Biomedical subjects

Samir Lababidi

Publications and source records attributed to Samir Lababidi.

7 recordsLinked to original sources

PubMed2003

GoMiner: a resource for biological interpretation of genomic and proteomic data.

We have developed GoMiner, a program package that organizes lists of 'interesting' genes (for example, under- and overexpressed genes from a microarray experiment) for biological interpretation in the context of the Gene Ontology. GoMiner provides quantitative and statistical output files and two useful visualizations. The first is a tree-like structure analogous to that in the AmiGO browser and the second is a compact, dynamically interactive 'directed acyclic graph'. Genes displayed in GoMiner are linked to major public bioinformatics resources.

Computer Graphics↗

PubMed2003

Apoptotic susceptibility of cancer cells selected for camptothecin resistance: gene expression profiling, functional analysis, and molecular interaction mapping.

To study the molecular mechanisms by which drug resistance develops, we compared DU145 humanprostate cancer cells with a subline selected for resistance to camptothecin. Differences in gene expression level were assessed by hybridizing the two cell types against each other using quadruplicate "Oncochip" cDNA microarrays that included 1648 cancer-related genes. Expression levels differing by a factor of >1.5 were detected for 181 of the genes. These differences were judged statistically reliable on the basis of a stratum-adjusted Kruskal-Wallis test, after taking into account a dye-dependent variable. The 181 expression-altered genes included a larger than expected number of the "apoptosis-related" genes (P = 0.04). To assess whether this observation reflected a generalized resistance of RCO.1 to apoptosis, we exposed the cells to a range of stresses (cisplatin, staurosporine, UV, ionizing radiation, and serum starvation) and found greatly reduced apoptotic responses for RC0.1 (relative to DU145) using flow cytometric Annexin V and terminal deoxynucleotidyl transferase-mediated nick end labeling assays. We next examined the apoptosis-related genes in the context of a molecular interaction map and found expression differences in the direction "expected" on the basis of the apoptosis-resistance of RC0.1 for BAD, caspase-6, and genes that signal via the Akt pathway. Exposure of the cells to wortmannin, an inhibitor of the Akt effector phosphatidylinositol 3-kinase, provided functional support for involvement of the Akt pathway. However, closer examination of the molecular interaction map revealed a paradox: many of the expression differences observed for apoptosis-related genes were in the direction "contrary" to that expected given the resistance of RC0.1. The map indicated that most of these unexpected expression differences were associated with genes involved in the nuclear factor kappa B and transforming growth factor beta pathways. Overall, the patterns that emerged suggested a two-step model for the selection process that led to resistance in RC0.1 cells. The first hypothesized step would involve a decrease in apoptotic susceptibility through changes in the apoptosis-control machinery associated with the Bcl-2 and caspase gene families, and also in antiapoptotic pathways operating through Akt/PKB. The second step would involve changes in multifunctional upstream genes (including some genes in the nuclear factor kappa B and transforming growth factor beta pathways) that can facilitate apoptosis but that would also tend to contribute to cell proliferation in the presence of drug. Thus, we propose that a downstream blockade of apoptosis was "permissive" for the selection of upstream pathway changes that would otherwise have induced apoptosis. This model is analogous to one suggested previously for the relationship between oncogene function and apoptosis in carcinogenesis.

Androstadienes↗

PubMed2003

Plasma carotenoids, tocopherols, and antioxidant capacity in a 12-week intervention study to reduce fat and/or energy intakes.

OBJECTIVE: We examined plasma levels of carotenoids, tocopherols, and total antioxidant activity in women before and after dietary intervention to reduce fat and/or energy intakes. Dietary fat and energy may affect intake and bioavailability of carotenoids and tocopherols, and these micronutrient levels in turn can contribute to the antioxidant capacity of plasma. METHODS: Women were randomized onto one of four diets for 12 wk: non-intervention, low fat (15% of energy from fat with maintenance of energy intake), low energy (25% energy reduction with maintenance of percentage of energy from fat), and combined low fat and low energy. Fasting plasma was available for analysis from a subset (n = 41) of women enrolled in the study. RESULTS: Levels of carotenoids and tocopherols did not change significantly over 12 wk on any diet arm, despite a modest but statistically significant increase in fruit and vegetable intake in the women following the low-fat diet (from 3.3 to 5.2 servings/d excluding potatoes). Levels of Trolox-equivalent antioxidant capacity (TEAC), total cholesterol, and two major plasma antioxidants (urate and bilirubin) also did not change significantly. Of the individual micronutrients measured, lycopene and lutein/zeaxanthin correlated most strongly with TEAC values, and the correlation with lycopene was statistically significant before intervention. CONCLUSION: The decreases in dietary fat and energy intakes in this study were quite large, but this did not appear to have detrimental effects on plasma micronutrient levels, nor did it appreciably affect plasma antioxidants. Because lycopene levels were significantly associated with plasma TEAC before intervention, interventions that increase levels of lycopene might be more likely to increase the antioxidant capacity of plasma.

Adult↗

PubMed2003

Cytochrome p450 and glutathione transferase expression in human breast cancer.

PURPOSE: The cytochrome P-450 (CYP) and glutathione S-transferase (GST) enzyme systems may influence the biological effects of carcinogens, including estrogens. As such, these enzymes may predict the developmental risk of breast cancer, as well as be potential targets for chemoprevention. The purpose of this study was to compare the expression of GST-Pi and CYPs 1A1, 2B6, 2E1, and 3A4 in paired samples of normal and malignant breast tissue from patients with breast cancer and women undergoing reduction mammoplasty. EXPERIMENTAL DESIGN: Expression of CYPs 1A1, 2B6, 2E1, 3A4, and GST-Pi was quantified in breast tissue from 33 patients with breast cancer and in 17 women without history of cancer who underwent reduction mammoplasty. The expression of CYP 1A1, 2B6, 2E1, 3A4, and GST-Pi was quantified by immunoblotting. RESULTS: CYP 1A1, 2E1, and 3A4 expression was significantly lower (P < 0.05) in malignant tissue as compared with morphologically normal adjacent tissue. Conversely, GST-Pi expression was marginally lower in the normal tissue (P = 0.08). No significant difference in enzyme expression was seen between the tissue from reduction mammoplasty and normal tissue from breast cancer patients. There was a trend for higher expression of CYP 2B6 and GST-Pi in the estrogen receptor expressing tumors than those tumors without expression (P > 0.28). CONCLUSION: The expression of these enzymes was similar in morphologically normal breast tissue from patients with or without breast cancer. The expression of CYPs was down-regulated in the tumor tissue. The clinical significance of CYP alterations in breast cancer will need further characterization.

Aryl Hydrocarbon Hydroxylases↗

PubMed2002

Effect of low-fat and/or low-energy diets on anthropometric measures in participants of the women's diet study.

OBJECTIVE: To compare the effects of low-fat, low-energy and combination low-fat/low-energy intervention on changes in six anthropometric measures in Caucasian and African-American free-living women. METHODS: The effects of dietary counseling strategies for fat and/or energy reduction were examined on anthropometric measures in 86 pre-menopausal women, average BMI of 28 kg/m2, who participated in a 12-week intervention trial called the Women's Diet Study. The dietary goals were 15% of energy from fat and/or 25% reduction in energy intake, relative to reported baseline intake, using a 2 x 2 factorial design. Analysis of covariance models were constructed to evaluate changes in anthropometric measures over the 12 weeks of study. RESULTS: The biggest difference by race was in women who were relatively heavier at baseline, in which case African-American women lost significantly less weight but decreased their waist:hip ratio to a significantly greater extent than Caucasian women. With regard to the effects of diet arm, weight loss varied depending on baseline weight, and in women with higher baseline weights, the combination low-fat/low-energy diet resulted in the most weight loss (6.7 kg, p < 0.05). Decreases in the other anthropometric measures at week 12 were more uniform across diet arms and did not depend on baseline values. After controlling for previous weight history and race, the decreases in BMI, percent body fat and waist circumference after 12 weeks were statistically equivalent with the low-fat, low-energy or combination low-fat/low-energy diets. The relatively greater decreases in percent body fat and waist circumference with the combination diet versus the low-fat or low-energy diets were not statistically significant. CONCLUSION: The low-fat, low-energy and combination diets all resulted in similar and statistically significant decreases in BMI, percent body fat and waist circumference over 12 weeks of intervention. The extent of weight loss, however, varied depending on baseline weight, and the combination diet was the only intervention to result in significant weight loss for women who were heavier at baseline. This indicates that, although there may be an advantage for reducing dietary fat in initially heavier women, any of these counseling strategies could be effective for improving anthropometric predictors of health risks associated with overweight status. This is useful since flexibility in dietary choices may facilitate adherence to dietary counseling in some individuals.

Adult↗

PubMed2002

Methods to increase fruit and vegetable intake with and without a decrease in fat intake: compliance and effects on body weight in the nutrition and breast health study.

Dietary patterns that involve a decrease in fat and an increase in fruit and vegetable (FV) intake have been suggested to decrease cancer risks. In this study, intervention methods to selectively modify dietary fat and/or FV intakes were developed. Compliance to the diets and the effects on body weight are shown, because both of these dietary changes can impact on and be confounded by changes in energy intake. A total of 122 women with a family history of breast cancer were randomized onto one of four diets for 12 mo. Counseling methods were devised to increase amount and variety of FV consumed with or without a decrease in fat intake using modified exchange list diets. Women on the low-fat and combination low-fat/high-FV diet arms decreased their fat intakes to approximately 16% of energy. Women on the high-FV and the combination low-fat/high-FV diet arms increased FV intakes to approximately 11 servings/day. Despite counseling efforts to maintain baseline energy intakes, mean body weight increased significantly by 6 pounds in women in the high-FV diet arm and decreased significantly by 5 pounds in women in the low-fat diet arm. Percent body fat also was increased in the high-FV diet arm and decreased in the low-fat diet arm. Body weight and percent body fat in the combination diet arm did not change significantly. Control of energy intake, therefore, appears to have been achieved only when the addition of FV to the diet was balanced by a decrease in fat intake and both dietary components were enumerated daily. Maintenance of energy intake, therefore, did not appear to be attained intrinsically when individuals were counseled to make changes in the composition of their diets.

Adipose Tissue↗

PubMed2000

An Evaluation of Plasma Antioxidant Levels and the Risk of Breast Cancer: A Pilot Case Control Study.

Antioxidant micronutrients found in fruits and vegetables have been shown in numerous studies to be protective against cancer. There is limited information on the relationship between blood antioxidant micronutrient levels and cancer among ethnic minorities. We conducted a pilot case-control study to evaluate the potential for accrual to a study of the association of plasma levels of beta-carotene, retinol, lycopene, alpha-tocopherol, and gamma-tocopherol with breast cancer risk among African American and Caucasian women seen at a large university medical center in Detroit. Cases included women with newly diagnosed invasive breast cancer who had not yet had any cancer-related therapy and who were age-matched to controls within 5 years. Plasma levels of micronutrients were analyzed by high-pressure liquid chromatography. Compared to the expected accrual based on cancer registry data, only 26% (11/42) of African American women with breast cancer enrolled, while 100% (16/16) of Caucasian cases enrolled. Control women were quickly accrued with only a 6% refusal rate. Among African American women, there was a weak inverse association between plasma lycopene levels and breast cancer risk, with a mean level of 0.17 &mgr;mol/L (SD = 0.18) among cases, and 0.24 &mgr;mol/L (SD = 0.18) among controls (p = 0.09). There was a weak direct association between plasma retinol levels and breast cancer risk among African American women, with a mean retinol level of 2.37 &mgr;mol/L (SD = 0.73) among cases and 1.98 &mgr;mol/L (SD = 0.49) among controls (p = 0.132). The interaction effect of race and lycopene was statistically significant (p = 0.048). Among the lowest lycopene tertile, the risk of breast cancer among Caucasian women was 0.76 and the risk of breast cancer among African American women was 2.29, although these odds ratios were not statistically significant. Our recruitment efforts were largely successful among Caucasian cases and controls, and African American controls, but were unsuccessful among African American cases. The results suggest a possible relationship between plasma lycopene level and breast cancer among African American women, but these results should be confirmed by a larger, more definitive study.

Journal Article↗