Scenario and future prospects of microRNAs in gastric cancer: A review

Carcinoma of the stomach is one of the major prevalent and principal causes of cancer-related deaths worldwide. Current advancement in technology has improved the understanding of the pathogenesis and pathology of gastric cancers (GC). But, high mortality rates, unfavorable prognosis and lack of clinical predictive biomarkers provide an impetus to investigate novel early diagnostic/prognostic markers and therapeutic targets for GC, which are sufficiently sensitive to GC. Current biomedical investigations have explored several budding GC biomarker by utilizing serum proteins, natural oncogenic genes during improvement in molecular technologies as microarray, and RNA/DNA-Seq. Recently, small non-coding microRNAs (miRNAs) are becoming vital regulators in oncogenesis pathways and can act as handy clinical biomarkers. The newly introduced class of biomarkers is rising as new molecules for cancer diagnosis and prognosis. For better understanding of the gastric carcinogenesis, miRNAs may help to elucidate the mechanisms of tumor growth and can help to discover novel untimely potent markers for early detection of GC. Here in this review, we summarize the recent research studies supporting the utility of miRNAs as novel early diagnostic/prognostic tools and therapeutic targets. Thus, here we introduce potential future treatment strategies for gastrointestinal (GI) cancers, which indicate the practicality and clinical applications of miRNAs in GC

A Study on Association of XRCC3 Gene Polymorphism in Gastric cancer risk

Gastric Cancer (GC) is among the common and fatal cancer in the world. DNA repair plays a critical role in protecting the genome of the cell from insults of cancer-causing agents. Inherited polymorphisms of DNA repair genes may contribute to variations in DNA Repair capacity (DRC) and genetic susceptibility to different c ancers. Mammalian cells are constantly exposed to a wide variety of genotoxic a gents from both endogenous and exogenous sources. In human beings, 70 genes are involve d in the five major DNA repair pathways: direct repair, NER, BER, mismatch repa ir and double-strand break repair. The X-ray repair complementing defective repa ir in Chinese hamster cells 3 (XRCC3) gene is a member of the RAD51 gene fami ly. It encodes an important protein that functions in the homologous rec ombination repair of DNA double-strand break. The Kashmir valley has an eleva ted incidence of GC and its etiology is not understood fully yet, though, we are ethni cally and demographically different from the other states of the country and world. The aim of this study was to determine whether single nucleotide poly morphism (SNP) of XRCC3 gene (Thr241Met) of exon7, can influence the risk of gastric cancer in Kashmiri population. About 80 histopathologically confirmed GC case s and 70 healthy controls, age ,gender, ethnicity matched for known genotypes of XRCC3 exon7 were analyzed. Patients medical history and dietary habits were taken for the study as well. The ge notype for this variant was determined using polymerase chain reaction- restriction fra gment length polymorphisms (PCR-RFLP) in 80 histologically confirmed GC patients and 70 frequency-matched healthy controls in Department of Biochemistr y, Government Medical College srinagar. The XRCC3 genotype and allele frequencies were not significantly different between cases and controls (P= 0.92 for ge notype; P= 0:72 for allele). The XRCC3 241Met allele frequency (6.6%) was signifi cantly lower in healthy Kashmiri controls than previously reported healthy US Caucasian controls (38.9%). Compared with the XRCC3241Thr/Thr genoty pe, the variant XRCC3241Thr/Met and Met/Met genotypes were not associated with an increased risk of gastric cancer (adjusted odds ratio (ORa), 1.19; 95% confiden ce interval (CI), 0.44-3.18). These finding s suggest that polymorphisms of XRCC3 Thr241Met may not play a role in the etiology of GC. Further studies with a larger number of subjects and simultaneous measurement of different pol ymorphisms in DNA repair genes in the same pathway are needed

A Study on Methylation Changes in Mismatch Repair Gene (hMLH1) in Esophageal Cancer Patients of Kashmir Valley

The Study was a Case Control undertaken to understand the etiology of esophageal cancer in the population of Kashmiri origin. This case control study was designed to assess the relationship of promoter hypermethylation of Mismatch Repair Gene MutL homolog 1 (hMLH1) with esophageal cancer. Also further an association of hypermethylation of hMLH1 gene with esophageal cancer in relation to clinicopathological features of Gender and Age was evaluated. Esophageal cancers are one of the most fatal cancers in the world and are considered to be the eighth most common malignancy. The prognosis of Esophageal Cancer is poor as its symptoms appear in the late stage of the disease. This cancer is one of the most prevalent cancers in Jammu and Kashmir region of India and has multi-factorial etiology involving dietary habits, genetic factors, and gene environmental interactions. Genetic abnormalities of proto-oncogenes, tumor suppressor genes and mis-match repair genes have been demonstrated to be involved frequently in esophageal carcinogenesis; chronic inflammation leading to malignancy in the esophagus may be due to errors in mismatch repair (MMR) genes such as hMLH1. Inactivation of the hMLH1 gene expression by aberrant promoter methylation plays an important role in the progression of esophageal carcinoma. In the present study the role of hMLH1 promoter methylation in 50 histopathologically confirmed esophageal cancer tissues and compared it with corresponding histopathologically confirmed Normal adjacent tissues was studied by methylation-specific polymerase chain reaction (MS-PCR). For evaluating the status of hMLH1 promoter hypermethylation and its association with Esophageal Cancer, a methylation specific polymerase chain reaction (MS-PCR) was used. DNA was extracted and treated with sodium bisulfite which converts unmethylated cytosines to uracil and does not affect methylated cytosines. The modified DNA was amplified in MS-PCR reaction by applying methylated and unmethylated promoter specific primers. Universally methylated DNA was used as positive control and DNA from normal lymphocytes used as negative control. The MS-PCR products were run on 3% agarose and bands were visualized under UV light. It was found that the frequency of promoter region hypermethylation of mismatch repair gene (hMLH1) in esophageal cancer cases was 56% (28 out of 50) and in histopathologically confirmed normals it was 15% (03 out of 20).Statistically the association of promoter region hypermethylation of mismatch repair gene (hMLH1) with esophageal cancer was evaluated using χ2-test (chi-square test) with odds ratio and was found significant and the p0.05.From the data it was concluded that The Frequency of MutL homolog 1 (hMLH1) gene promoter region hypermethylation was found high in Esophageal Cancer Cases of above 40 years of age (56%) and in controls (16%) and was significant as p0.05 and was evaluated by Fishers exact test. Observing similar level of hMLH1 promoter hypermethylation in patients with Esophageal Cancer in this high risk region and comparing it with other parts of the world could support the hypothesis that a common molecular mechanism might be involved in tumorigenesis of Esophageal Cancer. As regards promoter hypermethylation status of mismatch repair gene hMLH1 shows a significant increase in promoter region hypermethylation of esophageal cancer patients of Kashmiri origin as compared to controls was observed. This became more apparent when the data for hypermethylation was interpreted taking Gender into consideration here it was seen that Males shows higher frequency of promoter region hypermethylation as compared to females which was earlier reported in literature and also patients of above 40 years of age shows high frequency compared to below 40 years of age

COMBINATORIAL EFFECT OF LEPTIN, TUMOR NECROSIS FACTOR-ΑLPHA, AND VITAMIN D IN PROGRESSION OF TYPE 2 DIABETES IN KASHMIRI POPULATION

Objectives: Type 2 diabetes mellitus (T2DM) is a metabolic disorder usually characterized by hyperglycemia. Adipose tissue secretes bioactive substances known as adipocytokines including leptin, tumor necrosis factor-alpha (TNF-α), and adiponectin. These are considered as a bridge connecting obesity and insulin resistance. There is considerable epidemiological evidence to suggest a role of Vitamin D deficiency in the etiology of T2DM. This study was performed to evaluate and compare serum Vitamin D and adipocytokine levels in T2DM patients and healthy controls of Jammu and Kashmir region of India.Methods: A total of 200 T2DM patients and normal 200 healthy controls were considered for the study. Enzyme-linked immunosorbent assay was used to measure serum leptin and TNF-α levels. The Vitamin D levels were measured by chemiluminescent microparticle immunoassay method. Biochemical parameters were measured by the enzymatic method.Results: Our results concluded that basic metabolic parameters, TNF-α and leptin levels were significantly higher in cases than controls. The serum Vitamin D levels were found significantly lower among T2DM patients. No correlation of Vitamin D with leptin was observed in cases and controls. However, a positive correlation between leptin and TNF-α was noted in T2DM subjects as well as in controls with statistical significance being higher in females (r=0.500; p=0.001) as compared to males (r=0.298; p=0.036) in T2DM subjects as well as in controls (r=0.659; p=0.001; r=0.621; p=001).Conclusion: These results concluded that lowering of Vitamin D levels and upregulation of leptin and TNF-α altogether play an important role in the development of T2DM, and from correlation analysis, it could be predicted that leptin and TNF-α act in a synergistic manner toward the development of T2DM

Elucidation of Etiology of Colorectal Cancer: A Study on Silencing of MGMT Gene by Promoter Hypermethylation

Prevalence of Promoterhypermethylation of MGMT Gene in Colorectal Cancer Patients of Kashmir Valley. Colorectal cancer, one of the most aggressive cancers, occurs with a high incidence in most countries. Colorectal cancer (CRC) is one of the leading malignancies worldwide. Cancer development and progression is dictated by series of alterations in genes such as tumor suppressor genes, DNA repair genes, oncogenes and others. In this study, efforts were made to identify promoter hypermethylation of CpG islands of MGMT gene in CRC patients among the Kashmiri population. Methylation status of CpG islands in the promoter region of MGMT gene in colorectal cancers and normal corresponding colonic mucosa was analysed. Fresh tissue samples were obtained from 50 patients (age of 21 to 81 years) undergoing resective surgery for CRC with primary colorectal adenocarcinonia and corresponding histopathologically normal tissues. Methylation-specific polymerase chain reaction (MSP) was used for analysis of the promoter methylation status of MGMT gene. The male to female ratio of the disease came out to be 1.38. The epigenetic analysis of the cases and controls revealed that unlike other high risk regions, Kashmiri population has a different hypermethylation profile of MGMT gene promoter hypermethylation. The frequency of cases with MGMT promoter hypermethylation was more as compared to controls (54% vs. 20%) and was statistically significant (O.R = 4.69, 95% C.I = 1.37 – 16.05, P = 0.015) using χ2 test with Odds Ratio. It was also found that the frequency of male cases with promoter hypermethylation of MGMT gene was more as seen against male controls (72.41% vs. 30%), which also showed statistically significant results (O.R = 6.13, 95% C.I = 1.26 – 29.71, P = 0.026) using Fisher’s Exact test, though the frequency of promoter hypermethylation of MGMT gene of female cases was more as compared to female controls (28.57% vs. 10%), the data was found not to be statistically significant (O.R = 3.6, 95% C.I = 0.37 – 34.93, P = 0.37) using Fisher’s Exact. While for the male verses female cases of promoter hypermethylation of MGMT gene the results were statistically significant (O.R = 6.563, 95% C.I = 1.882 - 22.82, P = 0.0037) using Fisher’s Exact Test. In this study it was concluded that male gender is generally associated with higher methylation levels for most CpG islands hypermethylation of MGMT gene in normal as well as cancerous colonic mucosa. The results indicate that MGMT aberrant methylation may play an important role in colorectal cancer. This study clearly demonstrates that promoter hypermethylation of MGMT gene can be designated as epigenetic biomarker for early diagnosis and better prognosis of the disease

Graves’ Disease: Pathophysiology, Genetics and Management

Graves’ disease is an autoimmune disorder in which hyperthyroidism (over active thyroid) is caused by the autoantibodies against the TSH receptor. It is mainly characterized by the appearance of goiter. The symptoms are wide ranging as thyroid hormone affects many body systems. It is common in women and in people with age below than 40. Graves’ disease is caused by a combination of genetic and environmental factors while genetics being the main cause. Graves’ disease is not a single gene defect but has a complex pattern of inheritance. Today it is clear that genetic predisposition to Graves’ disease is caused by multiple genes. HLA gene is one the most studied gene predisposing to Graves’ disease. Lot of polymorphisms in this gene has been to be associated with the disease. Lymphoid tyrosine phosphatase encoded by the gene PTPN22 has been found to increase the risk of many autoimmune diseases including Graves’ disease. The best documented association of PTPN22 variants to autoimmune disorders including GD is rs2476601 (C1858T). Other genes associated with the risk of GD are thyrotropin receptor (TSHR), thyroglobulin gene, FCRL3, SCGB3A2, and CTLA4. This chapter will discuss in detail the genetics, pathophysiology, diagnosis and treatment of Graves’ hyperthyroidism

Elucidation of etiology of colorectal cancer: A study on silencing of p16 gene by promoter hypermethylation

Colorectal cancer (CRC), commonly known as bowel cancer is the third most common cause of cancer-related deaths in the western world. Colorectal cancer is one of the leading malignancies worldwide. CRC has been reported to show geographical variation in its incidence, even within areas of ethnic homogeneity. The usual treatment is surgery and subsequent chemotherapy and radiotherapy. Cancer development and progression is dictated by series of alterations in genes such as tumor suppressor genes, DNA repair genes, oncogenes and others. In colorectal carcinogenesis disturbances different from mutations called an epigenetic regulation are also taken into consideration. The aim of this study was to study the promoter hypermethylation of CpG islands of p16 gene in colorectal cancer patients among the Kashmiri population. The study included 70 surgically obtained colorectal samples among which 50 were obtained from colorectal cancer patients and 20 were histopathologically normal colorectal samples. All the samples were histopathologically confirmed before further processing. DNA was extracted from all the samples and was modified using bisulphite modification kit. Methylation-specific polymerase (MSP) chain reaction was used for analysis of the promoter hypermethylation status of p16 gene. The genetic analysis of the cases and controls by MSP- PCR method, for checking the promoter hypermethylation of CpG islands of p16 gene revealed that unlike other high risk regions, Kashmiri population has a different promoter hypermethylation profile of p16 gene. 66% of the cases showed p16 promoter hypermethylation while as 34% of the cases were nonhypermethylated. The study also revealed that 20% of the normal cases also had promoter hypermethylation of p16 gene and 80% did not showed promoter hypermethylation of p16 gene. The association of promoter hypermethylation with colorectal cancer was evaluated by χ2 (Chi square) test with Odds ratio and was found to be significant. Among 29 male cases and 21 female cases, the association of promoter hypermethylation with colorectal cancer was evaluated using Fisher’s exact test and was found to be significant in both males and females. Occurrence of p16 promoter hypermethylation was found to be unequally distributed in males and females with more frequency in males than in females but the difference was not statistically significant. When the frequency of p16 promoter hypermethylation was compared with clinical staging of the disease, p16 promoter hypermethylation was found to be certainly higher in Stage III/IV (83.33%) compared to Stage I/ II (56.25%) but the difference was not statistically significant. Also, the degree of p16 promoter hypermethylation increased with the increasing severity of the lesion but the difference was not again statistically significant. These results clearly suggest that p16 aberrant promoter hypermethylation in Kashmiri population contributes to the process of carcinogenesis in colorectal cancer and is reportedly one of the commonest epigenetic changes in the development of human CRC. It also demonstrates that hypermethylation of p16 gene can be designated as epigenetic biomarker for the screening, diagnosis and prognosis of colorectal cancer. The data gives a clue that p16 gene expression can be readily and fully restored and growth rate of cancer cells decreased by treatment of cancer cells with demethylating agents and DNA methylation inhibitors

MicroRNAs and its emerging role as breast cancer diagnostic marker- A review

Breast cancer causes severe mental stress on the affected woman during investigation, diagnosis and treatment as breast is regarded as a symbol of beauty, sexuality and motherhood. Over and above the primary function of feeding infant, breast symbolizes womanhood and serves as sexual object. Current biomedical research investigations have explored several potential breast cancer (BC) biomarker by utilizing serum proteins, natural oncogenic genes during improvement in molecular technologies as microarray and RNA/DNASeq. Recently smallest noncoding microRNAs are becoming the essential regulators in the oncogenesis pathways and they can act as handy noninvasive clinical diagnostic biomarkers. This newly introduced class of noninvasive biomarkers is rising as a new molecule for the cancer diagnosis and prognosis. A better understanding is the involvement of miRNAs in breast carcinogenesis can make available insights into the mechanisms of tumor development and could help to discover novel early potent noninvasive markers for early detection of breast Cancer. In recent clinical research the discovery of miRNAs in body fluids, such as serum and plasma opens the possibility of using them as noninvasive biomarkers of disease including breast cancer. Here in this review, we summarize the recent research studies supporting the utility of miRNAs as novel early diagnostic and prognostic tool. Thus, here we bring in potential future early stage detection strategies for breast cancer, which indicate the practicality and clinical applications of miRNAs in breast cancer

Molecular Pathogenesis of Inflammatory Cytokines in Insulin Resistance Diabetes Mellitus

Diabetes Mellitus Type 2 (T2DM) is a non-communicable and multifactorial disease. It is a leading cause of premature deaths worldwide. Inflammatory cytokines are reported that they have potential to enhance insulin resistance and hence T2DM. The current research was taken to investigate the possible role of inflammatory mediators: Tumor Necrosis Factor (TNF-α) and White blood cells (WBC’s) in mobilizing biological molecules mainly immunological nature. A total of 320 subjects were selected in this study among them 160 were T2DM cases and 160 were healthy controls. Serum concentration of Tumor Necrosis Factor-a (TNF-α) was quantified by ELISA method, WBC count was measured on Sysmax (Germany) hematology analyzer, biochemical and Immunoassay parameters were done on fully automatic analyzers. The expression of candidate pro-inflammatory cytokine (TNF-α), and (WBC’s) were elevated in T2DM. TNF-α shows association (p<0.001) with glycemic profile and insulin sensitivity in T2DM cases in comparison with healthy controls. Induction of inflammation and up regulation of pro-inflammatory cytokines has been purported to play a significant role in pathogenesis of T2DM and study confirms that the positive correlation of TNF-α with T2DM and hence to insulin sensitivity. These can act as early prediction biomarkers in diagnosis and prognosis of human disease i.e Diabetes Mellitus. Further studies are needed to help clinicians manage and treat T2DM effectively