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Fulvestrant does not significantly inhibit any of the major cytochrome p450 cyp ; isoenzymes in vitro, and results from a clinical pharmacokinetic trial involving co-administration of fulvestrant with midazolam also suggest that therapeutic doses of fulvestrant will have no inhibitory effects on cyp3a dosage adjustment is not necessary in patients co-prescribed cyp3a4 inhibitors or inducers.
7. Donnelly JP, Blijlevens NM, Verhagen CA: Can anything be done about oral mucositis? Ann Oncol 14: 505-507, 2003 Rubenstein EB, Peterson DE, Schubert M, et al: Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 100: 2026-2046, 2004 suppl ; 9. Mahood DJ, Dose AM, Loprinzi CL, et al: Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol 9: 449-452, 1991 Cascinu S, Fedeli A, Fedeli SL, et al: Oral cooling cryotherapy ; , an effective treatment for the prevention of 5-fluorouracil-induced stomatitis. Eur J Cancer B Oral Oncol 30B: 234-236, 1994 Rocke LK, Loprinzi CL, Lee JK, et al: A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracilrelated stomatitis. Cancer 72: 2234-2238, 1993 Rubin JS, Osada H, Finch PW, et al: Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci U S A 86: 802-806, 1989.
Pneumonia PCP ; and were noted. By 1982, the epidemiology and routes of transmission of AIDS were well under stood. In 1983, only 2 years after the epidemic was first recognized, HIV was isolated, paving the way for effective antiretroviral therapy. Compare this rapid progress in our understand ing of HIV with our knowledge of P carinii. Although it was first discovered in 1909, by Carlos Chagas, it was thought to represent a stage in the life cycle of trypansomes. In 1912, it was deter mined that it was in fact a new species. Due to its appearance and response to antiprotozoal antimi crobials, it was considered to be a protozoan. Although this was questioned in the 1970s, based.
With the degree of change in tumor volume observed after 3 months therapy 15 ; . Large randomized Phase III trials with the aromatase inhibitors letrozole and anastrozole confirm these drugs to be superior clinically to TAM in the advanced 20, 21 ; , neo-adjuvant 22, 23 ; , and adjuvant settings 24 ; . Thus, changes in biomarkers in experimental models may provide comparative data between different systemic drug treatments, and similar clinical pharmacodynamic studies can been undertaken in the preoperative neoadjuvant setting. As such an approach is not feasible in the adjuvant setting, this may be attractive to assess biological efficacy of new therapies in early-stage primary breast cancer. ARZ appeared equally effective at inhibiting E2-dependent MCF-7 breast tumor growth compared with TAM in this study. Analysis of the tumors revealed similar quantitative and time-dependent effects on all of the cell growth and hormone-related biomarkers studied. These data are in contrast with in vitro comparisons in MCF-7 cells, which suggested that ARZ was significantly more potent than TAM at inhibiting estrogen-dependent growth 6 ; . In that system, the most potent antiestrogen was the metabolite desmethyl-ARZ, although, we found levels of this metabolite to be very low in vivo. A similar discrepancy between the in vitro and in vivo antiestrogenic effects of ARZ and TAM was reported in experimental models of human endometrial cancer 25 ; . In vitro ARZ was significantly more potent than TAM at inhibiting estrogen-stimulated growth of ECC-1 TAMnaive human endometrial cancer cells, but in vivo, both drugs were equally effective at antagonizing estrogen-stimulated growth. However, one of the major reasons for developing ARZ was the potential for reduced agonist effects in comparison with TAM on target organs, including the uterus, endometrium, and breast. In vitro, neither ARZ nor its metabolite showed any stimulation of basal MCF-7 breast cancer cell growth in the absence of estrogen 6 ; . However, mixed effects have been reported in in vivo models of TAM-stimulated growth, with growth stimulation by ARZ reported in both EnCa101Tam endometrial tumors 25 ; and MCF-7: Tam breast tumors 26 ; . These effects may be model specific because lack of stimulation by ARZ and, hence, noncross-resistance with TAM was found in a TAM-stimulated T47-D xenograft model 26 ; . Thus, although triphenylethylene structures such as idoxifene are completely cross-resistant with TAM in these antiestrogen-stimulated models 27 ; , structurally different antiestrogens such as the steroidal compound fulvestrant and, to a lesser extent the benzothiophene ARZ, may be partially noncross-resistant 26, 27 ; . Previous experimental data suggesting differences with TAM encouraged clinical trials of ARZ to be undertaken both in patients with TAM-sensitive and TAM-resistant advanced breast cancer. In a Phase I study of 32 patients with advanced breast cancer, no change in endometrial thickness was seen over 12 weeks therapy, confirming a lack of agonist effect 28 ; . Two Phase II studies have compared two different doses 20 or 50 mg daily ; of ARZ, and although response rates of 30 36% were seen in hormone-sensitive ER advanced breast cancer, efficacy in TAM-resistant patients was low with a response rate of 10% 29, 30 ; . A multicenter Phase III trial of 20 mg of ARZ versus TAM as first-line therapy in postmenopausal women with ER advanced breast cancer was started, although it remains to be seen whether ARZ will offer any significant clinical advantage over TAM in this setting. In clinical trials with triphenyethylene-like SERMs e.g., idoxifene, toremifene, and droloxifene ; , no difference in clinical activity was found compared with TAM, with little or no activity in the setting of TAM resistance 31 ; . The evidence from our xenograft model would suggest there may be no difference in initial clinical response rates between ARZ and TAM in hormone-sensitive breast cancer. However, an antiestrogen with reduced agonist properties might be expected to prevent or delay the emergence of anties.
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In 2-Mnd K ; under conical ; colimits and merely epimorphic ; quotients. Similarly, by duality, for the 2-monads satisfying 2C ; and also, by Remark 2.7, for those satisfying 2M ; . Using Remark 4.3 c ; , we conclude that, for a complete K, the fully property-like 2-monads are closed in 2-Mnd K ; under conical ; colimits and co-fully-faithful quotients. The following result, although an immediate consequence of Proposition 5.1, is worth stating because many important structures see 5] ; are monadic not over Cat but only over Catg , the full sub-2-category of Cat with the same objects and arrows, but in which all non-invertible 2-cells have been discarded. 5.6. Proposition. If K is 2-category in which every 2-cell is invertible, then for 2-monads on K, the following conditions are equivalent: AUL ; , AUM ; , AUC ; , 2L ; , 2M ; , 2C ; thus in particular every property-like 2-monad on such a K is fully propertylike. We establish in this section various properties of those 2-monads T on K that satisfy the condition AEL ; as we said in the Introduction, such a 2-monad will be said to be lax-idempotent, while a 2-monad satisfying AEC ; will be said to be colax-idempotent. First recall from Section 3 that AEL AUL AUM ; and that using Proposition 3.2 ; AEL IEL IEM ; that is to say: 6.1. Proposition. Every lax-idempotent 2-monad and dually every colax-idempotent 2-monad ; is property-like. Recall that, in any 2-category K, we can speak of an adjunction : f a here u : A and f : B are morphisms in K, while the unit : 1 ! and the counit : fu ! are 2-cells satisfying the \triangular equations" u : u and f: f 1 for the elementary theory of such adjunctions, see for instance 21]. We shall be concerned below with the special case of an adjunction in K with identity counit, obtained by requiring above to be an identity. To give such an adjunction 1 : f give morphisms u : A and f : B with fu 1, along with a 2-cell : 1 ! uf satisfying u 1u and f 1f . Note that, given f and u with fu 1, such an is unique if it exists: for if we also have : 1 ! with u 1 and f 1, the commutativity of 1.
Cranioplastic surgery and cannula implantation. Surgery was performed under aseptic conditions. Rats were anesthetized Nembutal, 50 mg kg, ip ; and a cranioplastic cap was built up on the skull that permitted painlessly fixing the animal's head in the stereotaxic device. Using this technique, we lightly anesthetized the rats repeatedly to record neuronal activity. The details of this surgical procedure have been published several times 29, 31, 33 ; . At the same time, an ICV cannula [a 22-gauge guide stainless steel tube fitted with an obturator Biological Research Components, Roanoke, VA ; ] was implanted, using methods modified from previous studies 15, 35 ; . Briefly, the stereotaxic coordinates were 1.0 mm posterior to , 1.0 mm lateral to the sagital sinus, and 7.0 - 7.5 mm ventral to the dura depending on the size of the rat 350 g 7.0; 350 g 7.5 ; . The cannula shaft was angled toward the midline at 10 so that it would pass through both the left lateral ventricle and the third ventricle. The cannula was fixed to the skull with the larger cap using dental acrylic. Seven to 10 days after surgery, cannula placement was validated by giving a pulse ICV injection of 6.0 ng angiotensin II and then recording water intake for 15 minutes. All 10 rats drank more than 9.0 ml and fuzeon.
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G.S. Odin, Departement de Geologie dynamique, Universite Pierre et Marie Curie, 4 place Jussieu, 75252 Paris Cedex 05, France. A.J. Hurford, Laboratory for Isotope Geology, University of Berne, Erlachstrasse 9A, CH-3012, Berne, Switzerland. Description: The project intends to i n gate, realize and compile studies designed to improve our knowledge of the numerical timescale for the Phanerozoic era. I t is est to stratigraphers, geochemists and geochronologists. One of the essential a c t the Project is to bring together geologists specializing in these different fields of research. Achievements i n 1987 and gabitril.
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| Fulvestrant administrationUpdated information and services, including high-resolution figures, can be found in the online version of this article at: : sciencemag cgi content full 282 5397 2256 Downloaded from sciencemag on March 15, 2008 This article cites 4 articles, 1 of which can be accessed for free: : sciencemag cgi content full 282 5397 2256#otherarticles This article has been cited by 209 article s ; on the ISI Web of Science. This article has been cited by 4 articles hosted by HighWire Press; see: : sciencemag cgi content full 282 5397 2256#otherarticles This article appears in the following subject collections: Ecology : sciencemag cgi collection ecology Information about obtaining reprints of this article or about obtaining permission to reproduce this article in whole or in part can be found at: : sciencemag about permissions.dtl and garlic.
In the summer of 1992 the city of Montr6al celebrated its 350th anniversary with a series of special events. As part of this celebration, in early September CCA opened an exhibition focused on the growth and changes in this city during the pivotal 18th century. Opening the Gates of 18th-Centuy Montrhl featured documents, maps, and artefacts from more than 40 archives and repositories in Canada, the United States, France, and Britain. In addition, two videotapes and an interactive computer workstation were incorporated into the exhibition. The database and visualisation tools were used in four basic areas for this exhibit: historical research for preparing the exhibition, the creation of visual illustrations for the exhibition catalogue, the preparation of videotape installations that formed a part of the exhibition, and as an interactive tool that sat in the centre of the exhibition. The visualisation tools allowed researchers preparing the exhibit to view relationships that were difficult to see any other way, and to create visual aids that were incorporated into the exhibition catalogue. For example, two dimensional illustrations of changing land use in a particular neighbourhood complete with different shadings for different types of use ; were generated onto photographic film for the exhibition catalogue. Still and moving images generated from the database were edited into two videotapes which were an integral part of the exhibition. One videotape - The Fortifications of Montre'al - visually demonstrates the development of the town's fortifications in the context of the physical terrain, existing urban structures, and the expanding population. Attention is also given to the geometry of the walls to show how defence with muskets and cannons influenced the urban form. A second videotape - Changing Land Use - shows how Montreal evolved from a town of gardens and wood buildings in 1725 to a densely built town of stone in 1805. Factors that contributed to this change - population growth, increased commercial activity, and fire - are animated on maps of the town. For a number of aesthetic and practical reasons noise in the exhibition, attendees who spoke only French or only English ; , no audio was used. However, some text was necessary to convey a message, and this was kept to a minimum. An English and a French version of each tape was presented as part of the exhibition installation. The centre gallery of the exhibition was devoted to a presentation of the research methodology and preliminary findings, acting as a link between the galleries on economic development and settlement and that of the built environment. Centrally located within this gallery was the interactive workstation that demonstrated some of the potential of the database and visualisation tools. Using a touch-screen, visitors could select one of three areas for detailed viewing - the Place d'Armes, the old Place d u Marche, and the Place Jacques Cartier. Reconstructed lot plans, three-dimensional renderings, and 18th century plans and views vividly depicted these three sectors that were so important in the religious, commercial, and administrative life of the town. Exhibition visitors could use the interactive workstation to explore on their own the areas and themes depicted in the surrounding exhibition. Using touch-sensitive directional arrows and icons on the screen, visitors could step their way onscreen ; through 3-D renditions of various streets getting a feel for the height and spacing of buildings ; , could view and zoom in on relevant paintings, maps and land-grant.
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Table 4. Comparison of adaptive committees Combination method CCCC Adjusting Plurality Voting Plurality Voting Adjusting Best Best member classifier Member classifier average Error % DTW& SVM 8.0 10.1 10.2 Error % all DTW 9.3 10.3 10.4 and gefitinib.
| The Boys & Girls Club of Bay Mills has exciting news for all teens ages 13-18. Teen night at Boys & Girls Club is now structured differently. We will be taking teens on two field trips per month. The Youth Center gym will no longer be open every Friday evening. The field trips will vary but all expenses will be paid and will take place on designated Fridays only. Please check the club calendar monthly to find out about upcoming trips. January's Friday field trips include viewing the movie "Lord of the Rings" at Varsity Cinemas on Jan. 16 and cheering the Lakers Hockey Team on against Providence at the Norris Center on Jan. 23. The sign up sheets are located on Julie Hopper's office door as well as the permission slips. Permission slips must be signed in order to go. For more information, please contact Julie Hopper at 248-3241, ext. 3133. Boys & Girls Club offers a homework lab tutoring and career exploration opportunities on Tuesdays, Wednesdays, and Thursdays from 3: 30-4: 30. The lab will be located in the basement of the college library. For more information, please contact Aaron Tadgerson at 248-3241 ext. 3161. Every Wednesday from 8-9 p.m., the Boys and Girls Club offers an open gym for all teens who want to get out of the cold and play basketball.
Glucose: 16.3%w w glucose oxidase Aspergillus niger, 1.3IU 0.6%w w peroxidase horseradish, 3300 IU 7.0% w w potassium iodide; 76.1% w w buffer and non-reactive ingredients. Bilirubin: 0.4% w w 2, 4-dichloroaniline diazonium salt, balanced with buffer and non-reactive ingredients. Ketone: 7.7% w w sodium nitroprusside balanced with buffer and non-reactive ingredients. Specific Gravity: 2.8% w w bromothymol blue, 69.0%; poly methyl vinyl ether maleic anhydride 28.2% sodium hydroxide Blood: 6.6% w w cumene hydroperoxide; 4.0% w w 3, 3', 5, w w buffer and nonreactive ingredients. pH: 0.2% w w methyl red; 2.8% w w bromothymol blue; 97% w w nonreactive ingredients and gemcitabine
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Butorphenol tartrate, Fort Dodge Labs, Fort Dodge, IA ; . Nutritional Protocol Pigs were divided into two equal groups, one of which was placed on TPN 240 mLkg-1d-1; glucose, 25 gkg-1d-1; protein amino acids ; 13 gkg-1d-1; lipid Intralipid 20% Fresenius Kabi, Bad Homburg, Germany 5 gkg-1d-1 ; and the other fed liquid milk replacer AdvanceLiquiWean, Milk Specialties, Dundee, IL, 240 mLkg-1d-1 mixed 1: 5, powder to water ; for six days. The enteral feedings were divided evenly 5-6 times per day. The liquid milk replacer did not contain antibiotics. The nutritional support was continued until euthanasia. Total caloric intake was not different between the 2 groups ~ 840 kJkg-1d-1 and gemifloxacin.
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Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: An overview of the randomised trials. The Lancet 1998; 351 9114 ; : 1451-67. Abstract Ellis MJ. Importance of correlative science in advancing hormonal therapy and a new clinical paradigm for neoadjuvant therapy. Ann Surg Oncol 2004; 11 Suppl 1 ; : 9-17. Abstract Ellis MJ et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and or ErbB-2positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. J Clin Oncol 2001; 19 18 ; : 3808-16. Abstract Fisher B et al. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: Updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 2001; 93 9 ; : 68490. Abstract Fisher B et al. Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90 18 ; : 1371-88. Abstract Fisher B et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. The Lancet 1999; 353 9169 ; : 1993-2000. Abstract Forward DP et al. Clinical and endocrine data for goserelin plus anastrozole as second-line endocrine therapy for premenopausal advanced breast cancer. Br J Cancer 2004; 90 3 ; : 590-4. Abstract Garrone O et al. Endometrial effects of tamoxifen T ; and exemestane E ; in early breast cancer patients EBCP ; . A randomized phase III trial. Proc ASCO 2004; Abstract 819. Geisler J et al. Estrogens and bone metabolism in postmenopausal women with early breast cancer at low risk treated with exemestane: A randomized placebo-controlled study. Proc ASCO 2004; Abstract 531. Gnant M et al. Changes in bone mineral density caused by anastrozole or tamoxifen in combination with goserelin zoledronate ; as adjuvant treatment for hormone receptor-positive premenopausal breast cancer: Results of a randomized multicenter trial. Breast Cancer Res Treat 2002; 76 Suppl 1 ; : 31; Abstract 12. Goss PE, Strasser-Weippl K. Prevention strategies with aromatase inhibitors. Clin Cancer Res 2004; 10 1 Pt 2 ; 372S-9S. Abstract Goss PE et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for earlystage breast cancer. N Engl J Med 2003; 349 19 ; : 1793-802. Abstract Goss PE et al. Updated analysis of the NCIC CTG MA.17 randomized placebo P ; controlled trial of letrozole L ; after five years of tamoxifen in postmenopausal women with early stage breast cancer. Proc ASCO 2004; Abstract 847. Harvey JM et al. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999; 17 5 ; : 1474-81. Abstract Howell A. Postmenopausal women with advanced breast cancer who progress on fulvestrant or tamoxifen retain sensitivity to further endocrine therapies. Poster 251. San Antonio Breast Cancer Symposium, 2002. Abstract Howell A et al. A review of the efficacy of anastrozole in postmenopausal women with advanced breast cancer with visceral metastases. Breast Cancer Res Treat 2003; 82 3 ; : 215-22. Abstract Howell A et al. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: A multinational, double-blind, randomized trial. J Clin Oncol 2004; 22 9 ; : 1605-13. Abstract Howell A et al. Fulvestrant, formerly ICI 182, 780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 2002; 20 16 ; : 3396-403. Abstract Ingle JN. Sequencing of endocrine therapy in postmenopausal women with advanced breast cancer. Clin Cancer Res 2004; 10 1 Pt 2 ; 362S-7S. Abstract Jenkins V et al. Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psychooncology 2004; 13 1 ; : 61-6. Abstract Johnston S. Fulvestrant and the sequential endocrine cascade for advanced breast cancer. Br J Cancer 2004; 90 Suppl 1 ; : 158. Abstract Jones SE, Pippen J. A retrospective analysis of the proportion of patients responding for 1 year in two phase III studies of fulvestrant vs. anastrozole. Proc ASCO 2004; Abstract 737. Klijn JG et al; Combined Hormone Agents Trialists' Group and the European Organization for Research and Treatment of Cancer. Combined tamoxifen and luteinizing hormone-releasing hormone LHRH ; agonist versus LHRH agonist alone in premenopausal advanced breast cancer: A meta-analysis of four randomized trials. J Clin Oncol 2001; 19 2 ; : 343-53. Abstract Krag LE et al. Lipid and coagulation profile in postmenopausal women with early breast cancer at low risk treated with exemestane: A randomized, placebo-controlled study. Proc ASCO 2004; Abstract 650. Lipton A et al. Serum HER-2 neu and response to the aromatase inhibitor letrozole versus tamoxifen. J Clin Oncol 2003; 21 10 ; : 1967-72. Abstract Lonning PE et al. Effect of exemestane on bone: A randomized placebo controlled study in postmenopausal women with early breast cancer at low risk. Proc ASCO 2004; Abstract 518 and fulvestrant.
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Or more. Of the 21 patients who had received only an aromatase inhibitor as prior hormonal therapy, 11 52.3% ; experienced partial response or stable disease. The most common adverse reactions observed were hot flushes, fatigue, injection site pain and reactions, anorexia, arthralgia, peripheral nerve sensitivity and alopecia. Faslodex is already approved for use in postmenopausal women with advanced breast cancer whose disease has progressed after treatment with tamoxifen. In these new studies, AstraZeneca wanted to prove that Faslodex is also effective after aromatase inhibitor therapy. Two large-scale trials of Faslodex following aromatase inhibitor therapy are underway: EFECT trial Evaluation of Fulvestrant versus Exemestane Clinical Trial ; SOFEA trial Study of Faslodex, Exemestane and Arimidex and gemtuzumab
Disease; data from phase III clinical Tamoxifen tamoxifen megestrol acetate trials for adjuvant use of other AIs are unlikely to be available for 2-3 Anastrozole and letrozole shown to years. Since anastrozole has been be at least equivalent to tamoxifen as first-line therapy in metastatic breast shown to be more effective than Tamoxifen tamoxifen anastrozole letrozole cancer tamoxifen as adjuvant therapy Tamoxifen versus anastrozole, exemestane letrozole [16-18, 26] [21], it may become the preferred Fulvestrant shown to be as effective as choice for early-stage breast canTamoxifen anastrozole fulvestrant anastrozole following progression on letrozole megestrol acetate cer. Sequencing data for anastroprior endocrine treatment in metastatic breast cancer zole and tamoxifen [25] have Fulvestrant versus anastrozole, [8, 9] shown that tamoxifen is effective Anastrozole shown to be superior to after progression on anastrozole; tamoxifen as adjuvant therapy in EBC Anastrozole * tamoxifen fulvestrant tamoxifen is, therefore, likely to be Tamoxifen versus anastrozole [21] megestrol acetate effective in patients whose cancer * Until a longer follow-up for safety data is available for anastrozole in the adjuvant setting, has recurred after adjuvant anastro * tamoxifen remains the first-line adjuvant therapy [25] zole. Although longer follow-up is needed to assess the full benefit of adjuvant endocrine therapy for postmenopausal women anastrozole in the adjuvant setting in terms of its efficacy with hormone-responsive tumors. and safety, anastrozole currently provides a choice of.
A. Hengstermann1, C. Knoerr-Wittmann1, S. Gebel1, J. Alam2 and T. Mueller1. 1 PHILIP MORRIS Research Laboratories GmbH, Cologne, Germany and 2 Department of Molecular Genetics, Alton Ochsner Clinic Foundation, New Orleans, LA. Sponsor: H. Haussmann. Exposure of cells and tissues to cigarette smoke CS ; triggers a pronounced anti-oxidant response, which is hallmarked by the transcriptional up-regulation of heme oxygenase-1 hmox1 ; , initiating a self-protection mechanism resulting in the formation of endogenous antioxidant molecules, i.e., biliverdin and bilirubin from intracellular heme moieties. To characterize the regulatory elements involved in CS-mediated hmox1 expression, we studied the expression of various hmox1 promoter luciferase reporter constructs in NIH3T3 cells exposed to aqueous extracts of CS. The results showed that the CS-dependent expression of hmox1 is governed primarily by the distal enhancers 1 and 2, both of which contain three canonical anti-oxidant responsive element ARE ; -like stress responsive elements. These sites are potentially addressed by the transcription-factor Nrf2, a principal inducer of antioxidant and Phase II-related genes. As shown by Western-blot analysis, Nrf2 was strongly stabilized and became detectable in nuclear extracts in cells exposed to aqueous extracts of CS. Furthermore, nuclear localization of Nrf2 coincided with increased DNA binding of a putative Nrf2 MafK heterodimer to ARE, as determined by EMSA. Notably, siRNA-mediated knock-down of Nrf2 expression significantly compromised both CS-induced hmox1 promoter activation and HO-1 expression. Finally, by using this approach CS-induced expression of Phase II-related genes NAD P ; H: quinone oxidoreductase and glutamate-cysteine ligase, catalytic subunit was shown to be completely abrogated, as determined by Real Time quantitative PCR. Taken together, these results add to the understanding of the central role of Nrf2 in the context of CS-mediated oxidative stress by orchestrating an efficient transcriptional response aimed at resolving the stressing conditions and gemzar.
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