Association of interleukin 1 receptor antagonist (IL1RN) gene polymorphism with recurrent pregnancy loss risk in the North Indian Population and a meta-analysis.

An appropriate ratio of interleukin 1 beta to interleukin 1 receptor antagonist (IL1Ra) is required for successful pregnancy. Our objective was to study the genetic association between IL1RN variable numbers of tandem repeat (VNTR) polymorphism and recurrent pregnancy loss (RPL). To analyze the association between IL1RN VNTR allele and RPL, we investigated the IL1RN VNTR polymorphism in 136 RPL patients and in 200 healthy control women. Meta-analysis on this polymorphism was conducted to support our findings. PCR based approach was used to analyze IL1RN VNTR polymorphism and it was further confirmed by sequencing. Systematic review and meta-analysis was done using electronic database (Pub-Med, Google Scholar and Ovid) up to February 27, 2013. This meta-analysis was assessed by comprehensive meta-analysis software version 2. For meta-analysis 549 cases and 1,450 controls were included. The frequency of IL1RN genotype 2/2 was significantly higher in RPL compared to control group (AORs 3.10, 95 % CI 1.58-6.11, p = 0.001). The presence of rare allele also increased the risk of RPL significantly (ORs 1.63, 95 % CI 1.16-2.29, p = 0.004). The meta-analysis stratified by ethnicity showed that individuals with allele 2 had increased risk of RPL (OR 1.29, 95 % CI 1.04-1.61, p = 0.01), in Asians population by using fixed model. However the data of the present study clearly suggests that IL1RN VNTR polymorphism is a genetic risk factor for pregnancy loss in the study population.

KLF4 signalling in carcinogenesis and epigenetic regulation of hTERT.

Gene expression is crucial and tightly regulated to steer the development, differentiation, proliferation and even apoptosis of a cell. Each cell and tissue type shows a unique repertoire of transcription factors. Tissue micro-environmental regulation of epigenetic signature of a gene has been documented in many cases. Epigenetic factors play a significant role in the regulation of gene expression. KLF4 is a well-known transcription factor regulating the expression of several genes including hTERT. KLF4 functions both as a tumor suppressor and oncogene depending on cell type. hTERT, upregulated in the majority of cancers as against its undetectable expression in differentiated cells, is one of the target genes for KLF4. Here we hypothesize that KLF4 differentially regulates epigenetic modification of the promoter of hTERT and consequently its expression in different tissue microenvironments. The proposed hypothesis explains the dual role of KLF4 in two different tissue microenvironments with respect to the regulation of hTERT expression. Since both KLF4 and hTERT are key molecules to maintain the stemness and immortality of cancer cells, defining the crosstalk between these two molecules may open new avenues for cancer therapeutics. Also, exploring the proposed hypothesis may unravel the cause of ambiguous nature of KLF4 in carcinogenesis.

LPS-Challenged Macrophages Release Microvesicles Coated With Histones.

Histones are the protein component of nucleosomes, which are the basic packing unit of chromatin. However, histones are also found in the blood, both as components of nucleosomes leaked out from dead cells, or expelled from neutrophils in the active process of NET formation. Circulating histones contribute to inflammation, and to lethality in sepsis, a hyperinflammatory condition, by interacting with specific receptors, notably toll-like receptor 4 (TLR4). Here, we show that histones are also actively released by LPS-activated macrophages in association with extracellular vesicles. Vesicle-associated histones can be recovered from the plasma of mice with sepsis. Actively released histones are on the outer surface of vesicles and can interact with TLR4. Thus, activated macrophages release histones without dying, at the same time, making their DNA more accessible and communicating to other cells that infection is present.