The mTOR signaling pathway plays a very important role in the transmission of signals for initiation of mRNA translation and protein expression in mammalian cells. mTOR activates various downstream effectors to promote initiation of cap-dependent mRNA translation and mediate pro-mitogenic and pro-survival signals. Recent evidence has implicated effectors of this signaling cascade in mRNA translation for interferon stimulated genes (ISGs). In addition, it was recently shown that AKT/mTOR-mediated signals play important roles in the generation of IFN-dependent antiviral and growth inhibitory responses, suggesting that mTOR and its effectors can mediate diverse biological responses, depending on the cellular context and the triggering stimuli. In this review, the regulatory effects of various growth suppressive cytokines on the mTOR pathway are summarized and the emerging new functions of mTOR are discussed. Kroczynska, B. Kaur, S. Platanias, L. C. 0 2009-09-06T11:57:13Z 2009-08-13 2009-08-18 %0 Journal Article %A Kroczynska, B. %A Kaur, S. %A Platanias, L. C. %D 2009 %T Growth suppressive cytokines and the AKT/mTOR pathway. %J Cytokine %V 48 %N 1-2 %P 138-143 %M 19682919 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19682919 %X The mTOR signaling pathway plays a very important role in the transmission of signals for initiation of mRNA translation and protein expression in mammalian cells. mTOR activates various downstream effectors to promote initiation of cap-dependent mRNA translation and mediate pro-mitogenic and pro-survival signals. Recent evidence has implicated effectors of this signaling cascade in mRNA translation for interferon stimulated genes (ISGs). In addition, it was recently shown that AKT/mTOR-mediated signals play important roles in the generation of IFN-dependent antiviral and growth inhibitory responses, suggesting that mTOR and its effectors can mediate diverse biological responses, depending on the cellular context and the triggering stimuli. In this review, the regulatory effects of various growth suppressive cytokines on the mTOR pathway are summarized and the emerging new functions of mTOR are discussed. %+ Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School, 303 East Superior Street, Lurie 3-107, Chicago, IL 60611, USA. 4722 false false 1-2 Cytokine Cytokine 138-143 ppublish JOURNAL ARTICLE 19682919 In-Process 2009-09-23T06:13:48Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19682919 48 2009 OBJECTIVES: To evaluate the response rate and toxicity of a regimen comprised of monthly carboplatin and weekly paclitaxel for recurrent ovarian cancer. METHODS: We performed a retrospective chart review of patients with recurrent ovarian cancer treated between 2001 and 2006 at a single institution with carboplatin AUC 5 (day 1), and paclitaxel 80 mg/m(2) (days 1, 8, 15) of a 28-day cycle. Primary endpoints were response rate, progression-free survival and overall survival. RESULTS: Twenty patients were treated with this regimen from 2001 to 2006. Stage ranged from stages IC to IV. All received intravenous platinum and taxane as their initial therapy. Histologic subtypes included papillary serous (17), carcinosarcoma (1), and clear cell (2). The median number of prior regimens was 1 (range 1-3). The overall response rate was 85.0% (15 complete responses, 2 partial responses). Patients with tumors categorized as platinum sensitive had a response rate of 93.3% (14/15) and those with tumors deemed platinum resistant had a response rate of 60.0% (3/5). The median survival has not yet been reached after a median follow-up of 28 months. Neutropenia was the only grade 3/4 toxicity, occurring in 7 patients (35.0%). Platinum hypersensitivity reactions occurred in 5 patients (25.0%) who all successfully continued treatment using a carboplatin desensitization protocol. CONCLUSIONS: A monthly carboplatin and weekly paclitaxel regimen is highly active for women with recurrent platinum-sensitive and platinum-resistant epithelial ovarian cancer. The regimen is well tolerated. This pilot series demonstrates the potential for this regimen as treatment of choice among doublet first salvage regimens for patients with recurrent epithelial ovarian cancer, thus warranting multi-institutional study. Hoekstra, A. V. Hurteau, J. A. Kirschner, C. V. Rodriguez, G. C. 0 2009-10-07T06:12:54Z 2009-10-01 2009-10-06 %0 Journal Article %A Hoekstra, A. V. %A Hurteau, J. A. %A Kirschner, C. V. %A Rodriguez, G. C. %D 2009 %T The combination of monthly carboplatin and weekly paclitaxel is highly active for the treatment of recurrent ovarian cancer. %J Gynecol Oncol %V 115 %N 3 %P 377-381 %M 19800107 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19800107 %X OBJECTIVES: To evaluate the response rate and toxicity of a regimen comprised of monthly carboplatin and weekly paclitaxel for recurrent ovarian cancer. METHODS: We performed a retrospective chart review of patients with recurrent ovarian cancer treated between 2001 and 2006 at a single institution with carboplatin AUC 5 (day 1), and paclitaxel 80 mg/m(2) (days 1, 8, 15) of a 28-day cycle. Primary endpoints were response rate, progression-free survival and overall survival. RESULTS: Twenty patients were treated with this regimen from 2001 to 2006. Stage ranged from stages IC to IV. All received intravenous platinum and taxane as their initial therapy. Histologic subtypes included papillary serous (17), carcinosarcoma (1), and clear cell (2). The median number of prior regimens was 1 (range 1-3). The overall response rate was 85.0% (15 complete responses, 2 partial responses). Patients with tumors categorized as platinum sensitive had a response rate of 93.3% (14/15) and those with tumors deemed platinum resistant had a response rate of 60.0% (3/5). The median survival has not yet been reached after a median follow-up of 28 months. Neutropenia was the only grade 3/4 toxicity, occurring in 7 patients (35.0%). Platinum hypersensitivity reactions occurred in 5 patients (25.0%) who all successfully continued treatment using a carboplatin desensitization protocol. CONCLUSIONS: A monthly carboplatin and weekly paclitaxel regimen is highly active for women with recurrent platinum-sensitive and platinum-resistant epithelial ovarian cancer. The regimen is well tolerated. This pilot series demonstrates the potential for this regimen as treatment of choice among doublet first salvage regimens for patients with recurrent epithelial ovarian cancer, thus warranting multi-institutional study. %+ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, NorthShore University HealthSystem, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 8438 false false 3 Gynecologic oncology Gynecol Oncol 377-381 2009-12-01 ppublish JOURNAL ARTICLE 19800107 In-Process 2009-11-05T07:22:56Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19800107 115 2009 The creation of the pool of follicles available for selection and ovulation is a multi-faceted, tightly regulated process that spans the period from embryonic development through to the first reproductive cycle of the organism. In mice, this development can occur in mere weeks, but in humans, it is sustained for years. Embryonic germ cell development involves the migration of primordial germs cells to the genital ridge, and the mitotic division of germ cell nuclei without complete cytokinesis to form a multi-nucleated syncytia, or germ cell nest. Through combined actions of germ cell apoptosis and somatic cell migration, the germ cell nuclei are packaged, with surrounding granulosa cells, into primordial follicles to form the initial follicle pool. Though often dismissed as quiescent and possibly uninteresting, this initial follicle pool is actually quite dynamic. In a very strictly controlled mechanism, a large portion of the initial primordial follicles formed is lost by atresia before cycling even begins. Remaining follicles can undergo alternate fates of continued dormancy or selection leading to follicular growth and differentiation. Together, the processes involved in the fate decisions of atresia, sustained dormancy, or activation carve out the follicle pool of puberty, the pool of available oocytes from which all future reproductive cycles of the female can choose. The formation of the initial and pubertal follicle pools can be predictably affected by exogenous treatment with hormones or molecules such as activin, demonstrating the ways the ovary controls the quality and quantity of germ cells maintained. Here, we review the biological processes involved in the formation of the initial follicle pool and the follicle pool of puberty, address the alternate models for regulating germ cell number, and outline how the ovary quality-controls the germ cells produced. This work is supported by NIH/NICHD Hormone Signals that Regulate Ovarian Differentiation, P01 HD021921; NIH/NICHD. Tingen, C. Kim, A. Woodruff, T. K. 0 2009-09-06T11:59:25Z 2009-08-26 2009-08-28 %0 Journal Article %A Tingen, C. %A Kim, A. %A Woodruff, T. K. %D 2009 %T The primordial pool of follicles and nest breakdown in mammalian ovaries. %J Mol Hum Reprod %V 15 %N 12 %P 795-803 %M 19710243 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19710243 %X The creation of the pool of follicles available for selection and ovulation is a multi-faceted, tightly regulated process that spans the period from embryonic development through to the first reproductive cycle of the organism. In mice, this development can occur in mere weeks, but in humans, it is sustained for years. Embryonic germ cell development involves the migration of primordial germs cells to the genital ridge, and the mitotic division of germ cell nuclei without complete cytokinesis to form a multi-nucleated syncytia, or germ cell nest. Through combined actions of germ cell apoptosis and somatic cell migration, the germ cell nuclei are packaged, with surrounding granulosa cells, into primordial follicles to form the initial follicle pool. Though often dismissed as quiescent and possibly uninteresting, this initial follicle pool is actually quite dynamic. In a very strictly controlled mechanism, a large portion of the initial primordial follicles formed is lost by atresia before cycling even begins. Remaining follicles can undergo alternate fates of continued dormancy or selection leading to follicular growth and differentiation. Together, the processes involved in the fate decisions of atresia, sustained dormancy, or activation carve out the follicle pool of puberty, the pool of available oocytes from which all future reproductive cycles of the female can choose. The formation of the initial and pubertal follicle pools can be predictably affected by exogenous treatment with hormones or molecules such as activin, demonstrating the ways the ovary controls the quality and quantity of germ cells maintained. Here, we review the biological processes involved in the formation of the initial follicle pool and the follicle pool of puberty, address the alternate models for regulating germ cell number and outline how the ovary quality-controls the germ cells produced. %+ The Department of Obstetrics and Gynecology, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. 6748 false false 12 Molecular human reproduction Mol Hum Reprod 795-803 2009-12-01 ppublish JOURNAL ARTICLE 19710243 In-Process 2009-11-17T07:21:43Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19710243 15 2009 Tyrosine kinase inhibitors, such as imatinib, have dramatically improved the outcomes for patients with selected cancers. For imatinib, western blotting of phospho-CrkL was an insensitive, indirect, and descriptive method to determine drug efficacy. Greater use of targeted therapies should involve more quantitative evaluation of the target's dose-inhibition. The Src/Abl kinase inhibitor dasatinib has recently been approved for use in Ph+ leukemias after failure with imatinib. Src family kinases (SFK) also play a critical role in nonhematologic cancers. We have developed a flow cytometric assay to measure SFK autophosphorylation levels in blood mononuclear cells and observed a direct correlation between its inhibition and patient dosage. This method provides a sensitive, quick, and quantitative tool to assess drug efficacy. Pediatr Blood Cancer. (c) 2009 Wiley-Liss, Inc. Guerrouahen, B. S. Wieder, E. Blanchard, E. G. Lee, F. Y. Aplenc, R. Corey, S. J. 0 2009-09-06T12:00:16Z 2009-06-02 %0 Journal Article %A Guerrouahen, B. S. %A Wieder, E. %A Blanchard, E. G. %A Lee, F. Y. %A Aplenc, R. %A Corey, S. J. %D 2009 %T Flow cytometric determination of Src phosphorylation in pediatric patients treated with dasatinib. %J Pediatr Blood Cancer %V 53 %N 6 %P 1132-1135 %M 19484755 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19484755 %X Tyrosine kinase inhibitors, such as imatinib, have dramatically improved the outcomes for patients with selected cancers. For imatinib, western blotting of phospho-CrkL was an insensitive, indirect, and descriptive method to determine drug efficacy. Greater use of targeted therapies should involve more quantitative evaluation of the target's dose-inhibition. The Src/Abl kinase inhibitor dasatinib has recently been approved for use in Ph+ leukemias after failure with imatinib. Src family kinases (SFK) also play a critical role in nonhematologic cancers. We have developed a flow cytometric assay to measure SFK autophosphorylation levels in blood mononuclear cells and observed a direct correlation between its inhibition and patient dosage. This method provides a sensitive, quick, and quantitative tool to assess drug efficacy. %K Child %K Flow Cytometry %K Humans %K Methods %K Phosphorylation %K Pyrimidines/*therapeutic use %K Thiazoles/*therapeutic use %K src-Family Kinases/*metabolism %+ Division of Pediatrics, MD Anderson Cancer Center, Houston, Texas, USA. 7399 false false 6 Pediatric blood & cancer Pediatr Blood Cancer Child; Flow Cytometry; Humans; Methods; Phosphorylation; Pyrimidines/*therapeutic use; Thiazoles/*therapeutic use; src-Family Kinases/*metabolism 1132-1135 2009-12-01 ppublish JOURNAL ARTICLE 19484755 MEDLINE 2009-10-14T06:15:31Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19484755 53 2009 The newly described F-BAR (Fer/CIP4 and Bin, amphiphysin, Rvs) family of proteins includes Cdc42 interacting protein-4 (CIP4), FBP-17 and Toca-1, and drives membrane deformation and invagination. Membrane remodeling affects endocytosis, vesicle budding, and cargo selection. The F-BAR family presents a novel family of proteins, which little is known about their in vivo function. We investigated the physiological role of CIP4, by creating CIP4-null mice through homologous recombination. Compared to their wild-type littermates, the CIP4-null mice displayed lower early post-prandial glucose levels. Adipocytes isolated from CIP4-null mice exhibited increased 14C-2-deoxyglucose uptake compared to cells from wild-type mice. The enhanced insulin sensitivity was not due to higher levels of insulin or phospho-Akt, a critical player in the insulin signaling. However, higher GLUT4 levels were detected in muscle membrane fractions in CIP4-null mice under insulin stimulation. Mouse embryonic fibroblasts from CIP4-null mice demonstrated decreased transferrin uptake, FITC-dextran, and horseradish peroxidase uptake, indicating that CIP4 affects multiple modes of endocytosis. These studies demonstrate a physiological role for CIP4 in endocytosis leading to a whole animal phenotype. Feng, Y. Hartig, S. M. Bechill, J. E. Blanchard, E. G. Caudell, E. Corey, S. J. 0 2009-11-20T07:19:25Z 2009-11-17 2009-11-19 %0 Journal Article %A Feng, Y. %A Hartig, S. M. %A Bechill, J. E. %A Blanchard, E. G. %A Caudell, E. %A Corey, S. J. %D 2009 %T The Cdc42 interacting protein 4 (CIP4) gene knockout mouse reveals delayed and decreased endocytosis. %J J Biol Chem %M 19920150 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19920150 %X The newly described F-BAR (Fer/CIP4 and Bin, amphiphysin, Rvs) family of proteins includes Cdc42 interacting protein-4 (CIP4), FBP-17 and Toca-1, and drives membrane deformation and invagination. Membrane remodeling affects endocytosis, vesicle budding, and cargo selection. The F-BAR family presents a novel family of proteins, which little is known about their in vivo function. We investigated the physiological role of CIP4, by creating CIP4-null mice through homologous recombination. Compared to their wild-type littermates, the CIP4-null mice displayed lower early post-prandial glucose levels. Adipocytes isolated from CIP4-null mice exhibited increased 14C-2-deoxyglucose uptake compared to cells from wild-type mice. The enhanced insulin sensitivity was not due to higher levels of insulin or phospho-Akt, a critical player in the insulin signaling. However, higher GLUT4 levels were detected in muscle membrane fractions in CIP4-null mice under insulin stimulation. Mouse embryonic fibroblasts from CIP4-null mice demonstrated decreased transferrin uptake, FITC-dextran, and horseradish peroxidase uptake, indicating that CIP4 affects multiple modes of endocytosis. These studies demonstrate a physiological role for CIP4 in endocytosis leading to a whole animal phenotype. %+ Northwestern, United States; 8610 false false The Journal of biological chemistry J Biol Chem 2009-11-17 aheadofprint JOURNAL ARTICLE 19920150 Publisher 2009-11-20T07:19:25Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19920150 2009 PURPOSE: There is considerable variation in the quality of cancer care delivered in the United States. Assessing care by using quality indicators could help decrease this variability. The objectives of this study were to formally develop valid quality indicators for melanoma and to assess hospital-level adherence with these measures in the United States. METHODS: Quality indicators were identified from available literature, consensus guidelines, and melanoma experts. Thirteen experts ranked potential measures for validity on the basis of the RAND/University of California, Los Angeles Appropriateness Methodology. Adherence with individual valid indicators and a composite measure of all indicators were assessed at 1,249 Commission on Cancer hospitals by using the National Cancer Data Base (NCDB; 2004 through 2005). RESULTS: Of 55 proposed quality indicators, 26 measures (47%) were rated as valid. These indicators assessed structure (n = 1), process (n = 24), and outcome (n = 1). Of the 26 measures, 10 are readily assessable by using cancer registry data. Adherence with valid indicators ranged from 11.8% to 96.5% at the patient level and 3.7% to 83.0% at the hospital level. (Adherence required that >/= 90% of patients at a hospital receive concordant care). Most hospitals were adherent with 50% or fewer of the individual indicators (median composite score, five; interquartile range, four to seven). Adherence was higher for diagnosis and staging measures and was lower for treatment indicators. CONCLUSION: There is considerable variation in the quality of melanoma care in the United States. By using these formally developed quality indicators, hospitals can assess their adherence with current melanoma care guidelines through feedback mechanisms from the NCDB and can better direct quality improvement efforts. Bilimoria, K. Y. Raval, M. V. Bentrem, D. J. Wayne, J. D. Balch, C. M. Ko, C. Y. 0 2009-10-16T06:14:25Z 2009-10-13 2009-10-15 %0 Journal Article %A Bilimoria, K. Y. %A Raval, M. V. %A Bentrem, D. J. %A Wayne, J. D. %A Balch, C. M. %A Ko, C. Y. %D 2009 %T National assessment of melanoma care using formally developed quality indicators. %J J Clin Oncol %V 27 %N 32 %P 5445-5451 %M 19826131 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19826131 %X PURPOSE: There is considerable variation in the quality of cancer care delivered in the United States. Assessing care by using quality indicators could help decrease this variability. The objectives of this study were to formally develop valid quality indicators for melanoma and to assess hospital-level adherence with these measures in the United States. METHODS: Quality indicators were identified from available literature, consensus guidelines, and melanoma experts. Thirteen experts ranked potential measures for validity on the basis of the RAND/University of California, Los Angeles Appropriateness Methodology. Adherence with individual valid indicators and a composite measure of all indicators were assessed at 1,249 Commission on Cancer hospitals by using the National Cancer Data Base (NCDB; 2004 through 2005). RESULTS: Of 55 proposed quality indicators, 26 measures (47%) were rated as valid. These indicators assessed structure (n = 1), process (n = 24), and outcome (n = 1). Of the 26 measures, 10 are readily assessable by using cancer registry data. Adherence with valid indicators ranged from 11.8% to 96.5% at the patient level and 3.7% to 83.0% at the hospital level. (Adherence required that >OR= 90% of patients at a hospital receive concordant care.) Most hospitals were adherent with 50% or fewer of the individual indicators (median composite score, five; interquartile range, four to seven). Adherence was higher for diagnosis and staging measures and was lower for treatment indicators. CONCLUSION: There is considerable variation in the quality of melanoma care in the United States. By using these formally developed quality indicators, hospitals can assess their adherence with current melanoma care guidelines through feedback mechanisms from the NCDB and can better direct quality improvement efforts. %+ Department of Surgery, American College Surgeons, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3211, USA. kbilimoria@facs.org 8481 false false 32 Journal of clinical oncology : official journal of the American Society of Clinical Oncology J Clin Oncol 5445-5451 2009-11-10 ppublish JOURNAL ARTICLE 19826131 In-Process 2009-11-13T07:19:17Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19826131 27 2009 Wei, Y. Bishop, K. J. Kim, J. Soh, S. Grzybowski, B. A. 0 2009-11-11T07:22:59Z 2009-11-07 2009-11-10 %0 Journal Article %A Wei, Y. %A Bishop, K. J. %A Kim, J. %A Soh, S. %A Grzybowski, B. A. %D 2009 %T Making Use of Bond Strength and Steric Hindrance in Nanoscale "Synthesis" %J Angew Chem Int Ed Engl %M 19899173 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19899173 %+ Department of Chemistry, Department of Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208 (USA) http://dysa.northwestern.edu. 8581 false false Angewandte Chemie (International ed. in English) Angew Chem Int Ed Engl 2009-11-07 aheadofprint JOURNAL ARTICLE 19899173 Publisher 2009-11-11T07:22:59Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19899173 2009 BACKGROUND:: Studies have demonstrated volume-outcome relationships for numerous operations, providing an impetus for regionalization; however, volume-based regionalization may not be feasible or necessary. Our objective was to determine if low-risk patients undergoing surgery at Community Hospitals have perioperative mortality rates comparable with Specialized Centers. METHODS:: From the National Cancer Data Base, 940,718 patients from approximately 1430 hospitals were identified who underwent resection for 1 of 15 cancers (2003-2005). Patients were stratified by preoperative risk according to age and comorbidities. Separately for each cancer, regression modeling stratified by high- and low-risk groups was used to compare 60-day mortality at Specialized Centers (National Cancer Institute-designated and/or highest-volume quintile institutions), Other Academic Institutions (lower-volume, non-National Cancer Institute), and Community Hospitals. RESULTS:: Low-risk patients had statistically similar perioperative mortality rates at Specialized Centers and Community Hospitals for 13 of 15 operations. High-risk patients had significantly lower perioperative mortality rates at Specialized Centers compared with Community Hospitals for 9 of 15 cancers. Regardless of risk group, perioperative mortality rates were significantly lower for pancreatectomy and esophagectomy at Specialized Centers. Risk-based referral compared with volume-based regionalization of most patients would require fewer patients to change to Specialized Centers. CONCLUSIONS:: Perioperative mortality for low-risk patients was comparable at Specialized Centers and Community Hospitals for all cancers except esophageal and pancreatic, thus questioning volume-based regionalization of all patients. Rather, only high-risk patients may need to change hospitals. Mortality rates could be reduced if factors at Specialized Centers resulting in better outcomes for high-risk patients can be identified and transferred to other hospitals. Bilimoria, K. Y. Bentrem, D. J. Talamonti, M. S. Stewart, A. K. Winchester, D. P. Ko, C. Y. 0 2009-11-11T07:21:39Z 2009-11-05 2009-11-10 %0 Journal Article %A Bilimoria, K. Y. %A Bentrem, D. J. %A Talamonti, M. S. %A Stewart, A. K. %A Winchester, D. P. %A Ko, C. Y. %D 2009 %T Risk-based Selective Referral for Cancer Surgery: A Potential Strategy to Improve Perioperative Outcomes. %J Ann Surg %M 19898231 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19898231 %X BACKGROUND:: Studies have demonstrated volume-outcome relationships for numerous operations, providing an impetus for regionalization; however, volume-based regionalization may not be feasible or necessary. Our objective was to determine if low-risk patients undergoing surgery at Community Hospitals have perioperative mortality rates comparable with Specialized Centers. METHODS:: From the National Cancer Data Base, 940,718 patients from approximately 1430 hospitals were identified who underwent resection for 1 of 15 cancers (2003-2005). Patients were stratified by preoperative risk according to age and comorbidities. Separately for each cancer, regression modeling stratified by high- and low-risk groups was used to compare 60-day mortality at Specialized Centers (National Cancer Institute-designated and/or highest-volume quintile institutions), Other Academic Institutions (lower-volume, non-National Cancer Institute), and Community Hospitals. RESULTS:: Low-risk patients had statistically similar perioperative mortality rates at Specialized Centers and Community Hospitals for 13 of 15 operations. High-risk patients had significantly lower perioperative mortality rates at Specialized Centers compared with Community Hospitals for 9 of 15 cancers. Regardless of risk group, perioperative mortality rates were significantly lower for pancreatectomy and esophagectomy at Specialized Centers. Risk-based referral compared with volume-based regionalization of most patients would require fewer patients to change to Specialized Centers. CONCLUSIONS:: Perioperative mortality for low-risk patients was comparable at Specialized Centers and Community Hospitals for all cancers except esophageal and pancreatic, thus questioning volume-based regionalization of all patients. Rather, only high-risk patients may need to change hospitals. Mortality rates could be reduced if factors at Specialized Centers resulting in better outcomes for high-risk patients can be identified and transferred to other hospitals. %+ From the *Cancer Programs, Division of Research and Optimal Patient Care, American College of Surgeons, Chicago, IL; daggerDepartment of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL; double daggerDepartment of Surgery, NorthShore University Health System, Evanston, IL; and section signDepartment of Surgery, University of California, Los Angeles (UCLA) and VA Greater Los Angeles Healthcare System, Los Angeles, CA. 8578 false false Annals of surgery Ann Surg 2009-11-05 aheadofprint JOURNAL ARTICLE 19898231 Publisher 2009-11-11T07:21:39Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19898231 2009 Chen, H. Pazicni, S. Krett, N. L. Ahn, R. W. Penner-Hahn, J. E. Rosen, S. T. O'Halloran, T. V. 0 2009-11-08T07:20:58Z 2009-11-05 2009-11-07 %0 Journal Article %A Chen, H. %A Pazicni, S. %A Krett, N. L. %A Ahn, R. W. %A Penner-Hahn, J. E. %A Rosen, S. T. %A O'Halloran, T. V. %D 2009 %T Coencapsulation of Arsenic- and Platinum-based Drugs for Targeted Cancer Treatment. %J Angew Chem Int Ed Engl %V 48 %N 49 %P 9295-9299 %M 19894238 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19894238 %+ Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208 (USA), Fax: (+1) 847-491-7713. 8575 false false 49 Angewandte Chemie (International ed. in English) Angew Chem Int Ed Engl 9295-9299 2009-11-05 aheadofprint JOURNAL ARTICLE 19894238 Publisher 2009-11-18T07:16:22Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19894238 48 2009 HYPOTHESIS: Specific complications occur more frequently in elderly patients undergoing major gastrointestinal (GI) tract operations that may represent opportunities for quality improvement. DESIGN: Retrospective cohort study. SETTING: One hundred twenty-one hospitals participating in American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). PATIENTS: Using the ACS-NSQIP participant use file (2005-2006), patients undergoing upper gastrointestinal tract (n = 4115), hepatobiliary or pancreatic (n = 3364), and colorectal (n = 17 268) operations at 121 hospitals were examined. MAIN OUTCOME MEASURES: Risk-adjusted 30-day outcomes were assessed using regression modeling adjusting for patient characteristics, comorbidities, and surgical procedures. The elderly were defined as those older than 75 years. RESULTS: Between January 1, 2005, and December 31, 2006, a total of 54 747 patients who underwent major GI tract operations were identified from the ACS-NSQIP data file. In the elderly, overall perioperative morbidity was 1.2 to 2 times higher and mortality was 2.9 to 6.7 times higher than in younger patients after adjusting for differences in preoperative comorbidities. Irrespective of procedure type, the elderly were significantly more likely to experience cardiac (acute myocardial infarction and cardiac arrest), pulmonary (pneumonia, pulmonary embolism, and respiratory failure), and urologic (urinary tract infection and renal failure) complications. However, surgical site infections, postoperative bleeding events, deep venous thromboses, and rates of return to the operating room did not differ significantly by age. CONCLUSIONS: Morbidity and mortality are markedly higher in older patients. Quality measures for the elderly currently address only myocardial infarction, surgical site infection, and deep venous thrombosis. If care for the elderly is to be improved, quality improvement initiatives need to be expanded to include postoperative pulmonary and renal complications. Bentrem, D. J. Cohen, M. E. Hynes, D. M. Ko, C. Y. Bilimoria, K. Y. 0 2009-11-19T07:22:08Z 2009-11-18 %0 Journal Article %A Bentrem, D. J. %A Cohen, M. E. %A Hynes, D. M. %A Ko, C. Y. %A Bilimoria, K. Y. %D 2009 %T Identification of specific quality improvement opportunities for the elderly undergoing gastrointestinal surgery. %J Arch Surg %V 144 %N 11 %P 1013-1020 %M 19917937 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19917937 %X HYPOTHESIS: Specific complications occur more frequently in elderly patients undergoing major gastrointestinal (GI) tract operations that may represent opportunities for quality improvement. DESIGN: Retrospective cohort study. SETTING: One hundred twenty-one hospitals participating in American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). PATIENTS: Using the ACS-NSQIP participant use file (2005-2006), patients undergoing upper gastrointestinal tract (n = 4115), hepatobiliary or pancreatic (n = 3364), and colorectal (n = 17 268) operations at 121 hospitals were examined. MAIN OUTCOME MEASURES: Risk-adjusted 30-day outcomes were assessed using regression modeling adjusting for patient characteristics, comorbidities, and surgical procedures. The elderly were defined as those older than 75 years. RESULTS: Between January 1, 2005, and December 31, 2006, a total of 54 747 patients who underwent major GI tract operations were identified from the ACS-NSQIP data file. In the elderly, overall perioperative morbidity was 1.2 to 2 times higher and mortality was 2.9 to 6.7 times higher than in younger patients after adjusting for differences in preoperative comorbidities. Irrespective of procedure type, the elderly were significantly more likely to experience cardiac (acute myocardial infarction and cardiac arrest), pulmonary (pneumonia, pulmonary embolism, and respiratory failure), and urologic (urinary tract infection and renal failure) complications. However, surgical site infections, postoperative bleeding events, deep venous thromboses, and rates of return to the operating room did not differ significantly by age. CONCLUSIONS: Morbidity and mortality are markedly higher in older patients. Quality measures for the elderly currently address only myocardial infarction, surgical site infection, and deep venous thrombosis. If care for the elderly is to be improved, quality improvement initiatives need to be expanded to include postoperative pulmonary and renal complications. %+ Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. Bentrem, David J Cohen, Mark E Hynes, Denise M Ko, Clifford Y Bilimoria, Karl Y 8606 false false 11 Archives of surgery (Chicago, Ill. : 1960) Arch Surg 1013-1020 2009-11-01 ppublish Journal Article 19917937 In-Data-Review 2009-11-19T07:22:08Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19917937 144 2009 Woodruff, T. K. 0 2009-11-08T07:22:07Z 2009-11-07 %0 Journal Article %A Woodruff, T. K. %D 2009 %T Rock the cradle. %J Nat Med %V 15 %N 11 %P 1244 %M 19893551 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19893551 %+ Teresa K. Woodruff is The Thomas J. Watkins Professor of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. Woodruff, Teresa K 8577 false false 11 Nature medicine Nat Med 1244 2009-11-01 ppublish Journal Article 19893551 In-Data-Review 2009-11-08T07:22:07Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19893551 15 2009 Eklund, E. A. Platanias, L. C. 0 2009-11-05T07:22:22Z 2009-11-04 %0 Journal Article %A Eklund, E. A. %A Platanias, L. C. %D 2009 %T Screening for microRNAs in myelodysplastic syndromes. %J Leuk Lymphoma %V 50 %N 11 %P 1735-1736 %M 19883302 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19883302 %+ The Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA. e-eklund@northwestern.edu Eklund, Elizabeth A Platanias, Leonidas C 8559 false false 11 Leukemia & lymphoma Leuk Lymphoma 1735-1736 2009-11-01 ppublish Comment 19883302 In-Process 2009-11-05T07:22:22Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19883302 50 2009 There is accumulating evidence that the patterns of altered expression of microRNAs (miRNAs) correlate with distinct types of hematological malignancies. There is also emerging evidence for such miRNAs expression in multiple myeloma (MM), but the identity of the miRNAs that are abnormally expressed in this disease has not been elucidated. In the current study, we examined the miRNAs perturbed in CD138 positive MM cell lines and CD138 positive primary MM cells, using microarray analysis and quantitative real-time PCR. The expression levels in these cells were compared with the expression levels in CD138 positive plasma cells isolated from bone marrows of healthy donors. Our data demonstrate that multiple new miRNAs are commonly up-regulated and down-regulated including a new miRNA cluster, miR-193b-365, composed of two paralogs that were significantly up-regulated in MM. The organization and the sequences of the new miR-193b-365 cluster are highly conserved among vertebrates. Given that dysregulation of miR-193b-365 cluster has not been identified in other hematological malignancies examined to date, our findings suggest that miR-193b-365 cluster is part of the unique miRNA signature in MM. Unno, K. Zhou, Y. Zimmerman, T. Platanias, L. C. Wickrema, A. 0 2009-11-05T07:22:52Z 2009-11-04 %0 Journal Article %A Unno, K. %A Zhou, Y. %A Zimmerman, T. %A Platanias, L. C. %A Wickrema, A. %D 2009 %T Identification of a novel microRNA cluster miR-193b-365 in multiple myeloma. %J Leuk Lymphoma %V 50 %N 11 %P 1865-1871 %M 19883314 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19883314 %X There is accumulating evidence that the patterns of altered expression of microRNAs (miRNAs) correlate with distinct types of hematological malignancies. There is also emerging evidence for such miRNAs expression in multiple myeloma (MM), but the identity of the miRNAs that are abnormally expressed in this disease has not been elucidated. In the current study, we examined the miRNAs perturbed in CD138 positive MM cell lines and CD138 positive primary MM cells, using microarray analysis and quantitative real-time PCR. The expression levels in these cells were compared with the expression levels in CD138 positive plasma cells isolated from bone marrows of healthy donors. Our data demonstrate that multiple new miRNAs are commonly up-regulated and down-regulated including a new miRNA cluster, miR-193b-365, composed of two paralogs that were significantly up-regulated in MM. The organization and the sequences of the new miR-193b-365 cluster are highly conserved among vertebrates. Given that dysregulation of miR-193b-365 cluster has not been identified in other hematological malignancies examined to date, our findings suggest that miR-193b-365 cluster is part of the unique miRNA signature in MM. %+ Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Unno, Kenji Zhou, Ying Zimmerman, Todd Platanias, Leonidas C Wickrema, Amittha 8561 false false 11 Leukemia & lymphoma Leuk Lymphoma 1865-1871 2009-11-01 ppublish Journal Article 19883314 In-Process 2009-11-05T07:22:52Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19883314 50 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 Therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) is a long-term complication of pediatric cancer. We retrospectively studied pediatric t-MDS/AML patients treated at MD Anderson from 1975 to 2007. We also compared those patients to pediatric patients with de novo MDS/AML during this time interval. Among 2589 children with cancer treated at MD Anderson, we identified 22 patients with t-MDS/AML. Patients with t-MDS/AML had a median age of 14 years. There was a male and Hispanic predominance. The most common primary malignancies were osteosarcoma and Hodgkin lymphoma. The median latency period was 4.1 years. Three patients received supportive care only. Group 1 (n=5) underwent stem cell transplantation without induction chemotherapy. Group 2 (n=5) patients received AML-type chemotherapy and a stem cell transplant postremission (n=5). Group 3 (n=4) received a stem cell transplant as salvage therapy. The respective 2-year survival rates for groups 1, 2, and 3 were 20%, 40%, and 25% (P=0.85). Patients with de novo AML were younger (P=0.001) and higher rates of complete remission (P=0.03), and survival (P<0.0001). Independent factors predicting shorter survival were poor/intermediate-risk cytogenetics (P=0.01), lower hemoglobin level (P=0.0001), and t-MDS/AML (vs. de novo) (P=0.003). Childhood t-MDS/AML has a poor prognosis. Although patients benefited from AML-type induction chemotherapy followed by stem cell transplantation as postremission therapy, effective therapies, and prevention are needed. Aguilera, D. G. Vaklavas, C. Tsimberidou, A. M. Wen, S. Medeiros, L. J. Corey, S. J. 0 2009-10-07T06:13:28Z 2009-10-06 %0 Journal Article %A Aguilera, D. G. %A Vaklavas, C. %A Tsimberidou, A. M. %A Wen, S. %A Medeiros, L. J. %A Corey, S. J. %D 2009 %T Pediatric therapy-related myelodysplastic syndrome/acute myeloid leukemia: the MD Anderson Cancer Center experience. %J J Pediatr Hematol Oncol %V 31 %N 11 %P 803-811 %M 19801947 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19801947 %X Therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) is a long-term complication of pediatric cancer. We retrospectively studied pediatric t-MDS/AML patients treated at MD Anderson from 1975 to 2007. We also compared those patients to pediatric patients with de novo MDS/AML during this time interval. Among 2589 children with cancer treated at MD Anderson, we identified 22 patients with t-MDS/AML. Patients with t-MDS/AML had a median age of 14 years. There was a male and Hispanic predominance. The most common primary malignancies were osteosarcoma and Hodgkin lymphoma. The median latency period was 4.1 years. Three patients received supportive care only. Group 1 (n=5) underwent stem cell transplantation without induction chemotherapy. Group 2 (n=5) patients received AML-type chemotherapy and a stem cell transplant postremission (n=5). Group 3 (n=4) received a stem cell transplant as salvage therapy. The respective 2-year survival rates for groups 1, 2, and 3 were 20%, 40%, and 25% (P=0.85). Patients with de novo AML were younger (P=0.001) and higher rates of complete remission (P=0.03), and survival (P<0.0001). Independent factors predicting shorter survival were poor/intermediate-risk cytogenetics (P=0.01), lower hemoglobin level (P=0.0001), and t-MDS/AML (vs. de novo) (P=0.003). Childhood t-MDS/AML has a poor prognosis. Although patients benefited from AML-type induction chemotherapy followed by stem cell transplantation as postremission therapy, effective therapies, and prevention are needed. %+ Division of Pediatrics, The University of Texas MD Anderson Cancer Center, TX, USA. 8442 false false 11 Journal of pediatric hematology/oncology : official journal of the American Society of Pediatric Hematology/Oncology J Pediatr Hematol Oncol 803-811 2009-11-01 ppublish JOURNAL ARTICLE 19801947 In-Process 2009-11-07T07:18:23Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19801947 31 2009 Foxl2 is a forkhead transcription factor required for ovary development and ovarian follicle maturation. In this report, we identified and characterized a functional relationship between Foxl2 expression and estrogen receptor (ER)-alpha signaling. We show that Foxl2 has no effect on classical ERalpha-mediated transcription, which occurs through canonical estrogen response elements. However, Foxl2 suppresses ERalpha signaling through nonclassical tethered transcriptional pathways. Specifically, the selective ER modulator tamoxifen stimulates activator protein-1 (AP1)-dependent transcription via the ERalpha, and this enhancement is blocked by Foxl2. Two lines of evidence suggest that Foxl2 suppression is mediated by physical interactions with ERalpha rather than direct action at AP1 binding sites. First, ERalpha is coimmunoprecipitated with Foxl2. Second, activation of a upstream activating sequence (UAS) reporter by Gal4-cJun in the presence of ERalpha and tamoxifen was blocked by Foxl2, demonstrating suppression in the absence of an AP1 site. Cyclooxygenase-2 (COX2), which is required for ovulation, was identified through expression profiling as a candidate physiological target for nonclassical ERalpha signaling and thus modulation by ERalpha/Foxl2 interactions. This possibility was confirmed by two sets of experiments. COX2 protein levels were induced by ERalpha in the presence of tamoxifen, and protein expression was suppressed by Foxl2. In addition, ERalpha stimulation of the COX2 promoter was repressed by Foxl2. We conclude that ERalpha and Foxl2 interact and that Foxl2 selectively suppresses ERalpha-mediated transcription of AP1-regulated genes. These data provide a potential point of convergence for ERalpha and Foxl2 to regulate ovarian development and function. Kim, S. Y. Weiss, J. Tong, M. Laronda, M. M. Lee, E. J. Jameson, J. L. 0 2009-10-04T06:14:02Z 2009-09-24 2009-10-03 %0 Journal Article %A Kim, S. Y. %A Weiss, J. %A Tong, M. %A Laronda, M. M. %A Lee, E. J. %A Jameson, J. L. %D 2009 %T Foxl2, a forkhead transcription factor, modulates nonclassical activity of the estrogen receptor-alpha. %J Endocrinology %V 150 %N 11 %P 5085-5093 %M 19797124 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19797124 %X Foxl2 is a forkhead transcription factor required for ovary development and ovarian follicle maturation. In this report, we identified and characterized a functional relationship between Foxl2 expression and estrogen receptor (ER)-alpha signaling. We show that Foxl2 has no effect on classical ERalpha-mediated transcription, which occurs through canonical estrogen response elements. However, Foxl2 suppresses ERalpha signaling through nonclassical tethered transcriptional pathways. Specifically, the selective ER modulator tamoxifen stimulates activator protein-1 (AP1)-dependent transcription via the ERalpha, and this enhancement is blocked by Foxl2. Two lines of evidence suggest that Foxl2 suppression is mediated by physical interactions with ERalpha rather than direct action at AP1 binding sites. First, ERalpha is coimmunoprecipitated with Foxl2. Second, activation of a upstream activating sequence (UAS) reporter by Gal4-cJun in the presence of ERalpha and tamoxifen was blocked by Foxl2, demonstrating suppression in the absence of an AP1 site. Cyclooxygenase-2 (COX2), which is required for ovulation, was identified through expression profiling as a candidate physiological target for nonclassical ERalpha signaling and thus modulation by ERalpha/Foxl2 interactions. This possibility was confirmed by two sets of experiments. COX2 protein levels were induced by ERalpha in the presence of tamoxifen, and protein expression was suppressed by Foxl2. In addition, ERalpha stimulation of the COX2 promoter was repressed by Foxl2. We conclude that ERalpha and Foxl2 interact and that Foxl2 selectively suppresses ERalpha-mediated transcription of AP1-regulated genes. These data provide a potential point of convergence for ERalpha and Foxl2 to regulate ovarian development and function. %K Cell Line %K Cyclooxygenase 2/genetics/metabolism %K Estrogen Receptor alpha/genetics/*metabolism %K Forkhead Transcription Factors/genetics/*metabolism %K Humans %K Promoter Regions, Genetic %K Protein Binding %K Transcription Factor AP-1/genetics/metabolism %K *Transcriptional Activation %+ Morton 4-656, 303 East Chicago Avenue, Chicago, Illinois 60611, USA. 8431 false false 11 Endocrinology Endocrinology Cell Line; Cyclooxygenase 2/genetics/metabolism; Estrogen Receptor alpha/genetics/*metabolism; Forkhead Transcription Factors/genetics/*metabolism; Humans; Promoter Regions, Genetic; Protein Binding; Transcription Factor AP-1/genetics/metabolism; *Transcriptional Activation 5085-5093 2009-11-01 ppublish JOURNAL ARTICLE 19797124 MEDLINE 2009-11-17T07:20:54Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19797124 150 2009 Estrogen non-responsive estrogen receptor alpha (ERalpha) knock-in (ENERKI) mice have a mutation (glycine 525 to leucine, G525L) in the ligand-binding domain of ERalpha. The mutant ERalpha protein has a significantly lower affinity and response to endogenous estrogens, while not altering growth factor activated ligand-independent pathways. ENERKI females demonstrated signs of early follicle development as determined by a significant increase in antral follicle formation by 20 days of age. Adult ENERKI females were infertile, had hemorrhagic ovarian follicular cysts, and failed to develop corpora lutea in response to a superovulation regimen. These results illustrate the importance of ERalpha ligand-induced signaling for ovarian development and for estrogen feedback on the hypothalamus and pituitary. Although ERalpha ligand-induced signaling by endogenous estrogens is lost in ENERKI females, the ERalpha selective agonist propyl pyrazole triol (PPT), a synthetic nonsteroidal compound, is still able to activate G525L ERalphain vivo to increase uterine weight. To test whether PPT could restore ligand-dependent receptor activation, ENERKI females were treated with PPT and evaluated for spontaneous ovulation, ovarian hemorrhagic cysts, and LH serum levels. Daily PPT treatments beginning on day 4 of life prevented formation of ovarian hemorrhagic cysts in adult ENERKI animals. In accordance with this result, preputial gland weight and LH levels were also lowered in these animals, indicating PPT treatments most likely led to restoration of ERalpha negative feedback of the hypothalamic-pituitary axis. Sinkevicius, K. W. Woloszyn, K. Laine, M. Jackson, K. S. Greene, G. L. Woodruff, T. K. Burdette, J. E. 0 2009-09-06T11:59:25Z 2009-07-23 2009-07-28 %0 Journal Article %A Sinkevicius, K. W. %A Woloszyn, K. %A Laine, M. %A Jackson, K. S. %A Greene, G. L. %A Woodruff, T. K. %A Burdette, J. E. %D 2009 %T Characterization of the ovarian and reproductive abnormalities in prepubertal and adult estrogen non-responsive estrogen receptor alpha knock-in (ENERKI) mice. %J Steroids %V 74 %N 12 %P 913-919 %M 19631674 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19631674 %X Estrogen non-responsive estrogen receptor alpha (ERalpha) knock-in (ENERKI) mice have a mutation (glycine 525 to leucine, G525L) in the ligand-binding domain of ERalpha. The mutant ERalpha protein has a significantly lower affinity and response to endogenous estrogens, while not altering growth factor activated ligand-independent pathways. ENERKI females demonstrated signs of early follicle development as determined by a significant increase in antral follicle formation by 20 days of age. Adult ENERKI females were infertile, had hemorrhagic ovarian follicular cysts, and failed to develop corpora lutea in response to a superovulation regimen. These results illustrate the importance of ERalpha ligand-induced signaling for ovarian development and for estrogen feedback on the hypothalamus and pituitary. Although ERalpha ligand-induced signaling by endogenous estrogens is lost in ENERKI females, the ERalpha selective agonist propyl pyrazole triol (PPT), a synthetic nonsteroidal compound, is still able to activate G525L ERalphain vivo to increase uterine weight. To test whether PPT could restore ligand-dependent receptor activation, ENERKI females were treated with PPT and evaluated for spontaneous ovulation, ovarian hemorrhagic cysts, and LH serum levels. Daily PPT treatments beginning on day 4 of life prevented formation of ovarian hemorrhagic cysts in adult ENERKI animals. In accordance with this result, preputial gland weight and LH levels were also lowered in these animals, indicating PPT treatments most likely led to restoration of ERalpha negative feedback of the hypothalamic-pituitary axis. %+ The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA. 6749 false false 12 Steroids Steroids 913-919 2009-11-01 ppublish JOURNAL ARTICLE 19631674 In-Process 2009-09-16T06:16:04Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19631674 74 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 PURPOSE OF REVIEW: To highlight key studies providing rationale for and utility in targeting glycolysis for the treatment of hematological malignancies. RECENT FINDINGS: Several therapeutic strategies are capitalizing on the diagnostic utility of fluoro-deoxyglucose positron emission tomography that relies on increased glycolysis and glucose utilization in tumor cells. Although aerobic glycolysis was initially proposed by Warburg to be due to mitochondrial impairment, recent studies have shown a preferential switch to glycolysis in tumor cells with functional mitochondria. Increased glucose consumption can be advantageous for a tumor cell through stimulation of cellular biosynthetic, energetic, and pro-survival pathways. We now have a greater appreciation for the utilization of glucose in specific metabolic pathways that in some aspects can be complemented with other nutrients such as glutamine. Targeting glucose consumption for the treatment of hematological malignancies seems to be a promising field that will require characterization of tumor cell specific targets to inhibit glucose uptake and/or glycolysis. It is imperative to further our understanding of the tumor cell metabolome to target cellular bioenergetics in the treatment of cancer. SUMMARY: Targeting the glycolytic pathway for the treatment of hematological malignancies has sufficient rationale given the utility of fluoro-deoxyglucose positron emission tomography in diagnostic imaging. Further research is required in developing tumor cell specific therapeutics. Shanmugam, M. McBrayer, S. K. Rosen, S. T. 0 2009-09-06T11:57:36Z 2009-07-10 %0 Journal Article %A Shanmugam, M. %A McBrayer, S. K. %A Rosen, S. T. %D 2009 %T Targeting the Warburg effect in hematological malignancies: from PET to therapy. %J Curr Opin Oncol %V 21 %N 6 %P 531-536 %M 19587591 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19587591 %X PURPOSE OF REVIEW: To highlight key studies providing rationale for and utility in targeting glycolysis for the treatment of hematological malignancies. RECENT FINDINGS: Several therapeutic strategies are capitalizing on the diagnostic utility of 18fluoro-deoxyglucose positron emission tomography that relies on increased glycolysis and glucose utilization in tumor cells. Although aerobic glycolysis was initially proposed by Warburg to be due to mitochondrial impairment, recent studies have shown a preferential switch to glycolysis in tumor cells with functional mitochondria. Increased glucose consumption can be advantageous for a tumor cell through stimulation of cellular biosynthetic, energetic, and pro-survival pathways. We now have a greater appreciation for the utilization of glucose in specific metabolic pathways that in some aspects can be complemented with other nutrients such as glutamine. Targeting glucose consumption for the treatment of hematological malignancies seems to be a promising field that will require characterization of tumor cell specific targets to inhibit glucose uptake and/or glycolysis. It is imperative to further our understanding of the tumor cell metabolome to target cellular bioenergetics in the treatment of cancer. SUMMARY: Targeting the glycolytic pathway for the treatment of hematological malignancies has sufficient rationale given the utility of fluoro-deoxyglucose positron emission tomography in diagnostic imaging. Further research is required in developing tumor cell specific therapeutics. %+ Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA. mala@northwestern.edu 5110 false false 6 Current opinion in oncology Curr Opin Oncol 531-536 2009-11-01 ppublish JOURNAL ARTICLE 19587591 In-Process 2009-10-16T06:15:02Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19587591 21 2009 ADAMs (a disintegrin and metalloproteinases) are a family of multidomain transmembrane glycoproteins with diverse roles in physiology and diseases, with several members being drug targets for cancer and inflammation therapies. The spatial organization of the ADAM extracellular segment and its influence on the function of ADAMs have been unclear. Although most members of the ADAM family are active zinc-metalloproteinases, 8 of 21 ADAMs lack functional metalloproteinase domains, and are implicated in protein-protein interactions instead of membrane protein ectodomain shedding. One of such non-proteinase ADAMs, ADAM22, acts as a receptor on the surface of the postsynaptic neuron to regulate synaptic signal transmission. The crystal structure of the full ectodomain of mature human ADAM22 shows that it is a compact four-leaf clover with the metalloproteinase-like domain held in the concave face of a rigid module formed by the disintegrin, cysteine-rich, and EGF-like domains. The loss of metalloproteinase activity is ensured by the absence of critical catalytic residues, the filling of the substrate groove, and the steric hindrance by the cysteine-rich domain. The structure, combined with calorimetric experiments, suggests distinct roles of three putative calcium ions bound to ADAM22, with one in the metalloproteinase-like domain being regulatory and two in the disintegrin domain being structural. The metalloproteinase-like domain contacts the rest of ADAM22 with discontinuous, hydrophilic, and poorly complemented interactions, suggesting the possibility of modular movement of ADAM22 and other ADAMs. The ADAM22 structure provides a framework for understanding how different ADAMs exert their adhesive function and shedding activities. Liu, H. Shim, A. H. He, X. 0 2009-09-06T11:55:25Z 2009-08-18 2009-08-21 %0 Journal Article %A Liu, H. %A Shim, A. H. %A He, X. %D 2009 %T Structural characterization of the ectodomain of a disintegrin and metalloproteinase-22 (ADAM22), a neural adhesion receptor instead of metalloproteinase: insights on ADAM function. %J J Biol Chem %V 284 %N 42 %P 29077-29086 %M 19692335 %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19692335 %X ADAMs (a disintegrin and metalloproteinases) are a family of multidomain transmembrane glycoproteins with diverse roles in physiology and diseases, with several members being drug targets for cancer and inflammation therapies. The spatial organization of the ADAM extracellular segment and its influence on the function of ADAMs have been unclear. Although most members of the ADAM family are active zinc metalloproteinases, 8 of 21 ADAMs lack functional metalloproteinase domains and are implicated in protein-protein interactions instead of membrane protein ectodomain shedding. One of such non-proteinase ADAMs, ADAM22, acts as a receptor on the surface of the postsynaptic neuron to regulate synaptic signal transmission. The crystal structure of the full ectodomain of mature human ADAM22 shows that it is a compact four-leaf clover with the metalloproteinase-like domain held in the concave face of a rigid module formed by the disintegrin, cysteine-rich, and epidermal growth factor-like domains. The loss of metalloproteinase activity is ensured by the absence of critical catalytic residues, the filling of the substrate groove, and the steric hindrance by the cysteine-rich domain. The structure, combined with calorimetric experiments, suggests distinct roles of three putative calcium ions bound to ADAM22, with one in the metalloproteinase-like domain being regulatory and two in the disintegrin domain being structural. The metalloproteinase-like domain contacts the rest of ADAM22 with discontinuous, hydrophilic, and poorly complemented interactions, suggesting the possibility of modular movement of ADAM22 and other ADAMs. The ADAM22 structure provides a framework for understanding how different ADAMs exert their adhesive function and shedding activities. %+ Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. 1954 false false 42 The Journal of biological chemistry J Biol Chem 29077-29086 2009-10-16 ppublish JOURNAL ARTICLE 19692335 In-Process 2009-10-16T06:14:38Z http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19692335 284 2009