Bone mineral density,bone metabolism‐related factors,and microRNA‐218 are correlated with disease activities in Chinese ankylosing spondylitis patients

ObjectiveTo investigate bone mineral density (BMD), bone metabolism‐related factors, and microRNA‐218 in Chinese ankylosing spondylitis (AS) patients and to identify their correlation with disease activities and the treatment with TNF‐α inhibitors.MethodsA total of 89 AS patients were enrolled in the study. Patients’ information and laboratory examination results were collected. BMD of the anteroposterior lumbar spine (L2‐L4), left femoral neck, and whole body were measured and T‐scores were calculated. MicroRNA‐218 was extracted from PBMCs of AS patients and detected by RT‐PCR. Bone metabolism‐related factors were detected using protein chips and flow cytometer.ResultsOut of 86 patients undergoing whole‐body BMD measurement, 14 had osteopenia and 72 had normal BMD without osteoporosis or high BMD. Compared with short‐ (disease duration ≤3 years) and long‐term groups (disease duration ≥10 years), medium‐term group (disease duration ranges from 3 to 10 years) showed lowest BMD. Patients with onset age ≤20 years old had significantly lower BMD than the other groups (p < 0.05). The BMD of femoral neck had negative correlation with CRP (p < 0.05) and no correlation with BASDAI or ESR. Both whole‐body BMD and femoral neck BMD were negatively correlated with BASMI (p < 0.05). Dickkopf‐1 (DKK‐1), platelet‐derived growth factor‐BB (PDGF‐BB), and receptor activator of NF‐κB ligand (RANKL)/osteoprotegerin (OPG) were significantly increased, while Osteopontin (OPN) was significantly decreased in AS patients. Expression of microRNA‐218 in PBMC of AS patients was low and was positively correlated with BASMI (p < 0.05), but it was not correlated with the duration of disease, age of onset, BASDAI, ESR, or BMD.ConclusionLoss of bone mass mainly occurred at the inflammatory sites in AS patients, depending on the severity of inflammation. The alleviation of inflammation can improve loss of bone mass and bone metabolism disorders. Anti‐inflammatory treatment is critical for the treatment of secondary osteoporosis caused by AS.     

Diagnosis value of miR‐181, miR‐652, and CA72‐4 for gastric cancer

PurposeTo find a useful disease marker for early diagnosis of gastric cancer, we tried to explore the expression of serum miR‐181, miR‐652, and carbohydrate antigen 72‐4 (CA72‐4).Patients and MethodsAccording to clinical pathologic stages, 112 patients with gastric cancer were divided into early gastric cancer group (n = 60) and advanced gastric cancer group (n = 52), stage I‐II (n = 65), and stage III‐IV (n = 47). Another 50 cases of gastric benign lesions and 40 healthy controls were also selected. Real‐time quantitative PCR together with chemiluminescence were applied to detect expression levels. ROC curve was applied to judge their diagnostic efficiency. Pearson''s correlation analysis was put into use to investigate the relevance of three indicators.ResultsCompared with benign lesions group and control group, significantly higher expression levels were found in patients of gastric cancer (all p < 0.001). Similarly, compared with early gastric cancer group, significantly higher expression levels were found in advanced gastric cancer group (all p < 0.001). The same result was also found in stage III‐IV (all p < 0.001). The best cutoff values were 0.93, 2.38, and 16.94 U/ml, respectively. The area under the curve (0.917, 95%CI: 0.856–0.975) of the three combined diagnosis of early gastric cancer was the largest, and its sensitivity and specificity were 92.5% and 86.8%. And miR‐181 and miR‐652 were positively correlated with CA72‐4 (r = 0.772, p < 0.001, r = 0.853, p < 0.001).ConclusionSerum miR‐181, miR‐652, and CA72‐4 are closely linked to the occurrence and development of gastric cancer. Combination of three indicators has diagnostic value for early gastric cancer.     

Association of B‐cell lymphoma 2/microRNA‐497 gene expression ratio score with metastasis in patients with colorectal cancer: A propensity‐matched cohort analysis

BackgroundDeregulated microRNAs (miRs) significantly impact cancer development and progression. Our in silico analysis revealed that miR‐497 and its target gene B‐cell lymphoma‐2 (BCL2) could be related to poor cancer outcomes.PurposeTo investigate the BCL2/miRNA‐497 expression ratio in colorectal cancer (CRC) and explore its association with the clinicopathological characteristics and CRC prognosis.MethodsArchived samples from 106 CRC patients were enrolled. MiR‐497 and BCL2 gene expressions were detected by Taq‐Man Real‐Time quantitative polymerase chain reaction in propensity‐matched metastatic and nonmetastatic cohorts after elimination of confounder bias.ResultsB‐cell lymphoma‐2 gene was upregulated in metastatic samples (median = 1.16, 95%CI = 1.09–1.60) compared to nonmetastatic (median = 1.02, 95%CI = 0.89–1.25, p < 0.001). In contrast, lower levels of miR‐495 were detected in specimens with distant metastasis (median = 0.05, 95%CI = 0.04–0.20) than nonmetastatic samples (median = 0.54, 95%CI = 0.47–0.58, p < 0.001). Estimated BCL2/miR‐497 ratio yielded a significant differential expression between the two cohort groups. Higher scores were observed in metastasis group (median = 1.39, 95%CI = 0.9–1.51) than nonmetastatic patients (median = 0.29, 95%CI = 0.19–0.39, p < 0.001). Receiver operating characteristic curve analysis showed BCL2/miR‐497 ratio score to have the highest predictive accuracy for metastasis at presentation. The area under the curve was 0.90 (95%CI = 0.839–0.964, p < 0.001) at cut‐off of >0.525, with high sensitivity 81.1% (95%CI = 68.6%–89.4%) and specificity 92.5% (95%CI = 82.1%–97.0%). Also, the ratio score was negatively correlated with disease‐free survival (r = −0.676, p < 0.001) and overall survival times (r = −0.650, p < 0.001). Kaplan–Meier curves showed lower survival rates in cohorts with high‐score compared to low‐score patients.ConclusionThe BCL2/miR497 expression ratio is associated with poor CRC prognosis in terms of metastasis and short survival.     

MicroRNA‐146a and microRNA‐146b deficiency correlates with exacerbated disease activity,and their longitude increment relates to etanercept response in psoriasis patients

BackgroundMicroRNA (miR)‐146a and miR‐146b regulate autoimmunity, inflammation, and keratinocytes proliferation to engage in psoriasis pathology. The current study aimed to investigate their correlation with disease risk and clinical features, and the linkage of their longitudinal changes with clinical response to etanercept in psoriasis patients.MethodsPlasma samples were collected from 84 moderate‐to‐severe psoriasis patients who underwent etanercept treatment (at baseline (M0), 1 month (M1), 3 months (M3), and 6 months (M6)), 80 disease controls and 80 health controls (both after enrollment); afterward, miR‐146a and miR‐146b expressions were detected by RT‐qPCR. Furthermore, PASI75 and PASI90 responses were assessed in psoriasis patients.ResultsBoth miR‐146a and miR‐146b were decreased in psoriasis patients compared with disease controls and health controls (all p < 0.001), which also distinguished psoriasis patients from disease controls and health controls by receiver‐operating characteristic analyses. Furthermore, miR‐146a positively correlated with miR‐146b in psoriasis patients (p < 0.001) and disease controls (p = 0.005) but not in healthy controls (p = 0.062). In psoriasis patients, miR‐146a negatively related to psoriatic body surface area (p = 0.011) and PASI score (p = 0.003); miR‐146b negatively linked with PASI score (p = 0.020). At M1, M3, and M6 after etanercept treatment, PASI75 response rate was 14.3%, 32.1%, and 69.0%, respectively; PASI90 response rate was 1.2%, 17.9%, and 36.9%, respectively. During etanercept treatment, both miR‐146a and miR‐146b elevated gradually over time and their longitude increments were associated with PASI75 response (all p < 0.001).ConclusionMiR‐146a and miR‐146b might serve as indicators for optimizing etanercept application and improving treatment outcomes in psoriasis patients.     

Prognostic value of BRAF/MIR‐17 signature and B‐Raf protein expression in patients with colorectal cancer: A pilot study

BackgroundDespite the recent improvement in colorectal cancer (CRC) treatment, it still has a poor prognosis with a low survival rate. Genetic and epigenetic mechanisms have proved to play a substantial role in CRC tumorigenesis and progression. According to Gene Ontology and TargetScan analyses, the B‐Raf proto‐oncogene (BRAF) gene is one of the microRNA‐17 (miR‐17) targets. We aimed to explore the prognostic value of B‐Raf protein and BRAF/microRNA‐17 (MIR‐17) gene expression signature in CRC archived samples.MethodsB‐Raf protein expression was identified by immunohistochemistry, while gene expression studies were quantified by real‐time qPCR in 53 paired archived CRC specimens.ResultsThe BRAF showed higher expressions in CRC specimens relative to non‐cancer tissues (p = 0.006). MIR17 expression was inversely and significantly correlated with both B‐Raf protein (r = −0.79, p < 0.001) and gene expression (r = −0.35, p = 0.010) and showed a significant direct correlation with a high rate of relapse (p = 0.020). BRAF/miR‐17 expression in CRC was associated inversely with tumor size, high grade of colonic carcinoma, lymph node metastasis, and carcinoma subtype. Spearman correlation and Kaplan‐Meier survival curve analyses revealed that disease‐free survival and overall survival were inversely and significantly correlated with positive B‐Raf protein expression (r = −0.31 and −0.35, p = 0.023 and 0.011, respectively) and directly correlated with log BRAF/MIR17 ratio (r = 0.50 and 0.41, p < 0.001 and = 0.003, respectively). Cox hazard regression analysis revealed the BRAF/MIR17 ratio could predict both types of patients'' survival, among other variables.Conclusion BRAF/MIR17 ratio could have prognostic utility in patients with CRC. Further larger‐scale studies are warranted to confirm this utility.     

In‐hospital mortality in SARS‐CoV‐2 stratified by gamma‐glutamyl transferase levels

BackgroundThis study investigates in‐hospital mortality amongst patients with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and its relation to serum levels of gamma‐glutamyl transferase (GGT).MethodsPatients were stratified according to serum levels of gamma‐glutamyl transferase (GGT) (GGT<50 IU/L or GGT≥50 IU/L).ResultsA total of 802 participants were considered, amongst whom 486 had GGT<50 IU/L and a mean age of 48.1 (16.5) years, whilst 316 had GGT≥50 IU/L and a mean age of 53.8 (14.7) years. The chief sources of SARS‐CoV‐2 transmission were contact (366, 45.7%) and community (320, 40%). Most patients with GGT≥50 IU/L had either pneumonia (247, 78.2%) or acute respiratory distress syndrome (ARDS) (85, 26.9%), whilst those with GGT<50 IU/L had hypertension (141, 29%) or diabetes mellitus (DM) (147, 30.2%). Mortality was higher amongst patients with GGT≥50 IU/L (54, 17.1%) than amongst those with GGT<50 IU/L (29, 5.9%). More patients with GGT≥50 required high (83, 27.6%) or low (104, 34.6%) levels of oxygen, whereas most of those with GGT<50 had no requirement of oxygen (306, 71.2%). Multivariable logistic regression analysis indicated that GGT≥50 IU/L (odds ratio [OR]: 2.02, 95% confidence interval [CI]: 1.20–3.45, p=0.009), age (OR: 1.05, 95% CI: 1.03–1.07, p<0.001), hypertension (OR: 2.06, 95% CI: 1.19–3.63, p=0.011), methylprednisolone (OR: 2.96, 95% CI: 1.74–5.01, p<0.001) and fever (OR: 2.03, 95% CI: 1.15–3.68, p=0.016) were significant predictors of all‐cause cumulative mortality. A Cox proportional hazards regression model (B = −0.68, SE =0.24, HR =0.51, p = 0.004) showed that patients with GGT<50 IU/L had a 0.51‐times lower risk of all‐cause cumulative mortality than patients with GGT≥50 IU/L.ConclusionHigher levels of serum GGT were found to be an independent predictor of in‐hospital mortality.     

LncRNA UCA1, miR‐26a,and miR‐195 in coronary heart disease patients: Correlation with stenosis degree,cholesterol levels,inflammatory cytokines,and cell adhesion molecules

BackgroundLong noncoding RNA urothelial cancer‐associated 1 (lnc‐UCA1) targets microRNA‐26a (miR‐26a) and microRNA‐195 (miR‐195) to participate in coronary heart disease (CHD) progression via regulation of vascular smooth muscle cell and microvascular endothelial cell viability and mobility. Therefore, this study set out to further explore the relationship between lnc‐UCA1 and miR‐26a and miR‐195, along with their roles in the management of patients with CHD.MethodsOne hundred and thirty‐six CHD patients and 70 age‐/gender‐matched controls were recruited in this case‐control study. Their peripheral blood mononuclear cell samples were collected for lnc‐UCA1, miR‐26a, and miR‐195 measurement. Furthermore, serum samples from CHD patients were obtained for inflammatory cytokines and cell adhesion molecules measurement. The Gensini score was used to evaluate the stenosis severity in CHD patients.ResultsLnc‐UCA1 expression tend to be increased, while miR‐26a and miR‐195 expressions were reduced in patients with CHD compared to that of controls (all p < 0.001). In CHD patients, lnc‐UCA1 was negatively correlated with miR‐26a (p < 0.001) and miR‐195 (p = 0.014). Besides, lnc‐UCA1 was positively correlated with Gensini score (p < 0.001), total cholesterol (p = 0.019), low‐density lipoprotein cholesterol (p = 0.002), and C‐reactive protein (p < 0.001), while miR‐26a (p < 0.001) and miR‐195 (p = 0.002) were negatively correlated with Gensini score. What''s more, lnc‐UCA1 was positively correlated with tumor necrosis factor (TNF)‐α (p = 0.004), interleukin (IL)‐1β (p = 0.041), vascular cell adhesion molecule‐1 (VCAM‐1) (p = 0.010), and intercellular adhesion molecule‐1 (ICAM‐1) (p < 0.001). While miR‐26a was negatively correlated with some of the individual inflammatory cytokines and cell adhesion molecules.ConclusionLnc‐UCA1, miR‐26a, and miR‐195 may serve as potential biomarkers for CHD management.     

MiR‐221‐3p and miR‐92a‐3p enhances smoking‐induced inflammation in COPD

BackgroundSmoking is likely to facilitate airway inflammation and finally contributes to chronic obstructive pulmonary disease (COPD). This investigation was intended to elucidate miRNAs that were involved in smoking‐induced COPD.MethodsAltogether 155 COPD patients and 77 healthy volunteers were recruited, and their serum levels of miR‐221‐3p and miR‐92a‐3p were determined. Besides, human bronchial epithelial cells (16HBECs) were purchased, and they were treated by varying concentrations of cigarette smoke extract (CSE). The 16HBECs were, additionally, transfected by miR‐221‐3p mimic, miR‐92a‐3p mimic, miR‐221‐3p inhibitor or miR‐92a‐3p inhibitor, and cytokines released by them, including TNF‐α, IL‐8, IL‐1β, and TGF‐β1, were monitored using enzyme linked immunosorbent assay (ELISA) kits.ResultsChronic obstructive pulmonary disease patients possessed higher serum levels of miR‐221‐3p and miR‐92a‐3p than healthy volunteers (p < 0.05), and both miR‐221‐3p and miR‐92a‐3p were effective biomarkers in diagnosing stable COPD from acute exacerbation COPD. Moreover, viability of 16HBECs was undermined by CSE treatment (p < 0.05), and exposure to CSE facilitated 16HBECs’ release of TNF‐α, IL‐8, IL‐1β, and TGF‐β1 (p < 0.05). Furthermore, miR‐221‐3p/miR‐92a‐3p expression in 16HBECs was significantly suppressed after transfection of miR‐221‐3p/miR‐92a‐3p inhibitor (p < 0.05), which abated CSE‐triggered increase in cytokine production and decline in viability of 16HBECs (p < 0.05).ConclusionMiR‐221‐3p and miR‐92a‐3p were involved in CSE‐induced hyperinflammation of COPD, suggesting that they were favorable alternatives in diagnosing COPD patients with smoking history.     

Combined detection of procalcitonin,heparin‐binding protein,and interleukin‐6 is a promising assay to diagnose and predict acute pancreatitis

BackgroundAcute pancreatitis (AP), one of the most common clinical emergencies, is characterized by variable clinical features and inadequate diagnostic methods. At present, the commonly used indicators do not have high specificity and do not necessarily reflect disease severity. We therefore aimed to investigate diagnostic and prognostic value of plasma procalcitonin, heparin‐binding protein, and interleukin‐6 for acute pancreatitis by separate detection and joint detection.MethodsThe study involved 451 participants, including 343 AP patients and 108 healthy controls. We analyzed the association of the three biomarkers with the severity and prognosis of AP.ResultsA statistically significant increase in the mean plasma analyte levels was detected in the study group compared to the control group. Multivariate comparison showed that plasma levels of PCT, HBP, and IL‐6 were all significantly different among the three groups at different sampling times (1st, 3rd, 7th, and 10th day of admission) (p < 0.01). The combination of the three indicators had significantly higher diagnostic value than either the individual markers or pairwise combinations (p < 0.001). The levels of the three were all significantly higher in severe acute pancreatitis (SAP) patients than in non‐SAP patients (p < 0.001); meanwhile, patients with high levels had a worse prognosis than those with low levels (p < 0.05). In multivariate analysis adjusted for age and sex, high levels of PCT, HBP, and IL‐6 were found to be independently associated with the development of AP.ConclusionsIt dramatically improved the diagnostic power of AP when PCT, HBP, and IL‐6 were combined; high PCT, HBP, and IL‐6 levels within 3 days of admission may be the potentially useful indicators for predicting SAP.     

Upregulation of CD3ζ and L‐selectin in antigen‐specific cytotoxic T lymphocytes by eliminating myeloid‐derived suppressor cells with doxorubicin to improve killing efficacy of neuroblastoma cells in vitro

BackgroundAgglomeration of myeloid‐derived suppressor cells (MDSCs) in tumors impedes immunotherapeutic effects. Doxorubicin (DOX) is currently the most specific drug used for the selective removal of MDSCs. Here, we study the feasibility and mechanism of eliminating MDSCs by DOX to improve antigen‐specific cytotoxic T lymphocyte (CTL)‐killing neuroblastoma (NB) cells in vitro.MethodsCTL and MDSC were prepared; then, CTLs, NB cells, MDSCs, and DOX were mixed and cultivated in different collocation patterns and divided into different groups. The levels of cluster of differentiation 3ζ chain (CD3ζ) and L‐selectin in CTL in different groups were detected. Thereafter, the killing rate of NB cells and secretion of interleukin‐2 and interferon‐γ were measured and compared.ResultsBy real‐time polymerase chain reaction (PCR) and Western blot test respectively, the proliferation and killing effect of CTLs on NB cells were all inhibited by MDSC through downregulating CD3ζ (p = 0.002; p = 0.001) and L‐selectin (p = 0.006; p < 0.001). However, this inhibitory effect was reversed by DOX. Significant differences were observed in the levels of interleukin‐2 (p < 0.001), interferon‐γ (p < 0.001), and the killing rate (p < 0.001) among the groups, except between the CTL +SK‐N‐SH and CTL +SK‐N‐SH +DOX groups (p > 0.05).ConclusionsTargeted elimination of MDSCs by DOX can improve Ag‐specific CTL killing of NB cells in vitro by upregulating CD3ζ and L‐selectin. This study provides a novel method to enhance the immunotherapeutic effects of NB.