Anmei Deng

MiR‐138 Promotes Induced Pluripotent Stem Cell Generation Through the Regulation of the p53 Signaling

Induced pluripotent stem (iPS) cells, especially those reprogrammed from patient somatic cells, have a great potential usage in regenerative medicine. The expression of p53 has been proven as a key barrier limiting iPS cell generation, but how p53 is regulated during cell reprogramming remains unclear. In this study, we found that the ectopic expression of miR‐138 significantly improved the efficiency of iPS cell generation via Oct4, Sox2, and Klf4, with or without c‐Myc (named as OSKM or OSK, respectively), without sacrificing the pluripotent characteristics of the generated iPS cells. Exploration of the mechanism showed that miR‐138 directly targeted the 3′ untranslated region (UTR) of p53, significantly decreasing the expression of p53 and its downstream genes. Furthermore, the ectopic expression of p53 having a mutant 3′‐UTR, which cannot be bound by miR‐138, seriously impaired the effect of miR‐138 on p53 signaling and OSKM‐initiated somatic cell reprogramming. Combined with the fact that miR‐138 is endogenously expressed in fibroblasts, iPS cells, and embryonic stem cells, our study demonstrated that regulation of the p53 signaling pathway and promotion of iPS cell generation represent an unrevealed important function of miR‐138. STEM Cells2012;30:1645–1654

Lysine Acetyltransferase GCN5 Potentiates the Growth of Non-small Cell Lung Cancer via Promotion of E2F1, Cyclin D1, and Cyclin E1 Expression

Background: The role of the lysine acetyltransferase GCN5 in cancer development remains largely unknown. Results: GCN5 expression correlates with lung cancer tumor size, directly enhances the expression of E2F1, cyclin E1, and cyclin D1, and potentiates lung cancer growth. Conclusion: GCN5 potentiates lung cancer growth in an E2F1-dependent manner. Significance: GCN5 is critical for lung cancer growth and represents a potential target for the treatment of lung cancer. The lysine acetyltransferases play crucial but complex roles in cancer development. GCN5 is a lysine acetyltransferase that generally regulates gene expression, but its role in cancer development remains largely unknown. In this study, we report that GCN5 is highly expressed in non-small cell lung cancer tissues and that its expression correlates with tumor size. We found that the expression of GCN5 promotes cell growth and the G1/S phase transition in multiple lung cancer cell lines. Further study revealed that GCN5 regulates the expression of E2F1, cyclin D1, and cyclin E1. Our reporter assays indicated that the expression of GCN5 enhances the activities of the E2F1, cyclin D1, and cyclin E1 promoters. ChIP experiments suggested that GCN5 binds directly to these promoters and increases the extent of histone acetylation within these regions. Mechanistic studies suggested that GCN5 interacts with E2F1 and is recruited by E2F1 to the E2F1, cyclin D1, and cyclin E1 promoters. The function of GCN5 in lung cancer cells is abrogated by the knockdown of E2F1. Finally, we confirmed that GCN5 regulates the expression of E2F1, cyclin D1, and cyclin E1 and potentiates lung cancer cell growth in a mouse tumor model. Taken together, our results demonstrate that GCN5 specifically potentiates lung cancer growth by directly promoting the expression of E2F1, cyclin D1, and cyclin E1 in an E2F1-dependent manner. Our study identifies a specific and novel function of GCN5 in lung cancer development and suggests that the GCN5-E2F1 interaction represents a potential target for lung cancer treatment.

Red blood cell distribution width is a potential index to assess the disease activity of systemic lupus erythematosus

BACKGROUND General population-based investigations have revealed that red blood cell distribution width (RDW) is associated with inflammatory indexes such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Chronic inflammation is one of the major components of many autoimmune diseases and RDW may reflect the severity of these autoimmune diseases as well. Therefore, the objective of this study was to investigate the correlation between RDW and disease activity of systemic lupus erythematosus (SLE). METHODS The medical records of 131 SLE patients were retrospectively analyzed. Correlations between RDW and disease activity or other inflammatory indexes were analyzed. The effect of glucocorticoid treatment for three months on RDW was estimated in 3 newly diagnosed SLE cases. RESULTS Increased RDW was observed in SLE patients. RDW was positively correlated with serum IgM, CRP, ESR, and SLE Disease Activity Index 2000 (SLEDAI-2K). Glucocorticoid treatment decreased both SLEDAI-2K and RDW. CONCLUSION RDW may be a useful index to estimate the disease activity of SLE.

Red blood cell distribution width is a potential prognostic index for liver disease.

Abstract Background: Red blood cell distribution width (RDW) is increased in liver disease. Its clinical significance, however, remains largely unknown. The aim of this study was to identify whether RDW was a prognostic index for liver disease. Methods: We studied, retrospectively, 33 patients with non-cirrhotic HBV chronic hepatitis, 125 patients with liver cirrhosis after HBV infection, 81 newly diagnosed primary hepatocellular carcinoma (pHCC) patients, 17 alcoholic liver cirrhosis patients and 42 patients with primary biliary cirrhosis (PBC). Sixty-six healthy individuals represented the control cohort. We analyzed the relationship between RDW on admission and clinical features. The association between RDW and hospitalization outcome was estimated by receiver operating curve (ROC) analysis and a multivariable logistic regression model. Results: Increased RDW was observed in liver disease patients. RDW was positively correlated with serum bilirubin and creatinine levels, prothrombin time, and negatively correlated with platelet counts and serum albumin concentration. A subgroup analysis, considering the different etiologies, revealed similar findings. Among the patients with liver cirrhosis, RDW increased with worsening of Child-Pugh grade. In patients with PBC, RDW positively correlated with Mayo risk score. Increased RDW was associated with worse hospital outcome, as shown by the AUC [95% confidence interval (CI)] of 0.76 (0.67–0.84). RDW above 15.15% was independently associated with poor hospital outcome after adjustment for serum bilirubin, platelet count, prothrombin time, albumin and age, with the odds ratio (95% CI) of 13.29 (1.67–105.68). Conclusions: RDW is a potential prognostic index for liver disease.

Systematic review and meta-analysis of flow cytometry in urinary tract infection screening.

BACKGROUND Automated urine sediment analysis of white blood cells (WBCs) and bacteria is a promising approach for urinary tract infections (UTIs) screening. However, available data on their screening efficacy is inconsistent. METHODS English articles from Pubmed, EMBASE, and Web of Science published before December 1, 2012 were analyzed. The Quality Assessment for Studies of Diagnostic Accuracy (QUADAS) tool was used to evaluate the quality of eligible studies. Performance characteristics of WBCs and bacteria (sensitivity, specificity, and other measures of accuracy) were pooled and examined by random-effects models. RESULTS Nineteen studies containing 22,305 samples were included. Pooled sensitivities were 0.87 (95% confidence interval [CI], 0.86-0.89) for WBCs and 0.92 (95% CI, 0.91-0.93) for bacteria. Corresponding pooled specificities were 0.67 (95% CI, 0.66-0.68) for WBCs and 0.60 (95% CI, 0.59-0.61) for bacteria. Areas under the summary receiver operating characteristics curves were 0.87 and 0.93 for WBCs and bacteria, respectively. The major limitation of eligible studies was that enrolled subjects were often not representative of clinical patient populations in which UTI would be suspected. CONCLUSIONS WBC and bacterial measurements by the UF-100 and UF-1000i are useful indicators in UTI screening; however, the performances of these systems should be rigorously evaluated by additional studies.

Red blood cell distribution width and neutrophil/lymphocyte ratio are positively correlated with disease activity in primary Sjögren's syndrome

OBJECTIVE The red blood cell distribution width (RDW) and neutrophil/lymphocyte ratio (NLR) are increased in various inflammation related diseases, but their clinical significance in primary Sjögrens syndrome (pSS) has not been reported. The aim of the present study was to investigate the clinical significance of RDW and NLR in pSS patients. METHODS The medical records of pSS patients who were admitted to Changhai Hospital of the Second Military Medical University between April 2012 and December 2013 were retrospectively reviewed. Correlations between RDW, NLR and the patient clinical characteristics were analyzed using the Spearman approach and the multiple linear regression model. RESULTS Fifty-two pSS patients and 58 healthy controls were enrolled. RDW and NLR were increased in pSS patients and positively correlated with the Sjögrens syndrome disease activity index (SSDAI). CONCLUSION RDW and NLR may prove to be useful indices to estimate pSS disease activity.

β-Arrestin 1 Modulates Functions of Autoimmune T Cells from Primary Biliary Cirrhosis Patients

ObjectivesPrimary biliary cirrhosis (PBC) is an autoimmune disease, characterized by antimitochondrial antibodies and autoreactive T cells causing destruction of the primary bile ducts. The molecular mechanisms regulating the autoreactive T cells remain elusive. β-Arrestins (βarr) are multifunctional signaling molecules that are crucial to T cell survival. We hypothesized that βarr plays a critical regulatory function in the autoreactive T cells of PBC patients.MethodsPatients with hepatic biliary cirrhosis (n = 60) were evaluated. Cytokine expression, T cell proliferation, and transcription factors were evaluated to assess regulatory functions in autoreactive T cells from the patient.ResultsOur studies showed that expression of βarr1 was elevated significantly in T lymphocytes from patients with PBC. Moreover, the level of βarr1 mRNA positively correlated with Mayo risk score in PBC patients. Based on modulation of βarr in autoreactive T cell lines, overexpression of βarr1 increased T cell proliferation, augmented interferon production, downregulated activities of nuclear factor κB and AP-1, promoted acetylation of histone H4 in the promoter regions of CD40L, LIGHT, IL-17 and interferon-γ, while downregulating acetylation of histone H4 in the promoter regions of TRAIL, Apo2, and HDAC7A, thereby regulating expression of these genes.ConclusionsOur findings suggest that βarr1 contributes to the pathogenesis of PBC, having significant implications for novel therapy strategy, further providing information for investigating the mechanisms of autoimmune disease.

MicroRNA-200a Regulates Grb2 and Suppresses Differentiation of Mouse Embryonic Stem Cells into Endoderm and Mesoderm

The mechanisms by which microRNAs (miRNAs) affect cell fate decisions remain poorly understood. Herein, we report that miR-200a can suppress the differentiation of mouse embryonic stem (ES) cells into endoderm and mesoderm. Interestingly, miR-200a directly targets growth factor receptor-bound protein 2 (Grb2), which is a key adaptor in the Erk signaling pathway. Furthermore, high levels of miR-200a dramatically decrease Grb2 levels and suppress the appearance of mesoderm and endoderm lineages in embryoid body formation, as well as suppressing the activation of Erk. Finally, Grb2 supplementation significantly rescues the miR-200a-induced layer-formation bias and the Erk suppression. Collectively, our results demonstrate that miR-200a plays critical roles in ES cell lineage commitment by directly regulating Grb2 expression and Erk signaling.

Diagnostic power of the mid-regional pro-atrial natriuretic peptide for heart failure patients with dyspnea: A meta-analysis

OBJECTIVE To evaluate the diagnostic performance of the mid-regional portion of the pro-atrial natriuretic peptide (MR-proANP) for heart failure (HF) in dyspnea patients. DESIGN AND METHODS We performed a systematic review of English-language studies published during the past three decades. The performance characteristics (diagnostic sensitivity, specificity, and other measures of accuracy) were pooled and examined by random-effects models. RESULTS Five studies met the inclusion criteria, which included 1153 patients with HF and 1904 non-HF patients. The summary estimates for MR-proANP in HF diagnosis had a diagnostic sensitivity of 0.90 (95% confidence interval (CI), 0.88-0.92), a specificity of 0.68 (95% CI, 0.66-0.70), and a diagnostic odds ratio (DOR) of 22.89 (95% CI, 12.54-41.77). The area under the curve (AUC) and Q value for the summary receiver operating characteristic (sROC) curves were 0.88 and 0.81, respectively. CONCLUSION MR-proANP showed a high diagnostic accuracy for HF in dyspnea patients.

The accuracy of glial fibrillary acidic protein in acute stroke differential diagnosis: A meta-analysis.

Abstract We performed a systematic review of English-language studies published during the past three decades to investigate the diagnostic performance of serum glial fibrillary acidic protein (GFAP) for the differential diagnosis of acute stroke, including intracerebral hemorrhage (ICH) and cerebral ischemia (CI). QUADAS tools were used to evaluate the quality of the study. Performance characteristics (diagnostic sensitivity, specificity, and other measures of accuracy) were pooled and examined using fixed-effects models. Four studies met the inclusion criteria, and included 109 patients with ICH and 381 patients with CI. The summary estimates for GFAP in the ICH diagnoses had a diagnostic sensitivity of 0.80 (95% confidence interval 0.71–0.88), a specificity of 0.97 (95% confidence interval, 0.94–0.98), and a diagnostic odds ratio (DOR) of 119.55 (95% confidence interval: 51.75–276.19). The area under curve (AUC) and Q value for the sROC curves were 0.97 and 0.92, respectively. Therefore, GFAP showed high diagnostic accuracy for acute stroke differential diagnosis.