EXPLORING THE INTERRELATIONSHIP BETWEEN ELECTROLYTES, ANEMIA, AND GLYCOSYLATED HEMOGLOBIN (HBA1C) LEVELS IN TYPE 2 DIABETICS

  Objective: The aim of this study is to analyze the interrelationship and pattern of electrolyte imbalance and compare the correlation between serum electrolytes, glycosylated hemoglobin (HbA1C), and hemoglobin (Hb) levels between Type 2 diabetic patients and non-diabetic subjects.Methods: This study was conducted in 300 subjects (150 diabetics and 150 non-diabetics) and further categorized as anemic and non-anemic within each group. Blood samples were analyzed for HbA1C, hemoglobin, and serum electrolyte levels.Results: Sodium (Na+) levels in diabetics were significantly lower and potassium (K+) as well as chloride (Cl−) levels were significantly higher, when compared with non-diabetics. A significant positive correlation between HbA1C and potassium as well as chloride levels in contrast to negative correlation with sodium levels was observed in both genders. Among diabetics with anemia, we found significantly lower sodium and higher potassium and chloride.Conclusion: In diabetics, levels of sodium were significantly lower, and potassium as well as chloride was significantly higher when compared with non-diabetics. Our study clearly demonstrates an association between electrolytes, hemoglobin, and HbA1C levels in diabetes. This insight should pave the way for pathophysiology-directed therapy, thus contributing to the avoidance of several deleterious effects associated with electrolyte disorders and their treatment

Original Article

Phosphodiesterase specific for the hydrolysis of diphenylphosphate, one of aromatic phosphodiesters, was obtained from hog kidney by following procedure. To hog kidney homogenized in a Waring blendor with 3 volumes of distilled water was added solid sodium chloride to a final concentration of 1% and after adjusting of pH to 5 with ca. 5 N hydrochloric acid, it was shaken for 10 minutes with an equal volume of n-butanol, allowed to stand for one hour, and centrifuged. The aqueous extract present beneath the floating gel layer of protein and butanol mixture, was siphoned out and fractionated with ammonium sulfate. The precipitate obtained between 45 and 70 % saturation was dissolved in a small volume of distilled water, dialyzed for 48 hours against running tap water, and then, to inactivate the monoesterase, heated in water bath of 100° for 5 minutes, whereby the solution became faintly turbid. The enzyme solution, thus prepared, hydrolyzed diphenylphosphate, liberating phenol but no inorganic phosphate, while it was inactive to monophenylphosphate. Diphenylphosphate of a final concentration of 0.0005M could be hydrolyzed in one hour at the optimum pH 7 to the extent of 40%. At this pH, the enzyme activity was not influenced by addition of Mg^, Ca^, or CN^. Bis-dichloroisopropylphosphate, dibenzylphosphate, diethylphosphate, lysolecithin, RNA, and DNA were resistant to this enzyme. It is conceivable that these diesters are hydrolyzed by other enzymes different from the aromatic phosphodiesterase, presented in this paper

A Precisely Regulated Gene Expression Cassette Potently Modulates Metastasis and Survival in Multiple Solid Cancers

Successful tumor development and progression involves the complex interplay of both pro- and anti-oncogenic signaling pathways. Genetic components balancing these opposing activities are likely to require tight regulation, because even subtle alterations in their expression may disrupt this balance with major consequences for various cancer-associated phenotypes. Here, we describe a cassette of cancer-specific genes exhibiting precise transcriptional control in solid tumors. Mining a database of tumor gene expression profiles from six different tissues, we identified 48 genes exhibiting highly restricted levels of gene expression variation in tumors (n = 270) compared to nonmalignant tissues (n = 71). Comprising genes linked to multiple cancer-related pathways, the restricted expression of this “Poised Gene Cassette” (PGC) was robustly validated across 11 independent cohorts of ∼1,300 samples from multiple cancer types. In three separate experimental models, subtle alterations in PGC expression were consistently associated with significant differences in metastatic and invasive potential. We functionally confirmed this association in siRNA knockdown experiments of five PGC genes (p53CSV, MAP3K11, MTCH2, CPSF6, and SKIP), which either directly enhanced the invasive capacities or inhibited the proliferation of AGS cancer cells. In primary tumors, similar subtle alterations in PGC expression were also repeatedly associated with clinical outcome in multiple cohorts. Taken collectively, these findings support the existence of a common set of precisely controlled genes in solid tumors. Since inducing small activity changes in these genes may prove sufficient to potently influence various tumor phenotypes such as metastasis, targeting such precisely regulated genes may represent a promising avenue for novel anti-cancer therapies

Oncogenic Pathway Combinations Predict Clinical Prognosis in Gastric Cancer

Many solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-κB, and Wnt/β-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior. Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancer-related pathways interacting simultaneously in primary cancers, at a scale not currently achievable by other platforms

Delineation of HIF1a mediated transcription program and the oncogenic signaling pathways in gastric tumors

HIF1α is a transcription factor activated under hypoxic condition in many cancer types and has been implicated in cancer cell proliferation, invasion and energy metabolism. Towards understanding the role of HIF1α mediated transcription in gastric cancer, the HIF1α gene signatures established to date were analyzed for their expression across the mRNA profiles of gastric tumors. HIF1α regulated genes were identified to involve and associated with the signaling pathways and processes such as integrin signaling, Wnt, P53, EGF, FGF, VEGFA, PI3K, TGFβ and NFkB signaling pathways.  The HIF1a genes were identified to play a significant role in energy metabolism including glycolysis, drug resistance due to epithelial to mesenchymal transition and cancer cell survival. In gastric tumors, the HIF1α regulated genes were observed to express in diffuse, poorly differentiated and stage-3 tumors. The analyses reveal i) activation of HIF1 in a sub-set of gastric tumors, ii) the pathways associated with the HIF1 activation in gastric tumors, and iii) genes involved in HIF1α mediated transcription in gastric cancer. We are further investigating the drugs that would best suit for this sub-set of tumors with activated HIF1α

Functional Genomic investigation of Peroxisome Proliferator-Activated Receptor Gamma (PPARG) mediated transcription response in gastric cancer

Cancer is a complex and progressive multi-step disorder that results from the transformation of normal cells to malignant derivatives. Several oncogenic signaling pathways are involved in this transformation. PPARG (Peroxisome proliferator-activated receptor gamma) mediated transcription and signaling is involved in few cancers. We have investigated the PPARG in gastric tumors. The objective of the present study was to investigate the PPARG mediated transcriptional response in gastric tumors. Gene-set based and pathway focused gene-set enrichment analysis of available PPARG signatures in gastric tumor mRNA profiles shows that PPARG mediated transcription is highly activated in intestinal sub-type of gastric tumors. Further, we have derived the PPARG associated genes in gastric cancer and their expression was identified for the association with the better survival of the patients. Analysis of the PPARG associated genes reveals their involvement in mitotic cell cycle process, chromosome organization and nuclear division. Towards identifying the association with other oncogenic signaling process, E2F regulated genes were found associated with PPARG mediated transcription. The current results reveal the possible stratification of gastric tumors based on the PPARG gene expression and the possible development of PPARG targeted gastric cancer therapeutics. The identified PPARG regulated genes were identified to be targetable by pioglitazone and rosiglitazone. The identification of PPARG genes also in the normal stomach tissues reveal the possible involvement of these genes in the normal physiology of stomach and needs to be investigated

Breast tumors with elevated expression of 1q candidate genes confer poor clinical outcome and sensitivity to Ras/PI3K inhibition.

Genomic aberrations are common in cancers and the long arm of chromosome 1 is known for its frequent amplifications in breast cancer. However, the key candidate genes of 1q, and their contribution in breast cancer pathogenesis remain unexplored. We have analyzed the gene expression profiles of 1635 breast tumor samples using meta-analysis based approach and identified clinically significant candidates from chromosome 1q. Seven candidate genes including exonuclease 1 (EXO1) are consistently over expressed in breast tumors, specifically in high grade and aggressive breast tumors with poor clinical outcome. We derived a EXO1 co-expression module from the mRNA profiles of breast tumors which comprises 1q candidate genes and their co-expressed genes. By integrative functional genomics investigation, we identified the involvement of EGFR, RAS, PI3K / AKT, MYC, E2F signaling in the regulation of these selected 1q genes in breast tumors and breast cancer cell lines. Expression of EXO1 module was found as indicative of elevated cell proliferation, genomic instability, activated RAS/AKT/MYC/E2F1 signaling pathways and loss of p53 activity in breast tumors. mRNA-drug connectivity analysis indicates inhibition of RAS/PI3K as a possible targeted therapeutic approach for the patients with activated EXO1 module in breast tumors. Thus, we identified seven 1q candidate genes strongly associated with the poor survival of breast cancer patients and identified the possibility of targeting them with EGFR/RAS/PI3K inhibitors

Primers used for Real-time quantitative PCR.

<p>Primers used for Real-time quantitative PCR.</p