Hypermethylation, risk factors, clinical characteristics, and survival in 235 patients with laryngeal and hypopharyngeal cancers

BACKGROUND: It has been established that promoter hypermethylation occurs in several genes during the pathogenesis of head and neck cancer. The authors investigated the role played by the hypermethylation of 4 cancer-related genes in the survival of patients who had laryngeal and hypopharyngeal cancer and in the occurrence of second primary tumors. METHODS: Archival paraffin-embedded tissue (PET) samples were available from patients who were enrolled in a multicentric European case-control study that was performed between 1979 and 1982 and was followed up to 2000. Genomic DNA extracted from 235 PET samples were analyzed for promoter methylation status of the p16, O(6)-methylguanine-DNA methyltransferase (MGMT), death-associated protein kinase (DAP-K), and E-cadherin genes by using a methylation-specific polymerase chain reaction assay. RESULTS: Hypermethylation was present in 44% of samples for p16, in 27% of samples for MGMT, in 42% of samples for DAP-K, and in 43% of samples for E-cadherin. Hypermethylation of either individual genes or their combination was not associated with mortality from all causes, mortality from upper aerodigestive tract cancer, or the occurrence of second primary tumors. CONCLUSIONS: The analysis of a large series of patients with laryngeal and hypopharyngeal cancer suggested that hypermethylation is a frequent event in laryngeal and hypopharyngeal cancer, but it is not a predictor of mortality or second primary cancer.     

Structure-activity relationship of antiestrogens: a study using triarylbutenone, benzofuran, and triarylfuran analogues as models for triarylethylenes and triarylpropenones

In a study of the structure-activity relationship (SAR) of antiestrogens use has been made of certain 1,2,3-triarylbutenones, of 2-arylbenzofurans carrying aryl or aroyl substituents at C3, and of 2,3,4-triarylfurans as conformationally constrained models for triarylethylene (TAE) and triarylpropenone (TAP) prototypes. The position-specific contributions of substituents to receptor affinity and to agonist-antagonist profiles were used as aids in characterizing the relative binding orientation of the prototypes. Although most compounds were found to be weak receptor ligands and poorly active in vivo, the following conclusions could be drawn about their SAR: (i) (Z)-TAPs and TAEs interact with the receptor in an analogous manner using the trans-stilbene core, with their agonist-antagonist profiles depending on the nature of other substructures. (ii) Incorporation into the benzofuran framework introduces a stereoelectronic constraint that compromises the normal binding interactions of TAE, as well as TAP, prototypes, resulting in their poor affinities and weak biological activities. (iii) (E)-TAPs can interact with the receptor through their S-cis conformation, but such a binding mode is unlikely to account for their behavior as antagonists.     

A study on the impact of CYP2C19 genotype and platelet reactivity assay on patients undergoing PCI

Background

A thorough understanding of the patient''s genotype and their functional response to a medication is necessary for improving event free survival. Several outcome studies support this view particularly if the patient is to be started on clopidogrel due to the prevalence of clopidogrel resistance. Such guided therapy has reduced the incidence of Major Adverse Cardiac Events (MACE) after stent implantation.

Methods

Between August 2013 and August 2014, 200 patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) were prescribed any one of the anti-platelet medications such as clopidogrel, prasugrel or ticagrelor and offered testing to detect CYP2C19 gene mutations along with a platelet reactivity assay (PRA). Intended outcome was modification of anti-platelet therapy defined as either dose escalation of clopidogrel or replacement of clopidogrel with prasugrel or ticagrelor for the patients in clopidogrel arm, and replacement of ticagrelor or prasugrel with clopidogrel if those patients were non-carrier of mutant genes and also if they demonstrated bleeding tendencies in the ticagrelor and prasugrel arms.

Conclusion

Clopidogrel resistance was observed to be 16.5% in our study population. PRA was useful in monitoring the efficacy of thienopyridines. By having this test, one can be safely maintained on clopidogrel in non-carriers, or with increased dose of clopidogrel in intermediate metabolizers or with newer drugs such as ticagrelor or prasugrel in poor metabolizers. Patients on ticagrelor and prasugrel identified as non-carriers of gene mutations for clopidogrel metabolism could be offered clopidogrel resulting in economic benefits to the patients. Patients at high risk of bleeding were also identified by the PRA.     

Studies on the immunomodulatory effects of Boerhaavia diffusa alkaloidal fraction.

The alkaloidal fraction of Boerhaavia diffusa was studied for its effect on cellular and humoral functions in mice. Oral administration of the fraction (25-100 mg/kg) significantly inhibited SRBC-induced delayed hypersensitivity reactions in mice. However, the inhibition was observed only during post-immunisation drug treatment, while no effect during pre-immunisation drug treatment was observed. A significant dose-related increase in antibody titre was observed during pre- and post-immunisation treatment. The alkaloidal fraction failed to show any blastogenic responsiveness of murine splenocytes to Concanvalin A (Con A) and lipopolysaccharide (LPS). Similarly, it did not display any mitogenic activity. Thus, the present study has shown the in vivo immunostimulatory activity of B. diffusa alkaloidal fraction without an in vitro effect.     

Peak expiratory flow rates in elderly Indians

Peak expiratory flow rates were measured in 124 normal elderly men (55-85 yr) using the Wright's peak flow meter. In the less than 60 yrs age group (n = 32; mean age 57.7 yr) the PEFR was 431 +/- 13 lpm, while for the group greater than 60 yr (mean age 69.0 +/- 6.0; n = 92), the PEFR value was 373 +/- 11 1pm. These values are similar to those reported in other Indian studies, suggesting that the ethnic variations amongst Indian subjects do not affect the PEFR. However, the reported values are lower than those observed in Europeans, but greater than those of Chinese. The PEFR regressed at a rate of 4.47 1pm/year increase in age, but is positively correlated to the subjects' height (cm), and their FVC and FEVI. The smokers had a significantly higher PEFR as compared with the non-smokers. This finding was contrary to what was expected.     

Effect of pulmonary thromboembolism on circulating neutrophils in mice.

The role of free radical generation and its scavenging enzymes in circulating mice polymorphonuclear leukocytes (PMNLs) has been studied following pulmonary thromboembolism. Levels of malonaldehyde (MDA), 02- radical generation, activity of superoxide dismutase (SOD), catalase (CAT), lactate dehydrogenase (LDH), myeloperoxidase (MPO) and lysozyme were estimated in lysed neutrophil preparations. Activities of SOD and CAT were increased in neutrophils, while animals showed 60 +/- 4% thrombocytopenia. Levels of MDA in PMNLs were also elevated significantly following thrombosis. However, there was no significant change in superoxide radical generation, after thrombotic challenge, in mice neutrophils. The present study provides evidence for the involvement of free radicals in mice pulmonary thromboembolism.     

Effect of combined vitamins C and E supplementation on oxidant/antioxidant status in hemodialysis patients

The aim of this study was to evaluate the antioxidant supplementation effect on antioxidant system in hemodialysis patients. The study group consisted of 38 patients undergoing hemodialysis and 72 healthy subjects. The patients orally received combination of vitamins C (250 mg/time) and E (200 IU/time) three times per week for 2 months. Both, enzymatic antioxidants [superoxide dismutase (SOD) and glutathione peroxidase (GPx)] activities and non-enzymatic (vitamins E and C) levels and malondialdehyde (MDA) concentrations as lipid peroxidation product in patients were measured before and after supplementation compared with control group. The levels of antioxidants (vitamin E, C and SOD) (P < 0.0001) and GPx (P < 0.05) were significantly enhanced and MDA concentrations declined (P < 0.0001) during the supplementation period. The study demonstrates that combined supplementation of vitamins C and E can noticeably affect antioxidant status and protect against oxidative stress caused during hemodialysis.     

Role of free radicals in pulmonary thromboembolism in mice

Involvement of free radicals and their scavenging enzymes in mice pulmonary thromboembolism, induced by intravenous infusion of collagen and adrenaline, has been studied. Malonaldehyde (MDA) and activities of xanthine oxidase (XO), catalase (CAT) and superoxide dismutase (SOD) were estimated in platelets, heart and lung homogenates. MDA increased in all the tissues sharply, while animals showed 70-80% thrombocytopenia. Xanthine oxidase activity in these animals increase significantly in heart. However, increased SOD activity and decreased catalase activity was observed in platelets. Intravenous administration of superoxide dismutase (5 mg/kg), catalase (5 mg/kg) and mannitol (200 mg/kg) protected the mice against pulmonary thromboembolism. The importance of free radicals in mice pulmonary thromboembolism has been demonstrated.