No abstract

Aims Neutrophils have both detrimental and beneficial effects in myocardial infarction (MI), but little is known about the underlying pathways. S100A8/A9 is a pro-inflammatory alarmin abundantly expressed in neutrophils that is rapidly released in the myocardium and circulation after myocardial ischaemia. We investigated the role of S100A8/A9 in the innate immune response to MI. Methods and results In 524 patients with acute coronary syndrome (ACS), we found that high plasma S100A8/A9 at the time of the acute event was associated with lower left ventricular ejection fraction (EF) at 1-year and increased hospitalization for heart failure (HF) during follow-up. In wild-type C57BL/6 mice with MI induced by permanent coronary artery ligation, treatment with the S100A9 blocker ABR-238901 during the inflammatory phase of the immune response inhibited haematopoietic stem cell proliferation and myeloid cell egression from the bone marrow. The treatment reduced the numbers of neutrophils and monocytes/macrophages in the myocardium, promoted an anti-inflammatory environment, and significantly improved cardiac function compared with MI controls. To mimic the clinical scenario, we further confirmed the effects of the treatment in a mouse model of ischaemia/reperfusion. Compared with untreated mice, 3-day ABR-238901 treatment significantly improved left ventricular EF (48% vs. 35%, P = 0.002) and cardiac output (15.7 vs. 11.1 mL/min, P = 0.002) by Day 21 post-MI. Conclusion Short-term S100A9 blockade inhibits inflammation and improves cardiac function in murine models of MI. As an excessive S100A8/A9 release is linked to incident HF, S100A9 blockade might represent a feasible strategy to improve prognosis in ACS patients.

PD pathogenesis may involve the epigenetic control of enhancers that modify neuronal functions. Here, we comprehensively profile DNA methylation at enhancers, genome-wide, in neurons of 57 PD patients and 48 control individuals. We found a widespread increase in cytosine modifications at enhancers in PD neurons, which is partly explained by elevated hydroxymethylation levels. Epigenetic dysregulation of enhancers in PD converge on transcriptional abnormalities affecting neuronal signaling and immune activation pathways. In particular, PD patients exhibit an epigenetic and transcriptional upregulation of TET2, a masterregulator of cytosine modification status. TET2 inactivation in a neuronal cell line results in cytosine modification changes that are reciprocal to those observed in PD neurons.Furthermore, Tet2 inactivation in mice fully prevents dopaminergic neuronal loss in the substantia nigra induced by prior inflammation. Tet2 loss in mice also attenuates transcriptional immune responses to an inflammatory trigger. Thus, widespread epigenetic dysregulation of enhancers in PD neurons may, in part, be mediated by increased TET2 expression. Decreased Tet2 activity is neuroprotective, in vivo, and may be a novel therapeutic target for PD.

No abstract

Frequent somatic mutations of BRAF (v-raf murine sarcoma viral oncogene homolog B) exon T1799A, which are implicated in the initial events of promutagenic cellular proliferation, are detected in both malignant melanomas (MM) and melanocytic nevi (MN). Most of the data regarding BRAF exon T1799A mutation have been from Caucasian cohorts, and a comprehensive screening of a homogeneous population is lacking. A total of 379 cases of MN and 195 cases of MM were collected from Chinese Han living in three geographical regions in China, i.e., northeast, southwest, and northwest China. BRAF exon T1799A mutation was detected by PCR and sequencing from microdissected tumors. In all, 59.8% cases of MN harbored BRAF exon T1799A mutation. Samples from regions with high UV exposure had higher detection rates than regions with lower UV exposure (73.5, 67.0, and 38.9%, respectively; χ(2) = 31.674, P = 1.59E-7). There were no differences in mutation rates between congenital and acquired MN; however, acquired MN with advanced age of onset had a higher mutation rate than those with younger age of onset (χ(2) = 13.23, P = 0.02). In all, 15.0% cases of MM harbored the BRAF mutation. The mutation rate in MM was not affected by region, histological type, gender, pattern of UV exposure, and age. The study suggests that the mutation is not necessarily associated with malignant transformation.

We read with great interest the article entitled ''Ethnic Differences in Viral Dominance Patterns in Patients with Hepatitis B Virus and Hepatitis C Virus Dual Infection,'' recently published by Nguyen et al. in this journal. 1 The study was designed to evaluate and compare the demographic, clinical, and viral characteristics of multiethnic patients infected by hepatitis virus admitted at two large liver centers in the United States. The investigators defined the study design as a matched case-control study, in which the case group included patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) dual infection, and the control group comprised patients with HBV monoinfection. However, in our opinion, there is an important methodological issue in the reported data: The main conclusion of the article was not about the comparison between cases and controls, but rather it underscored a secondary analysis with cases only in which ethnic differences were examined in terms of viral dominance patterns among HBV and HCV dual-infected patients. It is our opinion that the investigators deviated from the scope of the case-control study originally proposed, because it is clear that the investigation was not delineated to test the hypothesis that ended up becoming the core conclusion, including the title of the article. Therefore, the investigators' conclusions regarding viral dominance were not consistent with the a priori study aims proposed.

MicroRNAs (miRNAs) are recently discovered small non-coding RNAs and can serve as serum biomarkers for disease diagnosis and prognoses. Lack of reliable serum miRNA endogenous references for normalization in miRNA gene expression makes single miRNA assays inaccurate. Using TaqMan® real-time PCR miRNA arrays with a global gene expression normalization strategy, we have analyzed serum miRNA expression profiles of 20 female mice of NOD/ShiLtJ (n = 8), NOR/LtJ (n = 6), and C57BL/6J (n = 6) at different ages and disease conditions. We identified five miRNAs, miR-146a, miR-16, miR-195, miR-30e and miR-744, to be stably expressed in all strains, which could serve as mouse serum miRNA endogenous references for single assay experiments.

T cell immunoglobulin and mucin-4 (TIM-4), mainly expressed on dendritic cells (DC) and macrophages, plays an essential role in regulating immune responses. Langerhans cells (LC), which are the sole DC subpopulation residing at the epidermis, are potent mediators of immune surveillance and tolerance. However, the significance of TIM-4 on epidermal LCs, along with other cutaneous DCs, remains totally unexplored. For the first time, we discovered that epidermal LCs expressed TIM-4 and displayed an increased level of TIM-4 expression upon migration. We also found that dermal CD207+ DCs and lymph node (LN) resident CD207−CD4+ DCs highly expressed TIM-4, while dermal CD207− DCs and LN CD207−CD4− DCs had limited TIM-4 expressions. Using TIM-4-deficient mice, we further demonstrated that loss of TIM-4 significantly upregulated the frequencies of epidermal LCs and LN resident CD207−CD4+ DCs. In spite of this, the epidermal LCs of TIM-4-deficient mice displayed normal phagocytic and migratory abilities, comparable maturation status upon the stimulation as well as normal repopulation under the inflamed state. Moreover, lack of TIM-4 did not affect dinitrofluorobenzene-induced contact hypersensitivity response. In conclusion, our results indicated that TIM-4 was differentially expressed in the distinct subsets of DCs in skin and skin-draining LNs, and specifically regulated epidermal LC and LN CD207−CD4+ DC homeostasis.