Patterns of global DNA and histone methylation appear to be similar in normal, dysplastic and neoplastic oral epithelium of humans

Although there is growing interest in the possibility that alterations in histone methylation may play a role in carcinogenesis, it has not been explored adequately in humans. Similarly, there are no reports of associations between this and a similar epigenetic event, DNA methylation. Using immunohistochemical staining, we compared the methylation of DNA and histones in histopathologically normal oral epithelium, dysplastic oral lesions, and squamous cell cancers (SCCs) from subjects with squamous cell cancer (n=48) with those of normal oral epithelium from subjects without oral cancer (n=93) who were matched on age and race. Monoclonal antibodies specific for 5 methyl cytosine (5-mc), lysine 4 of histone H_3 (H_3-Lys4), and lysine 9 of histone H_3 (H_3-Lys9) were used in this study. The percentages of cells positive and a weighted average of the immunostaining intensity scores were calculated for each of these tissues, and Spearman correlation analyses were employed to study associations between DNA and histone methylation. Correlations between DNA and histone methylation, H_3-Lys4 and H_3-Lys9 were positive and statistically significant in all tissue types; they were strongest in normal oral epithelium from non-cancer subjects (r=0.63, p < 0.001 and r=0.62, p < 0.001 respectively). Similarly, the positive correlations between H_3-Lys4 and H_3-Lys9 were statistically significant in all tissue types and strongest in normal oral epithelium from non-cancer subjects (r=0.77, p< 0.001). Patterns of DNA and histone methylation are similar in tissues across the spectrum of oral carcinogenesis, and there is a significant positive association between these two epigenetic mechanisms.     

TGFbeta1 haplotypes and asthma in Indian populations

BACKGROUND: Asthma is a complex disorder of the airways of the lungs. TGF-beta1 plays a key role in airway remodeling and asthma by having both proinflammatory and anti-inflammatory activities, making TGFbeta1 an important candidate gene to study. OBJECTIVE: To investigate the association of TGFbeta1 gene polymorphisms with asthma. METHODS: A case-control study was designed for identifying polymorphisms and haplotypes associated with asthma and associated phenotypes. We have verified our results in 2 independent cohorts collected from northern (number of patients, 187; number of controls, 187) and western India (number of patients, 209; number of controls, 190). We measured the serum TGF-beta1 levels of selected individuals and correlated them with genotypes and haplotypes. RESULTS: A novel (CT)n(CA)m repeat polymorphism (BV209662) 24.9 kb upstream of TGFbeta1 was identified. A significant association was seen at the level of alleles and genotypes with asthma in the 2 cohorts studied independently (P < .05). Interestingly, a novel 3-locus haplotype, 23_G_T, was found to be significantly associated with asthma (P = .00001 in cohorts A and B) as well as with higher serum TGF-beta1 level (P = .01). On the other hand, a novel haplotype, 22_G_C, was negatively associated with asthma (P = .00001 for cohorts A and B) and with lower serum TGF-beta1 level (P = .0019). CONCLUSION: This is the first study identifying novel risk and protective haplotypes--23_G_T and 22_G_C, respectively--in the TGFbeta1 gene that are associated with asthma. We also demonstrate the functional significance of these haplotypes with serum TGF-beta1 levels. These results would be valuable in elucidating the role of TGF-beta1 in asthma pathogenesis.     

Pattern of nonspecific (or global) DNA methylation in oral carcinogenesis

BACKGROUND: Although alterations in nonspecific (or global) DNA methylation (GDM) in specific cells are known to be involved in the process of lung carcinogenesis, similar associations have not been evaluated in other smoking-related cancers of the head and neck. METHODS: We evaluated the status of GDM by using monoclonal antibodies specific for 5-methylcytosine (5-mc) in oral squamous cell carcinoma (SCC) specimens of 48 cigarette smokers who had SCC develop and in 93 age-, race-, and sex-matched smokers who did not. RESULTS: Percentages of cells positive for 5-mc immunostaining of DNA of SCC and dysplastic lesions were significantly higher than those of normal oral epithelial cells from cancer subjects and from noncancer subjects. The degree of DNA methylation was unrelated to DNA content. CONCLUSIONS: The pattern of GDM in oral SCCs is different from that of lung SCCs. The differences in nutrient risk factor profiles that are related to GDM and differential activity of DNA methyltranferases between oral and lung SCCs may explain these observations.     

UV light from 290 to 325 nm, but not broad-band UVA or visible light, augments the formation of melanocytic nevi in a guinea-pig model for human nevi

We have previously described a guinea-pig model where pigmented nevi similar to human nevi can be produced by application of low-dose topical 7,12-dimethylbenzanthracene (DMBA) followed by solar-simulated light. Five groups of guinea-pigs were used to test the effect of various spectral bands of solar-simulated light on low-dose DMBA-induced melanocytic nevi. Animals were irradiated with either UVB to near UVA2 (290-325 nm), UVA, visible light, full solar spectrum or no irradiation three times per wk for 12 mo to determine the broad-band effect of nevi-inducing irradiation. There was a significant increase in nevi/animal in the UVB-treated group (mean 1.53) compared with all groups (versus UVA 0.3, p<0.001; versus visible light 0.24, p<0.001; versus full spectrum (UVB+UVA+visible) 0.68, p=0.02; versus control (nil irradiation) 0.37, p=0.01). No differences in skin thickness were found between any group (p=0.11). In conclusion, we present a report of the active waveband of melanocytic nevi induction; where UVB to near UVA2 is the likely responsible waveband. Furthermore, because there was a significant decrease in nevi/animal receiving the full solar spectrum compared with the UVB group, it is possible that broad-band UVA and or visible light may be inhibitory wavebands for nevi induction.     

Expression of nm23-H1 protein in relation to myometrial invasion in complete hydatidiform moles

OBJECTIVE: Although nm23-H1 protein expression has been related to invasion in many cancers, its expression and prognostic significance in complete hydatidiform moles has not yet been investigated. The search for biologic parameters in molar placentas, which are useful for identifying patients who show myometrial invasion of the tumor, is crucial. We examined the clinical significance of nm23-H1 expression in complete hydatidiform mole. METHODS: Sections of 105 cases of complete hydatidiform moles (including 25 cases of invasive mole) and 95 cases of gestational age--matched normal placentas were immunohistochemically stained with anti-nm23-H1 antibody, which recognizes the nm23-H1/NDP kinase A gene product. RESULTS: Expression of nm23-H1 was detected in the cytotrophoblasts and syncytiotrophoblasts of molar placentas and normal placentas, whereas it was not detected in stromal tissue. Expression of nm23-H1 showed a negative relation to invasion, suggesting its use as a potential marker of myometrial invasion in complete hydatidiform moles. CONCLUSION: nm23-H1 expression could be used as a marker for accurate evaluation of myometrial invasion in complete hydatidiform mole.     

Genetic variations at microRNA and processing genes and risk of oral cancer

Genetic variations at microRNA and microRNA processing genes are known to confer risk of cancer in different populations. Here, we studied variations at eight microRNA (miRNA) and four miRNA processing genes in 452 controls and 451 oral cancer patients by TaqMan genotyping assays. Variant allele-containing genotypes at mir-196a2 and variant allele homozygous genotype at Ran increased the risk of cancer significantly [adjusted odds ratio (OR) (95 % confidence interval (CI))?=?1.3 (1–1.7) and 2.3 (1.1–4.6), respectively]. Conversely, variant allele-containing genotypes at mir-34b and variant allele homozygous genotype at Gemin3 reduced the risk of cancer significantly [adjusted OR (95 % CI)?=?0.7 (0.5–0.9) and 0.6 (0.4–1), respectively]. Cumulative risk was also increased by three times with increase in the number of risk alleles at these four loci. In tobacco stratified analysis, variant allele homozygous genotypes at mir-29a and Ran increased [adjusted OR (95 % CI)?=?1.5 (1–2.3) and 3 (1.1-8.4) respectively], while variant allele-containing genotypes at mir-34b decreased [adjusted OR (95 % CI)?=?0.6 (0.4–0.9)] the risk of cancer significantly. Thus, genetic variation at miRNA and processing genes altered the risk of oral cancer in this population thereby corroborating studies in other populations. However, it is necessary to validate this result in different Indian sub populations with larger sample sizes and examine the effect of these variations in tumour tissues to explain the mechanism of risk alteration.     

Modifiable factors for prevention of childhood mortality

Objective

To know the disease-related causes of child mortality and identify socially modifiable factors affecting child mortality among hospitalized children aged >1 month-18 years in a referral hospital of North India.

Methods

Causes of death (ICD-10 based) were extracted retrospectively from hospital files (n=487) from 17 March 2003 to 30 June 2012. Modifiable factors were prospectively studied in 107 consecutive deaths from 6 October 2011 to 30 June 2012.

Results

Pneumonia, CNS infections and diarrhea were the most common disease-related causes of child mortality.

Conclusions

Amongst modifiable factors, administrative issues were most common followed by family-related reasons and medical-personnel related problems.     

Prospects of multitarget drug designing strategies by linking molecular docking and molecular dynamics to explore the protein–ligand recognition process

The designing of drugs that can simultaneously affect different protein targets is one novel and promising way to treat complex diseases. Multitarget drugs act on multiple protein receptors each implicated in the same disease state, and may be considered to be more beneficial than conventional drug therapies. For example, these drugs can have improved therapeutic potency due to synergistic effects on multiple targets, as well as improved safety and resistance profiles due to the combined regulation of potential primary therapeutic targets and compensatory elements and lower dosage typically required. This review analyzes in-silico methods that facilitate multitarget drug design that facilitate the discovery and development of novel therapeutic agents. Here presented is a summary of the progress in structure-based drug discovery techniques that study the process of molecular recognition of targets and ligands, moving from static molecular docking to improved molecular dynamics approaches in multitarget drug design, and the advantages and limitations of each.