We investigated the gene and protein expressions of V-type ATPase protein subunit C1 (ATP6V1C1) in cases of oral squamous cell carcinoma (OSCC) and contralateral normal mucosa in smokers, nonsmokers ...and former smokers. Subjects were separated into five groups of 15: group 1, smokers with OSCC; group 2, normal contralateral mucosa of OSCC patients; group 3, chronic smokers; group 4, former smokers who had stopped smoking 1 year earlier; group 5, individuals who had never smoked. Exfoliative cytology specimens from oral mucosa of smokers, former smokers and nonsmokers showed normal gene and protein expression. We found significantly greater gene expression in the OSCC group than in the nonsmoker groups. No difference in gene expression was observed between normal contralateral mucosa and nonsmoker groups, smoker and nonsmoker groups or former smoker and nonsmoker groups. We observed intense immunostaining for ATP6V1C1 protein in all cases of OSCC and weak or no staining in smoker, former smoker and nonsmoker groups. Significantly greater expression of ATP6V1C1 protein was observed in the OSCC group compared to the other groups, which supports the role of ATP6V1C1 in effecting changes associated with oral cancer. Analysis of the mucosae of chronic smokers, former smokers and the normal contralateral mucosa of patients with OSCC showed unaltered ATP6V1C1 gene and protein expression. Early stages of carcinogenesis, represented by altered epithelium of chronic smokers, had neither gene nor protein alterations as seen in OSCC. Therefore, we infer that the changes in ATP6V1C1 occur during later stages of carcinogenesis. Our preliminary study provides a basis for future studies of using ATP6V1C1 levels for detecting early stage OSCC.
Background: Lipoprotein lipase catalyzes the hydrolysis of the triglycerides contained in both very-low-density lipoproteins and chylomicrons for storage in the adipose tissue and muscle of fats of ...both hepatic and dietary origin. The S447X-Stop lipoprotein lipase is the most common polymorphism of the enzyme, affecting roughly 20% of the population and is accompanied by normal or diminished fasting triglycerides and perhaps lower incidence of coronary artery disease (CAD). Delay in the removal of chylomicron and remnant is now an established risk factor for CAD.
Methods: Currently, the chylomicron metabolism has been evaluated in 12 normolipidemic subjects with the S447X-Stop and in 13 age- and sex-paired control subjects with no mutation. The doubly labeled chylomicron-like emulsion method was used to evaluate chylomicron metabolism. The emulsions labeled with cholesteryl-oleate (
14C-CE) and tri9,10-
3Holeate (
3H-Tg) were injected intravenously and the decay curves of the labels were determined by blood sampling over 60 min followed by radioactive counting.
Results: The fractional clearance rate (FCR, min
−1) of the labels was not different in the S447X carriers compared with the noncarriers (FCR
3H-Tg 0.035±0.019 and 0.030±0.009 ; FCR
14C-CE 0.008±0.007 and 0.009±0.007, respectively).
Conclusions: The chylomicron intravascular lipolysis monitored by the
3H-Tg emulsion and the remnant removal monitored by the
14C-CE emulsion were not altered by the presence of this polymorphism of great populational impact.
Coronary artery disease (CAD) has a high prevalence in the Brazilian population. Nevertheless, studies of genetic risk factors for CAD in this country have not been sufficiently conducted. We used ...the
Pvu II polymorphism (intron 15) at the low-density lipoprotein receptor (LDLR) gene to study the effect of variation at this locus in determining plasma lipid concentrations in 128 white subjects presenting a lipid profile suggesting high risk for CAD (HRG) and 100 white normolipidemic individuals (controls, CG). The
Pvu II polymorphism was detected by PCR–RFLP. The P1P1 genotype for
Pvu II polymorphism (homozygous for absence of restriction site) was greater in HRG individuals than in CG subjects (57% vs. 38%,
P<0.05). Moreover, the P1P1 genotype was strongly associated with high concentrations of total cholesterol (
P=0.0001), triglycerides (
P=0.0295), LDL-C (
P=0.0001), and VLDL-C concentrations (
P=0.0280) and lower HDL-C concentrations (
P=0.0051) in HRG subjects. Similarly, the CG individuals with P1P1 genotype presented high concentrations of total cholesterol and LDL-C compared to other genotypes (
P=0.0001). This study demonstrates the influence of
Pvu II polymorphism of the LDLR on serum lipid concentrations of individuals with low and high risk for CAD from Brazil.
CpG Island Methylation in Colorectal Adenomas Rashid, Asif; Shen, Lanlan; Morris, Jeffrey S. ...
The American journal of pathology,
09/2001, Letnik:
159, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Methylation of cytosines in CpG islands silences gene expression. CpG island methylator phenotype (CIMP) in colorectal cancers is characterized by abnormal methylation of multiple CpG islands ...including those in several tumor suppressor genes such as
p16, hMLH1, and THBS1. CpG island methylation has not been well characterized in adenomas. We evaluated methylation status at
p16, MINT2, and MINT31 loci, which are frequently methylated in colorectal carcinomas, in 108 colorectal adenomas from a prospective study of 50 patients without cancer. Methylation at one or more loci was present in 48% (52 of 108) of adenomas with 25% (19 of 76) CIMP-high (two or more methylated loci) and 32% (24 of 76) CIMP-low (one methylated locus). The
p16 gene was methylated in 27% (19 of 71) of adenomas. Methylation status of different adenomas from the same patient was not correlated (odds ratio, 0.93;
P = 0.77). Adenomas with tubulovillous or villous histology were frequently methylated: 73% (17 of 26)
versus 41% (35 of 85) of tubular adenomas (odds ratio, 3.46;
P = 0.02). High levels of microsatellite instability were more frequent in adenomas without methylation (13%
versus 2%; odds ratio, 8.48;
P = 0.05). Our results indicate that methylation plays an important role early in colorectal tumorigenesis. CpG island methylation is more common in adenomas with tubulovillous/villous histology, a characteristic associated with more frequent predisposition to invasive carcinoma. Methylation is distinct from microsatellite instability and develops in individual adenomas rather than resulting from a field defect in an individual patient.
The CpG island methylator phenotype (CIMP) is a newly described mechanism for carcinogenesis in colorectal carcinomas and adenomas characterized by methylation of multiple CpG islands. The causes of ...CIMP are unknown. We studied CIMP in hyperplastic polyps (HPs), with emphasis on patients with multiple HPs (5 to 10 HPs), large HPs (one HP >1 cm) or hyperplastic polyposis (>20 HPs). Methylation of
p16, MINT1, MINT2, MINT31, and
hMLH1 was analyzed by methylation-specific polymerase chain reaction in 102 HPs, 8 serrated adenomas, 19 tubular adenomas, and 9 adenocarcinomas from 17 patients, with multiple/large HPs or hyperplastic polyposis and in 16 sporadic HPs from 14 additional patients. Sporadic HPs were CIMP-negative (not methylated at any locus), but 43% of HPs from multiple/large HPs, or hyperplastic polyposis were CIMP-high (two or more methylated loci,
P = 0.00001). Methylation among the four loci was correlated within HPs (odds ratio, 3.41;
P = 0.002), and the methylation status of HPs within the same patient was also correlated (odds ratio, 5.92;
P = 0.0001). CIMP-high HPs were present primarily in patients with a predominance of HPs in the right colon and/or serrated adenomas (
P = 0.0009) and were associated with the absence of K-ras proto-oncogene mutations (odds ratio, 5.08;
P = 0.03). Our findings of concordant CpG island methylation of HPs in multiple/large HPs or hyperplastic polyposis supports the concept that some patients have a hypermethylator phenotype characterized by methylation of multiple HPs and other colorectal lesions. The hypermethylator phenotype is related to patient-specific factors, such as carcinogenic exposure or genetic predisposition.
Severe acute respiratory syndrome (SARS) is an emerging infectious disease that first manifested in humans in China in November 2002 and has subsequently spread worldwide.
To describe the clinical ...characteristics and short-term outcomes of SARS in the first large group of patients in North America; to describe how these patients were treated and the variables associated with poor outcome.
Retrospective case series involving 144 adult patients admitted to 10 academic and community hospitals in the greater Toronto, Ontario, area between March 7 and April 10, 2003, with a diagnosis of suspected or probable SARS. Patients were included if they had fever, a known exposure to SARS, and respiratory symptoms or infiltrates observed on chest radiograph. Patients were excluded if an alternative diagnosis was determined.
Location of exposure to SARS; features of the history, physical examination, and laboratory tests at admission to the hospital; and 21-day outcomes such as death or intensive care unit (ICU) admission with or without mechanical ventilation.
Of the 144 patients, 111 (77%) were exposed to SARS in the hospital setting. Features of the clinical examination most commonly found in these patients at admission were self-reported fever (99%), documented elevated temperature (85%), nonproductive cough (69%), myalgia (49%), and dyspnea (42%). Common laboratory features included elevated lactate dehydrogenase (87%), hypocalcemia (60%), and lymphopenia (54%). Only 2% of patients had rhinorrhea. A total of 126 patients (88%) were treated with ribavirin, although its use was associated with significant toxicity, including hemolysis (in 76%) and decrease in hemoglobin of 2 g/dL (in 49%). Twenty-nine patients (20%) were admitted to the ICU with or without mechanical ventilation, and 8 patients died (21-day mortality, 6.5%; 95% confidence interval CI, 1.9%-11.8%). Multivariable analysis showed that the presence of diabetes (relative risk RR, 3.1; 95% CI, 1.4-7.2; P =.01) or other comorbid conditions (RR, 2.5; 95% CI, 1.1-5.8; P =.03) were independently associated with poor outcome (death, ICU admission, or mechanical ventilation).
The majority of cases in the SARS outbreak in the greater Toronto area were related to hospital exposure. In the event that contact history becomes unreliable, several features of the clinical presentation will be useful in raising the suspicion of SARS. Although SARS is associated with significant morbidity and mortality, especially in patients with diabetes or other comorbid conditions, the vast majority (93.5%) of patients in our cohort survived.
Patients with hyperplastic polyposis have multiple hyperplastic polyps (HPs) and increased risk of colorectal carcinomas. Aberrant crypt foci (ACF) are postulated to be the earliest precursor lesions ...in colorectal carcinogenesis. We evaluated
BRAF
mutations by DNA sequencing in 53 ACF from patients with sporadic colorectal carcinomas and familial adenomatous polyposis, in 18 sporadic HPs from patients with resected colorectal cancer, and in 70 HPs, 4 serrated adenomas, 3 admixed hyperplastic-adenomatous polyps, 10 tubular adenomas, and 6 carcinomas from 17 patients with multiple/large HPs and/or hyperplastic polyposis.
BRAF
mutation status was compared with clinicopathological features and other genetic alterations by marginal logistic regression.
BRAF
mutation was present in only 2% of ACF and 6% of sporadic HPs. In contrast,
BRAF
mutation was present in 43% of HPs (
P
= 0.01 versus sporadic HPs), 75% of serrated adenomas, 33% of admixed hyperplastic-adenomatous polyps, 30% of tubular adenomas, and 33% of carcinomas from patients with multiple/large HPs and/or hyperplastic polyposis.
BRAF
mutation status in patients with multiple/large HPs and/or hyperplastic polyposis correlated with HPs from the same patient (odds ratio, 5.8;
P
= 0.0002) but associated with younger age (odds ratio, 0.83;
P
= 0.006 compared to older age), with a large HP (odds ratio, 22.5;
P
= 0.01 compared with patients with multiple HPs), with location of HPs in the right colon (odds ratio, 3.0;
P
= 0.03), and with methylation of the
p16
gene and the MINT31 locus odds ratio, 12.2 (
P
= 0.0001) and 4.4 (
P
= 0.02), respectively. Our study shows that
BRAF
mutation status is heterogeneous among patients with multiple/large HPs and/or hyperplastic polyposis, suggesting differences in pathogenesis of HPs that indicate subsets within this phenotype.
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