of Henan Provincial People's Hospital from October 20, 2020 to February 20, 2021 were enrolled. The patients were divided into two groups: sepsis ICUAW group and sepsis non-ICUAW group. The data of gender, age, body mass index (BMI), acute physiology and chronic health evaluation II (APACHE II) score, complications, mechanical ventilation, duration of ICUAW, length of stay in ICU, fasting blood glucose, blood lactic acid (Lac), procalcitonin (PCT), C-reactive protein (CRP), sequential organ failure assessment (SOFA) score, outcome, antimicrobial agent, glucocorticoid, sedatives and analgesics drugs and vasoactive drugs were collected. Risk factors were screened by univariate Logistic regression analysis, and odds ratio (OR) was adjusted by multivariate binary logistic regression, P < 0.05 was considered as independent risk factors. Finally, the receiver operating characteristic curve (ROC curve) was drawn to analyze the predictive value of independent risk factors. RESULTS: The APACHE II score of the sepsis ICUAW group was significantly higher than that of the sepsis non-ICUAW group (23.05±8.17 vs. 15.33±4.89, P < 0.05), the total length of stay in the ICU was significantly longer than that of the sepsis non-ICUAW group (days: 15.1±9.2 vs. 8.5±3.4, P < 0.05), the improvement rate of patients was significantly lower than that of the sepsis non-ICUAW group [45.0% (9/20) vs. 95.0% (38/40), P < 0.05]. After univariate Logistic regression and multicollinearity test analysis, 7 factors including APACHE II score, average SOFA score, blood lactic acid, proportion of mechanical ventilation, sedatives and analgesics drugs, type of antibiotics and type of vasoactive drugs were included in the binary Logistic regression model [OR: 1.21, 2.05, 2.26, 0.21, 1.54, 2.07, 1.38, 95% confidence interval (95%CI): 1.09-1.35, 1.42-2.94, 1.12-4.57, 0.05-0.66, 1.03-2.29, 1.27-3.37, 0.96-2.00, all P < 0.05]. Hosmer-Lemchaw test P = 0.901, and the correct percentage of prediction was 85%, indicating good model fit. Multivariate binary Logistic regression analysis showed that APACHE II score and average SOFA score were independent risk factors for the occurrence of ICUAW in septic patients (APACHE II score: OR = 1.17, 95%CI was 1.004-1.376, P = 0.044; average SOFA score: OR = 1.86, 95%CI was 1.157-2.981, P = 0.01). ROC curve analysis showed that the mean value of APACHE II score, average SOFA score and their combined detection had a certain predictive value for the occurrence of ICUAW in sepsis patients, areas under ROC curve (AUC) were 0.787, 0.881, 0.905, 95%CI was 0.646-0.928, 0.791-0.972, 0.828-0.982, all P < 0.05. When the cut-off value was 19.500, 6.225, 0.375, the sensitivity was 75%, 90%, 90%, and the specificity were 80%, 80%, 85%, respectively. CONCLUSIONS: APACHE II score and average SOFA score can be used as independent risk factors for the occurrence of ICUAW in sepsis, and their combined predictive value is better than that of individual index.