Cathepsin D is a lysosomal hydrolase involved in intra- and extracellular proteolysis. This enzyme is aberrantly produced and processed in malignancy, and most notably is over-secreted into the tumor cell microenvironment. This hyper-secretion may lead to excessive degradation of the extracellular matrix, and contribute to tumor progression and metastases. These phenomena have been established in vitro, and there is evidence that Cathepsin D is similarly dysregulated in human breast cancer patients. Because breast cancer lacks an effective screening or surveillance biomarker, here we address the hypothesis that serum Cathepsin D activity may be useful to assess the presence or progression of breast cancer in females. While representative histologic sections from various disease-specific cohorts confirm previous findings that increased Cathepsin D production and secretion correlate with tumor progression, we report no difference in serum Cathepsin D activity between patients who are disease free, patients with pre-invasive or limited invasive disease, and patients with metastatic disease. Furthermore, in patients with known metastatic disease, there were no clinical variables associated with significantly different serum Cathepsin D activity. However, the immunohistochemical localization of Cathepsin D expression in histopathologic sections from breast cancer patients correlates with disease progression. Based on the serum results, and in contradistinction to Cathepsin D localization in breast cancer tissues, our findings support using Cathepsin D as a reliable histopathology biomarker for disease progression, but not for serum screening. Abbott, D. E. Margaryan, N. V. Jeruss, J. S. Khan, S. Kaklamani, V. Winchester, D. Hansen, N. Rademaker, A. Khalkhali-Ellis, Z. Hendrix, M. J. 0 2009-11-21T07:19:50Z 2010-01-15 2009-11-20 %0 Journal Article %A Abbott, D. E. %A Margaryan, N. V. %A Jeruss, J. S. %A Khan, S. %A Kaklamani, V. %A Winchester, D. %A Hansen, N. %A Rademaker, A. %A Khalkhali-Ellis, Z. %A Hendrix, M. J. %D 2010 %T Reevaluating cathepsin D as a biomarker for breast cancer: Serum activity levels versus histopathology. %J Cancer Biol Ther %V 9 %N 1 %M 19923884 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19923884 %X Cathepsin D is a lysosomal hydrolase involved in intra- and extracellular proteolysis. This enzyme is aberrantly produced and processed in malignancy, and most notably is over-secreted into the tumor cell microenvironment. This hyper-secretion may lead to excessive degradation of the extracellular matrix, and contribute to tumor progression and metastases. These phenomena have been established in vitro, and there is evidence that Cathepsin D is similarly dysregulated in human breast cancer patients. Because breast cancer lacks an effective screening or surveillance biomarker, here we address the hypothesis that serum Cathepsin D activity may be useful to assess the presence or progression of breast cancer in females. While representative histologic sections from various disease-specific cohorts confirm previous findings that increased Cathepsin D production and secretion correlate with tumor progression, we report no difference in serum Cathepsin D activity between patients who are disease free, patients with pre-invasive or limited invasive disease, and patients with metastatic disease. Furthermore, in patients with known metastatic disease, there were no clinical variables associated with significantly different serum Cathepsin D activity. However, the immunohistochemical localization of Cathepsin D expression in histopathologic sections from breast cancer patients correlates with disease progression. Based on the serum results, and in contradistinction to Cathepsin D localization in breast cancer tissues, our findings support using Cathepsin D as a reliable histopathology biomarker for disease progression, but not for serum screening. %+ Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 8611 false false 1 Cancer biology & therapy Cancer Biol Ther 2010-01-15 aheadofprint JOURNAL ARTICLE 19923884 Publisher 2009-11-21T07:19:50Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19923884 9 2010 Background: Free radical Injury is associated with cancer, but how the extent of oxidative stress correlates with the FIGO (International Federation of Gynecology and Obstetrics) stage in Carcinoma Cervix (Ca Cx), and its significance as a prognostic marker, is not clear and needs an in-depth study. Aim: To correlate the blood levels of Lipid Peroxidation (LPO), Reduced Glutathione (GSH), Superoxide Dismutase (SOD), and Vitamin A and E levels with the clinical stage in Ca Cx. Settings and Design: This is a Prospective Case Control Study. Materials and Methods: LPO, SOD, reduced GSH were estimated by Bio Chemical Assays and Vitamins by High Performance Liquid Chromatography (HPLC). Statistical Analysis: The cases and controls were compared using One Way ANOVA and different stages over different time periods were individually compared by Repeated Measure Analysis of Variance. Results: The results indicated a statistically significant increase of LPO vis-a-vis the FIGO stage of Ca Cx and control, while the antioxidant status as depicted by GSH and SOD decreased. Vitamin A and E levels were significantly lower in cancer cases as compared to the control. Conclusion: Increased LPO and reduced antioxidant levels may be taken as associated predictive markers, thus suggesting that Ca Cx cases should get nutritive supplements to contain the blood LPO level and maintain a positive balance of antioxidants for a better outcome in terms of delayed recurrence and better Quality of Life (QOL). Srivastava, S. Natu, S. M. Gupta, A. Pal, K. A. Singh, U. Agarwal, G. G. Singh, U. Goel, M. M. Srivastava, A. N. 0 2009-09-23T06:13:24Z 2009-09-15 %0 Journal Article %A Srivastava, S. %A Natu, S. M. %A Gupta, A. %A Pal, K. A. %A Singh, U. %A Agarwal, G. G. %A Singh, U. %A Goel, M. M. %A Srivastava, A. N. %D 2009 %T Lipid peroxidation and antioxidants in different stages of cervical cancer: Prognostic significance. %J Indian J Cancer %V 46 %N 4 %P 297-302 %M 19749459 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19749459 %X BACKGROUND: Free radical Injury is associated with cancer, but how the extent of oxidative stress correlates with the FIGO (International Federation of Gynecology and Obstetrics) stage in Carcinoma Cervix (Ca Cx), and its significance as a prognostic marker, is not clear and needs an in-depth study. AIM: To correlate the blood levels of Lipid Peroxidation (LPO), Reduced Glutathione (GSH), Superoxide Dismutase (SOD), and Vitamin A and E levels with the clinical stage in Ca Cx. SETTINGS AND DESIGN: This is a Prospective Case Control Study. MATERIALS AND METHODS: LPO, SOD, reduced GSH were estimated by Bio Chemical Assays and Vitamins by High Performance Liquid Chromatography (HPLC). STATISTICAL ANALYSIS: The cases and controls were compared using One Way ANOVA and different stages over different time periods were individually compared by Repeated Measure Analysis of Variance. RESULTS: The results indicated a statistically significant increase of LPO vis-a-vis the FIGO stage of Ca Cx and control, while the antioxidant status as depicted by GSH and SOD decreased. Vitamin A and E levels were significantly lower in cancer cases as compared to the control. CONCLUSION: Increased LPO and reduced antioxidant levels may be taken as associated predictive markers, thus suggesting that Ca Cx cases should get nutritive supplements to contain the blood LPO level and maintain a positive balance of antioxidants for a better outcome in terms of delayed recurrence and better Quality of Life (QOL). %+ Department of Pathology, Lucknow University, India. Srivastava, S Natu, S M Gupta, A Pal, K A Singh, U Agarwal, G G Singh, Uma Goel, M M Srivastava, A N 8306 false false 4 Indian journal of cancer Indian J Cancer 297-302 ppublish Journal Article 19749459 In-Process 2009-09-30T06:14:27Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19749459 46 2009 Traditionally, pathologic determinations of tumor size, lymph node status, endocrine receptor status, and human epidermal growth factor receptor 2 (HER2) status have driven prognostic predictions and adjuvant therapy recommendations for patients with early stage breast cancer. However, these prognostic and predictive factors are relatively crude measures, resulting in many patients being overtreated or undertreated. As a result of gene expression assays, there is growing recognition that breast cancer is a molecularly heterogeneous disease. Evidence from gene expression microarrays suggests the presence of multiple molecular subtypes of breast cancer. The recent commercial availability of gene expression profiling techniques that predict risk of disease recurrence as well as potential chemotherapy benefit have shown promise in refining clinical decision making. These techniques will be reviewed in this article. Cianfrocca, M. Gradishar, W. 0 2009-09-06T11:55:09Z 2009-09-05 %0 Journal Article %A Cianfrocca, M. %A Gradishar, W. %D 2009 %T New molecular classifications of breast cancer. %J CA Cancer J Clin %V 59 %N 5 %P 303-313 %M 19729680 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19729680 %X Traditionally, pathologic determinations of tumor size, lymph node status, endocrine receptor status, and human epidermal growth factor receptor 2 (HER2) status have driven prognostic predictions and adjuvant therapy recommendations for patients with early stage breast cancer. However, these prognostic and predictive factors are relatively crude measures, resulting in many patients being overtreated or undertreated. As a result of gene expression assays, there is growing recognition that breast cancer is a molecularly heterogeneous disease. Evidence from gene expression microarrays suggests the presence of multiple molecular subtypes of breast cancer. The recent commercial availability of gene expression profiling techniques that predict risk of disease recurrence as well as potential chemotherapy benefit have shown promise in refining clinical decision making. These techniques will be reviewed in this article. %K Breast Neoplasms/*classification/diagnosis/genetics/pathology %K Cost-Benefit Analysis %K Female %K Gene Expression Profiling %K Gene Expression Regulation, Neoplastic %K Humans %K *Molecular Diagnostic Techniques/economics %K Oligonucleotide Array Sequence Analysis/economics %K Prognosis %K Reverse Transcriptase Polymerase Chain Reaction %+ Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA. m-cianfrocca@northwestern.edu Cianfrocca, Mary Gradishar, William 1301 false false 5 CA: a cancer journal for clinicians CA Cancer J Clin Breast Neoplasms/*classification/diagnosis/genetics/pathology; Cost-Benefit Analysis; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; *Molecular Diagnostic Techniques/economics; Oligonucleotide Array Sequence Analysis/economics; Prognosis; Reverse Transcriptase Polymerase Chain Reaction 303-313 ppublish Journal Article 19729680 MEDLINE 2009-09-24T06:15:10Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19729680 59 2009 Calcifying fibrous pseudotumor (CFP) is classified as a benign fibrous lesion, and is a rare pathologic entity. Previous reports have described CFPs in the extremities, chest wall, pleura, scrotum, mediastinum, neck, and visceral peritoneum. We present the first reported case of a CFP in the breast. CFP should be considered in the differential diagnosis for patients presenting with coarse indeterminate calcifications of the breast. Mangat, A. Schiller, C. Mengoni, P. Reynolds, C. Jeruss, J. S. 0 2009-09-06T11:55:45Z 2009-08-04 %0 Journal Article %A Mangat, A. %A Schiller, C. %A Mengoni, P. %A Reynolds, C. %A Jeruss, J. S. %D 2009 %T Calcifying fibrous pseudotumor of the breast. %J Breast J %V 15 %N 3 %P 299-301 %M 19645787 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19645787 %X Calcifying fibrous pseudotumor (CFP) is classified as a benign fibrous lesion, and is a rare pathologic entity. Previous reports have described CFPs in the extremities, chest wall, pleura, scrotum, mediastinum, neck, and visceral peritoneum. We present the first reported case of a CFP in the breast. CFP should be considered in the differential diagnosis for patients presenting with coarse indeterminate calcifications of the breast. %K Adult %K Breast Diseases/diagnosis %K Breast Neoplasms/*diagnosis %K Calcinosis/*diagnosis/pathology/surgery %K Diagnosis, Differential %K Female %K Fibroma/*diagnosis/pathology/surgery %K Follow-Up Studies %K Humans %K Neoplasms, Fibrous Tissue/*diagnosis/pathology/surgery %+ Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Mangat, Amrit Schiller, Carol Mengoni, Patricia Reynolds, Carol Jeruss, Jacqueline S 2571 false false 3 The breast journal Breast J Adult; Breast Diseases/diagnosis; Breast Neoplasms/*diagnosis; Calcinosis/*diagnosis/pathology/surgery; Diagnosis, Differential; Female; Fibroma/*diagnosis/pathology/surgery; Follow-Up Studies; Humans; Neoplasms, Fibrous Tissue/*diagnosis/pathology/surgery 299-301 ppublish Journal Article 19645787 MEDLINE 2009-10-20T06:20:03Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19645787 15 2009 Khan, S. A. 0 2009-10-16T06:14:43Z 2009-10-13 2009-10-15 %0 Journal Article %A Khan, S. A. %D 2009 %T Axillary Reverse Mapping to Prevent Lymphedema After Breast Cancer Surgery: Defining the Limits of the Concept. %J J Clin Oncol %V 27 %N 33 %P 5494-5496 %M 19826108 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19826108 8483 false false 33 Journal of clinical oncology : official journal of the American Society of Clinical Oncology J Clin Oncol 5494-5496 2009-11-20 ppublish JOURNAL ARTICLE 19826108 Publisher 2009-11-20T07:17:36Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19826108 27 2009 Van Horn, L. 0 2009-10-29T06:22:49Z 2009-10-28 %0 Journal Article %A Van Horn, L. %D 2009 %T No Wonder Less IS More! %J J Am Diet Assoc %V 109 %N 11 %P 1829 %M 19857620 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19857620 Van Horn, Linda 8536 false false 11 Journal of the American Dietetic Association J Am Diet Assoc 1829 2009-11-01 ppublish Editorial 19857620 In-Data-Review 2009-10-29T06:22:49Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19857620 109 2009 Context: Progesterone and its receptor (PR) play key roles in uterine leiomyoma growth. Previously, using chromatin immunoprecipitation-based cloning, we uncovered L-type amino acid transporter 2 (LAT2) as a novel PR target gene. LAT2 forms heterodimeric complexes with 4F2 heavy chain (4F2hc), a single transmembrane domain protein essential for LAT2 to exert its function in the plasma membrane. Until now, little is known about the roles of LAT2/4F2hc in the regulation of the growth of human uterine leiomyoma. Objective: The aim of the study is to investigate the regulation of LAT2 and 4F2hc by progesterone and the antiprogestin mifepristone and their functions in primary human uterine leiomyoma smooth muscle (LSM) cells and tissues from 39 premenopausal women. Results: In primary LSM cells, progesterone significantly induced LAT2 mRNA levels, and this was blocked by cotreatment with mifepristone. Progesterone did not alter 4F2hc mRNA levels, whereas mifepristone significantly induced 4F2hc mRNA expression. Small interfering RNA knockdown of LAT2 or 4F2hc markedly increased LSM cell proliferation. LAT2, PR-B, and PR-A levels were significantly higher in freshly isolated LSM cells vs. adjacent myometrial cells. In vivo, mRNA levels of LAT2 and PR but not 4F2hc were significantly higher in leiomyoma tissues compared with matched myometrial tissues. Conclusion: We present evidence that progesterone and its antagonist mifepristone regulate the amino acid transporter system LAT2/4F2hc in leiomyoma tissues and cells. Our findings suggest that products of the LAT2/4F2hc genes may play important roles in leiomyoma cell proliferation. We speculate that critical ratios of LAT2 to 4F2hc regulate leiomyoma growth. Luo, X. Yin, P. Reierstad, S. Ishikawa, H. Lin, Z. Pavone, M. E. Zhao, H. Marsh, E. E. Bulun, S. E. 0 2009-10-09T06:13:22Z 2009-10-06 2009-10-08 %0 Journal Article %A Luo, X. %A Yin, P. %A Reierstad, S. %A Ishikawa, H. %A Lin, Z. %A Pavone, M. E. %A Zhao, H. %A Marsh, E. E. %A Bulun, S. E. %D 2009 %T Progesterone and mifepristone regulate L-type amino acid transporter 2 and 4F2 heavy chain expression in uterine leiomyoma cells. %J J Clin Endocrinol Metab %V 94 %N 11 %P 4533-4539 %M 19808856 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19808856 %X CONTEXT: Progesterone and its receptor (PR) play key roles in uterine leiomyoma growth. Previously, using chromatin immunoprecipitation-based cloning, we uncovered L-type amino acid transporter 2 (LAT2) as a novel PR target gene. LAT2 forms heterodimeric complexes with 4F2 heavy chain (4F2hc), a single transmembrane domain protein essential for LAT2 to exert its function in the plasma membrane. Until now, little is known about the roles of LAT2/4F2hc in the regulation of the growth of human uterine leiomyoma. OBJECTIVE: The aim of the study is to investigate the regulation of LAT2 and 4F2hc by progesterone and the antiprogestin mifepristone and their functions in primary human uterine leiomyoma smooth muscle (LSM) cells and tissues from 39 premenopausal women. RESULTS: In primary LSM cells, progesterone significantly induced LAT2 mRNA levels, and this was blocked by cotreatment with mifepristone. Progesterone did not alter 4F2hc mRNA levels, whereas mifepristone significantly induced 4F2hc mRNA expression. Small interfering RNA knockdown of LAT2 or 4F2hc markedly increased LSM cell proliferation. LAT2, PR-B, and PR-A levels were significantly higher in freshly isolated LSM cells vs. adjacent myometrial cells. In vivo, mRNA levels of LAT2 and PR but not 4F2hc were significantly higher in leiomyoma tissues compared with matched myometrial tissues. CONCLUSION: We present evidence that progesterone and its antagonist mifepristone regulate the amino acid transporter system LAT2/4F2hc in leiomyoma tissues and cells. Our findings suggest that products of the LAT2/4F2hc genes may play important roles in leiomyoma cell proliferation. We speculate that critical ratios of LAT2 to 4F2hc regulate leiomyoma growth. %+ Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. s-bulun@northwestern.edu 8450 false false 11 The Journal of clinical endocrinology and metabolism J Clin Endocrinol Metab 4533-4539 2009-11-01 ppublish JOURNAL ARTICLE 19808856 In-Process 2009-11-07T07:16:57Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19808856 94 2009 Aromatase (CYP19A1) catalyzes the conversion of C19 steroids to estrogens. Aromatase and its product estradiol (E2) are crucial for the sexually dimorphic development of the fetal brain and the regulation of gonadotropin secretion and sexual interest in adults. The regulation of aromatase expression in the brain is not well understood. The aromatase (Cyp19a1) gene is selectively expressed in distinct neurons of the hypothalamus through a distal brain-specific promoter I.f located ~36 kb upstream of the coding region. Here, we investigated a short feedback effect of E2 on aromatase mRNA expression and enzyme activity using estrogen receptor alpha (ESR1, also known as ERalpha)-positive or negative mouse embryonic hypothalamic neuronal cell lines that express aromatase via promoter I.f. E2 regulated aromatase mRNA expression and enzyme activity in a time and dose-dependent manner, whereas an E2 antagonist reversed these effects. The nt -200/-1 region of promoter I.f conferred E2-responsiveness. Two activator protein 1 (AP-1) elements in this region were essential for induction of promoter activity by E2. ESR1 and JUN (c-Jun) bound to these AP-1 motifs in intact cells and under cell-free conditions. The addition of an ESR1 mutant that interacts with JUN but not directly with DNA enhanced E2-dependent promoter I.f activity. Independently, we demonstrated an interaction between ESR1 and JUN in hypothalamic cells. Knockdown of ESR1 abolished E2-induced aromatase mRNA and enzyme activity. Taken together, E2 regulates Cyp19a1 expression via promoter I.f by enhanced binding of an ESR1/JUN complex to distinct AP-1 motifs in hypothalamic cells. We speculate that this mechanism may in part regulate gonadotropin secretion and sexual activity. Yilmaz, M. B. Wolfe, A. Cheng, Y. H. Glidewell-Kenney, C. Jameson, J. L. Bulun, S. E. 0 2009-09-06T11:54:52Z 2009-07-15 2009-07-17 %0 Journal Article %A Yilmaz, M. B. %A Wolfe, A. %A Cheng, Y. H. %A Glidewell-Kenney, C. %A Jameson, J. L. %A Bulun, S. E. %D 2009 %T Aromatase promoter I.f is regulated by estrogen receptor alpha (ESR1) in mouse hypothalamic neuronal cell lines. %J Biol Reprod %V 81 %N 5 %P 956-965 %M 19605792 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19605792 %X Aromatase (CYP19A1) catalyzes the conversion of C(19) steroids to estrogens. Aromatase and its product estradiol (E(2)) are crucial for the sexually dimorphic development of the fetal brain and the regulation of gonadotropin secretion and sexual interest in adults. The regulation of aromatase expression in the brain is not well understood. The aromatase (Cyp19a1) gene is selectively expressed in distinct neurons of the hypothalamus through a distal brain-specific promoter I.f located approximately 36 kb upstream of the coding region. Here, we investigated a short feedback effect of E(2) on aromatase mRNA expression and enzyme activity using estrogen receptor alpha (ESR1; also known as ER alpha)-positive or ESR1-negative mouse embryonic hypothalamic neuronal cell lines that express aromatase via promoter I.f. Estradiol regulated aromatase mRNA expression and enzyme activity in a time- and dose-dependent manner, whereas an E(2) antagonist reversed these effects. The nucleotide -200/-1 region of promoter I.f conferred E(2) responsiveness. Two activator protein 1 (AP-1) elements in this region were essential for induction of promoter activity by E(2). ESR1 and JUN (c-Jun) bound to these AP-1 motifs in intact cells and under cell-free conditions. The addition of an ESR1 mutant that interacts with JUN but not directly with DNA enhanced E(2)-dependent promoter I.f activity. Independently, we demonstrated an interaction between ESR1 and JUN in hypothalamic cells. Knockdown of ESR1 abolished E(2)-induced aromatase mRNA and enzyme activity. Taken together, E(2) regulates Cyp19a1 expression via promoter I.f by enhanced binding of an ESR1/JUN complex to distinct AP-1 motifs in hypothalamic cells. We speculate that this mechanism may, in part, regulate gonadotropin secretion and sexual activity. %+ Division of Reproductive Biology Research, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. 601 false false 5 Biology of reproduction Biol Reprod 956-965 2009-11-01 ppublish JOURNAL ARTICLE 19605792 In-Process 2009-10-30T06:22:00Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19605792 81 2009 In this work, the performance of integrated photocatalytic and biological treatment was studied for the degradation of 4-chlorophenol (MCP) present in wastewaters. Photocatalysis was used as a pre-treatment to biological degradation. Pollutant removal efficiency was quantified using MCP removal and total organic carbon (TOC) removal. Both photocatalytic as well as biological treatments were carried out in batch reactors, using TiO(2) as the photocatalyst. The inoculum for biological experiments was obtained from paper mill effluent treatment plant and was developed through a process of selection and acclimatization. Effect of TiO(2) concentration on the photocatalytic degradation of MCP was studied along with the effect of the duration of photochemical oxidation and glucose concentrations (0g/L, 1g/L and 2g/L) on the biodegradation of MCP. Integrated biological and photochemical degradation was found to be more effective in treating MCP, especially at higher concentrations (400mg/L). An initial MCP concentration of 400mg/L required 96h for complete mineralization when treated with the process combination, whereas the treatment went on up to 264h when biodegradation alone was employed. Goel, M. Chovelon, J. M. Ferronato, C. Bayard, R. Sreekrishnan, T. R. 0 2009-11-18T07:16:09Z 2009-10-20 2009-11-17 %0 Journal Article %A Goel, M. %A Chovelon, J. M. %A Ferronato, C. %A Bayard, R. %A Sreekrishnan, T. R. %D 2009 %T The remediation of wastewater containing 4-chlorophenol using integrated photocatalytic and biological treatment. %J J Photochem Photobiol B %M 19914843 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19914843 %X In this work, the performance of integrated photocatalytic and biological treatment was studied for the degradation of 4-chlorophenol (MCP) present in wastewaters. Photocatalysis was used as a pre-treatment to biological degradation. Pollutant removal efficiency was quantified using MCP removal and total organic carbon (TOC) removal. Both photocatalytic as well as biological treatments were carried out in batch reactors, using TiO(2) as the photocatalyst. The inoculum for biological experiments was obtained from paper mill effluent treatment plant and was developed through a process of selection and acclimatization. Effect of TiO(2) concentration on the photocatalytic degradation of MCP was studied along with the effect of the duration of photochemical oxidation and glucose concentrations (0g/L, 1g/L and 2g/L) on the biodegradation of MCP. Integrated biological and photochemical degradation was found to be more effective in treating MCP, especially at higher concentrations (400mg/L). An initial MCP concentration of 400mg/L required 96h for complete mineralization when treated with the process combination, whereas the treatment went on up to 264h when biodegradation alone was employed. %+ Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi 110 016, India. 8598 false false Journal of photochemistry and photobiology. B, Biology J Photochem Photobiol B 2009-10-20 aheadofprint JOURNAL ARTICLE 19914843 Publisher 2009-11-18T07:16:09Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19914843 2009 ABSTRACT: INTRODUCTION: Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared to the general population. However, risk estimates range from 20-80% suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations. METHODS: A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for single nucleotide polymorphisms (SNPs) in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1), IGFBP2, IGFBP5, and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed and for single SNP analyses no additivity assumptions were made. RESULTS: Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P-values of 0.011 for LD block 2 and 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P-value of 0.0145)was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers. CONCLUSIONS: This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations. Neuhausen, S. L. Brummel, S. Ding, Y. C. Singer, C. F. Pfeiler, G. Lynch, H. T. Nathanson, K. L. Rebbeck, T. R. Garber, J. E. Couch, F. Weitzel, J. Narod, S. A. Ganz, P. A. Daly, M. B. Godwin, A. Isaacs, C. Olopade, O. I. Tomlinson, G. Rubinstein, W. S. Tung, N. Blum, J. L. Gillen, D. L. 0 2009-10-23T06:21:23Z 2009-10-20 2009-10-22 %0 Journal Article %A Neuhausen, S. L. %A Brummel, S. %A Ding, Y. C. %A Singer, C. F. %A Pfeiler, G. %A Lynch, H. T. %A Nathanson, K. L. %A Rebbeck, T. R. %A Garber, J. E. %A Couch, F. %A Weitzel, J. %A Narod, S. A. %A Ganz, P. A. %A Daly, M. B. %A Godwin, A. K. %A Isaacs, C. %A Olopade, O. I. %A Tomlinson, G. %A Rubinstein, W. S. %A Tung, N. %A Blum, J. L. %A Gillen, D. L. %D 2009 %T Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers. %J Breast Cancer Res %V 11 %N 5 %P R76 %M 19843326 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19843326 %X ABSTRACT: INTRODUCTION: Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations. METHODS: A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made. RESULTS: Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers. CONCLUSIONS: This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations. %+ Department of Epidemiology, University of California Irvine, 224 Irvine Hall, Irvine, CA 92697, USA. sneuhaus@uci.edu. 8516 false false 5 Breast cancer research : BCR Breast Cancer Res R76 2009-10-20 aheadofprint JOURNAL ARTICLE 19843326 Publisher 2009-11-12T07:25:38Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19843326 11 2009 Kaklamani, V. G. Cianfrocca, M. Ciccone, J. Kindy, K. Rademaker, A. Wiley, E. L. Gradishar, W. O'Regan, R. M. 0 2009-10-22T06:20:44Z 2009-10-19 2009-10-21 %0 Journal Article %A Kaklamani, V. G. %A Cianfrocca, M. %A Ciccone, J. %A Kindy, K. %A Rademaker, A. %A Wiley, E. L. %A Gradishar, W. %A O'Regan, R. M. %D 2009 %T Increased HER2/neu expression in recurrent hormone receptor-positive breast cancer. %J Biomarkers %M 19839717 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19839717 %+ Division of Hematology/Oncology, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. 8503 false false Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals Biomarkers 2009-10-19 aheadofprint JOURNAL ARTICLE 19839717 Publisher 2009-10-22T06:20:44Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19839717 2009 Members of Snail family of transcription factors play an important role in oral cancer progression by inducing epithelial-mesenchymal transition, by promoting invasion and by increasing matrix metalloproteinase (MMP) expression. Although Snail (Snai1) is the best characterized and the most extensively studied member of this family, the role and regulation of Slug (Snai2) in oral cancer progression is less well understood. In this report, we show that transforming growth factor-beta1 (TGF-beta1) increases Slug levels in tert-immortalized oral keratinocytes and in malignant oral squamous cell carcinoma (OSCC) cells. Inhibiting ERK1/2 signaling, but not PI3-kinase signaling, blocked TGF-beta1-induced Slug expression in the malignant UMSCC1 cells. To further examine the role of Slug in OSCC progression, we generated UMSCC1 cells with inducible expression of Slug protein. Induction of Slug in UMSCC1 cells did not repress E-cadherin levels or regulate individual movement of UMSCC1 cells. Instead, Slug enhanced cohort migration and Matrigel invasion by UMSCC1 cells. Slug increased MMP-9 levels and MMP-9-specific siRNA blocked Slug-induced Matrigel invasion. Interestingly, Slug-specific siRNA attenuated TGF-beta1-induced MMP-9 expression and Matrigel invasion. These data demonstrate that TGF-beta1 increases Slug via ERK1/2 signaling, and thereby contributes to OSCC progression. J. Cell. Biochem. (c) 2009 Wiley-Liss, Inc. Joseph, M. J. Dangi-Garimella, S. Shields, M. A. Diamond, M. E. Sun, L. Koblinski, J. E. Munshi, H. G. 0 2009-09-06T11:56:51Z 2009-08-15 %0 Journal Article %A Joseph, M. J. %A Dangi-Garimella, S. %A Shields, M. A. %A Diamond, M. E. %A Sun, L. %A Koblinski, J. E. %A Munshi, H. G. %D 2009 %T Slug is a downstream mediator of transforming growth factor-beta1-induced matrix metalloproteinase-9 expression and invasion of oral cancer cells. %J J Cell Biochem %V 108 %N 3 %P 726-736 %M 19681038 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19681038 %X Members of Snail family of transcription factors play an important role in oral cancer progression by inducing epithelial-mesenchymal transition, by promoting invasion and by increasing matrix metalloproteinase (MMP) expression. Although Snail (Snai1) is the best characterized and the most extensively studied member of this family, the role and regulation of Slug (Snai2) in oral cancer progression is less well understood. In this report, we show that transforming growth factor-beta1 (TGF-beta1) increases Slug levels in tert-immortalized oral keratinocytes and in malignant oral squamous cell carcinoma (OSCC) cells. Inhibiting ERK1/2 signaling, but not PI3-kinase signaling, blocked TGF-beta1-induced Slug expression in the malignant UMSCC1 cells. To further examine the role of Slug in OSCC progression, we generated UMSCC1 cells with inducible expression of Slug protein. Induction of Slug in UMSCC1 cells did not repress E-cadherin levels or regulate individual movement of UMSCC1 cells. Instead, Slug enhanced cohort migration and Matrigel invasion by UMSCC1 cells. Slug increased MMP-9 levels and MMP-9-specific siRNA blocked Slug-induced Matrigel invasion. Interestingly, Slug-specific siRNA attenuated TGF-beta1-induced MMP-9 expression and Matrigel invasion. These data demonstrate that TGF-beta1 increases Slug via ERK1/2 signaling, and thereby contributes to OSCC progression. %+ Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. 4206 false false 3 Journal of cellular biochemistry J Cell Biochem 726-736 2009-10-15 ppublish JOURNAL ARTICLE 19681038 In-Process 2009-09-30T06:14:47Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19681038 108 2009 BACKGROUND: In the post-intervention period of the Women's Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period. METHODS: The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50-79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611. FINDINGS: After a mean of 5.6 years (SD 1.3) of treatment and 2.4 years (0.4) of additional follow-up, 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0.16%vs 0.13%; hazard ratio [HR] 1.23, 95% CI 0.92-1.63, p=0.16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0.14%vs 0.11%; HR 1.28, 0.94-1.73, p=0.12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0.11%vs 0.06%; HR 1.71, 1.16-2.52, p=0.01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0.09%vs 0.05%; HR 1.87, 1.22-2.88, p=0.004). Incidence and mortality rates of small-cell lung cancer were similar between groups. INTERPRETATION: Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer. These findings should be incorporated into risk-benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer. FUNDING: National Heart, Lung and Blood Institute, National Institutes of Health. Chlebowski, R. T. Schwartz, A. G. Wakelee, H. Anderson, G. L. Stefanick, M. L. Manson, J. E. Rodabough, R. J. Chien, J. W. Wactawski-Wende, J. Gass, M. Kotchen, J. M. Johnson, K. C. O'Sullivan, M. J. Ockene, J. K. Chen, C. Hubbell, F. A. 0 2009-10-17T06:19:35Z 2009-09-18 2009-09-22 %0 Journal Article %A Chlebowski, R. T. %A Schwartz, A. G. %A Wakelee, H. %A Anderson, G. L. %A Stefanick, M. L. %A Manson, J. E. %A Rodabough, R. J. %A Chien, J. W. %A Wactawski-Wende, J. %A Gass, M. %A Kotchen, J. M. %A Johnson, K. C. %A O'Sullivan, M. J. %A Ockene, J. K. %A Chen, C. %A Hubbell, F. A. %D 2009 %T Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial. %J Lancet %V 374 %N 9697 %P 1243-1251 %M 19767090 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19767090 %X BACKGROUND: In the post-intervention period of the Women's Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period. METHODS: The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50-79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611. FINDINGS: After a mean of 5.6 years (SD 1.3) of treatment and 2.4 years (0.4) of additional follow-up, 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0.16%vs 0.13%; hazard ratio [HR] 1.23, 95% CI 0.92-1.63, p=0.16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0.14%vs 0.11%; HR 1.28, 0.94-1.73, p=0.12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0.11%vs 0.06%; HR 1.71, 1.16-2.52, p=0.01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0.09%vs 0.05%; HR 1.87, 1.22-2.88, p=0.004). Incidence and mortality rates of small-cell lung cancer were similar between groups. INTERPRETATION: Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer. These findings should be incorporated into risk-benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer. FUNDING: National Heart, Lung and Blood Institute, National Institutes of Health. %K Aged %K Carcinoma, Non-Small-Cell Lung/chemically induced/epidemiology %K Cause of Death %K Double-Blind Method %K Estrogen Replacement Therapy/*adverse effects/methods %K Female %K Follow-Up Studies %K Humans %K Incidence %K Kaplan-Meiers Estimate %K *Lung Neoplasms/chemically induced/epidemiology %K Middle Aged %K *Postmenopause/drug effects %K Proportional Hazards Models %K Risk Factors %K Smoking/adverse effects/epidemiology %K United States/epidemiology %K Women's Health %+ Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA. rchlebowski@gmail.com Chlebowski, Rowan T Schwartz, Ann G Wakelee, Heather Anderson, Garnet L Stefanick, Marcia L Manson, JoAnn E Rodabough, Rebecca J Chien, Jason W Wactawski-Wende, Jean Gass, Margery Kotchen, Jane Morley Johnson, Karen C O'Sullivan, Mary Jo Ockene, Judith K Chen, Chu Hubbell, F Allan 8487 false false 9697 Lancet Lancet Aged; Carcinoma, Non-Small-Cell Lung/chemically induced/epidemiology; Cause of Death; Double-Blind Method; Estrogen Replacement Therapy/*adverse effects/methods; Female; Follow-Up Studies; Humans; Incidence; Kaplan-Meiers Estimate; *Lung Neoplasms/chemically induced/epidemiology; Middle Aged; *Postmenopause/drug effects; Proportional Hazards Models; Risk Factors; Smoking/adverse effects/epidemiology; United States/epidemiology; Women's Health 1243-1251 2009-10-10 ppublish Journal Article 19767090 MEDLINE 2009-10-30T06:22:55Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19767090 374 2009 Post-translational stabilization of beta-catenin is a key step in Wnt signaling, but the features of beta-catenin required for stabilization are incompletely understood. We show that forms of beta-catenin lacking the unstructured C-terminal domain (CTD) show faster turnover than full-length or minimally truncated beta-catenins. Mutants that exhibit faster turnover show enhanced association with Axin in co-transfected cells, and excess CTD polypeptide can compete binding of the beta-catenin armadillo (arm) repeat domain to Axin in vitro, indicating that the CTD may restrict beta-catenin binding to the Axin-scaffold complex. FRET analysis of a CFP-Arm-CTD-YFP beta-catenin reveals that the CTD of beta-catenin can become spatially close to the N-terminal arm repeat region of beta-catenin. FRET activity is strongly diminished by the co-expression of beta-catenin binding partners, indicating that an unliganded groove is absolutely required for an orientation that allows FRET. Amino acids 733-759 are critical for beta-catenin FRET activity and stability. These data indicate that an N-terminal orientation of the CTD is required for beta-catenin stabilization, and suggest a model where the CTD extends towards the N-terminal arm repeats, shielding these repeats from the Axin-degradation complex. Mo, R. Chew, T. L. Maher, M. T. Bellipanni, G. Weinberg, E. S. Gottardi, C. J. 0 2009-09-06T11:55:06Z 2009-08-25 2009-08-27 %0 Journal Article %A Mo, R. %A Chew, T. L. %A Maher, M. T. %A Bellipanni, G. %A Weinberg, E. S. %A Gottardi, C. J. %D 2009 %T The terminal region of beta-catenin promotes stability by shielding the Armadillo repeats from the axin-scaffold destruction complex. %J J Biol Chem %V 284 %N 41 %P 28222-28231 %M 19706613 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19706613 %X Post-translational stabilization of beta-catenin is a key step in Wnt signaling, but the features of beta-catenin required for stabilization are incompletely understood. We show that forms of beta-catenin lacking the unstructured C-terminal domain (CTD) show faster turnover than full-length or minimally truncated beta-catenins. Mutants that exhibit faster turnover show enhanced association with axin in co-transfected cells, and excess CTD polypeptide can compete binding of the beta-catenin armadillo (arm) repeat domain to axin in vitro, indicating that the CTD may restrict beta-catenin binding to the axin-scaffold complex. Fluorescent resonance energy transmission (FRET) analysis of cyan fluorescent protein (CFP)-arm-CTD-yellow fluorescent protein beta-catenin reveals that the CTD of beta-catenin can become spatially close to the N-terminal arm repeat region of beta-catenin. FRET activity is strongly diminished by the coexpression of beta-catenin binding partners, indicating that an unliganded groove is absolutely required for an orientation that allows FRET. Amino acids 733-759 are critical for beta-catenin FRET activity and stability. These data indicate that an N-terminal orientation of the CTD is required for beta-catenin stabilization and suggest a model where the CTD extends toward the N-terminal arm repeats, shielding these repeats from the beta-catenin destruction complex. %K Amino Acid Sequence %K Animals %K Cell Line %K Fluorescence Resonance Energy Transfer %K Humans %K Models, Molecular %K Molecular Sequence Data %K *Protein Structure, Tertiary %K Repressor Proteins/genetics/*metabolism %K Signal Transduction/physiology %K Two-Hybrid System Techniques %K Wnt Proteins/genetics/metabolism %K Zebrafish Proteins/chemistry/genetics/metabolism %K beta Catenin/*chemistry/genetics/*metabolism %+ Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. 1213 false false 41 The Journal of biological chemistry J Biol Chem Amino Acid Sequence; Animals; Cell Line; Fluorescence Resonance Energy Transfer; Humans; Models, Molecular; Molecular Sequence Data; *Protein Structure, Tertiary; Repressor Proteins/genetics/*metabolism; Signal Transduction/physiology; Two-Hybrid System Techniques; Wnt Proteins/genetics/metabolism; Zebrafish Proteins/chemistry/genetics/metabolism; beta Catenin/*chemistry/genetics/*metabolism 28222-28231 2009-10-09 ppublish JOURNAL ARTICLE 19706613 MEDLINE 2009-11-11T07:21:46Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19706613 284 2009 Dietary compounds and epigenetic influences are well recognized factors in cancer progression. Resveratrol (Res), a dietary compound from grapes, has anticancer properties; however its epigenetic effects are understudied. Metastasis-associated protein 1 (MTA1) is a part of the nucleosome remodeling deacetylation (NuRD) co-repressor complex that mediates posttranslational modifications of histones and non-histone proteins resulting in transcriptional repression. MTA1 overexpression in prostate cancer (PCa) correlates with tumor aggressiveness and metastasis. In this study we have identified a novel MTA1-mediated mechanism, by which Res restores p53-signaling pathways in PCa cells. We show, for the first time, that Res causes down-regulation of MTA1 protein, leading to destabilization of MTA1/NuRD thus allowing acetylation/ activation of p53. We demonstrated that MTA1 decrease by Res was concomitant with accumulation of Ac-p53. MTA1 knockdown further sensitized PCa cells to Res-dependent p53 acetylation and recruitment to the p21 and Bax promoters. Furthermore, MTA1 silencing maximized the levels of Res-induced apoptosis and pro-apoptotic Bax accumulation. HDAC inhibitor SAHA, like MTA1 silencing, increased Res-dependent p53 acetylation and showed cooperative effect on apoptosis. Our results indicate a novel epigenetic mechanism that contributes to Res anticancer activities: the inhibition of MTA1/NuRD complexes due to MTA1 decrease which suppresses its deacetylation function and allows p53 acetylation and subsequent activation of pro-apoptotic genes. Our study identifies MTA1 as a new molecular target of Res that may have important clinical applications for PCa chemoprevention and therapy, and points to the combination of Res with HDAC inhibitors as an innovative therapeutic strategy for the treatment of PCa. (c) 2009 UICC. Kai, L. Samuel, S. K. Levenson, A. S. 0 2009-10-09T06:13:37Z 2009-10-06 2009-10-08 %0 Journal Article %A Kai, L. %A Samuel, S. K. %A Levenson, A. S. %D 2009 %T Resveratrol enhances p53 acetylation and apoptosis in prostate cancer by inhibiting MTA1/NuRD complex. %J Int J Cancer %M 19810103 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19810103 %X Dietary compounds and epigenetic influences are well recognized factors in cancer progression. Resveratrol (Res), a dietary compound from grapes, has anticancer properties; however its epigenetic effects are understudied. Metastasis-associated protein 1 (MTA1) is a part of the nucleosome remodeling deacetylation (NuRD) co-repressor complex that mediates posttranslational modifications of histones and non-histone proteins resulting in transcriptional repression. MTA1 overexpression in prostate cancer (PCa) correlates with tumor aggressiveness and metastasis. In this study we have identified a novel MTA1-mediated mechanism, by which Res restores p53-signaling pathways in PCa cells. We show, for the first time, that Res causes down-regulation of MTA1 protein, leading to destabilization of MTA1/NuRD thus allowing acetylation/ activation of p53. We demonstrated that MTA1 decrease by Res was concomitant with accumulation of Ac-p53. MTA1 knockdown further sensitized PCa cells to Res-dependent p53 acetylation and recruitment to the p21 and Bax promoters. Furthermore, MTA1 silencing maximized the levels of Res-induced apoptosis and pro-apoptotic Bax accumulation. HDAC inhibitor SAHA, like MTA1 silencing, increased Res-dependent p53 acetylation and showed cooperative effect on apoptosis. Our results indicate a novel epigenetic mechanism that contributes to Res anticancer activities: the inhibition of MTA1/NuRD complexes due to MTA1 decrease which suppresses its deacetylation function and allows p53 acetylation and subsequent activation of pro-apoptotic genes. Our study identifies MTA1 as a new molecular target of Res that may have important clinical applications for PCa chemoprevention and therapy, and points to the combination of Res with HDAC inhibitors as an innovative therapeutic strategy for the treatment of PCa. (c) 2009 UICC. %+ Department of Urology and Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. 8452 false false International journal of cancer. Journal international du cancer Int J Cancer 2009-10-06 aheadofprint JOURNAL ARTICLE 19810103 Publisher 2009-10-09T06:13:37Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19810103 2009 Collagen antibody induced arthritis is a robust murine model of arthritis that histologically recapitulates the inflammatory characteristics of rheumatoid arthritis including pannus formation and destruction of articular cartilage and bone. PECAM is a molecule expressed by both leukocytes and endothelial cells that has been shown to play a major role in the extravasation of leukocytes into sites of inflammation. Genetic deletion of many molecules will blunt the onset and progression of arthritis in murine models, as will administration of various anti-inflammatory therapies given prior to the onset of disease. However, patients seek medical attention when symptomatic, which means that the disease is well established. We investigated whether blocking PECAM interactions would inhibit progression of established disease in the collagen antibody induced arthritis model. We report that treatment of symptomatic mice with a PECAM-Fc chimera significantly reduced inflammation and virtually eliminated cartilage and bone destruction. The results suggest that therapies that block PECAM function may be beneficial in the treatment of established arthritis. Dasgupta, B. Chew, T. Deroche, A. Muller, W. A. 0 2009-10-07T06:13:24Z 2009-10-02 2009-10-06 %0 Journal Article %A Dasgupta, B. %A Chew, T. %A Deroche, A. %A Muller, W. A. %D 2009 %T Blocking platelet/endothelial cell adhesion molecule 1 (PECAM) inhibits disease progression and prevents joint erosion in established collagen antibody-induced arthritis. %J Exp Mol Pathol %M 19800878 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19800878 %X Collagen antibody-induced arthritis is a robust murine model of arthritis that histologically recapitulates the inflammatory characteristics of rheumatoid arthritis including pannus formation and destruction of articular cartilage and bone. PECAM is a molecule expressed by both leukocytes and endothelial cells that has been shown to play a major role in the extravasation of leukocytes into sites of inflammation. Genetic deletion of many molecules will blunt the onset and progression of arthritis in murine models, as will administration of various anti-inflammatory therapies given prior to the onset of disease. However, patients seek medical attention when symptomatic, which means that the disease is well established. We investigated whether blocking PECAM interactions would inhibit progression of established disease in the collagen antibody-induced arthritis model. We report that treatment of symptomatic mice with a PECAM-Fc chimera significantly reduced inflammation and virtually eliminated cartilage and bone destruction. The results suggest that therapies that block PECAM function may be beneficial in the treatment of established arthritis. %+ Department of Pathology, Northwestern University Feinberg School of Medicine, Ward Building 3-140, 303 E. Chicago Avenue, Chicago, IL 60611, USA. 8441 false false Experimental and molecular pathology Exp Mol Pathol 2009-10-02 aheadofprint JOURNAL ARTICLE 19800878 Publisher 2009-10-10T06:15:35Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19800878 2009 The use of epidemiologic research designs and analytical methods is common in dietetics research. Food and nutrition professionals who seek to perform evidence-based practice or participate in research design, analysis, and communication need skills in the essentials of epidemiology. This is one of a series of monographs on research methodology that addresses these needs and supports the goals of the Board of Editors of the Journal of the American Dietetic Association to further enhance competency and skills. This monograph focuses on statistical approaches for univariate analyses used with the primary observational study designs associated with epidemiology. Tables illustrating the presentation and interpretation of these results are included. Bruemmer, B. Harris, J. Gleason, P. Boushey, C. J. Sheean, P. M. Archer, S. Van Horn, L. 0 2009-09-30T06:15:10Z 2009-09-29 %0 Journal Article %A Bruemmer, B. %A Harris, J. %A Gleason, P. %A Boushey, C. J. %A Sheean, P. M. %A Archer, S. %A Van Horn, L. %D 2009 %T Publishing nutrition research: a review of epidemiologic methods. %J J Am Diet Assoc %V 109 %N 10 %P 1728-1737 %M 19782172 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19782172 %X The use of epidemiologic research designs and analytical methods is common in dietetics research. Food and nutrition professionals who seek to perform evidence-based practice or participate in research design, analysis, and communication need skills in the essentials of epidemiology. This is one of a series of monographs on research methodology that addresses these needs and supports the goals of the Board of Editors of the Journal of the American Dietetic Association to further enhance competency and skills. This monograph focuses on statistical approaches for univariate analyses used with the primary observational study designs associated with epidemiology. Tables illustrating the presentation and interpretation of these results are included. %K Confidence Intervals %K *Data Interpretation, Statistical %K Dietetics/methods/*standards %K *Epidemiologic Research Design %K Evidence-Based Medicine %K Humans %K Odds Ratio %K Research/*methods %K Risk %+ Graduate Program in Nutritional Sciences and Graduate Coordinated Program in Dietetics, University of Washington, Seattle, WA 98195, USA. bbruemme@u.washington.edu Bruemmer, Barbara Harris, Jeffrey Gleason, Phil Boushey, Carol J Sheean, Patricia M Archer, Sujata Van Horn, Linda 8410 false false 10 Journal of the American Dietetic Association J Am Diet Assoc Confidence Intervals; *Data Interpretation, Statistical; Dietetics/methods/*standards; *Epidemiologic Research Design; Evidence-Based Medicine; Humans; Odds Ratio; Research/*methods; Risk 1728-1737 2009-10-01 ppublish Journal Article 19782172 MEDLINE 2009-10-29T06:22:49Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19782172 109 2009 Van Horn, L. 0 2009-09-30T06:15:11Z 2009-09-29 %0 Journal Article %A Van Horn, L. %D 2009 %T Cultural complexities in dietary assessment and treatment. %J J Am Diet Assoc %V 109 %N 10 %P 1671 %M 19782161 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19782161 %K *Acculturation %K Diet/*standards/trends %K Emigration and Immigration %K Humans %K *Nutrition Assessment %K Obesity/prevention & control %K United States Van Horn, Linda 8411 false false 10 Journal of the American Dietetic Association J Am Diet Assoc *Acculturation; Diet/*standards/trends; Emigration and Immigration; Humans; *Nutrition Assessment; Obesity/prevention & control; United States 1671 2009-10-01 ppublish Editorial 19782161 MEDLINE 2009-10-29T06:22:49Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19782161 109 2009 Dimri, G. P. 0 2009-09-24T06:15:11Z 2009-10-01 2009-09-23 %0 Journal Article %A Dimri, G. P. %D 2009 %T c-Myc and telomerase activation. %J Cell Cycle %V 8 %N 19 %P 3075-3076 %M 19770580 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19770580 8389 false false 19 Cell cycle (Georgetown, Tex.) Cell Cycle 3075-3076 2009-10-01 ppublish JOURNAL ARTICLE 19770580 In-Process 2009-10-17T06:18:48Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19770580 8 2009 PURPOSE: Lymph node metastases are the most significant prognostic indicator for patients with breast cancer. Sentinel node biopsy (SNB) has led to an increase in the detection of micrometastases in the sentinel node (SN). This prospective study was designed to determine the survival impact of micrometastases in SNs of patients with invasive breast cancer. This study is based on the new sixth edition of the American Joint Committee on Cancer (AJCC) staging criteria. PATIENTS AND METHODS: Between January 1, 1992 and April 30, 1999, 790 patients entered this prospective study at the John Wayne Cancer Institute. The SN was examined first by hematoxylin and eosin (HE), and if the SN was negative with HE, then immunohistochemical staining was performed. The patients were then divided into four groups based on AJCC nodal staging: pN0(i-), no evidence of tumor (n = 486); pN0(i+), tumor deposit </= 0.2 mm (n = 84); pN1mi, tumor deposit more than 0.2 mm but </= 2 mm (n = 54), and pN1, tumor deposit more than 2 mm (n = 166). Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used to determine differences in DFS and OS of patients from different groups. RESULTS: At a median follow-up of 72.5 months, the size of SN metastases was a significant predictor of DFS and OS. CONCLUSION: Patients with micrometastatic tumor deposits, pN0(i+) or pN1mi, do not seem to have a worse 8-year DFS or OS compared with SN-negative patients. As expected, there was a significant decrease in 8-year DFS and OS in patients with pN1 disease in the SN. Hansen, N. M. Grube, B. Ye, X. Turner, R. R. Brenner, R. J. Sim, M. S. Giuliano, A. E. 0 2009-09-06T11:55:24Z 2009-08-31 2009-09-02 %0 Journal Article %A Hansen, N. M. %A Grube, B. %A Ye, X. %A Turner, R. R. %A Brenner, R. J. %A Sim, M. S. %A Giuliano, A. E. %D 2009 %T Impact of micrometastases in the sentinel node of patients with invasive breast cancer. %J J Clin Oncol %V 27 %N 28 %P 4679-4684 %M 19720928 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19720928 %X PURPOSE: Lymph node metastases are the most significant prognostic indicator for patients with breast cancer. Sentinel node biopsy (SNB) has led to an increase in the detection of micrometastases in the sentinel node (SN). This prospective study was designed to determine the survival impact of micrometastases in SNs of patients with invasive breast cancer. This study is based on the new sixth edition of the American Joint Committee on Cancer (AJCC) staging criteria. PATIENTS AND METHODS: Between January 1, 1992 and April 30, 1999, 790 patients entered this prospective study at the John Wayne Cancer Institute. The SN was examined first by hematoxylin and eosin (HE), and if the SN was negative with HE, then immunohistochemical staining was performed. The patients were then divided into four groups based on AJCC nodal staging: pN0(i-), no evidence of tumor (n = 486); pN0(i+), tumor deposit < or = 0.2 mm (n = 84); pN1mi, tumor deposit more than 0.2 mm but < or = 2 mm (n = 54), and pN1, tumor deposit more than 2 mm (n = 166). Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used to determine differences in DFS and OS of patients from different groups. RESULTS: At a median follow-up of 72.5 months, the size of SN metastases was a significant predictor of DFS and OS. CONCLUSION: Patients with micrometastatic tumor deposits, pN0(i+) or pN1mi, do not seem to have a worse 8-year DFS or OS compared with SN-negative patients. As expected, there was a significant decrease in 8-year DFS and OS in patients with pN1 disease in the SN. %K Breast Neoplasms/*pathology %K Female %K Follow-Up Studies %K Humans %K Kaplan-Meiers Estimate %K Lymphatic Metastasis/*diagnosis %K Middle Aged %K Multivariate Analysis %K Neoplasm Staging %K Proportional Hazards Models %K Prospective Studies %K Sentinel Lymph Node Biopsy/*methods/statistics & numerical data %+ John Wayne Cancer Institute, Santa Monica, CA 90404, USA. 1927 false false 28 Journal of clinical oncology : official journal of the American Society of Clinical Oncology J Clin Oncol Breast Neoplasms/*pathology; Female; Follow-Up Studies; Humans; Kaplan-Meiers Estimate; Lymphatic Metastasis/*diagnosis; Middle Aged; Multivariate Analysis; Neoplasm Staging; Proportional Hazards Models; Prospective Studies; Sentinel Lymph Node Biopsy/*methods/statistics & numerical data 4679-4684 2009-10-01 ppublish JOURNAL ARTICLE 19720928 MEDLINE 2009-10-27T06:20:43Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19720928 27 2009