The traditional diet of Greece and cancer.

[R.B.]

The omega 3:6 balance, inflammation, COX 2 pathways and downstream products are factors in BC.

See also COX 2 posts.

http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum




1: Nutr Cancer. 2007;59(1):14-20.Links
Effects of eicosapentaenoic and docosahexaenoic n-3 fatty acids from fish oil and preferential Cox-2 inhibition on systemic syndromes in patients with advanced lung cancer.
Cerchietti LC, Navigante AH, Castro MA.

Translational Research Unit, Angel H Roffo Cancer Institute, Universidad de Buenos Aires, Buenos Aires, Argentina. lcerchie@aecom.yu.edu

Under the common denomination of Systemic Immune-Metabolic Syndrome (SIMS), we grouped many symptoms that share a similar pathophysiologic background. SIMS is the result of the dysfunctional interaction of tumor cells, stroma cells, and the immune system, leading to the release of cytokines and other systemic mediators such as eicosanoids. SIMS includes systemic syndromes such as paraneoplastic hemopathies, hypercalcemia, coagulopathies, fatigue, weakness, cachexia, chronic nausea, anorexia, and early satiety among others. Eicosapentaenoic and docosahexaenoic n-3 fatty acids from fish oil can help in the management of persistent chronic inflammatory states, but treatment's compliance is generally poor. Preferentially, Cox-2 inhibition can create a favorable pattern of cytokines by decreasing the production of certain eicosanoids, although their role in SIMS is unknown. The aim of this study was to test the hypothesis that by modulating systemic inflammation through an eicosanoid-targeted approach, some of the symptoms of the SIMS could be controlled. We exclusively evaluated 12 patients for compliance. Patients were assigned 1 of the 4 treatment groups (15-, 12-, 9-, or 6-g dose, fractionated every 8 h). For patients assigned to 15 and 12 doses, the overall compliance was very poor and unsatisfactory for patients receiving the 9-g dose. The maximum tolerable dose was calculated to be around 2 capsules tid (6 g of fish oil per day). A second cohort of 22 patients with advanced lung cancer and SIMS were randomly assigned to receive either fish oil, 2 g tid, plus placebo capsules bid (n = 12) or fish oil, 2 g tid, plus celecoxib 200 mg bid (n = 10). All patients in both groups received oral food supplementation. After 6 wk of treatment, patients receiving fish oil + placebo or fish oil + celecoxib showed significantly more appetite, less fatigue, and lower C-reactive protein (C-RP) values than their respective baselines values (P < 0.02 for all the comparisons). Additionally, patients in the fish oil + celecoxib group also improved their body weight and muscle strength compared to baseline values (P < 0.02 for all the comparisons). Comparing both groups, patients receiving fish oil + celecoxib showed significantly lower C-RP levels (P = 0.005, t-test), higher muscle strength (P = 0.002, t-test) and body weight (P = 0.05, t-test) than patients receiving fish oil + placebo. The addition of celecoxib improved the control of the acute phase protein response, total body weight, and muscle strength. Additionally, the consistent nutritional support used in our patients could have helped to maximize the pharmacological effects of fish oil and/or celecoxib. This study shows that by modulating the eicosanoid metabolism using a combination of n-3 fatty acids and cyclooxygenase-2 inhibitor, some of the signs and symptoms associated with a SIMS could be ameliorated.

[TSund]

RB- what is celecoxib? A Cox2 inhibitor of some sort I assume?

And, do you think this would applicable to mom who suffers multiple immune system problems, probably stemming from her chronic leukemia, along with muscle wasting/fibromylagia.
Thanks

TRS

[R.B.]

Hi T Sund

Here is a link for celecoxib.

http://en.wikipedia.org/wiki/Celebrex

I cannot in any way give advice on specific conditions in relation to individual circumstances. I have no training to do so. I can only draw your attention to the generality of relevant trials for your consideration.

Omega 3 and 6 do impact on the immune function through a number of mechanisms. IF there is dietary excess of Omega 6 and a lack of Omega 3 fats from plant sources (eg vegetable oils) AND a lack of long chain Omega 3s DHA and EPA or blocked conversion pathways there is significant evidence this can negatively impact on the immune function.

As posted already there is some evidence that increasing the intake of long chain omega 3s may help in some circumstances with fatigue etc.

These are listed as symptoms of CFS

http://www.spineuniverse.com/display...rticle155.html

Symptoms of Fibromyalgia include:

—Multiple tender points and muscle pain

—Disturbed sleep with morning fatigue and stiffness

—Aggravation of signs and symptoms by modulating factors (emotional stress, temperature changes)

—Subjective swelling and numbness

—Chronic headaches

—Irritable bowel syndrome

—Cold intolerance (Raynaud's Phenomenon)

—Dysmenorrhea - painful menstruation

—Exercise intolerance

—Weakness

A number of them have also been linked at some level with Omega 3:6 imbalances.


A search under leukemia or CFS and DHA or Omega 3 etc on Pubmed http://www.ncbi.nlm.nih.gov/ will produce some trials.


CFS
There are a few for CFS. This is an example suggesting CFS sufferers have a lack of Omega 3 and excess Omega 6

Neuro Endocrinol Lett. 2005 Dec;26(6):745-51.Links
In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation.
Maes M, Mihaylova I, Leunis JC.

M-Care4U Outpatient Clinics, and the Clinical Research Center for Mental Health, Antwerp, Belgium.

ABSTRACT

"There is now evidence that major depression is accompanied by decreased levels of omega3 poly-unsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). There is a strong comorbidity between major depression and chronic fatigue syndrome (CFS). The present study has been carried out in order to examine PUFA levels in CFS. In twenty-two CFS patients and 12 normal controls we measured serum PUFA levels using gas chromatography and mass spectrometry. We found that CFS was accompanied by increased levels of omega6 PUFAs, i.e. linoleic acid and arachidonic acid (AA), and mono-unsaturated fatty acids (MUFAs), i.e. oleic acid. The EPA/AA and total omega3/omega6 ratios were significantly lower in CFS patients than in normal controls. The omega3/omega6 ratio was significantly and negatively correlated to the severity of illness and some items of the FibroFatigue scale, i.e. aches and pain, fatigue and failing memory. The severity of illness was significantly and positively correlated to linoleic and arachidonic acid, oleic acid, omega9 fatty acids and one of the saturated fatty acids, i.e. palmitic acid. In CFS subjects, we found significant positive correlations between the omega3/omega6 ratio and lowered serum zinc levels and the lowered mitogen-stimulated CD69 expression on CD3+, CD3+ CD4+, and CD3+ CD8+ T cells, which indicate defects in early T cell activation. The results of this study show that a decreased availability of omega3 PUFAs plays a role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS. The results suggest that patients with CFS should respond favourably to treatment with--amongst other things- --omega3 PUFAs, such as EPA and DHA."

http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum

So have a look at some more.

LEUKEMIA

There has been some work in the area of leukemia which seems to suggest possible benefits for EPA for example or usage as a treatment adjunct.

http://www.ncbi.nlm.nih.gov/sites/en...20%20omega%203


GOOD CLINICAL BOOK ON ACUTE INFLAMMATION

This is expensive but an excellent book you could give to your doctor. It is rare in being clinically orientated It is a powerful book. It is not an easy read but your friend just needs to get the jist and give it to her doctor as a basis for dietary discussion.

Omega 3 Fatty Acids in Clinical Nutrition by Heller, Stehr and Koch.

AND FINALLY

Your friend must tell to her doctor before any significant change in diet. I would suggest doing some more reading on Omega 3 and 6 and CFS etc printing the information and taking it to the doctor at the time of visit.

[R.B.]

Another mechanism by which Omega 6 linoleic acid induces tissue formation , migration and proliferation.

Oxidised Omega 6 linoleic acid induces rapid dose dependent upregulation of Syndecan-4

http://www.ncbi.nlm.nih.gov/pubmed/16636895

Breast Cancer Res Treat. 2006 Jul;98(1):91-8. Epub 2006 Apr 25.Click here to read Links
Syndecan-1 and syndecan-4 are overexpressed in an estrogen receptor-negative, highly proliferative breast carcinoma subtype.
Baba F, Swartz K, van Buren R, Eickhoff J, Zhang Y, Wolberg W, Friedl A.

Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53792, USA.

Members of the syndecan and glypican families of cell surface heparan sulfate proteoglycans (HSPGs) are modulators of growth factor signaling and cell adhesion. Both loss and gain in expression of syndecans and glypicans has been associated with malignant progression. The goal of this project was to investigate a possible relationship between expression of cell surface HSPGs (syndecan-1, syndecan-4 and glypican-1) and established prognostic factors or clinical outcome in breast carcinomas. Tissue arrays containing 207 human breast carcinoma samples in duplicate were immuno-labeled with antibodies to syndecan-1, syndecan-4, glypican-1, Ki67, E-cadherin, estrogen receptor (ER) and progesterone receptor (PR). Clinical follow-up information was available for up to 18.6 years (median follow-up 6.2 years). Syndecan-1 and syndecan-4 expression in carcinoma cells ranged from complete loss to high expression, but glypican-1 was detected only in a small subset of breast carcinomas. Expression of all three HSPGs was significantly associated with the Ki67 proliferation index (syndecan-1: p=0.0025; syndecan-4: p<0.0001; glypican-1 p=0.01). Syndecan-1 and syndecan-4 expression correlated with ER negativity, grade, and size of the primary tumors. Syndecan-1 expression (but not syndecan-4 nor glypican-1) predicted patient outcome (DFS: p=0.0054; OS: p=0.0086). However, multivariate analysis failed to identify syndecan-1 as an independent prognostic marker, which was due to its significant association with established prognostic factors. The strong association between cell surface HSPGs and the Ki67 proliferation marker would support a biologic role in carcinoma growth regulation. Furthermore, the close correlation between syndecan expression and negative ER status raises the possibility of hormonal regulation or more likely an association with an aggressive, ER-negative carcinoma phenotype.

http://www.asco.org/ASCO/Abstracts+&...tractID=202291



Specific Induction of Syndecan-4 in Vascular Endothelial Cells of Breast Cancer - Implications for FGF-2-Induced Angiogenesis.
Sub-category:


Proc Am Soc Clin Oncol 19: 2000 (abstr 2603)
Author(s):

Christoph Mundhenke, Sally Drew, Zhen Chang, Aung Choon, Andreas Friedl
Abstract:

Introduction: Fibroblast growth factor-2 (FGF-2) is a potent angiogenic stimulator. Binding of FGF-2 to its receptor tyrosine kinases (RTKs) and cellular signaling are modulated by heparan sulfate proteoglycans (HSPGs) via their heparin-like heparan sulfate (HS) side chains. HS can be specific positive or negative regulators of FGF signaling depending on their ability to bind to both FGF ligand and RTK. Aim: The goal of this study was to localize different cell surface HSPGs in breast cancer and normal breast tissue and to examine their roles in FGF signaling. Materials and Methods: HSPGs were detected immunohistochemically in paraffin embedded tissues using antibodies directed against the HSPG core proteins of glypican-1, syndecan-1 and syndecan-4. The ability of HSPGs to promote FGF-2 signaling complex assembly was tested by using FGF-2 ligand and soluble RTK fusion protein (FR1-AP) as binding probes (Chang et al. FASEB J., in press). Results: HSPGs are induced in the stroma of infiltrating carcinomas in a striking tissue compartment and cell type-specific fashion. Syndecan-4 is dramatically induced in activated endothelial cells within infiltrating carcinoma tissue, while endothelial cells in normal breast gland are syndecan-4 negative. Syndecan-1 is strongly up-regulated in fibroblasts within the desmoplastic stroma surrounding infiltrating cancer cells. Glypican-1 is found in stromal fibroblasts in the immediate vicinity of cancer cells. FGF-2 binds to HSPGs in all stromal compartments. FR1-AP binds to FGF-2 immobilized on stromal fibroblast and endothelial cell HSPGs, suggesting, that syndecan-1 on fibroblasts and syndecan-4 on endothelial cells promote FGF-2 signaling complex assembly. Summary: Syndecan-4 is induced in tumor vessel endothelial cells of infiltrating carcinomas of the breast, facilitating FGF-2 signaling and thereby likely promoting angiogenesis.




http://ajpcell.physiology.org/cgi/co...ull/288/2/C458
ABSTRACT

Syndecan-4, a heparan sulfate proteoglycan that is widely expressed in the vascular wall and as a cell surface receptor, modulates events relevant to acute tissue repair, including cell migration and proliferation, cell-substrate interactions, and matrix remodeling. While syndecan-4 expression is regulated in response to acute vascular wall injury, its regulation under chronic proatherogenic conditions such as those characterized by prolonged exposure to oxidized lipids has not been defined. In this investigation, arterial smooth muscle cells were treated with 13-hydroperoxy-9,11-octadecadienoic acid (HPODE) and 13-hydroperoxy-10,12-octadecadienoic acid, oxidized products of linoleic acid, which is the major oxidizable fatty acid in LDL. Both oxidized fatty acids induced a dose-dependent, rapid upregulation of syndecan-4 mRNA expression that was not attenuated by cycloheximide. This response was inhibited by pretreatment with N-acetylcysteine, catalase, or MEK1/2 inhibitors, but not by curcumin or lactacystin, known inhibitors of NF-{kappa}B. These data suggest that oxidized linoleic acid induces syndecan-4 mRNA expression through the initial generation of intracellular hydrogen peroxide with subsequent activation of the extracellular signal-regulated kinase signaling pathway via MEK1/2. Notably, the HPODE-induced enhancement of syndecan-4 mRNA was accompanied by accelerated shedding of syndecan-4. In principle, alterations in both the cell surface expression and shedding of syndecan-4 may augment a variety of proatherogenic events that occur in response to oxidized lip

[R.B.]

PPAR gamma has made a previous appearance as having a link with BC. The trial below suggest that the products of oxidation of Omega 6 linoleic acid promote PPAR gamma which is suggested to be a tumour promoter in BC.



http://genesdev.cshlp.org/cgi/content/abstract/18/5/528

ABSTRACT

"These results suggest that once an initiating event has taken place, increased PPAR{gamma} signaling serves as a tumor promoter in the mammary gland."


http://carcin.oxfordjournals.org/cgi...act/24/11/1717

ABSTRACT

Activation of PPAR {gamma} in colon tumor cell lines by oxidized metabolites of linoleic acid, endogenous ligands for PPAR {gamma}

Arthur W. Bull1,4, Knut R. Steffensen2, Jörg Leers2 and Joseph J. Rafter3

1 Oakland University, Department of Chemistry, Rochester MI 48309-4477, USA, 2 Center for Biotechnology, Karolinska Institute, NOVUM, 141 86 Huddinge, Sweden and 3 Department of Medical Nutrition, Karolinska Institute, NOVUM, 141 86 Huddinge, Sweden

The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) {gamma} plays an important role in the differentiation of intestinal cells and other tissues. Real-time PCR examination of PPAR mRNA for {gamma}1, {gamma}2 and {gamma}3, in Caco-2 and HCT-116 colon cell lines showed that {gamma}3 is the most abundant message in both lines. Treatment of Caco-2 cells with sodium butyrate, which induces cell differentiation, also leads to an increase in all three PPAR mRNAs. In contrast, treatment of HCT-116 cells with sodium butyrate, which does not lead to differentiation of these cells, causes a decrease in the amount of all three PPAR mRNAs. Furthermore, the amount of PPAR mRNA is greater in Caco-2 cells than in HCT-116 cells at all times examined. As several oxidative metabolites of linoleic acid, including 13-hydroxyoctadecadienoic acid (13-HODE) and 13-oxooctadecadienoic acid (13-OXO) have been shown to bind PPAR, and there is a strong positive correlation between enzymes for metabolism of linoleate oxidation products, intestinal cell differentiation and the distribution of PPAR, we also performed a detailed investigation of the activation of PPAR {gamma} by 13-HODE and 13-OXO. For these experiments, Caco-2 and HCT-116 cells were transfected with constructs containing PPAR {gamma}1 or {gamma}2 then a PPRE-luc reporter construct. Exposure of transfected cells to micromolar concentrations of 13-HODE or 13-OXO produced concentration-dependent increases in luciferase activity. In addition, the two linoleate metabolites activate endogenous PPAR in these cell lines transfected with only PPRE-luc. The data substantiate the contention that oxidation products of linoleic acid are metabolically produced endogenous ligands for PPAR {gamma} and that PPAR {gamma} plays an important role in the differentiation of intestinal cells.

[R.B.]

Linoleic Acid-Induced VCAM-1 Expression in Human Microvascular Endothelial Cells Is Mediated by the NF-κβ-Dependent Pathway
Authors: Hyen Joo Park; Yong Woo Lee; Bernhard Hennig; Michal Toborek
DOI: 10.1207/S15327914NC41-1&2_18
Publication Frequency: 6 issues per year
Published in: journal Nutrition and Cancer, Volume 41, Issue 1 & 2 September 2001 , pages 126 - 134


Abstract
Vascular cell adhesion molecule-1 (VCAM-1) has been reported to play an important role in cancer metastasis via the adhesive interaction between tumor cells and endothelial cells. In this study, we examined the effects of linoleic acid on VCAM-1 expression and its transcriptional regulatory mechanism in human microvascular endothelial cells (HMEC-1). Time- and dose-dependent increases of VCAM-1 mRNA levels were observed in linoleic acid-treated HMEC-1 as detected by reverse transcriptase-polymerase chain reaction. Flow cytometry analysis showed a significant and dose-dependent upregulation of VCAM-1 expression in HMEC-1 stimulated with linoleic acid compared with controls. To clarify the transcriptional regulatory pathway, we investigated the role of nuclear factor-κβ (NF-κβ) in the expression of VCAM-1 by linoleic acid in HMEC-1. Nuclear extracts from HMEC-1 stimulated with linoleic acid showed a dose-dependent increase in binding activity to the NF-kB consensus sequences. These effects were preventable by cotreatment with inhibitors of NF-κβ activity, such as sodium salicylate, aspirin, or pyrrolidine dithiocarbamate. In addition, pretreatment with NF-κβ inhibitors markedly suppressed the ability of linoleic acid to induce VCAM-1 gene expression. The role of NF-κβ in linoleic acid-induced VCAM-1 expression was confirmed by functional promoter studies in HMEC-1 transfected with reporter constructs of the VCAM-1 promoter with or without mutated NF-κβ binding site. These results indicate that linoleic acid upregulates VCAM-1 expression in HMEC-1 through the NF-κβ-dependent pathway.

[R.B.]

Fat -1 is a gene in worms that converts omega 6 to omega 3. Animals and humans do not have that ability.

They have done trial where they insert the gene into pigs and mice and they make Omega 6 into Omega 3 and tend to balance the two.

Here they are seeing what happens to cancer cells if the fat gene is inserted into cancer cells and the cells put into mice.

The fat gene inhibited cell proliferation in prostate cancer.

In essence once again a balance of Omega 3s and 6s / lower Omega 6s may help inhibit cancer.

RB



Expression of the fat-1 gene diminishes prostate cancer growth in vivo through enhancing apoptosis and inhibiting GSK-3{beta} phosphorylation.
Lu Y, Nie D, Witt WT, Chen Q, Shen M, Xie H, Lai L, Dai Y, Zhang J.

Department of Medicine, University of Pittsburgh, VA Pittsburgh Healthcare Systems, Room 2E146, University Drive, Pittsburgh, PA 15240. zhangj2@upmc.edu.

Epidemiologic studies inclusively indicate that "unhealthy" dietary fat intake is one of the potential risk factors for cancer. In dietary fat, there are two types of polyunsaturated fatty acids (PUFA), omega-3 (n-3) and omega-6 (n-6). Numerous studies support that the ratio of n-6/n-3 affects tumorigenesis. It was reported that adenoviral transfer of the fat-1 gene, which converts n-6 to n-3, into breast and lung cancer cells had an antitumor effect in vitro. However, the effects of the fat-1 gene expression on tumor growth in vivo have not been studied and the mechanisms remain unclear. Accordingly, prostate cancer DU145 and PC3 cells were transfected with either the fat-1 gene or a control vector. The cells that expressed the fat-1 gene had a lower n-6/n-3 PUFA ratio compared with the cells that expressed the control vector. The fat-1 gene expression significantly inhibited prostate cancer cell proliferation and invasion in vitro. The fat-1 and control vector-transfected prostate cancer cells were s.c. implanted into severe combined immunodeficient mice for 6 weeks. The fat-1 gene expression significantly diminished tumor growth in vivo, but the control vector had no effect. Finally, we evaluated signaling pathways that may be important for fat-1 gene function. Administration of n-3 PUFA induced caspase-3-mediated prostate cancer cell apoptosis in vitro. The fat-1 gene expression inhibited prostate cancer cell proliferation via reduction of GSK-3beta phosphorylation and subsequent down-regulation of both beta-catenin and cyclin D1. These results suggest that fat-1 gene transfer directly into tumor cells could be used as a novel therapeutic approach. [Mol Cancer Ther 2008;7(10):3203-11].

[R.B.]

Arachidonic acid is the long chain Omega 6 and raw material of the Omega 6 chemicals. COX 2 is one of the enzymes that converts arachidonic acid to its down stream products.

This is another confirmation of a link between oestrogen production and Omega 6.

The vegetable based Omega 6 increases COX 2 expression.

The only place you can get Omega 6 is in the diet you cannot make it.

Long chain Omega 3 has a blocking effect on COX2 Omega 6 products by a variety of mechanisms.


RB



Cyclooxygenase-2 mRNA expression correlates with aromatase expression in human breast cancer.
Salhab M, Singh-Ranger G, Mokbel R, Jouhra F, Jiang WG, Mokbel K.

St. George's University of London, Tooting, London, United Kingdom.

INTRODUCTION: The cyclooxygenase-2 (COX-2), responsible for the conversion of arachidonic acid into prostaglandin (PG) E2, is known to increase intracellular cAMP and estrogen production in malignant breast tissue. The aromatase enzyme complex is responsible for local production of estrogens in breast cancer. Increasing evidence supports a role for COX-2 in upregulation of aromatase activity. The aim of this study was to examine the relationship between COX-2 and aromatase mRNA expression in human breast cancer. METHODS: A total of 160 breast samples (127 tumor tissues and 33 normal tissues) were analyzed. Levels of transcription were determined using real-time quantitative PCR. COX-2 and aromatase mRNA expression were normalized against CK19. Levels of expression of COX-2 were correlated with those of aromatase using Pearson's correlation method. RESULTS: Levels of expression of COX-2/CK19 of both benign and malignant tissues were positively correlated with aromatase/CK19 transcript levels (correlation coefficient = +0.536, P < 0.0001). When we compared levels of expression of both genes in malignant samples only, there was a highly significant positive correlation (r = +0.611, P < 0.00001). CONCLUSION: This study demonstrates a strong positive relationship between COX-2 and aromatase mRNA expression, and lends further support to the hypothesis that COX-2 is an upregulator of aromatase in breast tissue.

[R.B.]

1: Breast Cancer Res Treat. 2007 Jan;101(1):7-16. Epub 2006 Jul 6.Click here to read Links
Differential effects of omega-3 and omega-6 Fatty acids on gene expression in breast cancer cells.
Hammamieh R, Chakraborty N, Miller SA, Waddy E, Barmada M, Das R, Peel SA, Day AA, Jett M.

Division of Pathology, Walter Reed Army Institute of Research, 503 Robert Grant Road, Silver Spring, MD 20910, USA.

Essential fatty acids have long been identified as possible oncogenic factors. Existing reports suggest omega-6 (omega-6) essential fatty acids (EFA) as pro-oncogenic and omega-3 (omega-3) EFA as anti-oncogenic factors. The omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), inhibit the growth of human breast cancer cells while the omega-6 fatty acids induces growth of these cells in animal models and cell lines. In order to explore likely mechanisms for the modulation of breast cancer cell growth by omega-3 and omega-6 fatty acids, we examined the effects of arachidonic acid (AA), linoleic acid (LA), EPA and DHA on human breast cancer cell lines using cDNA microarrays and quantitative polymerase chain reaction. MDA-MB-231, MDA-MB-435s, MCF-7 and HCC2218 cell lines were treated with the selected fatty acids for 6 and 24 h. Microarray analysis of gene expression profiles in the breast cancer cells treated with both classes of fatty acids discerned essential differences among the two classes at the earlier time point. The differential effects of omega-3 and omega-6 fatty acids on the breast cancer cells were lessened at the late time point. Data mining and statistical analyses identified genes that were differentially expressed between breast cancer cells treated with omega-3 and omega-6 fatty acids. Ontological investigations have associated those genes to a broad spectrum of biological functions, including cellular nutrition, cell division, cell proliferation, metastasis and transcription factors etc., and thus presented an important pool of biomarkers for the differential effect of omega-3 and omega-6EFAs.

[R.B.]

Changing your Omega 3 6 intake shows up quite quickly in breast tissue (3 months).

It take about 680 day to change half of your adipose fat.

Fats in blood change quite quickly but still reflect stored Omega 6.

The body heavily stores Omega 6 (Omega 6 is 3-30% of body fat dependent on the amount in the diet) but stores very little Omega 3 (Omega 3 is usually under 1% of body fat and in the West often a fraction of a percent).

Omega 6 increases the risk of cancer and Omega 3s reduce the risk of cancer.

Does concentration of Omega 6 in the breast where the diet is high in Omega 6 could explain why breasts are more susceptible to cancer than part of the body that are less reliant on Omega 3 and 6..

These patients were given 1.8 gram EPA and 1.2 grams DHA a day. The full trial is free.

http://jnci.oxfordjournals.org/cgi/reprint/89/15/1123




Dietary modulation of omega-3/omega-6 polyunsaturated fatty acid ratios in patients with breast cancer.
Bagga D, Capone S, Wang HJ, Heber D, Lill M, Chap L, Glaspy JA.

Department of Medicine, School of Medicine, University of California at Los Angeles, 90095-6956, USA.

BACKGROUND: Polyunsaturated fatty acids of the omega-6 (omega-6) class, as found in corn and safflower oils, can act as precursors for intermediates involved in the growth of mammary tumors when fed to animals, whereas polyunsaturated fatty acids of the omega-3 (omega-3) class, as found in fish oil, can inhibit these effects. The effects of dietary intervention on the ratios of these fatty acids in breast and other adipose tissues have not previously been prospectively studied. PURPOSE: The present investigation was conducted to study the impact on the ratio of omega-3 and omega-6 polyunsaturated fatty acid in plasma and in adipose tissue of the breast and buttocks when women with breast cancer consume a low-fat diet and fish oil supplements. METHODS: Twenty-five women with high-risk localized breast cancer were enrolled in a dietary intervention program that required them to eat a low-fat diet and take a daily fish oil supplement throughout a 3-month period. Breast and gluteal fat biopsy specimens were obtained from each woman before and after dietary intervention. The fatty acid compositions of specimens of plasma, breast fat, and gluteal fat were determined by gas-liquid chromatography. Statistical analysis involved use of a two-sided paired t test. RESULTS: After dietary intervention, a reduction in the level of total omega-6 polyunsaturated fatty acids in the plasma was observed (P<.0003); moreover, total omega-3 polyunsaturated fatty acids increased approximately three-fold (P<.0001) and the omega-3/omega-6 polyunsaturated fatty acids ratio increased approximately fourfold (i.e., mean values increased from 0.09 to 0.41; P = .0001). An increase in total omega-3 polyunsaturated fatty acids in breast adipose tissue was observed following dietary intervention (P = .04); the omega-3/omega-6 polyunsaturated fatty acid ratio increased from a mean value of 0.05 to 0.07 (P = .0001). An increase in total omega-3 polyunsaturated fatty acids was observed in gluteal adipose tissue following the intervention (P = .05); however, the ratio of omega-3 to omega-6 polyunsaturated fatty acids (mean ratio values of 0.036-0.045; P = .06) was unchanged. CONCLUSION: Short-term dietary intervention can lead to statistically significant increases in omega-3/omega-6 polyunsaturated fatty acid ratios in plasma and breast adipose tissue. Breast adipose tissue changed more rapidly than gluteal adipose tissue in response to the dietary modification tested in this study. Therefore, gluteal adipose tissue may not be a useful surrogate to study the effect of diet on breast adipose tissue.

[R.B.]

This is technical and relates to pancreatic cancer and not BC (although it mentions it) and posted for specialists who keep an eye on this thread if any.

But the pathways under discussion are so basic there is undoubtedly some communality, as in the impact of COX blockers like aspirin in BC.

Linoleic acid is the plant based Omega 6.

A way of reducing Omega 6 COX and LOX activity is not to eat excess Omega 6 in the first place, and Omega 3 DHA has been shown to be a natural COX blocker.

The article gives an idea as to how widespread the effects of the products of Omega 6 are.

Lipoxygenase and cyclooxygenase metabolism: new insights in treatment and chemoprevention of pancreatic cancer
Xian-Zhong Ding,1 Rene Hennig,1 and Thomas E Adriancorresponding author1
1Department of Surgery and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Tarry 4-711, Chicago, IL 60611, U.S.A


http://www.pubmedcentral.nih.gov/art...i?artid=149414


"COX and LOX metabolism of linoleic and arachidonic acids leads to the formation of a variety of metabolically active products with different roles in carcinogenesis. Our understanding of these roles is steadily increasing. This new information is providing a theoretical basis for development of new cancer chemoprevention approaches targeted to COX and LOX activity."

[R.B.]

Erythrocyte fatty acids and risk of proliferative and nonproliferative fibrocystic disease in women in Shanghai, China.
Shannon J, King IB, Lampe JW, Gao DL, Ray RM, Lin MG, Stalsberg H, Thomas DB.

Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, OR.

BACKGROUND: Although benign breast changes are more common than breast cancer, little evidence regarding risk factors for benign breast conditions is available. Omega-3 (n-3) fatty acids have antiinflammatory and antiproliferative actions and may be important in reducing the risk of benign conditions. There is a lack of research on the association of n-3 fatty acids with risk of benign fibrocystic breast changes. OBJECTIVES: The objectives of the study were to evaluate the role of n-3 and other fatty acids in the development of benign proliferative fibrocystic conditions (PFCs) and nonproliferative fibrocystic conditions (NPFCs) in the breast and to evaluate the progression of fibrocystic changes in breast cancer. DESIGN: We conducted a case-control study to determine erythrocyte fatty acid concentrations in 155 women with NPFCs, 185 women with PFCs, 241 women with breast cancer (127 with nonproliferative and 114 with proliferative changes in the noncancerous extratumoral mammary epithelium), and 1030 control subjects. We estimated the relative risk of NPFCs, PFCs, and breast cancer with proliferative and nonproliferative changes in extratumoral tissue compared with the risk of these changes alone. RESULTS: Women in the highest quartile of eicosapentaenoic acid concentrations were 67% less likely to have an NPFC alone or with breast cancer and 49% less likely to have breast cancer than were women with PFCs. gamma-Linolenic acid (18:3n-6) was positively associated with all fibrocystic and cancerous conditions. Palmiticalmitoleic acid (n-7 saturation index) was inversely associated with risk in all comparisons. CONCLUSION: Our results support a protective effects of n-3 fatty acid intake and the n-7 saturation index against benign fibrocystic breast changes and the progression of proliferative changes to breast cancer.

[R.B.]

ALA is the plant based Omega 3.

Nuts are high in Omega 6, as are many processed foods.

Processed foods may also contain oxidised fats, and be low on antioxidants.

Fruit and veg contain antioxidants.

Again the trial generally underlines the importance of diet.

RB



1: Int J Cancer. 2009 Feb 15;124(4):924-31.Click here to read Links
Dietary intakes of omega-6 and omega-3 polyunsaturated fatty acids and the risk of breast cancer.
Thiébaut AC, Chajès V, Gerber M, Boutron-Ruault MC, Joulin V, Lenoir G, Berrino F, Riboli E, Bénichou J, Clavel-Chapelon F.

INSERM, ERI-20, Institut Gustave Roussy, Villejuif Cedex, France.

Experimental studies suggest detrimental effects of omega-6 polyunsaturated fatty acids (PUFA), and beneficial effects of omega-3 PUFAs on mammary carcinogenesis, possibly in interaction with antioxidants. However, PUFA food sources are diverse in human diets and few epidemiologic studies have examined whether associations between dietary PUFAs and breast cancer risk vary according to food sources or antioxidant intakes. The relationship between individual PUFA intakes estimated from diet history questionnaires and breast cancer risk was examined among 56,007 French women. During 8 years of follow-up, 1,650 women developed invasive breast cancer. Breast cancer risk was not related to any dietary PUFA overall; however, opposite associations were seen according to food sources, suggesting other potential effects than PUFA per se. Breast cancer risk was inversely associated with alpha-linolenic acid (ALA) intake from fruit and vegetables [highest vs. lowest quintile, hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.63, 0.88; p trend < 0.0001], and from vegetable oils (HR 0.83; 95% CI 0.71, 0.97; p trend 0.017). Conversely, breast cancer risk was positively related to ALA intake from nut mixes (p trend 0.004) and processed foods (p trend 0.068), as was total ALA intake among women in the highest quintile of dietary vitamin E (p trend 0.036). A significant interaction was also found between omega-6 and long-chain omega-3 PUFAs, with breast cancer risk inversely related to long-chain omega-3 PUFAs in women belonging to the highest quintile of omega-6 PUFAs (p interaction 0.042). These results emphasize the need to consider food sources, as well as interactions between fatty acids and with antioxidants, when evaluating associations between PUFA intakes and breast cancer risk.

[R.B.]

Role of fatty acids in malignancy and visual impairment: epidemiological evidence and experimental studies.
Tsubura A, Yuri T, Yoshizawa K, Uehara N, Takada H.

Department of Pathology II, Kansai Medical University, Takii Hospital, Moriguchi, Osaka, Japan. tsubura@takii.kmu.ac.jp

International variation in breast and colon cancer incidence is positively related to total fat intake. However, total fat consists of different fatty acid families, e.g., saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and n-3 and n-6 polyunsaturated fatty acids (PUFAs). Epidemiological evidence and experimental studies suggest that these fatty acid families have different effects on breast and colon carcinogenesis. Therefore the action of each fatty acid on carcinogenesis should be evaluated separately. Although it is difficult to establish firm conclusions on the effect of each fatty acid in human epidemiological studies, experimental studies on animals and cultured cells suggest that n-6 PUFAs (linoleic acid and arachidonic acid) may have a tumor promoting effect, while n-3 PUFAs (eicosapentaenoic acid, docosahexaenoic acid and alpha-linolenic acid) and conjugated fatty acids (CFAs; a mixture of positional and geometric isomers of PUFAs with conjugated double bonds) exert an inhibitory effect on tumor growth. SFAs such as palmitic acid and stearic acid show little or no tumor promoting effect, and the action of oleic acid, a MUFA, is inconclusive. In addition to regulation of abnormal cell growth seen in cancers, fatty acids also control cell loss seen in degenerative eye diseases, such as degeneration of lens material in cataract and degeneration of photoreceptor cells in retinitis pigmentosa. Experiments suggest that n-6 PUFAs cause deleterious effects, while n-3 PUFAs result in beneficial effects on the lens and retina. In particular, docosahexaenoic acid is known to be effective in rescuing photoreceptor cells from damage. Thus, understanding the function of each fatty acid is likely to be important for making progress in treating these and other diseases.

[R.B.]

To correlate breast cancer outcomes with Omega 3: tissue status you arguably need to look at breast fat at the time of biopsy.

This trial suggests central adipose tissue is not a good marker. Dietary modulation of omega-3/omega-6 polyunsaturated fatty acid ratios in patients with breast cancer. (below)

Adipose buttock tissue saves fats differently again and tends to accumulate more Omega 3 and 6, and significant changes are seen in 3 months. http://www.ncbi.nlm.nih.gov/pubmed/11489728

Modulation of omega-3/omega-6 polyunsaturated ratios with dietary fish oils in men with prostate cancer.

For me this throws into question Omega 3:6 trials on breast cancer looking a buttock fat after the event. http://jnci.oxfordjournals.org/cgi/reprint/85/10/785

Fatty Acid Composition of the Subcutaneous
Adipose Tissue and Risk of Proliferative
Benign Breast Disease and Breast Cancer

Breasts are designed to make milk so probably have fat accumulation and conversion rules all of their own, which might make them more susceptible to fat imbalances (more reading required when I have time).


http://grande.nal.usda.gov/ibids/ind...s&therow=81227

Dietary modulation of omega-3/omega-6 polyunsaturated fatty acid ratios in patients with breast cancer.

BACKGROUND: Polyunsaturated fatty acids of the omega-6 (omega-6) class, as found in corn and safflower oils, can act as precursors for intermediates involved in the growth of mammary tumors when fed to animals, whereas polyunsaturated fatty acids of the omega-3 (omega-3) class, as found in fish oil, can inhibit these effects. The effects of dietary intervention on the ratios of these fatty acids in breast and other adipose tissues have not previously been prospectively studied. PURPOSE: The present investigation was conducted to study the impact on the ratio of omega-3 and omega-6 polyunsaturated fatty acid in plasma and in adipose tissue of the breast and buttocks when women with breast cancer consume a low-fat diet and fish oil supplements. METHODS: Twenty-five women with high-risk localized breast cancer were enrolled in a dietary intervention program that required them to eat a low-fat diet and take a daily fish oil supplement throughout a 3-month period. Breast and gluteal fat biopsy specimens were obtained from each woman before and after dietary intervention. The fatty acid compositions of specimens of plasma, breast fat, and gluteal fat were determined by gas-liquid chromatography. Statistical analysis involved use of a two-sided paired t test. RESULTS: After dietary intervention, a reduction in the level of total omega-6 polyunsaturated fatty acids in the plasma was observed (P less than .0003); moreover, total omega-3 polyunsaturated fatty acids increased approximately three-fold (P less than .0001) and the omega-3/omega-6 polyunsaturated fatty acids ratio increased approximately fourfold (i.e., mean values increased from 0.09 to 0.41; P = .0001). An increase in total omega-3 polyunsaturated fatty acids in breast adipose tissue was observed following dietary intervention (P = .04); the omega-3/omega-6 polyunsaturated fatty acid ratio increased from a mean value of 0.05 to 0.07 (P = .0001). An increase in total omega-3 polyunsaturated fatty acids was observed in gluteal adipose tissue following the intervention (P = .05); however, the ratio of omega-3 to omega-6 polyunsaturated fatty acids (mean ratio values of 0.036-0.045; P = .06) was unchanged. CONCLUSION: Short-term dietary intervention can lead to statistically significant increases in omega-3/omega-6 polyunsaturated fatty acid ratios in plasma and breast adipose tissue. Breast adipose tissue changed more rapidly than gluteal adipose tissue in response to the dietary modification tested in this study. Therefore, gluteal adipose tissue may not be a useful surrogate to study the effect of diet on breast adipose tissue.

[R.B.]

Long-chain n-3-to-n-6 polyunsaturated fatty acid ratios in breast adipose tissue from women with and without breast cancer.
Bagga D, Anders KH, Wang HJ, Glaspy JA.

Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095, USA.

Animal studies suggest that dietary polyunsaturated fatty acids (PUFAs) of the n-6 class, found in corn and safflower oils, may be precursors of intermediates involved in the development of mammary tumors, whereas long-chain (LC) n-3 PUFAs, found in fish oil, can inhibit these effects. This case-control study was designed to examine the relationship between the PUFA composition of breast adipose tissue and the risk of breast cancer. Using fatty acid levels in breast adipose tissue as a biomarker of past qualitative dietary intake of fatty acids, we examined the hypothesis that breast cancer risk is negatively associated with specific LC n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid) and positively associated with n-6 PUFAs (linoleic acid and arachidonic acid). Breast adipose tissue was collected from 73 breast cancer patients and 74 controls with macromastia. The fatty acid levels were determined by gas-liquid chromatography. A logistic regression model was used to obtain odds ratio estimates while adjusting for age. The age-adjusted n-6 PUFA (linoleic acid and arachidonic acid) content was significantly higher in cases than in controls (P = 0.02). There was a trend in the age-adjusted data suggesting that, at a given level of n-6 PUFA, LC n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid) may have a protective effect (P = 0.06). A similar inverse relationship was observed with LC n-3-to-n-6 ratio when the data were adjusted for age (P = 0.09). We conclude that total n-6 PUFAs may be contributing to the high risk of breast cancer in the United States and that LC n-3 PUFAs, derived from fish oils, may have a protective effect.

[R.B.]

N-3 and N-6 fatty acids in breast adipose tissue and relative risk of breast cancer in a case-control study in Tours, France.
Maillard V, Bougnoux P, Ferrari P, Jourdan ML, Pinault M, Lavillonnière F, Body G, Le Floch O, Chajès V.

Laboratoire de Biologie des Tumeurs, Clinique d'Oncologie-Radiothérapie, Service de Gynécologie-Obstétrique, E.A. 2103, Unité de Recherche Associée Université-INRA, CHU, Tours, France.

Experimental studies have indicated that n-3 fatty acids, including alpha-linolenic acid (18:3 n-3) and long-chain n-3 polyunsaturated fatty acids inhibit mammary tumor growth and metastasis. Earlier epidemiological studies have given inconclusive results about a potential protective effect of dietary n-3 polyunsaturated fatty acids on breast cancer risk, possibly because of methodological issues inherent to nutritional epidemiology. To evaluate the hypothesis that n-3 fatty acids protect against breast cancer, we examined the fatty acid composition in adipose tissue from 241 patients with invasive, nonmetastatic breast carcinoma and from 88 patients with benign breast disease, in a case-control study in Tours, central France. Fatty acid composition in breast adipose tissue was used as a qualitative biomarker of past dietary intake of fatty acids. Biopsies of adipose tissue were obtained at the time of surgery. Individual fatty acids were measured as a percentage of total fatty acids, using capillary gas chromatography. Unconditional logistic regression modeling was used to obtain odds ratio estimates while adjusting for age, height, menopausal status and body mass index. We found inverse associations between breast cancer-risk and n-3 fatty acid levels in breast adipose tissue. Women in the highest tertile of alpha-linolenic acid (18:3 n-3) had an odds ratio of 0.39 (95% confidence intervals [CI] = 0.19-0.78) compared to women in the lowest tertile (trend p = 0.01). In a similar way, women in the highest tertile of docosahexaenoic acid (22:6 n-3) had an odds ratio of 0.31 (95% CI = 0.13-0.75) compared to women in the lowest tertile (trend p = 0.016). Women in the highest tertile of the long-chain n-3/total n-6 ratio had an odds ratio of 0.33 (95% confidence interval = 0.17-0.66) compared to women in the lowest tertile (trend p = 0.0002). In conclusion, our data based on fatty acids levels in breast adipose tissue suggest a protective effect of n-3 fatty acids on breast cancer risk and support the hypothesis that the balance between n-3 and n-6 fatty acids plays a role in breast cancer. Copyright 2001 Wiley-Liss, Inc.

[R.B.]

Not as certain as looking at breast tissue but interesting none the less.

A prospective study of association of monounsaturated fat and other types of fat with risk of breast cancer.
Wolk A, Bergström R, Hunter D, Willett W, Ljung H, Holmberg L, Bergkvist L, Bruce A, Adami HO.

Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden.

BACKGROUND: Animal studies suggest that monounsaturated and polyunsaturated fat may have opposite effects on the risk of breast cancer. METHODS: We performed a population-based prospective cohort study, including 61,471 women aged 40 to 76 years from 2 counties in central Sweden who did not have any previous diagnosis of cancer; 674 cases of invasive breast cancer occurred during an average follow-up of 4.2 years. All subjects answered a validated 67-item food frequency questionnaire at baseline. Cox proportional hazards models were used to obtain adjusted rate ratio (RR) estimates with 95% confidence intervals (CIs). RESULTS: After mutual adjustment of different types of fat, an inverse association with monounsaturated fat and a positive association with polyunsaturated fat were found. The RR for each 10-g increment in daily intake of monounsaturated fat was 0.45 (95% CI, 0.22-0.95), whereas the RR for a 5-g increment of polyunsaturated fat was 1.69 (95% CI, 1.02-2.78); the increments correspond to approximately 2 SDs of intake in the population. Comparing the highest quartile of intake with the lowest, we found an RR of 0.8 (95% CI, 0.5-1.2) for monounsaturated fat and 1.2 (95% CI, 0.9-1.6) for polyunsaturated fat. Saturated fat was not associated with the risk of breast cancer. CONCLUSIONS: Our results indicate that various types of fat may have specific opposite effects on the risk of breast cancer that closely resemble the corresponding effects in experimental animals. Research investigations and health policy considerations should take into account the emerging evidence that monounsaturated fat might be protective for risk of breast cancer.

[R.B.]

Off the track of Omega 3s and 6s but interesting that increased protein decreased risk significantly. It would be interesting to see the whole paper to get a better idea what was going on in their diet, what sort of protein, how it related to fats carbs Omega 3 and 6s etc.


Dietary factors and survival from breast cancer.
Author: Rohan, T E : Hiller, J E : McMichael, A J
Citation: Nutr-Cancer. 1993; 20(2): 167-77

The association between self-reported intake of various dietary factors at diagnosis and survival from breast cancer was studied in a population-based cohort of breast cancer patients in Adelaide, South Australia. These patients had been recruited between 1982 and 1984 into a case-control study of diet and incident breast cancer. Of the 451 patients recruited originally, 412 were followed for a median interval of 5.5 years. There were decreases in the risk of death from breast cancer ranging from 25 to 40% at all levels of energy and protein intake above the baseline, whereas for fat intake there was a 40% increase in risk at the uppermost quintile level. There was also some reduction in risk at the upper levels of intake of beta-carotene and vitamin C. However, there were no dose-dependent variations in risk of death by level of intake for any of the dietary factors studied, and most of the variation in risk that was observed was relatively insubstantial.

[R.B.]

Melatonin is an very powerful antioxidant and is an Omega 6 inflammatory chemical blocker.

Found as usual whilst looking for something else.(-:

Melatonin production in general terms falls post menopause. Obesity and poor sleep are associated with lower melatonin.

Application of melatonin improved mood and reduced depression in post menopausal women.

Depressed melatonin has been noted in some cancers.

Melatonin
By S. R. Pandi-Perumal, Daniel P. Cardinali
http://books.google.com/books?id=m_6...efox-a#PPR7,M1



RB



http://cancerres.aacrjournals.org/cg...ct/65/23/11174

Melatonin-Depleted Blood from Premenopausal Women Exposed to Light at Night Stimulates Growth of Human Breast Cancer Xenografts in Nude Rats


The increased breast cancer risk in female night shift workers has been postulated to result from the suppression of pineal melatonin production by exposure to light at night. Exposure of rats bearing rat hepatomas or human breast cancer xenografts to increasing intensities of white fluorescent light during each 12-hour dark phase (0-345 µW/cm2) resulted in a dose-dependent suppression of nocturnal melatonin blood levels and a stimulation of tumor growth and linoleic acid uptake/metabolism to the mitogenic molecule 13-hydroxyoctadecadienoic acid. Venous blood samples were collected from healthy, premenopausal female volunteers during either the daytime, nighttime, or nighttime following 90 minutes of ocular bright, white fluorescent light exposure at 580 µW/cm2 (i.e., 2,800 lx). Compared with tumors perfused with daytime-collected melatonin-deficient blood, human breast cancer xenografts and rat hepatomas perfused in situ, with nocturnal, physiologically melatonin-rich blood collected during the night, exhibited markedly suppressed proliferative activity and linoleic acid uptake/metabolism. Tumors perfused with melatonin-deficient blood collected following ocular exposure to light at night exhibited the daytime pattern of high tumor proliferative activity. These results are the first to show that the tumor growth response to exposure to light during darkness is intensity dependent and that the human nocturnal, circadian melatonin signal not only inhibits human breast cancer growth but that this effect is extinguished by short-term ocular exposure to bright, white light at night. These mechanistic studies are the first to provide a rational biological explanation for the increased breast cancer risk in female night shift workers.

David E. Blask1, George C. Brainard2, Robert T. Dauchy1, John P. Hanifin2, Leslie K. Davidson1, Jean A. Krause1, Leonard A. Sauer1, Moises A. Rivera-Bermudez3, Margarita L. Dubocovich3, Samar A. Jasser2, Darin T. Lynch1, Mark D. Rollag4 and Frederick Zalatan1

1 Laboratory of Chrono-Neuroendocrine Oncology, Bassett Research Institute, The Mary Imogene Bassett Hospital, Cooperstown, New York; 2 Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania; 3 Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and 4 Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland

Requests for reprints: David E. Blask, Laboratory of Chrono-Neuroendocrine Oncology, Bassett Research Institute, The Mary Imogene Bassett Hospital, Cooperstown, NY 13326. Phone: 607-547-3677;