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While there are opportunities for expanded use of foods, and their components, to achieve one's genetic potential, increase productivity and reduce the risk of disease.. Hippocrates Proclaimedalmost 2500 years ago:Let thy food be thy medicine and thy medicine be thy food. Charts, Maps, Tables, The World Health Report, WHO 2003.

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2. Accelerate pace of discoveries Translate research more rapidly from laboratories to patients and back Explore novel approaches orders of magnitude more effective than current Develop new strategies, 2nd road mapAccelerate pace of discoveries Translate research more rapidly from laboratories to patients and back Explore novel approaches orders of magnitude more effective than current Develop new strategies, 2nd road map

7. WHO proposes a new global goal: to reduce the projected increase of chronic disease death rates by 2% each year until 2015. WHO proposes a new global goal: to reduce the projected increase of chronic disease death rates by 2% each year until 2015.

9. In supplements, vitamins grew 3%, herbs & botanicals 2%, minerals 4%, sports supplements 6%, liquid meal supplements –3% and specialty supplements 12%. In supplements, vitamins grew 3%, herbs & botanicals 2%, minerals 4%, sports supplements 6%, liquid meal supplements –3% and specialty supplements 12%.

12. Added Studies Key TJ, Sharp GB, Appleby PN et al. Soya foods and breast cancer risk: a prospective study in Hiroshima and Nagasaki, Japan. British Journal of Cancer, Dec 1999. Zheng W, Dai Q, Custer LJ, et al. Urinary excretion of isoflavonoids and the risk of breast cancer. Cancer epidemiology biomarkers and prevention, Jan 1999. Wu AH, Wan P, Hankin J, et al. Adolescent and adult soy intake and risk of breast cancer in Asian-Americans. Carcinogenesis, Sep 2002. Yamamoto S, Sobue T, Kobayashi M, et al. Soy, isoflavones, and breast cancer risk in Japan. Journal of the National cancer Institute, Jan 2003. Wu C, Ray RM, Lin MG, et al. A case-control study of risk factors for fibrocystic breast conditions: Shanghai Nutrition and Breast Disease Study, China, 1995-2000. American Journal of Epidemiology, Nov 2004. Witte JS, Ursin G, Siemiatycki J, et al. Diet and premenopausal bilateral breast cancer: a case-control study. Breast cancer research and treatment, Feb 1997. Horn-Ross PL, John EM, Lee M et al. Phytoestrogen consumption and breast cancer risk in a multiethnic population: the Bay Area Breast Cancer Study. American journal of epidemiology, Sep 2001. Linseisen J, Piller R, Hermann S, et al. Dietary phytoestrogen intake and premenopausal breast cancer risk in a German case-control study. International Journal of Cancer, Jun 2004.Added Studies Key TJ, Sharp GB, Appleby PN et al. Soya foods and breast cancer risk: a prospective study in Hiroshima and Nagasaki, Japan. British Journal of Cancer, Dec 1999. Zheng W, Dai Q, Custer LJ, et al. Urinary excretion of isoflavonoids and the risk of breast cancer. Cancer epidemiology biomarkers and prevention, Jan 1999. Wu AH, Wan P, Hankin J, et al. Adolescent and adult soy intake and risk of breast cancer in Asian-Americans. Carcinogenesis, Sep 2002. Yamamoto S, Sobue T, Kobayashi M, et al. Soy, isoflavones, and breast cancer risk in Japan. Journal of the National cancer Institute, Jan 2003. Wu C, Ray RM, Lin MG, et al. A case-control study of risk factors for fibrocystic breast conditions: Shanghai Nutrition and Breast Disease Study, China, 1995-2000. American Journal of Epidemiology, Nov 2004. Witte JS, Ursin G, Siemiatycki J, et al. Diet and premenopausal bilateral breast cancer: a case-control study. Breast cancer research and treatment, Feb 1997. Horn-Ross PL, John EM, Lee M et al. Phytoestrogen consumption and breast cancer risk in a multiethnic population: the Bay Area Breast Cancer Study. American journal of epidemiology, Sep 2001. Linseisen J, Piller R, Hermann S, et al. Dietary phytoestrogen intake and premenopausal breast cancer risk in a German case-control study. International Journal of Cancer, Jun 2004.

14. We’ve learned from you that we must interrupt the process. We’ve learned from you that we must interrupt the process.

15. $140 Billion current global market. Skeptics suggest nutrigenomics for Rich world activity and not global issue Adds confusion to already complex public health approaches Shifts investments from other challenges: inequalities, etc. Ethical Minefield$140 Billion current global market. Skeptics suggest nutrigenomics for Rich world activity and not global issue Adds confusion to already complex public health approaches Shifts investments from other challenges: inequalities, etc. Ethical Minefield

17. Variation in Glucosinolate Among Cruciferous vegetables (µmol/g DryWeight) Cruciferous vegetables are relatively unique in our diet as a source of glucosinolates, a series of plant secondary metabolites derived from amino acids with a thioglucose and an N-sulfate moiety. We surveyed a large number of different varieties of crucifers, identifying that there are 4 glucosinolates that are predominant. The profile of these glucosinolates is relatively similar for Brussels sprouts, cabbage, cauliflower and kale, being particularly high in sinigrin. This glucosinolate, upon hydrolysis, releases allyl isothiocyanate whih is responsible for the spicey bite in the core of white cabbage. The american public prefers the less spicey flavor of broccoli, which has little or no sinigrin. However, the total GS level is similar between broccoli and the other cruciferous vegetables, the difference being made up by glucoraphanin. In recent years, Talalay and colleagues have reported numerous publications on sulforaphane, an hydroollysis product of suforaphane, showing that it is potent in upregulating quinone reductase in mouse hepatoma cell cultlres Cruciferous vegetables are the principle dietary source of ITCs, but the types of crucifers frequently consumed by humans are limited. Examples of popular crucifers that are particularly rich in certain ITCs include mustard and horseradish—allyl-ITC (AITC) [9], watercress—phenethyl-ITC (PEITC) [10], dikon—dehydroerucin [1] and [11], and broccoli and broccoli sprouts—sulforaphane (SF) 30 g watercress containing 21.6 mg of gluconasturtiin by each study subject, an average of 47% of the dosed gluconasturtiin was recovered Cruciferous vegetables are relatively unique in our diet as a source of glucosinolates, a series of plant secondary metabolites derived from amino acids with a thioglucose and an N-sulfate moiety. We surveyed a large number of different varieties of crucifers, identifying that there are 4 glucosinolates that are predominant. The profile of these glucosinolates is relatively similar for Brussels sprouts, cabbage, cauliflower and kale, being particularly high in sinigrin. This glucosinolate, upon hydrolysis, releases allyl isothiocyanate whih is responsible for the spicey bite in the core of white cabbage. The american public prefers the less spicey flavor of broccoli, which has little or no sinigrin. However, the total GS level is similar between broccoli and the other cruciferous vegetables, the difference being made up by glucoraphanin. In recent years, Talalay and colleagues have reported numerous publications on sulforaphane, an hydroollysis product of suforaphane, showing that it is potent in upregulating quinone reductase in mouse hepatoma cell cultlres Cruciferous vegetables are the principle dietary source of ITCs, but the types of crucifers frequently consumed by humans are limited. Examples of popular crucifers that are particularly rich in certain ITCs include mustard and horseradish—allyl-ITC (AITC) [9], watercress—phenethyl-ITC (PEITC) [10], dikon—dehydroerucin [1] and [11], and broccoli and broccoli sprouts—sulforaphane (SF) 30 g watercress containing 21.6 mg of gluconasturtiin by each study subject, an average of 47% of the dosed gluconasturtiin was recovered

21. Plasma and Tissue Concentrations Are Not Always Identical Values (total amount of each catechin) are means ± SEM of 5 male Sprague-Dawley rats that received 0.6% (wt/vol) green tea polyphenol solution as sole source of drinking fluid for 8 days before sacrifice at 9 AM. Protocol I gave slightly higher and more reproducible results than Protocol II. Values (total amount of each catechin) are means ± SEM of 5 male Sprague-Dawley rats that received 0.6% (wt/vol) green tea polyphenol solution as sole source of drinking fluid for 8 days before sacrifice at 9 AM. Protocol I gave slightly higher and more reproducible results than Protocol II.

22. Individuals will be genetically tested to determine whether or not they are likely to respond to certain drugs. In the example shown (Fig. 8), children who have an arginine at codon 27 in the -adrenergic receptor for both alleles respond much better to albuterol than if they are homozygous for glycine.20 Clearly, if oncologists could predict which patients would respond to specific chemotherapies, unnecessary side effects could be avoided and better response rates observed. However, such prediction methods are not yet effective and it would be unfortunate to deny a patient a therapy that otherwise would have been helpful. Genomics, proteomics, and the new paradigm in biomedical research Joshua LaBaer, MD, PhD Genet Med 2002:4(6, Supplement):2S–9S. Individuals will be genetically tested to determine whether or not they are likely to respond to certain drugs. In the example shown (Fig. 8), children who have an arginine at codon 27 in the -adrenergic receptor for both alleles respond much better to albuterol than if they are homozygous for glycine.20 Clearly, if oncologists could predict which patients would respond to specific chemotherapies, unnecessary side effects could be avoided and better response rates observed. However, such prediction methods are not yet effective and it would be unfortunate to deny a patient a therapy that otherwise would have been helpful. Genomics, proteomics, and the new paradigm in biomedical research Joshua LaBaer, MD, PhD Genet Med 2002:4(6, Supplement):2S–9S.

23. Dietary Calcium, VDR FokI Genotype and Colon Cancer Risk

26. BACKGROUND: The role of caffeine as a risk factor for bone loss is controversial. OBJECTIVE: Our goals were 1) to compare in both a cross-sectional study and a 3-y longitudinal study the bone mineral density (BMD) of postmenopausal women consuming high or low amounts of caffeine and 2) to study the interaction between caffeine intake, vitamin D receptor (VDR)polymorphism, and BMD in the longitudinal study. DESIGN: The results are derived from cross-sectional measurements of BMD in 489 elderly women (aged 65-77 y) and from longitudinal measurements made in 96 of these women who were treatedwith a placebo for 3 y. Changes in BMD were adjusted for confounding factors and were compared between groups with eitherlow (< or =300 mg/d) or high (>300 mg/d) caffeine intakes and between the VDR genotype subgroups of the low- andhigh-caffeine groups. RESULTS: Women with high caffeine intakes had significantly higher rates of bone loss at the spine than did those with low intakes (-1.90 +/- 0.97% compared with 1.19 +/- 1.08%; P = 0.038). When the data were analyzed according to VDR genotype and caffeine intake, women with the tt genotype had significantly (P = 0.054) higher rates of boneloss at the spine (-8.14 +/- 2.62%) than did women with the TT genotype (-0.34 +/- 1.42%) when their caffeine intake was>300 mg/d. CONCLUSIONS: Intakes of caffeine in amounts >300 mg/d ( approximately 514 g, or 18 oz, brewed coffee) accelerate bone loss at the spine in elderly postmenopausal women. Furthermore, women with the tt genetic variant of VDRappear to be at a greater risk for this deleterious effect of caffeine on bone.BACKGROUND: The role of caffeine as a risk factor for bone loss is controversial. OBJECTIVE: Our goals were 1) to compare in both a cross-sectional study and a 3-y longitudinal study the bone mineral density (BMD) of postmenopausal women consuming high or low amounts of caffeine and 2) to study the interaction between caffeine intake, vitamin D receptor (VDR)polymorphism, and BMD in the longitudinal study. DESIGN: The results are derived from cross-sectional measurements of BMD in 489 elderly women (aged 65-77 y) and from longitudinal measurements made in 96 of these women who were treatedwith a placebo for 3 y. Changes in BMD were adjusted for confounding factors and were compared between groups with eitherlow (< or =300 mg/d) or high (>300 mg/d) caffeine intakes and between the VDR genotype subgroups of the low- andhigh-caffeine groups. RESULTS: Women with high caffeine intakes had significantly higher rates of bone loss at the spine than did those with low intakes (-1.90 +/- 0.97% compared with 1.19 +/- 1.08%; P = 0.038). When the data were analyzed according to VDR genotype and caffeine intake, women with the tt genotype had significantly (P = 0.054) higher rates of boneloss at the spine (-8.14 +/- 2.62%) than did women with the TT genotype (-0.34 +/- 1.42%) when their caffeine intake was>300 mg/d. CONCLUSIONS: Intakes of caffeine in amounts >300 mg/d ( approximately 514 g, or 18 oz, brewed coffee) accelerate bone loss at the spine in elderly postmenopausal women. Furthermore, women with the tt genetic variant of VDRappear to be at a greater risk for this deleterious effect of caffeine on bone.

27. Scientists have identified about 5-8 million locations where single-base DNA differences (SNPs) occur in humans.Scientists have identified about 5-8 million locations where single-base DNA differences (SNPs) occur in humans.

28. Nutrigenomic Testing Promises versus Reality! Commercial Nutrition-Gene Test Genelex Sciona 19 genes including MTHFR $395 Gene Care CVD nutritional genetic test (South Africa) MTHFR (Hcyst), apoA1 (HDL) +9 others $400 Exceeding complex area since about 30, 000 Genes, 5-8 Million SNPs

29. Transgenic and Knockout Models Key to Identifying Sites of Action of Food Components

31. Diet May Influence Genetic and Epigenetics! Epigenetics: The study of heritable changes in gene expression that occur without a change in DNA sequence. DNA methylation- CpG islands Histone posttranslational modifications: Acetylation of lysines Methylation of lysines and arginines Phosphorylations of serines and threonines ADP-ribosylation of glutamic acids Ubiquitination of lysine residues Sumolyation of lysine residues Biotinylation of lysines Recently, in human cells small-interfering RNAs (siRNAs) have been shown to mediate transcriptional gene silencing (Morris KV, Cell Mol. Life Sci. 62:3057-3066, 2005).

32. Dr. Law (England) mentioned programming in the neonate. Permanently alters structure and function. Such is the case with this study.Dr. Law (England) mentioned programming in the neonate. Permanently alters structure and function. Such is the case with this study.

36. Transcriptomic Studies Are Providing Clues About Molecular Targets for Specific Food Components

39. A naturally occurring, cocoa-derived pentameric procyanidin (pentamer) was previously shown to cause G0/G1 cell cycle arrest in human breast cancer cells by an unknown molecular mechanism. Here, we show that pentamer selectively inhibits the proliferation of human breast cancer cells (MDA MB-231, MDA MB-436, MDA MB-468, SKBR-3, and MCF-7) and benzo(a)pyrene-immortalized 184A1N4 and 184B5 cells. In contrast, normal human mammary epithelial cells in primary culture and spontaneously immortalized MCF-10A cells were significantly resistant. We evaluated whether this differential response to pentamer may involve depolarization of the mitochondrial membrane. Pentamer caused significant depolarization of mitochondrial membrane in MDA MB231 cells but not the more normal MCF-10A cells, whereas other normal and tumor cell lines tested gave variable results. Further investigations, using a proteomics approach with pentamer-treated MDA MB-231, revealed a specific dephosphorylation, without changes in protein expression, of several G1-modulatory proteins: Cdc2 (at Tyr15), forkhead transcription factor (at Ser256, the Akt phosphorylation site) and p53 (Ser392). Dephosphorylation of p53 (at Ser392) by pentamer was confirmed in MDA MB-468 cells. However, both expression and phosphorylation of retinoblastoma protein were decreased after pentamer treatment. Our results show that breast cancer cells are selectively susceptible to the cytotoxic effects of pentameric procyanidin, and suggest that inhibition of cellular proliferation by this compound is associated with the site-specific dephosphorylation or down-regulation of several cell cycle Pentamer selectively inhibits the growth of human breast cancer cells compared with spontaneously immortalized and normal mortal HMECs. Human breast cancer MDA MB-231 (A) and MDA MB-436 (B), nontransformed spontaneously immortalized MCF-10A (C), and normal mortal HMEC (D) cells were grown in triplicate in 96-well plates and treated with 100 µg/mL of pentamer (hashed line) or DMSO vehicle (solid line) for up to 10 d as described in Materials and Methods. Samples were collected at the indicated days post-pentamer treatment and analyzed by crystal violet assay as described. The data presented are an average from triplicate wells from two to three independent experiments. Bars, SD; *, statistical significance compared with DMSO treated controls (P < 0.0001). A naturally occurring, cocoa-derived pentameric procyanidin (pentamer) was previously shown to cause G0/G1 cell cycle arrest in human breast cancer cells by an unknown molecular mechanism. Here, we show that pentamer selectively inhibits the proliferation of human breast cancer cells (MDA MB-231, MDA MB-436, MDA MB-468, SKBR-3, and MCF-7) and benzo(a)pyrene-immortalized 184A1N4 and 184B5 cells. In contrast, normal human mammary epithelial cells in primary culture and spontaneously immortalized MCF-10A cells were significantly resistant. We evaluated whether this differential response to pentamer may involve depolarization of the mitochondrial membrane. Pentamer caused significant depolarization of mitochondrial membrane in MDA MB231 cells but not the more normal MCF-10A cells, whereas other normal and tumor cell lines tested gave variable results. Further investigations, using a proteomics approach with pentamer-treated MDA MB-231, revealed a specific dephosphorylation, without changes in protein expression, of several G1-modulatory proteins: Cdc2 (at Tyr15), forkhead transcription factor (at Ser256, the Akt phosphorylation site) and p53 (Ser392). Dephosphorylation of p53 (at Ser392) by pentamer was confirmed in MDA MB-468 cells. However, both expression and phosphorylation of retinoblastoma protein were decreased after pentamer treatment. Our results show that breast cancer cells are selectively susceptible to the cytotoxic effects of pentameric procyanidin, and suggest that inhibition of cellular proliferation by this compound is associated with the site-specific dephosphorylation or down-regulation of several cell cycle Pentamer selectively inhibits the growth of human breast cancer cells compared with spontaneously immortalized and normal mortal HMECs. Human breast cancer MDA MB-231 (A) and MDA MB-436 (B), nontransformed spontaneously immortalized MCF-10A (C), and normal mortal HMEC (D) cells were grown in triplicate in 96-well plates and treated with 100 µg/mL of pentamer (hashed line) or DMSO vehicle (solid line) for up to 10 d as described in Materials and Methods. Samples were collected at the indicated days post-pentamer treatment and analyzed by crystal violet assay as described. The data presented are an average from triplicate wells from two to three independent experiments. Bars, SD; *, statistical significance compared with DMSO treated controls (P < 0.0001).

41. Critical to Understanding the Physiological Effects of Bioactive Food Components Captures information about: Gene expression patterns Post-translational modifications Cross-talk within and across cells.Critical to Understanding the Physiological Effects of Bioactive Food Components Captures information about: Gene expression patterns Post-translational modifications Cross-talk within and across cells.

42. Metabolomic Analysis of the Biochemical Effects of Dietary Isoflavones

44. Components are “complex mixtures” - act synergistically

45. Combination of Dietary Components

46. Soy Phytochemicals and Green Tea Inhibit Human Mammary Tumors in Mice

52. Fig. 8. 1a-OHase activity in primary cultures of normal, BPH, and prostate cancer (CaP), and in human prostate cancer cell lines, DU 145, PC-3, and LNCaP cells. Bars are standard deviations of three determinations. The four primary prostate cultures were obtained from a 63-year-old Caucasian (P1), a 50-year-old African American (P2), a 67- year-old Caucasian (P3) and a 53-year-old Caucasian (P4) with prostate cancer. Three normal cultures were obtained from histologically normal prostates of a 21-year-old and a 27-year-old donor and a 42-year-old African American organ donor. BPH cultures were derived from open prostatectomy specimens of a 58-year-old and a 60-year-old Caucasian. (Reprinted from Whitlatch et al. 2002, with permission.) Whitlatch LW, Young MV, Schwartz GG, Flanagan JN, Burnstein KL, Lokeshwar BL, Rich ES, Holick MF, Chen TC. 25-Hydroxyvitamin D-1-alphahydroxylase activity is diminished in human prostate cancer cells and is enhanced by gene transfer. Journal of Steroid Biochemistry & Molecular Fig. 8. 1a-OHase activity in primary cultures of normal, BPH, and prostate cancer (CaP), and in human prostate cancer cell lines, DU 145, PC-3, and LNCaP cells. Bars are standard deviations of three determinations. The four primary prostate cultures were obtained from a 63-year-old Caucasian (P1), a 50-year-old African American (P2), a 67- year-old Caucasian (P3) and a 53-year-old Caucasian (P4) with prostate cancer. Three normal cultures were obtained from histologically normal prostates of a 21-year-old and a 27-year-old donor and a 42-year-old African American organ donor. BPH cultures were derived from open prostatectomy specimens of a 58-year-old and a 60-year-old Caucasian. (Reprinted from Whitlatch et al. 2002, with permission.) Whitlatch LW, Young MV, Schwartz GG, Flanagan JN, Burnstein KL, Lokeshwar BL, Rich ES, Holick MF, Chen TC. 25-Hydroxyvitamin D-1-alphahydroxylase activity is diminished in human prostate cancer cells and is enhanced by gene transfer. Journal of Steroid Biochemistry & Molecular Biology, 81:135–140, 2002. Fig. 8. 1a-OHase activity in primary cultures of normal, BPH, and prostate cancer (CaP), and in human prostate cancer cell lines, DU 145, PC-3, and LNCaP cells. Bars are standard deviations of three determinations. The four primary prostate cultures were obtained from a 63-year-old Caucasian (P1), a 50-year-old African American (P2), a 67- year-old Caucasian (P3) and a 53-year-old Caucasian (P4) with prostate cancer. Three normal cultures were obtained from histologically normal prostates of a 21-year-old and a 27-year-old donor and a 42-year-old African American organ donor. BPH cultures were derived from open prostatectomy specimens of a 58-year-old and a 60-year-old Caucasian. (Reprinted from Whitlatch et al. 2002, with permission.) Whitlatch LW, Young MV, Schwartz GG, Flanagan JN, Burnstein KL, Lokeshwar BL, Rich ES, Holick MF, Chen TC. 25-Hydroxyvitamin D-1-alphahydroxylase activity is diminished in human prostate cancer cells and is enhanced by gene transfer. Journal of Steroid Biochemistry & Molecular Fig. 8. 1a-OHase activity in primary cultures of normal, BPH, and prostate cancer (CaP), and in human prostate cancer cell lines, DU 145, PC-3, and LNCaP cells. Bars are standard deviations of three determinations. The four primary prostate cultures were obtained from a 63-year-old Caucasian (P1), a 50-year-old African American (P2), a 67- year-old Caucasian (P3) and a 53-year-old Caucasian (P4) with prostate cancer. Three normal cultures were obtained from histologically normal prostates of a 21-year-old and a 27-year-old donor and a 42-year-old African American organ donor. BPH cultures were derived from open prostatectomy specimens of a 58-year-old and a 60-year-old Caucasian. (Reprinted from Whitlatch et al. 2002, with permission.) Whitlatch LW, Young MV, Schwartz GG, Flanagan JN, Burnstein KL, Lokeshwar BL, Rich ES, Holick MF, Chen TC. 25-Hydroxyvitamin D-1-alphahydroxylase activity is diminished in human prostate cancer cells and is enhanced by gene transfer. Journal of Steroid Biochemistry & Molecular Biology, 81:135–140, 2002.

54. So how do these incredible achievements align themselves within a national nutrition strategy… Basic research leading to ongoing studies SELECT WINS WHELSSo how do these incredible achievements align themselves within a national nutrition strategy… Basic research leading to ongoing studies SELECT WINS WHELS

56. The Future of Nutrigenomics

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