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ABSTRACT: Molecular diagnostic adjuncts could improve the specificity of cervical cancer screening. Since persistent infection with human papillomavirus (HPV) is found in virtually 100% of cervical cancer cases, testing for markers of HPV integration may have a role in identifying underlying high-grade lesions in patients with low-grade cytologic abnormalities. Several proteins associated with the cell cycle are known to be affected by HPV integration into the host's DNA. Immunocytochemical identification of these upregulated proteins can assist in the identification of small numbers of pre-neoplastic or neoplastic cells in routine cytologic sampling.
Methods in molecular biology (Clifton, N.J.) 02/2009; 511:297-310.
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ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is rarely curable due to regional/metastatic spread at diagnosis. Identification of molecular markers may enhance diagnosis and early detection of PDA. The 2-electron reductase, NAD(P)H:quinone oxidoreductase (NQO1) has been found to be overexpressed in many solid tumors including PDA, and may be a useful clinically relevant diagnostic marker of malignancy. For this study, we used 37 surgical resection cases: 24 PDAs and 13 benign pancreatic tissue specimens. An additional 16 specimens from pancreatic endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) were included as a pilot series. NQO1 was detected by avidin-biotin based immunohistochemical and immunocytochemical methods. Both staining intensity and proportion of NQO1 positive tumor cells were scored. Moderate to strong (2 to 3+) staining for NQO1 was detected in 22/24 (92%) surgically resected PDAs, 9/9 (100%) EUS-FNAs with malignant diagnoses, one cytologically atypical but not diagnostic for malignancy EUS-FNA, and 1/6 (17%) EUS-FNAs initially diagnosed as negative for malignancy. Subsequent histologic assessment confirmed malignancy in all 9 cytologically positive EUS-FNAs and in the atypical case. The NQO1 positive case initially diagnosed as negative for malignancy showed no evidence of carcinoma on subsequent tissue biopsy. NQO1 staining was also observed in some benign ducts/cells; however, correlation of NQO1 expression with cellular morphology assessment minimizes the risk of false positive diagnosis. NQO1 is consistently overexpressed in PDA. Although NQO1 is observed in some benign tissue components, this marker may be a clinically useful diagnostic adjunct for detection of PDA, independent of tumor grade/stage.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 02/2008; 16(1):24-31. · 1.63 Impact Factor
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ABSTRACT: Cervical cancer is the second most common cancer in women worldwide. Human papillomavirus (HPV) is the etiologic agent for the vast majority of premalignant and malignant lesions, and high-risk HPV types can be detected in almost all cases of cervical dysplasia and carcinoma. HPV testing has been widely adopted for the triage of patients after a cervical cytology screening test (Papanicolaou smear or liquid-based cervical cytology such as ThinPrep or SurePath) interpretation of atypical squamous cells of undetermined significance (ASCUS), and HPV testing is increasingly used for screening in conjunction with cervical cytology. Although cervical cytology is a highly effective screening test for cancer, it has limited specificity for clinically significant lesions in cases with low-grade cytologic abnormalities. Up to a quarter of all patients may have a false-negative result on the basis of cervical cytology testing alone. This review focuses on HPV testing methods and molecular markers and their clinical relevance. HPV testing and surrogate molecular markers of HPV infection (p16INK4a) may help identify cases that are associated with underlying high-grade premalignant or malignant lesions and may also reduce aggressive treatment of patients with low-grade lesions.
Cancer 03/2007; 111(1):1-14. · 4.77 Impact Factor
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ABSTRACT: Cervical cancer is the second most common cancer in women worldwide. Human papillomavirus (HPV) is the etiologic agent for the vast majority of premalignant and malignant lesions, and high-risk HPV types can be detected in almost all cases of cervical dysplasia and carcinoma. HPV testing has been widely adopted for the triage of patients after a cervical cytology screening test (Papanicolaou smear or liquid-based cervical cytology such as ThinPrep or SurePath) interpretation of atypical squamous cells of undetermined significance (ASCUS), and HPV testing is increasingly used for screening in conjunction with cervical cytology. Although cervical cytology is a highly effective screening test for cancer, it has limited specificity for clinically significant lesions in cases with low-grade cytologic abnormalities. Up to a quarter of all patients may have a false-negative result on the basis of cervical cytology testing alone. This review focuses on HPV testing methods and molecular markers and their clinical relevance. HPV testing and surrogate molecular markers of HPV infection (p16INK4a) may help identify cases that are associated with underlying high-grade premalignant or malignant lesions and may also reduce aggressive treatment of patients with low-grade lesions. Cancer (Cancer Cytopathol) 2007;. © 2007 American Cancer Society.
Cancer 02/2007; 111(1):1 - 14. · 4.77 Impact Factor
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ABSTRACT: NAD(P)H:quinone oxidoreductase 1 (NQO1) has been proposed to stabilize p53 via a redox mechanism involving oxidation of NAD(P)H as a consequence of the catalytic activity of NQO1. We report that treatment of HCT-116 human colon carcinoma cells with the NQO1 inhibitor ES936 had no effect on the levels of p53 protein. ES936 is a mechanism-based inhibitor of NQO1 that irreversibly blocks the catalytic function of the enzyme. This suggests that a redox mechanism involving NQO1-mediated NAD(P)H oxidation is not responsible for the stabilization of p53. We also examined the ability of the NQO1 protein to associate with p53 using co-immunoprecipitation experiments. Results from these experiments demonstrated co-immunoprecipitation of NQO1 with p53 and vice versa. The association between p53 and NQO1 was not affected by treatment of HCT-116 cells with ES936, demonstrating that the association was not dependent on the catalytic activity of NQO1. A comparison of isogenic HCT-116 p53+/+ and HCT-116 p53-/- cells demonstrated an interaction of NQO1 and p53 only in the p53+/+ cells. Experiments performed in an in vitro transcription/translation system utilizing rabbit reticulocyte lysates confirmed the interaction of NQO1 and p53. In these experiments a full-length p53 coding region was used to express p53 in the presence of recombinant NQO1 protein. An association of p53 and NQO1 was also observed in primary human keratinocytes and mammary epithelial cells. In studies where mdm-2 co-immunoprecipitated with p53, no association of mdm-2 with NQO1 was observed. These data demonstrate an association between p53 and NQO1 that may represent an alternate mechanism of p53 stabilization by NQO1 in a wide variety of human cell types.
Journal of Biological Chemistry 04/2003; 278(12):10368-73. · 4.77 Impact Factor
