D-loop somatic mutations and ∼5 kb "common" deletion in mitochondrial DNA: important molecular markers to distinguish oral precancer and cancer.

Apart from genomic DNA, mutations at mitochondrial DNA (mtDNA) have been hypothesized to play vital roles in cancer development. In this study, ∼5 kb deletion and D-loop mutations in mtDNA and alteration in mtDNA content were investigated in buccal smears from 104 healthy controls and 74 leukoplakia and 117 cancer tissue samples using Taqman-based quantitative assay and re-sequencing. The ∼5 kb deletion in mtDNA was significantly less (9.8 and 10.5 folds, P < 0.0001) in cancer tissues compared to control and leukoplakia tissues, respectively. On the other hand, somatic mutations in D-loop, investigated in 54 controls, 50 leukoplakias and 56 cancer patients, were found to be significantly more in cancer tissues, but not in leukoplakia tissues, compared to control (Z-score = 5.4). MtDNA contents were observed to be significantly more in leukoplakia (2.1 folds, P = 0.004) and cancer (1.6 folds, P = 0.03) tissues compared to control tissues. So, D-loop somatic mutations and ∼5 kb deletion patterns could be used as distinguishing markers between precancer and cancer tissues. This observation further suggests that somatic mutations in D-loop may facilitate carcinogenesis and cancer cells with less ∼5 kb deletion, i.e., intact mtDNA, may become resistant to apoptosis.

Antiplatelet drug resistance in patients with recurrent acute coronary syndrome undergoing conservative management.

AIMS AND OBJECTIVES: Recurrent ischemic events continue to occur despite combination anti-platelet therapy. Currently aspirin, clopidogrel and dual resistance are increasingly recognized entities. The relationship of such resistance to recurrent ischemic events is largely unknown. In this study, we tried to gain an insight into the role of antiplatelet drug resistance with recurrent Acute Coronary Syndrome (ACS). MATERIALS AND METHODS: The antiplatelet effect of aspirin and clopidogrel was studied in 40 recurrent ACS patients and 170 patients with first episode of ACS, after > or = 7 days of dual antiplatelet therapy. Platelet aggregation study was done with optical aggregometer. Resistance to aspirin and clopidogrel was defined as > or = 50% aggregation with collagen and ADP respectively. RESULTS: Aspirin, clopidogrel and dual drug resistance were encountered respectively in 35%, 72.5% and 32.5% patients with recurrent ACS. The corresponding figures for the patients with first episode of ACS were 25.3%, 42.3% and 18.8% respectively. P values for the comparisons were 0.237 for aspirin, 0.0007 for clopidogrel and 0.084 for dual drugs. Patients with recurrent ACS were relatively younger and had a higher prevalence of conventional risk factors like hypertension, diabetes and elevated LDL. CONCLUSION: Antiplatelet drug resistance is likely to play an important role in recurrent ACS alongside other conventional risk factors. Further research is required in this field to have a definitive conclusion.

Variant haplotypes at XRCC1 and risk of oral leukoplakia in HPV non-infected samples.

BACKGROUND: One of the mechanisms in human papillomavirus (HPV)-related carcinogenesis is inhibition of DNA repair by HPV oncoprotein. In this study, we investigated whether polymorphisms at XRCC1, one of the DNA repair loci, could modulate the risk of tobacco-related leukoplakia and cancer in HPV-infected individuals. METHODS: Tissue DNA from 83 oral cancer, 91 leukoplakia and 100 healthy controls were screened for HPV 16/18 infection and polymorphisms at XRCC1 by PCR-RFLP to estimate the risk of diseases independently and jointly. RESULTS: Human papillomavirus infection was significantly associated with increased risk of leukoplakia and cancer (OR = 2.8, 95% CI = 1.2-6.5 and OR = 5.5, 95% CI = 1.6-19, respectively). Independently, genotypes at three polymorphic sites on XRCC1 did not modulate the risk of diseases but pooled variant haplotypes increased the risk of leukoplakia in overall and HPV non-infected (OR = 1.8, 95% CI = 1.2-2.8; OR = 2.2, 95% CI = 1.2-4.0, respectively) samples but not that of cancer. CONCLUSION: The association between variant haplotypes at XRCC1 and risk of leukoplakia is pronounced in non-infected individuals since HPV oncoprotein could inhibit directly the DNA repair activity of XRCC1. But more samples of leukoplakia and cancer are essential to validate these results.

Pharmacogenomics of anti-TB drugs-related hepatotoxicity.

Anti-TB drug (ATD)-related hepatotoxicity is a worldwide serious medical problem among TB patients. Apart from acting on the bacteria, isoniazid, the principal ATD, is also metabolized by human enzymes to generate toxic chemicals that might cause hepatotoxicity. It has been proposed that the production and elimination of the toxic metabolites depends on the activities of several enzymes, such as N-acetyl transferase 2 (NAT2), cytochrome P450 oxidase (CYP2E1) and glutathione S-transferase (GSTM1). There is now evidence that DNA sequence variations or polymorphisms at these loci (NAT2, CYP2E1 and GSTM1) could modulate the activities of these enzymes and, hence, the risk of hepatotoxicity. Since the prevalence of polymorphisms is different in worldwide populations, the risk of ATD hepatotoxicity varies in the populations. Thus, the knowledge of polymorphisms at these loci, prior to medication, may be useful in evaluating risk and controlling ATD hepatotoxicity.