Crosstalk Aware Bandwidth Modelling for VLSI RC Global Interconnects using 2-π Model
W1963 Molecular Mechanisms of SFN in the Chemoprevention of Colorectal Cancer: Crosstalk Between...
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AGA Abstracts affected polyp size. These effects are associated with cox-2 inhibition. The strong anti-cox- 2 activity and the absence of toxicity make 99% purified EPA an excellent candidate for the chemoprevention of colorectal cancer. W1960 Non-Polypoid Colorectal Neoplasms: Clinico-Pathological Features in a Dutch Population Eveline Rondagh, Mirthe E. van der Valk, Manon Engeland, Adriaan P. de Bruine, Ad Masclee, Silvia Sanduleanu It is widely accepted that the majority of colorectal cancers develop through polypoid growth. Emerging evidence indicates that non-polypoid colorectal neoplasms (NP-CRNs), known as flat lesions, also contribute to the development of colorectal cancer. These lesions are difficult to detect during routine colonoscopy. Moreover, it has been suggested that NP-CRNs are associated with a more aggressive behavior than polypoid colorectal neoplasms (P-CRNs). Most data originate from Japan, and so far, there are only a few studies to reflect the Western experience. Our aim was, to compare the clinico-pathological features of NP-CRNs and P- CRNs in a prospective, case-control study. All endoscopists at our center were trained to recognize NP-CRNs, by systematic sessions including video training. CRNs were classified according to the Paris classification. Selective chromoendoscopy was used to clarify the borders of NP-CRNs before endoscopic removal. According to size, lesions were categorized as diminutive (<6mm), small (6-9mm) and large (>9mm). Starting from August 2007, clinico-pathological data are prospectively collected from NP- and P-CRNs. Here we report the first results of this ongoing study, comparing data from 90 NP-CRNs (60 patients) and 94 P-CRNs (53 patients). Both groups underwent colonoscopy for screening, surveillance or GI symptoms. Of the NP-CRNs, 95% were slightly elevated, 2% were completely flat and 3% were slightly depressed. NP-CRNs did not differ from P-CRNs with regard to: i) demographic characteristics (median age: 65.0 vs. 65.0 years; gender: 58.3% vs. 56.6% males); ii) distribution of size; and iii) prevalences of tubular, (tubulo)villous, serrated adenomas and hyperplastic polyps. Of the 124 adenomas found, 61 were NP-adenomas and 63 were P-adenomas. In contrast to P-adenomas, NP-adenomas were characterized by: i) more frequent location in the proximal colon: 41 (67.2%) vs. 28 (44.4%), p=0.011; and ii) significantly higher prevalence of high-grade dysplasia (HGD): 19 (31.1%) vs. 9 (14.3%), p=0.025. Additionally, patients with a positive family history of colorectal cancer harbored more frequently HGD in flat adenomas than patients without a positive family history: 10 (52.6%) vs. 9 (21.4%), p=0.02. Conclusion: Non-polypoid colorectal neoplasms are com- monly observed by trained endoscopists during routine colonoscopy. NP-adenomas harbor significantly more frequently HGD than P-adenomas. These findings underline the import- ance of clinical awareness and training to recognize and adequately remove such lesions. Larger prospective data are needed to further characterize the high-risk NP-adenomas. W1961 Gender-Related Differential Susceptibility to Celecoxib On Adenoma Formation: Potential Role of Estrogen-Receptor Beta Jennifer Koetsier, Ramesh K. Wali, John Hart, Dhananjay Kunte, Laura K. Bianchi, Hemant K. Roy Background:Men and women differ markedly in colonic neoplasia biology (e.g. MSI status) and epidemiology (proximal distribution, etc.). From a chemopreventive point of view, the WHI studies showed estrogens markedly reduced CRC occurrence in women. The mechan- isms remain unclear, but there is compelling evidence from MIN mouse studies to suggest that estrogen receptor beta (ERβ) acts as a tumor suppressor gene (Cho et al., Cancer Res 2007, Giroux et al., Int J Cancer 2008). The effect of gender on NSAID chemoprevention has not been elucidated. We, therefore, investigated this with MIN mice to avoid lifestyle factors that may confound epidemiological studies. Methods:16 female and 18 male MIN mice were randomized to celecoxib 1500 ppm or standard chow at 6 weeks old and euthanized at 16 weeks. ERβ was examined in the uninvolved mucosa by immunohistochem- istry. Scoring was done by a GI pathologist blinded to treatment group. Results:While celecoxib caused a suppression of tumorigenesis in both male and female mice (42.7±17.4 tumors in control mice vs. 7.72±4.5 tumors in celecoxib mice, p<0.005), the effect was more dramatic in females (9.1% of control in females vs. 27.5% of control in males, p<0.005). Indeed, celecoxib's anti-neoplastic efficacy was more than a third greater in females than males. ERβ expression in the control MIN mice resulted in no significant difference between the male and female mice. However, with celecoxib treatment, there was a dramatic induction in ERβ in females with no significant change in males (see Figure 1). Conclusions: We demonstrate herein for the first time that celecoxib's tumorigenesis suppression was more pronouced in females than males. Our data also suggests a novel mechanism through induction of ERβ. The gender-specific efficacy is of major importance in designing chemop- reventive efficacy. A-762 AGA Abstracts W1962 Genetic Variation in the Ugt1a6 Enzyme, Aspirin Use, and Adenoma “Rebound” Associated with Withdrawal of Celecoxib Treatment Andrew T. Chan, Meier Hsu, Ann G. Zauber, Monica M. Bertagnolli Background: Aspirin reduces risk of colorectal adenoma and genetic variants in the UGT1A6 enzyme are associated with impaired aspirin metabolism. It is unclear if “aspirin-resistant” adenomas, or tumors that develop despite chronic aspirin exposure, differ biologically and if such differences are more apparent among individuals with variant, slow-metabolizer UGT1A6 genotypes. Methods: We genotyped the UGT1A6 T181A and R184S variant alleles among patients enrolled in the Adenoma Prevention with Celecoxib trial. Patients with adenoma removed at entry were stratified by baseline use of low-dose (≤325 mg qod or 162.5 mg qd) aspirin, randomized to receive 3 years of placebo, low-dose celecoxib (200mg bid), or high-dose celecoxib (400mg bid), and underwent colonoscopy at Year 1 and 3. At Year 5, a subset of patients had another colonoscopy, which assessed drug withdrawal since >90% discontinued treatment >1 year previously. Recurrence of adenomas was compared using the life-table extension of the Mantel-Haenszel test. Results: Among 1,647 patients, 717 (44%) were wild-type and 930 (56%) were variant UGT1A6 genotypes (≥1 variant allele). Overall, variant genotype was not associated with risk of recurrent adenoma by Year 3 (RR, 0.97; CI, 0.86-1.10). The cumulative incidence of adenoma by Year 3 was 59.8% for patients receiving placebo, as compared with 43.3% for low-dose (RR, 0.68; CI, 0.59- 0.79), and 36.8% for high-dose celecoxib (RR, 0.54; CI, 0.46-0.64). These results did not vary according to baseline aspirin use or genotype. At Year 5, among 538 patients, the risk of recurrent adenoma associated with withdrawal of treatment with high-dose celecoxib compared to placebo differed according to baseline aspirin use among those with variant genotypes (adjusted p for heterogeneity=0.02). Among aspirin users with variant genotypes, the RR of recurrent adenoma, compared to placebo, was 1.60 (CI, 0.81-3.15) for those withdrawn from low-dose and 1.98 (CI, 1.06-3.70) for those withdrawn from high-dose celecoxib. In contrast, there was no increased risk of recurrent adenoma associated with celecoxib withdrawal among non-aspirin users with variant genotypes or aspirin users and non-users with wild-type genotypes. Conclusions: Among individuals with variant, slow- metabolizer UGT1A6 genotypes and a history of adenoma while on low-dose aspirin, cessation of celecoxib is associated with a rebound in risk of recurrent adenoma. These findings suggest that adenomas that develop despite exposure to high levels of aspirin may initially respond to celecoxib treatment, but withdrawal of drug results in re-emergence of disease at an accelerated rate. W1963 Molecular Mechanisms of SFN in the Chemoprevention of Colorectal Cancer: Crosstalk Between TGF-β and the Protooncogenes COX-2 and ODC Bettina M. Ecker, Stefan Marcel Loitsch, Christoph Jochem, Jurgen Stein, Sandra Ulrich Introduction: Epidemiological data indicate an inverse relationship between cruciferous vegetable intake and cancer risk at several sites, including the colon. One of the major chemopreventive compounds in crucifers is the isothiocyanate sulforaphane, whereas the mode of action remains largely unknown. Multiple studies indicate that inhibition of the protooncogenes Ornithine decarboxylase (ODC) and Cyclooxygenase-2 (COX-2) is associ- ated with reduced cell growth in several human cancers. Thus, the objective of this study was to elucidate a possible regulation of ODC and COX-2 by the natural occurring histone deacetylase inhibitor (HDACi) sulforaphane and to further identify a possible role of the transforming growth factor-β (TGF-β)-signaling pathway. Methods: Caco-2 and SW-620 cells were cultured under standard conditions. Protein levels were examined by Western blot analysis. Ornithine decarboxylase activity was assayed radiometrically measuring [14CO2] liberation. Acetyl-Histone H3 immunoprecipitation (ChIP) assay was performed, followed by RT-PCR with TGF-β-receptor II promoter specific primers. Results: Both, in Caco-2 and SW620 cells, a dose-dependent reduction of COX-2 protein levels (***p<0.001) as well as ODC protein (***p<0.001) and activity (***p<0.001) could be observed after 6 and 24 hours of incubation with SFN [1-50μM], which closely correlates with a distinct time-and dose-dependent cell growth inhibition (***p<0.001). This was further confirmed by the addition of exogenous PGE2 [2.5-5μM] and polyamines [1-10μM], which significantly coun- teracted cell growth inhibitory effects of SNF (**p<0.01). SFN [5-50μM] also leads to an obvious dose-dependent increase of TGF-β protein levels after 2 hours of incubation (**p<0.01), as well as a prominent phosphorylation of Smad2/3 (~40 at SFN [50μM]), a downstream component of TGFβ signaling. Furthermore, SFN causes an accumulation of acetylated H3 in chromatin associated with TGF-β-receptor II gene (**p<0.01) as well as a dose-dependent induction of TGFβ receptor I and II protein expression after 1 and 3 hours. The coherency of these results was confirmed by co-treatment with TGF-β receptor kinase inhibitor SB431542 [10μM], which largely abolished inhibitory effects of SFN on COX-2 and ODC protein expression (*p<0.05). Conclusion: These data provide evidence for regulatory effects of sulforaphane on gene expression of the protooncogenes COX-2 and ODC in colorectal cancer cells, whereby the activation of the TGFβ signaling pathway seems to play a pivotal role. W1964 A Combination of Bifidobacterium Lactis and Resistant Starch Can Protect Against Colorectal Cancer Development in Rats Richard K. Le Leu, Ying Hu, Ian L. Brown, Graeme P. Young Background/Objectives: There exists a potential role for foods that contain probiotics and/ or prebiotics, to change the colonic microflora in a way that might prevent diseases such as colorectal cancer. This study has evaluated in rats, the effect of a probiotic bacteria ‘Bifidobacterium lactis', a prebiotic ‘resistant starch' (RS) and their combination (synbiotic), on their ability to protect against the development of colorectal cancer. Bifidobacterium lactis is a probiotic that has previously been shown to utilise resistant starch as a major substrate (1). Methods: Sprague-Dawley rats (n = 180) were divided into 6 equal groups and fed semi-purified diets for 30 weeks. The experimental groups were as follows: Control;
Transcript of W1963 Molecular Mechanisms of SFN in the Chemoprevention of Colorectal Cancer: Crosstalk Between...
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saffected polyp size. These effects are associated with cox-2 inhibition. The strong anti-cox-2 activity and the absence of toxicity make 99% purified EPA an excellent candidate forthe chemoprevention of colorectal cancer.
W1960
Non-Polypoid Colorectal Neoplasms: Clinico-Pathological Features in a DutchPopulationEveline Rondagh, Mirthe E. van der Valk, Manon Engeland, Adriaan P. de Bruine, AdMasclee, Silvia Sanduleanu
It is widely accepted that the majority of colorectal cancers develop through polypoid growth.Emerging evidence indicates that non-polypoid colorectal neoplasms (NP-CRNs), known asflat lesions, also contribute to the development of colorectal cancer. These lesions are difficultto detect during routine colonoscopy. Moreover, it has been suggested that NP-CRNs areassociated with a more aggressive behavior than polypoid colorectal neoplasms (P-CRNs).Most data originate from Japan, and so far, there are only a few studies to reflect the Westernexperience. Our aim was, to compare the clinico-pathological features of NP-CRNs and P-CRNs in a prospective, case-control study. All endoscopists at our center were trained torecognize NP-CRNs, by systematic sessions including video training. CRNs were classifiedaccording to the Paris classification. Selective chromoendoscopy was used to clarify theborders of NP-CRNs before endoscopic removal. According to size, lesions were categorizedas diminutive (<6mm), small (6-9mm) and large (>9mm). Starting from August 2007,clinico-pathological data are prospectively collected from NP- and P-CRNs. Here we reportthe first results of this ongoing study, comparing data from 90 NP-CRNs (60 patients) and94 P-CRNs (53 patients). Both groups underwent colonoscopy for screening, surveillanceor GI symptoms. Of the NP-CRNs, 95% were slightly elevated, 2% were completely flatand 3% were slightly depressed. NP-CRNs did not differ from P-CRNs with regard to: i)demographic characteristics (median age: 65.0 vs. 65.0 years; gender: 58.3% vs. 56.6%males); ii) distribution of size; and iii) prevalences of tubular, (tubulo)villous, serratedadenomas and hyperplastic polyps. Of the 124 adenomas found, 61 were NP-adenomasand 63 were P-adenomas. In contrast to P-adenomas, NP-adenomas were characterized by:i) more frequent location in the proximal colon: 41 (67.2%) vs. 28 (44.4%), p=0.011; andii) significantly higher prevalence of high-grade dysplasia (HGD): 19 (31.1%) vs. 9 (14.3%),p=0.025. Additionally, patients with a positive family history of colorectal cancer harboredmore frequently HGD in flat adenomas than patients without a positive family history: 10(52.6%) vs. 9 (21.4%), p=0.02. Conclusion: Non-polypoid colorectal neoplasms are com-monly observed by trained endoscopists during routine colonoscopy. NP-adenomas harborsignificantly more frequently HGD than P-adenomas. These findings underline the import-ance of clinical awareness and training to recognize and adequately remove such lesions.Larger prospective data are needed to further characterize the high-risk NP-adenomas.
W1961
Gender-Related Differential Susceptibility to Celecoxib On AdenomaFormation: Potential Role of Estrogen-Receptor BetaJennifer Koetsier, Ramesh K. Wali, John Hart, Dhananjay Kunte, Laura K. Bianchi,Hemant K. Roy
Background:Men and women differ markedly in colonic neoplasia biology (e.g. MSI status)and epidemiology (proximal distribution, etc.). From a chemopreventive point of view, theWHI studies showed estrogens markedly reduced CRC occurrence in women. The mechan-isms remain unclear, but there is compelling evidence from MIN mouse studies to suggestthat estrogen receptor beta (ERβ) acts as a tumor suppressor gene (Cho et al., Cancer Res2007, Giroux et al., Int J Cancer 2008). The effect of gender on NSAID chemopreventionhas not been elucidated. We, therefore, investigated this with MIN mice to avoid lifestylefactors that may confound epidemiological studies. Methods:16 female and 18 male MINmice were randomized to celecoxib 1500 ppm or standard chow at 6 weeks old andeuthanized at 16 weeks. ERβ was examined in the uninvolved mucosa by immunohistochem-istry. Scoring was done by a GI pathologist blinded to treatment group. Results:Whilecelecoxib caused a suppression of tumorigenesis in both male and female mice (42.7±17.4tumors in control mice vs. 7.72±4.5 tumors in celecoxib mice, p<0.005), the effect wasmore dramatic in females (9.1% of control in females vs. 27.5% of control in males, p<0.005).Indeed, celecoxib's anti-neoplastic efficacy was more than a third greater in females thanmales. ERβ expression in the control MIN mice resulted in no significant difference betweenthe male and female mice. However, with celecoxib treatment, there was a dramatic inductionin ERβ in females with no significant change in males (see Figure 1). Conclusions: Wedemonstrate herein for the first time that celecoxib's tumorigenesis suppression was morepronouced in females than males. Our data also suggests a novel mechanism throughinduction of ERβ. The gender-specific efficacy is of major importance in designing chemop-reventive efficacy.
A-762AGA Abstracts
W1962
Genetic Variation in the Ugt1a6 Enzyme, Aspirin Use, and Adenoma“Rebound” Associated with Withdrawal of Celecoxib TreatmentAndrew T. Chan, Meier Hsu, Ann G. Zauber, Monica M. Bertagnolli
Background: Aspirin reduces risk of colorectal adenoma and genetic variants in the UGT1A6enzyme are associated with impaired aspirin metabolism. It is unclear if “aspirin-resistant”adenomas, or tumors that develop despite chronic aspirin exposure, differ biologically andif such differences are more apparent among individuals with variant, slow-metabolizerUGT1A6 genotypes. Methods: We genotyped the UGT1A6 T181A and R184S variant allelesamong patients enrolled in the Adenoma Prevention with Celecoxib trial. Patients withadenoma removed at entry were stratified by baseline use of low-dose (≤325 mg qod or162.5 mg qd) aspirin, randomized to receive 3 years of placebo, low-dose celecoxib (200mgbid), or high-dose celecoxib (400mg bid), and underwent colonoscopy at Year 1 and 3. AtYear 5, a subset of patients had another colonoscopy, which assessed drug withdrawal since>90% discontinued treatment >1 year previously. Recurrence of adenomas was comparedusing the life-table extension of the Mantel-Haenszel test. Results: Among 1,647 patients,717 (44%) were wild-type and 930 (56%) were variant UGT1A6 genotypes (≥1 variantallele). Overall, variant genotype was not associated with risk of recurrent adenoma by Year3 (RR, 0.97; CI, 0.86-1.10). The cumulative incidence of adenoma by Year 3 was 59.8%for patients receiving placebo, as compared with 43.3% for low-dose (RR, 0.68; CI, 0.59-0.79), and 36.8% for high-dose celecoxib (RR, 0.54; CI, 0.46-0.64). These results did notvary according to baseline aspirin use or genotype. At Year 5, among 538 patients, the riskof recurrent adenoma associated with withdrawal of treatment with high-dose celecoxibcompared to placebo differed according to baseline aspirin use among those with variantgenotypes (adjusted p for heterogeneity=0.02). Among aspirin users with variant genotypes,the RR of recurrent adenoma, compared to placebo, was 1.60 (CI, 0.81-3.15) for thosewithdrawn from low-dose and 1.98 (CI, 1.06-3.70) for those withdrawn from high-dosecelecoxib. In contrast, there was no increased risk of recurrent adenoma associated withcelecoxib withdrawal among non-aspirin users with variant genotypes or aspirin users andnon-users with wild-type genotypes. Conclusions: Among individuals with variant, slow-metabolizer UGT1A6 genotypes and a history of adenomawhile on low-dose aspirin, cessationof celecoxib is associated with a rebound in risk of recurrent adenoma. These findingssuggest that adenomas that develop despite exposure to high levels of aspirin may initiallyrespond to celecoxib treatment, but withdrawal of drug results in re-emergence of diseaseat an accelerated rate.
W1963
Molecular Mechanisms of SFN in the Chemoprevention of Colorectal Cancer:Crosstalk Between TGF-β and the Protooncogenes COX-2 and ODCBettina M. Ecker, Stefan Marcel Loitsch, Christoph Jochem, Jurgen Stein, Sandra Ulrich
Introduction: Epidemiological data indicate an inverse relationship between cruciferousvegetable intake and cancer risk at several sites, including the colon. One of the majorchemopreventive compounds in crucifers is the isothiocyanate sulforaphane, whereas themode of action remains largely unknown. Multiple studies indicate that inhibition of theprotooncogenes Ornithine decarboxylase (ODC) and Cyclooxygenase-2 (COX-2) is associ-ated with reduced cell growth in several human cancers. Thus, the objective of this studywas to elucidate a possible regulation of ODC and COX-2 by the natural occurring histonedeacetylase inhibitor (HDACi) sulforaphane and to further identify a possible role of thetransforming growth factor-β (TGF-β)-signaling pathway. Methods: Caco-2 and SW-620cells were cultured under standard conditions. Protein levels were examined by Western blotanalysis. Ornithine decarboxylase activity was assayed radiometrically measuring [14CO2]liberation. Acetyl-Histone H3 immunoprecipitation (ChIP) assay was performed, followedby RT-PCR with TGF-β-receptor II promoter specific primers. Results: Both, in Caco-2 andSW620 cells, a dose-dependent reduction of COX-2 protein levels (***p<0.001) as well asODC protein (***p<0.001) and activity (***p<0.001) could be observed after 6 and 24hours of incubation with SFN [1-50μM], which closely correlates with a distinct time-anddose-dependent cell growth inhibition (***p<0.001). This was further confirmed by theaddition of exogenous PGE2 [2.5-5μM] and polyamines [1-10μM], which significantly coun-teracted cell growth inhibitory effects of SNF (**p<0.01). SFN [5-50μM] also leads to anobvious dose-dependent increase of TGF-β protein levels after 2 hours of incubation(**p<0.01), as well as a prominent phosphorylation of Smad2/3 (~40 at SFN [50μM]), adownstream component of TGFβ signaling. Furthermore, SFN causes an accumulation ofacetylated H3 in chromatin associated with TGF-β-receptor II gene (**p<0.01) as well asa dose-dependent induction of TGFβ receptor I and II protein expression after 1 and 3hours. The coherency of these results was confirmed by co-treatment with TGF-β receptorkinase inhibitor SB431542 [10μM], which largely abolished inhibitory effects of SFN onCOX-2 and ODC protein expression (*p<0.05). Conclusion: These data provide evidencefor regulatory effects of sulforaphane on gene expression of the protooncogenes COX-2 andODC in colorectal cancer cells, whereby the activation of the TGFβ signaling pathway seemsto play a pivotal role.
W1964
A Combination of Bifidobacterium Lactis and Resistant Starch Can ProtectAgainst Colorectal Cancer Development in RatsRichard K. Le Leu, Ying Hu, Ian L. Brown, Graeme P. Young
Background/Objectives: There exists a potential role for foods that contain probiotics and/or prebiotics, to change the colonic microflora in a way that might prevent diseases suchas colorectal cancer. This study has evaluated in rats, the effect of a probiotic bacteria‘Bifidobacterium lactis', a prebiotic ‘resistant starch' (RS) and their combination (synbiotic),on their ability to protect against the development of colorectal cancer. Bifidobacteriumlactis is a probiotic that has previously been shown to utilise resistant starch as a majorsubstrate (1). Methods: Sprague-Dawley rats (n = 180) were divided into 6 equal groupsand fed semi-purified diets for 30 weeks. The experimental groups were as follows: Control;
