PPIA rs6850: A > G single-nucleotide polymorphism is associated with raised plasma cyclophilin A levels in patients with coronary artery disease.

Plasma level of cyclophilin A is a promising marker of vascular disease in patients with type 2 diabetes. Genetic variants in the peptidylprolyl isomerase A gene, encoding human cyclophilin may alter protein synthesis thus affecting its activity, function, and circulating plasma levels. We examined the effect of single-nucleotide polymorphisms (SNPs) within the PPIA gene on plasma levels of cyclophilin A and coupled this with status of vascular disease in patients with and without type 2 diabetes in 212 South Indian subjects. The regulatory region of PPIA gene was sequenced for SNPs. The association of SNPs with known blood markers of type 2 diabetes and coronary artery disease such as HbA1c, low- and high-density lipoproteins, triglycerides, fasting and postprandial blood sugar levels, and cyclophilin A were probed. We identified three SNPs namely, rs6850: A > G; (AG/-) c.*227_*228delAG and (-/T) c.*318_*319insT. Welchs two-sample t test indicated an association of SNP rs6850: A > G, located at the 5' UTR region with increased plasma levels of cyclophilin A in patients with coronary artery disease and with coronary artery disease associated with diabetes. The presence of rs6850: A > G variant was significantly associated with coronary artery disease irrespective of whether the patients had diabetes or not. In silico analysis of the sequence using different tools and matrix libraries did not predict any significant differential binding sites for rs6850: A > G, c.*227_*228delAG and c.*318_*319insT. Our results indicate that the SNP rs6850: A > G is associated with increased risk for elevated plasma levels of cyclophilin A and coronary artery disease in patients with and without type 2 diabetes.

Proteomic profiling of high glucose primed monocytes identifies cyclophilin A as a potential secretory marker of inflammation in type 2 diabetes.

Hyperglycemia is widely recognized to be a potent stimulator of monocyte activity, which is a crucial event in the pathogenesis of atherosclerosis. We analyzed the monocyte proteome for potential markers that would enhance the ability to screen for early inflammatory status in Type 2 diabetes mellitus (T2DM), using proteomic technologies. Monocytic cells (THP-1) were primed with high glucose (HG), their protein profiles were analyzed using 2DE and the downregulated differentially expressed spots were identified using MALDI TOF/MS. We selected five proteins that were secretory in function with the help of bioinformatic programs. A predominantly downregulated protein identified as cyclophilin A (sequence coverage 98%) was further validated by immunoblotting experiments. The cellular mRNA levels of cyclophilin A in various HG-primed cells were studied using qRT-PCR assays and it was observed to decrease in a dose-dependent manner. LC-ESI-MS was used to identify this protein in the conditioned media of HG-primed cells and confirmed by Western blotting as well as ELISA. Cyclophilin A was also detected in the plasma of patients with diabetes. We conclude that cyclophilin A is secreted by monocytes in response to HG. Given the paracrine and autocrine actions of cyclophilin A, the secreted immunophilin could be significant for progression of atherosclerosis in type 2 diabetes. Our study also provides evidence that analysis of monocyte secretome is a viable strategy for identifying candidate plasma markers in diabetes.

C-T variant in a miRNA target site of BCL2 is associated with increased risk of human papilloma virus related cervical cancer--an in silico approach.

MicroRNAs control gene expression at the posttranscriptional level by base-pairing to the 3'-UTR of their target mRNAs, thus leading to mRNA degradation of protein fabrication. We hypothesize, SNPs within miRNAs and their targets could be of significance to an individual's risk of developing cancer. We analyzed in silico SNP information on cervical cancer associated aberrant alleles and further investigated this in a case-control study by examining eleven SNPs from different genes. It was observed that a C to T polymorphism in putative miRNA target site of BCL2 was significantly conspicuous for the aberrant SNP allele in cancer tissues as compared to controls. This study provides evidence that SNPs in miRNA-binding sites may play an important role in increasing risk of cancer. The results also paves way for future studies to validate these results in other well-characterized populations as well as to explore the biological significance of these particular SNPs.

Identification and analysis of novel microRNAs from fragile sites of human cervical cancer: computational and experimental approach.

Accurate identification of mature miRNAs is an important requirement for exploring the post-transcriptional regulatory mechanism of organisms. In this work we present a novel computational tool 'Mpred' which first identifies pre-miRNAs and then predicts its mature miRNAs. We first use our method to learn with high accuracy characteristic features of human miRNA precursors from miRbase registry and then apply to sequences from fragile site regions related to cervical cancer in search of novel miRNA genes. The study identified 13 putative miRNA-like sequences and most of them were not related to each other and do not share homology with annotated sequences. Finally, four of the top scoring predictions were verified experimentally using quantitative RT-PCR validation. Expression profile studies revealed that four novel miRs were present in cervical tissues and these data compiled here provide a regulatory framework of miRNA genes that may have roles in tumorigenesis.

Comprehensive patterns in microRNA regulation of transcription factors during tumor metastasis.

In spite of a large body of information about the upstream regulators of metastasis, a process that often plays a limiting factor in therapeutic outcome of cancer patients, the impact of regulatory microRNA patterns remains obscure. This review describes computational analysis of coordinated regulation of genes by di-directional regulation of microRNA and transcription factors that specifically regulate the process of metastasis. We discovered several unexpected modes of regulatory patterns between microRNAs and transcription factors. For example, we found a double positive feedback loop regulated by the hub transcription factor ZEB1 and miR-200 during epithelial-mesenchymal transition. This review further explains flow of information and how such components coordinate various adaptable controls of microRNAs and thus, contribute to regulation of transcription factors in context of cancer metastasis. Information described here provides a regulatory framework for future experimental analyses and discoveries of new insights into post-transcriptional gene regulation at the microRNA level in cancer metastasis.

Preparation, characterization and dielectric studies on carbonyl iron/cellulose acetate hydrogen phthalate core/shell nanoparticles for drug delivery applications.

A method to prepare composite colloidal nanoparticles, consisting of a magnetic core (carbonyl iron) and a biodegradable polymeric shell (cellulose acetate hydrogen phthalate) was described and also particle size was characterized by Optical Microscope and Scanning Electron Microscopy. Dielectric properties of Cellulose Acetate Hydrogen Phthalate (CAP) and carbonyl iron/CAP (core/shell) tablets were studied in the frequency range of 70 Hz-400 kHz at 300 K using LCR meter and compared the dielectric parameters of core/shell and ordinary phase of CAP tablets. From the dielectric results, the importance of core/shell nanoparticles in controlled drug delivery was discussed.

An unusual presentation of ghost cell odontogenic carcinoma: A case report with review of literature.

Ghost cell odontogenic carcinoma (GCOC) is a malignant odontogenic epithelial tumor which is an exceedingly rare, highly aggressive, rapidly growing, and infiltrative tumor forming the malignant counterpart of long-standing benign cystic lesions coming in the spectrum of calcifying odontogenic cysts. To date, only a few cases have been reported in the medical literature. A case of unusual presentation of GCOC is presented and the clinical, histopathological, and immunohistochemical features are discussed along with a literature review. Our case report further emphasizes the bizarre biological behavior of this tumor and the need for strict long-term surveillance of the patients as metastasis to distant sites has been reported.

Cytoplasmic translocation of MTA1 coregulator promotes de-repression of SGK1 transcription in hypoxic cancer cells.

Chromatin remodeling factor metastatic tumor protein 1 (MTA1), one of the most upregulated oncogene in human cancer, has an important role in gene expression, cell survival and promoting hypoxic response. Successful cancer progression is dependent on the ability of cells to utilize its survival pathways for adapting to hypoxic microenvironment. Although MTA1 is a stress-responsive gene, but whether hypoxia modulates its function and its role in engaging other core stress-responsive survival pathway(s) remains unknown. Here we have discovered that MTA1 is a novel corepressor of serum and glucocorticoid-inducible kinase 1 (SGK1). Surprisingly, this regulatory corepressive function of MTA1 is lost under hypoxia, allowing upregulation of SGK1 expression and engaging the MTA1-SGK1 axis for the benefit of the cell survival. The underlying mechanism of the noticed stimulation of SGK1 expression by hypoxia includes de-repression of SGK1 transcription because of hypoxia-triggered nucleus-to-cytoplasmic translocation of MTA1. In addition, the newly recognized cytoplasmic translocation of MTA1 was dependent on the chaperoning function of heat shock protein 90 (HSP90) and co-accompanied by the formation of MTA1, HSP90 and HIF1α complex under hypoxic condition but not under normoxic condition. Hypoxia-triggered redistribution of MTA1, SGK1 upregulation and cell survival functions were compromised by a pharmacological SGK1 inhibitor. In summary, for the first time, we report MTA1 regulation of SGK1 expression, hypoxia-dependent MTA1 translocation to the cytoplasm and de-repression of SGK1 transcription. These findings illustrate how cancer cells utilize a chromatin remodeling factor to engage a core survival pathway to support its cancerous phenotypes, and reveal new facets of MTA1-SGK1 axis by a physiologic signal in cancer progression.

An unusual presentation of ghost cell odontogenic carcinoma: A case report with review of literature

Ghost cell odontogenic carcinoma (GCOC) is a malignant odontogenic epithelial tumor which is an exceedingly rare, highly aggressive, rapidly growing, and infiltrative tumor forming the malignant counterpart of long-standing benign cystic lesions coming in the spectrum of calcifying odontogenic cysts. To date, only a few cases have been reported in the medical literature. A case of unusual presentation of GCOC is presented and the clinical, histopathological, and immunohistochemical features are discussed along with a literature review. Our case report further emphasizes the bizarre biological behavior of this tumor and the need for strict long-term surveillance of the patients as metastasis to distant sites has been reported.

Oncogenic microRNAs as biomarkers of oral tumorigenesis and minimal residual disease.

OBJECTIVES: Classical diagnostic methods are not sensitive enough in detecting oral lesions that may progress to cancer and in assessing minimal residual disease (MRD) in oral surgical margins. Altered expression of microRNAs (miRNAs) contributes to human cancer, including oral cancer. Although there are many studies on microRNAs in oral cancer, there is no reported study comparing the expression of microRNAs during oral tumor progression and in oral surgical margins. MATERIALS AND METHODS: This study analyzed the expression of 72 miRNAs that were reported (till June 2011) to be differentially expressed in oral cancer, during phases of oral cancer progression and in oral surgical margins. RESULTS: Of the 72 miRNAs analyzed, four (hsa-miR-125a, hsa-miR-184, hsa-miR16 and hsa-miR-96) showed a common pattern of expression in both sets of tissues. We further analyzed the downstream target genes of hsa-miR-16 BCL2 and CCND1. The in silico network analysis of these four microRNAs and their target genes revealed presence of genes involved in tumor progression and transcription factors. CONCLUSIONS: The findings suggest that the combinatorial regulation by these miRNAs and their target transcription factors might play a substantial role in oral tumorigenesis. Here we report for the first time that a decreased expression of hsa-miR-125a, hsa-miR-184 and hsa-miR-16 and an increased expression of hsa-miR-96 could be useful in predicting oral tumorigenesis and importantly in the detection of MRD and decision-making process for postoperative treatment modalities.

Beyond HPV: oncomirs as new players in cervical cancer.

MicroRNAs (miRNAs) are a recently discovered family of 18-24 nucleotide non-coding RNAs that can negatively regulate target mRNAs. All studied multicellular eukaryotes utilize miRNAs to regulate basic cellular functions including proliferation, differentiation, and death. It is now apparent that abnormal miRNA expression is a common feature of human malignancies. This review discusses the various cancer-relevant miRNAs (oncomirs) especially in cervical tumorigenesis and the potential role of oncomirs as therapeutic agents and targets for the treatment of cervical cancer.