Glutathione S-transferase M1 and T1 null genotypes as risk factors for oral leukoplakia in ethnic Indian betel quid/tobacco chewers.
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Oral cancer is the most common cancer in males and third most common in females in India, the main causative agent being the use of chewing tobacco with or without betel quid (BQ). However, nothing is known about the role of the host metabolic genes in oral cancer in ethnic Indian population. In this study, the prevalence of GSTM1 and GSTT1 null genotypes (GSTM1*2 and GSTT1*2) in oral premalignant leukoplakia cases and controls was ascertained in genomic DNA by a multiplex PCR technique. Biopsies taken from 98 oral leukoplakia patients and exfoliated cells from 82 healthy controls both of Indian ethnicity were analysed. GSTM1*1 (active) was present in 83% and GSTT1*1 (active) was present in 78% of all control subjects, while prevalence of GSTM1*2 and GSTT1*2 null genotypes was significantly higher among oral leukoplakia cases. The prevalence of GSTM1*2 in leukoplakia cases was 81.6% compared with 17% in controls [odds ratio (OR), 22; 95% confidence interval (CI), 1047] and GSTT1*2 was 75.5% in the cases versus 22% in controls (OR, 11; 95% CI, 5-22). Combined null genotypes of GSTM1 and GSTT1 prevailed in 60.2% of the cases with none detected in controls. Glutathione S-transferase M1 and T1 enzymes are both known to catalyse detoxification of reactive oxygen species, lipid peroxidation products and tobacco-derived carcinogens that have been found in the saliva of BQ/tobacco chewers. Our results, still requiring confirmation by a larger study, demonstrate that the null genotypes of both GSTM1 and GSTT1 increase with high penetrance, separately or in combination, the risk for developing leukoplakia in an Indian ethnic population. (+info)
Smokeless tobacco potentiates VIP-induced DNA synthesis and inactivates NEP 24.11 in oral keratinocytes.
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The purpose of this study was to determine whether exposure of cultured chemically transformed hamster oral keratinocytes (HCPC-1) to an aqueous extract of smokeless tobacco (STE) potentiates DNA synthesis elicited by vasoactive intestinal peptide (VIP), an autocrine neuropeptide, and, if so, whether this response is associated with inactivation of neutral endopeptidase 24.11 (NEP 24. 11), an ectoenzyme that cleaves and inactivates VIP very effectively, in these cells. I found that STE and VIP each elicited a modest, albeit significant, increase in DNA synthesis in cultured HCPC-1 cells (P < 0.05). However, incubation of HCPC-1 cells with STE together with VIP evoked a significant, concentration- dependent increase in DNA synthesis that was mediated by VIP receptors. The effects of STE and VIP were synergistic. Maximal response was observed after a 48-h incubation. STE significantly attenuated NEP 24.11 activity in HCPC-1 cells at a time when VIP-induced DNA synthesis was maximal. Collectively, these data indicate that STE potentiates VIP-induced DNA synthesis in cultured oral keratinocytes, and that this response is temporally related to STE-induced inactivation of NEP 24.11 in these cells. I suggest that NEP 24.11 modulates the mitogenic effects of smokeless tobacco in the oral epithelium, in part, by inactivating VIP. (+info)
Association between polymorphism in p21(Waf1/Cip1) cyclin-dependent kinase inhibitor gene and human oral cancer.
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The cyclin-dependent kinase inhibitor gene p21(Waf1/Cip1) plays a central role in inducing cellular growth arrest, terminal differentiation, and apoptosis. Alterations in this gene may adversely affect regulation of these processes and increase susceptibility for cancer. We have recently reported a novel polymorphism in the p21(Waf1/Cip1) gene in the Indian population and its association with esophageal cancer. An A-->G transition at codon 149 resulted in amino acid substitution from aspartate to glycine in the proliferating cell nuclear antigen binding COOH-terminal domain of p21(Waf1/Cip1) that may affect PCNA-p21(Waf1/Cip1) interactions, thereby affecting regulation of cellular proliferation, and may increase susceptibility for development of cancer. In a parallel study in our laboratory, we searched for putative p21(Waf1/Cip1) mutations in oral premalignant and malignant lesions. No somatic mutation was detected in exon 2 of p21(Waf1/Cip1). Interestingly, a codon 149 polymorphism variant (A-->G) was identified in 11 of 30 (37%) premalignant lesions (7 of 19 hyperplastic lesions and 4 of 11 dysplastic lesions) and 11 of 30 (37%) squamous cell carcinomas (SCCs). This codon 149 variant was also identified in paired lymphocytes of all of the patients with premalignant lesions and SCCs harboring the variant allele, suggesting the occurrence of a polymorphism. Lymphocyte DNA isolated from 50 unrelated age- and gender-matched healthy subjects was screened for this polymorphism. Seven of 50 (14%) normal controls harbored the A-->G codon 149 variant allele. Immunohistochemical analysis of p21(Waf1/Cip1) protein expression showed immunoreactivity in 19 of these 30 (63%) oral premalignant lesions and 16 of 30 (53%) SCCs. The most intriguing features of the study were: (a) the significant increase in frequency of this polymorphism not only in patients with oral SCCs (P = 0.038), but also in patients with premalignant lesions (P = 0.038), compared with normal controls; and (b) the significantly higher frequency of p21(Waf1/Cip1) variants (codon 149) in oral premalignant lesions (10 of 11 cases) and SCCs (11 of 11 cases) with wild-type p53 (P = 0.045) than in lesions with p53 mutations, suggesting that this polymorphism affects the p53 pathway and may play a vital role in oral tumorigenesis. Furthermore, overexpression of p21 protein in oral lesions harboring missense mutations in the p53 gene suggest a p53-independent role for p21 in the pathogenesis of oral cancer. (+info)
Propensity of HIV patients to seek urgent and emergent care. HIV Cost and Services Utilization Study Consortium.
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OBJECTIVE: To assess the propensity of HIV-infected adults to seek care for common symptoms, and to determine whether they would seek care in the emergency department (ED) or with their primary care provider. DESIGN: Cross-sectional interview study. SETTING: Patients in care in the 48 contiguous United States. PARTICIPANTS: A nationally representative group of HIV- infected adults selected using multistage probability sampling. MEASUREMENTS: Subjects were interviewed between January 1996 and April 1997. Patients with advanced disease (past AIDS diagnosis and/or CD4 cell count <200/microL) and early disease were asked how they would seek care for key HIV-associated symptom complexes. Three advanced disease and 3 early disease symptom scenarios were used. MAIN RESULTS: Most advanced disease patients (78% to 87%) would seek care right away from the ED or primary care provider for the symptoms asked. Most early disease patients (82%) would seek care right away for new respiratory symptoms; fewer would do so for headache (46%) or oral white patches (62%). In a multivariate model, independent predictors of propensity to use the ED for advanced disease symptoms included African-American ethnicity (adjusted odds ratio [OR], 2.5; 95% confidence interval [95% CI], 1.8 to 3.4); less education (adjusted OR, 1.4; 95% CI, 1.1 to 1.7); drug dependence (adjusted OR, 1.4; 95% CI, 1.1 to 1.7); annual income less than $5,000 (adjusted OR, 1.5; 95% CI, 1.0 to 2.3); and lower psychological well-being (adjusted OR, 0.9; 95% CI, 0.9 to 1.0). In early disease, the following independently predicted ED use: African American (adjusted OR, 4.7; 95% CI, 3.1 to 7.1) or Hispanic ethnicity (adjusted OR 2.4; 95% CI, 1.4 to 4.3), female gender (adjusted OR, 1.6; 95% CI, 1.2 to 2.2), annual income less than $5,000 (adjusted OR, 1.8; 95% CI, 1.1 to 3. 0), and lower psychological well-being (adjusted OR, 0.9; 95% CI, 0. 8 to 1.0). CONCLUSIONS: Many patients would use the ED instead of same-day primary care for several common symptoms of HIV disease. African Americans, the poor, and patients with psychological symptoms had a higher propensity to use the ED. (+info)
Clinical modulation of oral leukoplakia and protease activity by Bowman-Birk inhibitor concentrate in a phase IIa chemoprevention trial.
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Bowman-Birk inhibitor is a protease inhibitor derived from soybeans that has demonstrated chemopreventive activity in a number of in vitro and animal systems. We conducted a 1-month phase IIa clinical trial of Bowman-Birk inhibitor concentrate (BBIC) in patients with oral leukoplakia. BBIC was administered to 32 subjects with oral leukoplakia for 1 month. We assessed toxicity and clinical and histological response of the lesions, and oral mucosal cell protease activity (PA) and serum micronutrient levels were measured. Clinical response was determined by measurement of pre- and posttreatment individual and total lesion areas and analysis of blinded clinical judgments of photographs. On the basis of prespecified response criteria, 31% of patients achieved a clinical response (two with complete and eight with partial responses). BBIC was nontoxic in doses up to 1066 chymotrypsin inhibitory units. The mean pretreatment total lesion area decreased from 615 to 438 mm2 after BBIC treatment (P < 0.004). A linear fit of the dose-response relationship between dose of BBIC and decrease in total lesion area was suggested (P < 0.08), and analysis of blinded clinical impression from lesion photographs confirmed this relationship (P < 0.01). Overall, at all doses tested, a 24.2% decrease in total lesion area was observed following treatment (sign rank = -142; P < 0.004). High pretreatment PA was associated with greater decreases in PA after BBIC administration (P < 0.02). BBIC demonstrated clinical activity after oral administration to patients with oral leukoplakia. These results indicate that BBIC should be investigated for chemopreventive activity in a randomized clinical trial. (+info)
A clinico-pathological study of vulval dermatoses.
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A long-term review of 108 women suffering from various forms of vulval dermatosis is described and a detailed analysis of those with chronic hypertrophic vulvitis, lichen sclerosus et atrophicus, and neurodermatitis is made. One case of neurodermatitis and two cases of lichen sclerosus progressed to carcinoma but no case of chronic hypertrophic vulvitis became malignant. It is possible that vulval dermatoses occur more commonly in the nulliparous than in the parous women and there is a slight preponderance of women who are blood group A. It is suggested that the term "leukoplakia" should be abandoned and that vulval lesions should be described in precise and meaningful histological terms. (+info)
Prognosis of oral pre-malignant lesions: significance of clinical, histopathological, and molecular biological characteristics.
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The concept of a two-step process of cancer development in the oral mucosa, i.e., the initial presence of a precursor subsequently developing into cancer, is well-established. Oral leukoplakia is the best-known precursor lesion. The evidence that oral leukoplakias are pre-malignant is mainly derived from follow-up studies showing that between < 1 and 18% of oral pre-malignant lesions will develop into oral cancer; it has been shown that certain clinical sub-types of leukoplakia are at a higher risk for malignant transformation than others. The presence of epithelial dysplasia may be even more important in predicting malignant development than the clinical characteristics. Three major problems, however, are attached to the importance of epithelial dysplasia in predicting malignant development: (1) The diagnosis is essentially subjective, (2) it seems that not all lesions exhibiting dysplasia will eventually become malignant and some may even regress, and (3) carcinoma can develop from lesions in which epithelial dysplasia was not diagnosed in previous biopsies. There is, therefore, a substantial need to improve the histologic assessment of epithelial dysplasia or, since epithelial dysplasia does not seem to be invariably associated with or even a necessary prerequisite for malignant development, it may be necessary to develop other methods for predicting the malignant potential of pre-malignant lesions. As a consequence of these problems, numerous attempts have been made to relate biological characteristics to the malignant potential of leukoplakias. Molecular biological markers have been suggested to be of value in the diagnosis and prognostic evaluation of leukoplakias. Markers of epithelial differentiation and, more recently, genomic markers could potentially be good candidates for improving the prognostic evaluation of precursors of oral cancer. As yet, one or a panel of molecular markers has not been determined that allows for a prognostic prediction of oral pre-cancer which is any more reliable than dysplasia recording. However, these new markers could be considered complementary to conventional prognostic evaluation. (+info)
Allelic imbalance at chromosome 11 in head and neck squamous cell carcinoma in an Indian patient population.
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BACKGROUND: Genetic instability of chromosome 11 is a frequent event in many solid tumours, including head and neck squamous cell carcinoma (HNSCC). AIMS: To perform allelic imbalance analysis of cytogenetically mapped altered regions of human chromosome 11 in patients with HNSCC from eastern India. METHODS: Genomic alterations were investigated using highly polymorphic microsatellite markers in both HNSCC and leukoplakia tissues. RESULTS: Microsatellite markers D11S1758 from 11p13-15 and D11S925 from 11q23.3-24 had the highest frequency (38% and 32%, respectively) of loss of heterozygosity among all the markers analysed. Allelic loss at the marker D11S925 was seen in both leukoplakia and in all stages of HNSCC tumour tissues suggesting that it is an early event in HNSCC tumorigenesis. Microsatellite size alteration was also found to be high (> 20%) in several markers. In leukoplakia samples microsatellite instability was seen at a higher frequency than loss of the allele, indicating such alterations might initiate the process of tumorigenesis in HNSCC. CONCLUSIONS: The high rate of chromosomal alterations at 11q21-24 in HNSCC suggests the presence of a putative tumour suppressor gene in this region. (+info)