Ashim Ghatak

Oxy free radical system in heart failure and therapeutic role of oral vitamin E

Twenty patients of heart failure and ten matched healthy controls were included in the trial. Out of these 20 patients of heart failure, 12 patients were also studied prospectively. Plasma levels of superoxide anion and malonyldialdehyde were increased while the levels of superoxide dismutase, catalase and glutathione reductase were decreased in patients of heart failure as compared to control subjects. The alteration in oxidative stress and antioxidant system did not correlate with the age and sex of patients or the etiology of heart failure. With the increasing severity of heart failure the malonyldialdehyde and superoxide anion increased significantly and catalase, glutathione reductase and superoxide dismutase levels decreased. The group of heart failure patients with ejection fraction < 40% (n = 7) exhibited significantly higher levels of malonyldialdehyde than those with an ejection fraction > 40% (n = 13). The superoxide anion and malonyldialdehyde levels were significantly higher in patients of heart failure in the pre-treatment state as compared to those in post-treatment state. Conversely catalase, glutathione reductase and superoxide dismutase were higher in the post-treatment period as compared to their values before treatment. The addition of vitamin E in doses of 400 mg once a day orally for 4 weeks significantly reduced the malonyldialdehyde and superoxide anion levels and produced an elevation of the antioxidant enzymes. Thus, there is an apparent normalisation of the indices of oxidative stress following treatment of heart failure and a markedly improved response on vitamin E supplementation which may be more beneficial.

The free radical system in ischemic heart disease

The present work was conducted to evaluate the oxygen free radical system in 29 patients and comparing them with nine matched healthy controls of acute and chronic myocardial ischemic syndromes. The parameters assessed for oxidative stress were superoxide anion and malonyldialdehyde, and for the antioxidant defence system were superoxide dismutase, catalase and glutathione reductase. Both oxidative stress and the antioxidant defence system were altered in myocardial ischemia. Subset analysis revealed that in unstable angina and acute myocardial infarction, superoxide anion, malonyldialdehyde and glutathione reductase were elevated while superoxide dismutase and catalase levels were reduced. In stable angina only increased levels of superoxide anion and decreased levels of superoxide dismutase were found. However, this alteration was less marked than in unstable angina and acute myocardial infarction. In the post myocardial infarction group there was no alteration in any of these parameters.

Gefitinib, Methotrexate and Methotrexate plus 5-Fluorouracil as palliative treatment in recurrent head and neck squamous cell carcinoma

This study compared the efficacy and toxicity of Gefitinib, Methotrexate and Methotrexate plus 5-Fluorouracil (5-FU) in patients of recurrent squamous cell carcinoma of head and neck (SCCHN) treated with palliative intent. Patients with recurrent SCCHN not amenable to curative treatment were randomly assigned to Gefitinib, Methotrexate or Methotrexate plus 5-FU arm. The primary end point was overall survival. Secondary end points of interest were objective response rate, toxicity and quality of life. Total 117 patients were analyzed. Median overall survival and objective response rates were 8.8 months, 7.8 months and 8.1 months and 7.7%, 5.0% and 7.9% in Gefitinib, Methotrexate and Methotrexate plus 5-FU arms respectively with no statistically significant difference between 3 arms. Gefitinib had different toxicity profile compared with other arms. Majority of toxicities were Grade 1 or Grade 2. Gefitinib had significant improvement in quality of life during initial months over Methotrexate. There was no suggestion that Gefitinib significantly prolonged overall survival compared with Methotrexate and Methotrexate plus 5-FU. However, improved Quality of Life with manageable toxicities was observed.

Monocyte chemoattractant protein‐1 gene polymorphism and its serum level have an impact on anthropometric and biochemical risk factors of metabolic syndrome in Indian population

Monocyte chemoattractant protein‐1 (MCP‐1), encoded by gene CCL‐2 (Chemokine C‐C motif 2), is the ligand of chemokine receptor CCR‐2. Concurrent clinical alteration in several metabolic aspects, including central obesity, dysglycemia, dyslipidemia and hypertension, is clinically characterized as metabolic syndrome (MetS). Role of MCP‐1 in each of these aspects has been established in vitro and in animal studies as well. We here report genetic association of −2518 A>G MCP‐1 (rs 1024611) gene polymorphism and level of MCP‐1 with MetS in North Indian subjects. We analysed (n = 386, controls and n = 384, MetS subjects) for MCP‐1 gene polymorphism using PCR‐RFLP, its serum level using ELISA, anthropometric (body mass index, waist and hip circumferences, waist–hip ratio and blood pressure) and biochemical (serum lipids, plasma glucose and insulin levels) variables in a genetic association study. The body mass index, waist circumference, hip circumference, waist–hip ratio, blood pressure, serum lipids, insulin and fasting plasma glucose level were significantly high in MetS subjects. Regression analysis showed significant correlation of body mass index, waist and hip circumference, systolic/diastolic blood pressure, fasting glucose, total cholesterol, high‐density lipoprotein, low‐density lipoprotein fasting insulin and HOMA‐IR with MetS. MCP‐1 allele and genotype were significantly associated with MetS. Serum MCP‐1 level was high in overall cases. In conclusions, the MCP‐1 2518A>G (rs 1024611) polymorphism has significant impact on risk of MetS, and MCP‐1 level correlates with anthropometric and biochemical risk factors of MetS.

Correlation between expressions of Cyclin-D1, EGFR and p53 with chemoradiation response in patients of locally advanced oral squamous cell carcinoma

Introduction Cyclin-D1, p53 and EGFR are molecular markers that regulate the cell cycle and play an important role in tumor progression and development. The present study evaluates the prognostic significance of these markers with chemoradiation response in patients of locally advanced oral squamous cell carcinoma (OSCC). Material and method A total of 97 OSCC patients (females = 19 and males = 78), aged 20–67 years and stage III/IV were recruited. Treatment response was assessed according to WHO criteria. Cyclin-D1, p53 and EGFR expressions in tumor tissue was estimated by immunohistochemical (IHC) method and quantified as percentage positive nuclei. Results The positive expression rates of molecular markers were 86.6% for Cyclin-D1, 92.8% for EGFR and 85.6% for p53. The strong positive expressions of both Cyclin-D1 and p53 showed significant association with poor response. The Cox multivariate regression analysis showed coexpressions of Cyclin-D1 and p53 a significant and independent predictor of overall survival (OR = 1.90, 95% CI = 1.45–4.82, p = 0.046) after adjusting the demographic, clinicopathological and radiological response. The strong positive expressions of Cyclin-D1 and p53 and coexpressions of Cyclin-D1, EGFR and p53 showed significant (p < 0.05 or p < 0.01 or p < 0.001) and lower survival as compared to negative or moderate positive expressions and coexpressions, respectively. Conclusion Expressions and coexpressions of Cyclin-D1 and p53 may serve as a prognostic marker in OSCC patients.

Association of IL-10 gene (−1082A>G, −819C>T and −592C>A) polymorphism and its serum level with metabolic syndrome of north Indian subjects

Metabolic syndrome (MetS) is an inflammatory disorder, in which various cytokines play important role in tilting balance towards disease state. Interleukin-10 (IL-10) is an important antiinflammatory cytokine, but its genetic polymorphisms and serum levels in Indian MetS subjects are unknown. Three IL-10 gene polymorphisms (−1082A >G (rs1800896), −819C >T (rs1800872) and −592C >A (rs1800871)) were genotyped with PCR-RFLP in MetS subjects (n = 384) and age/sex matched control subjects (n = 386). Serum IL-10 was measured using enzyme-linked immunosorbent assay. Serum IL-10 level was significantly low in MetS subject and significantly correlated with clinicobiochemical parameters of MetS. Of three investigated promoter polymorphisms, IL-10 –819C > T and –592C >A were significantly associated with risk of MetS. The mutant alleles −819T and −592A of IL-10 gene polymorphism were significantly higher in MetS subjects compared to controls. Of the four different haplotypes obtained, common ACC haplotype and rare GTA haplotype of IL-10 polymorphisms were associated with MetS. The mean of fasting insulin and HOMA-IR were significantly different between the genotypes of both −819 C >T and −592C >A polymorphisms of IL-10 in MetS subjects. These results suggested that polymorphisms in IL-10 gene (−819C >T and −592C >A), haplotypes (ACC and GTA) and serum level are significantly associated with risk of MetS. IL-10 −819C >T and −592C >A polymorphic variants are also significantly associated with insulin level and homeostasis model assessment-insulin resistance in north Indian MetS subjects.

IL-6 gene expression in adipose tissue of postmenopausal women and its association with metabolic risk factors

Adipose tissue secretes various kinds of adipokines that controls the glucose and lipid metabolism in humans. The abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) both are associated with metabolic syndrome and insulin resistance. IL-6 is one of the adipokines, which promotes insulin resistance and dyslipidemia in humans. The association of adipokines with metabolic syndrome at protein levels are well documented. However, their association at gene expression level are lacking. The present study was design to investigate IL-6 mRNA expression in adipose tissues (VAT and SAT) and its correlation with metabolic risk factors and insulin resistance (HOMA) in post menopausal women. A total of 108 Asian North Indian post menopausal women, 54 without metabolic syndrome (controls) and 54 with metabolic syndrome (cases) were recruited and evaluated. Overnight fasting blood samples were collected at admission and abdominal visceral and subcutaneous adipose tissues were collected during open abdomen surgery. The results showed significantly (p < 0.05 or p < 0.01 or p < 0.001) higher mean SBP, glucose, insulin, HOMA, TG, VLDL and serum IL-6 while significantly (p < 0.001) lower HDL and estrogen in cases as compared to controls. In cases, the relative mean SAT IL-6 expression was also significantly (p < 0.05) higher as compared to VAT. Further, in cases, the VAT IL-6 expression showed significant (p < 0.05 or p < 0.001) and negative correlation with WC, WHR, glucose, HOMA, TC, LDL and estrogen while SAT IL-6 expression also showed significant (p < 0.05 or p < 0.01 or p < 0.001) and negative correlation with WC, WHR and estrogen. The Cox regression analysis found VAT IL-6 mRNA expression the significant (p < 0.05 or p < 0.01) an independent predictor of WC, HOMA, TC, LDL and estrogen while SAT IL-6 mRNA expression the significant (p < 0.01) an independent predictor of TG and VLDL. The study concluded that IL-6 expressions of both visceral and subcutaneous tissues may be associated with metabolic risk factors in postmenopausal Asian North Indian women.

Understanding molecular markers in recurrent oral squamous cell carcinoma treated with chemoradiation

Introduction Oral cancer accounts for approximately 2.1% of all cancers worldwide. In India, oral squamous cell carcinoma (OSCC) is the most common cancer with half a million new cases diagnosed every year. More than 50% of patients eventually develop local recurrence or metastasis usually within the first 2-years following completion of treatment. It is beneficial to analyze the prognostic significance of Cyclin D1, p53 and EGFR which are critical mediators in the pathogenesis of OSCC. The objective of this study was to assess the association of expression of these markers with recurrence and pattern of recurrence in OSCC patients undergoing chemoradiation. Materials and Methods A Total 290 OSCC cases of locally advanced stage (III, IV) oral cancer with World Health Organization (W.H.O.) performance status of grade 0/1 in the year 2009–2012 were enrolled in the study. Treatment response was assessed according to W.H.O. criteria. Cyclin D1, EGFR and p53 expression in tumor tissue was estimated by immunohistochemical (IHC) method and quantified as percentage positive nuclei. Results During the 2-years follow up, 56 (19.3%) patients recurred, out of which, 47 (83.9%) were locoregional and 9 (16.1%) distant sites. On correlating, χ2 test showed significant (P < 0.05 or P < 0.01 or P < 0.001) association of marker expressions (Cyclin D1, EGFR and p53) with recurrence. The strong positive expressions of all three markers showed significant association with early time of recurrence. The multivariate logistic regression analysis showed significant (P < 0.05 or P < 0.01 or P < 0.001) association of recurrence with primary site, differentiation, Cyclin D1 and p53 expressions indicating these as an independent predictors of recurrence in OSCC. The Cyclin D1, EGFR and p53 expressions also showed significant (P < 0.001) poor survivals (OS, DFS and RFS) in patients with positive/strong positive expressions than negative expression suggesting their prognosis in OSCC. Conclusion Our results signifies that tumors over expressing Cyclin D1, EGFR and p53 are resistant to chemoradiation and are associated with increased risk of locoregional recurrence and metastasis in OSCC patients undergoing chemoradiation.

Impact of EGFR and p53 expressions on survival and quality of life in locally advanced oral squamous cell carcinoma patients treated with chemoradiation

EGFR and p53 are molecular markers which play important role in tumor progression and development. The objective of this study was to assess the association between EGFR and p53 expression and survival, and to determine whether EGFR and p53 expression levels were associated with differences quality of life in OSCC patients undergoing chemoradiation. A total of 120 OSCC patients aged 20–67 y and stage III/IV were recruited. Treatment response was assessed according to W.H.O. (1979). EGFR and p53 expression in tumor tissue was estimated by immunohistochemical (IHC) method and quantified as percentage positive nuclei. Molecular marker expressions of both EGFR and p53 were found significantly (P < 0.01 or P < 0.001) associated with overall response, survivals and quality of life. Neither EGFR nor p53 expression was associated with hematologic or non-hematologic toxicity. EGFR and p53 molecular marker expressions may have significant association with survival and QOL in OSCC patients undergoing chemoradiation.

SEROTONIN: UBIQUITOUS NEUROMODULATOR IN THE FAILING HEART

Serotonin exhibits various cardiovascular effects and evidence of its role in various cardiovascular disorders is emerging. Serotonin levels in whole blood and the platelet serotonin uptake were significantly increased in patients with heart failure compared to control subjects. However, the intraplatelet serotonin content was not significantly different in the two groups. We conclude that serotonin is involved in the syndrome of heart failure both directly and indirectly through its action on cardiac contractility, heart rate, preload, and afterload.