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Most survivors of sexual assault who disclose their experience do so within their social network. Prior research on disclosure among individuals who experience sexual trauma has mainly focused on childhood sexual abuse, college-aged women, or disclosure to formal sources of support (e.g., treatment providers). There is limited research on disclosure among veteran survivors of military sexual assault (MSA). The current qualitative study aimed to explore the disclosure experiences of treatment-seeking survivors of MSA. Participants were 17 veterans (n = 13 women, n = 4 men), aged 33-65 years, who reported experiencing MSA. During semistructured interviews, participants were asked about their experiences disclosing MSA to informal support persons (e.g., family members, partners, friends). A narrative thematic analysis identified 11 themes that emerged throughout different aspects of the disclosure, including (a) preparation and reason for disclosure (reactive or spontaneous disclosures, disclosure as an explanation/obligation), (b) expectations about the disclosure experience (no expectations, negative expectations grounded in socialized beliefs, positive expectations based on specific relationships, mismatch between experience and expectation), (c) the actual disclosure experience (negative experiences of personalization, supportive responses, share shame), and (d) military context (disclosing to another member of the military, reporting dynamics). Additional subthemes were nested within these categories. The findings indicated common experiences across participants, particularly regarding disclosure rationale. Key differences were largely influenced by contextual factors (e.g., response of the disclosure recipient). These findings hold implications for clinicians working with survivors of MSA who are preparing for and coping with the consequences of disclosure., (© 2022 International Society for Traumatic Stress Studies.)

Background: The experience of Military Sexual Trauma (MST) in the form of sexual assault and sexual harassment is common during service in the U.S. Armed Forces and often leads to adverse health outcomes including posttraumatic stress disorder (PTSD). Improving treatment of MST-related PTSD across settings is important to optimize treatment for survivors. The delivery of Cognitive Processing Therapy (CPT) in an intensive treatment program (ITP) shows promise for rapid reduction of PTSD symptoms for veterans and service members (veterans). However, a recent outcome study suggested that this modality is significantly less effective in reducing symptoms of PTSD for survivors of MST compared to veterans recovering from combat trauma., Methods: -The current study examines the utility of modifications made to a CPT-based ITP designed to treat PTSD secondary to MST in a mixedgender sample (N = 285). Treatment modifications included the introduction of skills-based groups in emotion regulation and interpersonal domains. Individual skills-consultation sessions were also offered to participants on an as-needed basis. Further, training was provided to both clinical and non-clinical staff to increase understanding of the unique experiences and needs of MST survivors., Results: Program changes proved beneficial, resulting in PTSD treatment outcomes that were comparable for survivors of MST and combat traumas., Limitations: Further research is needed to determine which of these specific program changes were most impactful in improving symptom outcomes., Conclusions: Our findings suggest that short-term, intensive PTSD treatment for MST survivors may be improved by integrating present-focused, skills-based therapies and staff sensitivity training., Competing Interests: Declaration of Competing Interest Alyson Zalta is supported by a career development award from the National Institute of Mental Health (K23 MH103394). Philip Held is supported by a career development from the National Center for Advancing Translational Sciences of the National Institutes of Health (5KL2TR002387-03), and receives grant support from Wounded Warrior Project, the Boeing Company, and the Robert R. McCormick Foundation. Mark Pollack receives support from the Wounded Warrior Project and research funding from National Institute of Health and Janssen Pharmaceuticals;he provides consultation to Aptinyx, Clintara, and Palo Alto Health Sciences; he has equity in Argus, Doyen Medical, Mensante Corporation, Mindsite, and Targia Pharmaceuticals; he receives royalties from SIGH-A, SAFER interviews. All other authors declare that they have no competing interests., (Copyright © 2020. Published by Elsevier B.V.)

Background: Unique aspects of military sexual trauma (MST) may result in specific maladaptive cognitions among survivors. Understanding which posttraumatic cognitions are particularly strong among MST survivors could help clinicians target and improve treatment for these individuals. This study explored the impact of experiencing MST on posttraumatic cognitions among veterans with posttraumatic stress disorder (PTSD)., Methods: Veterans enrolled in an Intensive Outpatient Program for PTSD (N = 226) were assessed for MST, PTSD severity, depression severity, and posttraumatic cognitions as part of a standard clinical intake. Multivariate analyses examined differences in posttraumatic cognitions between veterans who did and did not experience MST., Results: MST survivors (n = 88) endorsed significantly stronger posttraumatic cognitions related to self-blame compared to non-MST counterparts (n = 138), even when accounting for current symptom severity. Specifically, MST predicted the following cognitions: "The event happened to me because of the sort of person I am," "Somebody else would have stopped the event from happening," "Somebody else would not have gotten into this situation," and "There is something about me that made the event happen," after controlling for severity of PTSD and depression., Limitations: Study population was a treatment-seeking sample of veterans diagnosed with PTSD from a non-VA clinic. Veterans in MST group endorsed either sexual harassment, sexual assault, or both. Sample size of males who endorsed MST (n = 21) may be too small to generalize to all males., Conclusions: Beliefs related to self-blame may be important treatment targets for MST survivors., (Copyright © 2018. Published by Elsevier B.V.)

This article discusses the scope and impact of military sexual trauma (MST) in the U.S. Armed Forces. The authors explore aspects of the military setting that may make recovery from this form of sexual violence particularly difficult. Risk factors for MST as well as associated mental, physical, sexual, and relational health consequences are reviewed. The authors also introduce clinical issues unique to male and lesbian, gay, bisexual, and transgender (LGBT) survivors. Finally, first-line psychotherapies and pharmacotherapies for subsequent mental health difficulties are reviewed, as are strategies for reducing barriers to health care for this population., (Copyright © 2017 by the American Psychiatric Association.)

Background: We have established a new cohort study, the Canadian Study of Diet, Lifestyle, and Health, to investigate the relationship between diet, lifestyle factors, molecular markers, and cancer incidence in Canada., Methods: The cohort was established predominantly by recruiting alumni from the Universities of Alberta, Toronto, and Western Ontario between 1995 and 1998, but also includes a small contingent recruited mostly in 1992 through the Canadian Cancer Society. Participants completed baseline lifestyle and food frequency questionnaires, measured waist and hip circumferences, and provided hair and toenail specimens., Results: Seventy-three thousand nine hundred and nine individuals (34,291 males and 39,618 females) were recruited, with representation from all Canadian provinces and territories; 97% provided biological specimens. The mean (S.D.) ages of the male and female participants at recruitment were 51.6 (15.6) and 46.1 (15.2) years, respectively. Data from a random sample of the study subjects at baseline show that approximately one-half of the males and one-third of the females were overweight (BMI>or=25kg/m(2)), and approximately one-quarter of all participants reported that they walked at least 4h/week. Mean (S.D.) daily caloric intake was 2341 (697)kcal for males and 2091 (612)kcal for females., Conclusions: Given the rich repository of questionnaire and biological data, and an average follow-up time for cohort members of 10.4 years, the study is poised to make a major Canadian contribution towards understanding the roles of diet, lifestyle factors, and molecular markers in influencing cancer risk.

Iron deficiency may lead to anemia and may result in compromised endurance exercise performance. Iron deficiency has also been reported to adversely affect the immune system and has been associated with attenuation of natural killer cell (NK) activity. This study was conducted to examine the relationship between iron status and NK activity in highly conditioned female athletes. Ten collegiate female swimmers (SWM) and 9 inactive females (SED) participated in this investigation. Resting blood samples were obtained and analyzed for serum iron and ferritin. NK activity (% lysis) was determined using a whole blood method (51Cr release assay). No significant relationship was found between iron and NK activity (r = 0.55, p =.09), nor between serum ferritin and NK activity (r = 0.33, p =.35) for SWM. ANOVA revealed significantly greater NK activity for SWM (51.63 +/- 15.79%) versus SED (30.34 +/- 13.67%). Serum ferritin levels were not significantly different between SWM (20.38 +/- 8.62 hg á ml-1) and SED (16.79 +/- 10.53 hg á ml-1), nor were iron values different between groups (16.54 +/- 2. 17 mmol á L-1 SWM; 11.92 +/- 2.61 mmol á L-1 SED). A significant relationship between iron status and resting immune function could not be established. Exercise training may affect NK activity; however, the influence of iron status on immune function requires further evaluation.

The activation of LDL receptors was described recently in a human hepatoma cell line (Hep G2) exposed both to alpha + alpha' subunits from 7S soy globulin and to Croksoy(R)70, a commercial isoflavone-poor soy concentrate. To assess the final identity of the peptide(s) putatively responsible for the biochemical effect, experiments were performed in Hep G2 cells, exposed either to synthetic peptides corresponding to specific sequences of 7S soy globulin or to peptides from the in vitro digestion of Croksoy(R)70. Moreover, the ability of the whole 7S globulin, its subunits and whole Croksoy(R)70 to interfere in the apolipoprotein B (apo B) secretion in the medium as well as in sterol biosynthesis was evaluated in the same model. Increased (125)I-LDL uptake and degradation vs. controls were shown after Hep G2 incubation with a synthetic peptide (10(-)(4) mol/L, MW 2271 Da) corresponding to positions 127-150 of the 7S globulin. Cells exposed to Croksoy(R)70 enzyme digestion products showed a more marked up-regulation of LDL receptors vs. controls, compared with vs. Hep G2 cells incubated with undigested Croksoy(R)70. Among soy-derived products, only the 7S globulin inhibited apo B secretion and (14)C-acetate incorporation when tested in Hep G2 cells at a concentration of 1.0 g/L. These findings support the hypothesis that if one or more peptides can reach the liver after intestinal digestion, they may elicit a cholesterol-lowering effect. Moreover, the protein moiety, devoid of isoflavone components, is likely to be responsible for this major biochemical effect of soy protein.

Previous experiments from our laboratory showed that in rabbits fed an amino acid diet corresponding to 30% casein, enrichment of the diet with L-lysine and L-methionine caused a marked increase in serum total and LDL cholesterol levels as well as a substantial body weight loss. Both effects were partially prevented by supplementation with L-arginine. The present studies were designed to extend this earlier observation by assessing the role of different dietary amino acids in modulation of cholesterolemic responses and body weights. In the first experiment, the original lysine and methionine-enriched diet was supplemented with glycine in an attempt to modify methionine metabolism, and thus to reduce body weight loss. In addition, the mechanism of action of lysine and methionine was investigated by quantitation of major liver phospholipids. The results showed that glycine addition had no effect on weight loss or hypercholesterolemia, nor did it alter plasma levels of homocyst(e)ine, an intermediate in methionine metabolism. However, enrichment of the diet with lysine and methionine (with or without glycine) significantly increased liver levels of phosphatidylcholine and the ratio of phosphatidylcholine to phosphatidylethanolamine, apparently through increased enzymatic conversion. These changes were consistent with higher lipoprotein levels and thus may explain the hypercholesterolemia. A second experiment showed that similar effects on body weights and serum cholesterol could be obtained by adding lysine and methionine to a diet containing amino acids equivalent to only 15% casein, or 15% intact casein. This approach is more physiologic and also reduces the expense of experiments designed to study the effects of lysine and methionine in more detail.

Our previous studies showed that replacing the drinking water of rabbits fed a casein-containing diet with either orange juice or grapefruit juice reduced serum low density lipoprotein cholesterol and hepatic cholesteryl ester concentrations. To determine whether the changes observed in rabbits were due to flavonoids present in the juices acting directly on the liver, the effects of hesperetin and naringenin on net apolipoprotein B (apoB) secretion by HepG2 cells were investigated. These flavanones dose-dependently reduced net apoB secretion by up to 81% after a 24 h incubation, while doses of 60 micrograms/mL reduced net apoB secretion by 50% after 4 h. Coincubation with the proteasome inhibitor, MG-132, did not alter the ability of the flavonoids to reduce net apoB secretion over 4 h, suggesting that the flavonoid-induced changes in apoB metabolism were not due to a direct increase in proteasomal activity. However, the flavonoids were unable to reduce net apoB secretion after 4 h in the presence of oleate, suggesting that these compounds may interfere with the availability of neutral lipids for lipoprotein assembly. Furthermore, our 14C-acetate-labeling studies showed a 50% reduction in cholesteryl ester synthesis in the presence of either flavonoid, which could account for the reduction in net apoB secretion caused by incubation with these compounds. These in vitro studies suggest that hesperetin and naringenin may, in part, reduce net apoB secretion by HepG2 cells by inhibiting cholesteryl ester synthesis and that these compounds are good candidates for further in vivo studies to determine whether they are responsible for the cholesterol-lowering properties of dietary citrus juices.

It will be apparent from this review that dietary fat can exert both specific and non-specific effects on carcinogenesis, at least in experimental animals. The non-specific effects appear to be related primarily to effects of dietary fat on energy balance. Although a positive energy balance can be achieved on a high-carbohydrate low-fat diet, it is much more likely to occur on a high-fat diet because of the high energy density of fat [101] and the fact that dietary fat is less capable of imparting a sense of satiety [102]. A continuing state of positive energy balance leads to obesity which has been associated with increased risk of cancer at a number of sites, including endometrium [103-106], postmenopausal breast cancer [107-113], renal cancer [114,115] and possibly cancers of the colorectum [116-122], pancreas [103,123] and prostate [124]. Whereas the non-specific effects of dietary fat appear to be deleterious for cancer, the specific effects in some cases can be beneficial. Examples are long-chain n-3 polyunsaturated fatty acids. CLA and tocotrienols. It is still too early to predict whether these may be of value in the prevention and/or treatment of human cancer but they seem worthy of further investigation. Knowledge of their mechanism of action may suggest novel approaches to the cancer problem and, as in the case of vitamins A and D, it may be possible to find analogues with more potent anti-cancer activity.

These experiments were conducted to see whether the hypercholesterolemia produced by a diet enriched in lysine (Lys) and methionine (Met) can be reproduced by feeding these amino acids separately, and whether dietary arginine (Arg) counteracts their hypercholesterolemic effects. Another aim was to investigate the mechanisms involved in modulations of serum cholesterol levels by these amino acids. The results of this study, which were in agreement with the results of earlier experiments in our laboratory, showed that feeding a low-fat, cholesterol-free, semipurified amino acid diet enriched with Lys + Met to rabbits caused a marked increase in serum total and low density lipoprotein cholesterol and apolipoprotein B levels, whereas a similar diet enriched in essential ketogenic amino acids (EketoAA) resulted in a more moderate increase in these parameters. Supplementing the diet with either Lys or Met alone was also less effective in inducing hypercholesterolemia than increasing levels of both amino acids. Dietary Arg partially counteracted the hypercholesterolemic effect of Lys + Met but not that of the EketoAA or of Lys and Met fed separately. The growth performance of rabbits fed the Lys + Met diet was inferior to that of those fed the other diets. Liver total phospholipid levels and the ratio of phosphatidylcholine to phosphatidylethanolamine were higher in rabbits fed the Lys + Met-enriched diet than in those animals fed a diet in which Arg was supplemented. In conclusion, our results indicate that high levels of both Lys and Met are needed to cause a maximum elevation of serum cholesterol and that the moderately antihypercholesterolemic effect of Arg is seen only when both amino acids are supplemented. They also suggest that these essential amino acids may affect cholesterol metabolism partly through alteration of liver phospholipids.

In conclusion, obesity has been associated with increased risk for a number of different types of cancer. The evidence has been most consistent for endometrial cancer, breast cancer in postmenopausal women, and renal cell cancer. More variable results have been reported for colorectal, prostate and pancreatic cancer. Possible mechanisms by which obesity may influence cancer risk include alteration in hormonal patterns, including sex hormones and insulin, and factors such as the distribution of body fat and changes in adiposity at different ages. The increasing prevalence of obesity in many parts of the world emphasizes the importance of learning more about the relationship between obesity and cancer and the mechanisms involved in their interaction.

Previous results suggested that changes in the activity of nitric oxide (NO) can influence metabolism of apo B-containing lipoproteins. Therefore, we studied effects of exogenous NO donors and physiological NO precursors on metabolism of these lipoproteins. In rabbits, addition of 0.03% sodium nitroprusside (NaNP) to a semipurified, cholesterol-free, casein diet counteracted the elevation of LDL cholesterol induced by this diet but did not alter liver lipids after 4 weeks of feeding. In HepG2 cells, addition of nontoxic concentrations of another NO donor, S-nitroso-N-acetylpenicillamine (SNAP) to culture medium caused a dose-dependent reduction of medium apo B after 24 h. At the concentration 0.5 mM, SNAP significantly decreased medium apo B by 50% without altering total synthesis and secretion of proteins and without altering rates of cellular sterol synthesis. In cells incubated with L-arginine, reduction of medium apo B was not associated with increased NO production whereas in those exposed to N-OH-Arg medium apo B levels were not altered. We concluded that synthetic NO donors can reduce hypercholesterolemia by affecting apo B metabolism directly in the liver, via the sterol-independent mechanism., (Copyright 1998 Elsevier Science B.V. All rights reserved.)

Chronic fatigue syndrome, which can occur after acute infection and last for years, is characterized by severe and persistent fatigue. Others have reported decreases in mouse running activity following infection and have suggested this may provide an animal model for studying chronic fatigue. Voluntary running is a highly motivated activity in mice, which will often run 5-7 mi/day in our laboratory. Following 2 weeks of acclimation to running wheels with food and water available ad lib, female BALB/c mice received 0.2-mL tail vein injections of killed Brucella abortus (BA) or saline vehicle. Subsequently the effects on voluntary running and grooming behavior were determined. Injection of BA caused an immediate large decrease in running and a lack of grooming. Vehicle injections produced no changes in behavior. After the first several days of reduced running behavior, levels of running and grooming slowly returned back to normal over the next 2-4 weeks, with substantial individual differences in the rate of recovery. The pattern of running during recovery was intriguing in that BA mice first ran at normal levels just after the lights went out, but they stopped after only 1-2 h. As recovery proceeded, they gradually increased the duration of the running bout during the night. Because this model uses voluntary exertion and the ability to run for longer periods of time characterizes recovery, the model may be a good one for studying the biologic underpinnings of chronic fatigue.

Double strength orange juice given to the rats in place of drinking water inhibited mammary tumorigenesis induced in female Sprague-Dawley rats by DMBA more effectively than double strength grapefruit juice. This may mean that hesperetin retains its effectiveness in vivo better than naringenin, since the flavonoids are present in the juices at similar levels. It is also possible that orange juice contains other compounds that have anti-cancer activity and that may act synergistically with hesperetin. Citrus flavonoids are effective inhibitors of both estrogen receptor-negative MDA-MB-435 and estrogen receptor-positive MCF-7 human breast cancer cell in vitro. Furthermore, 1:1 combinations of flavonoids with tocotrienols and/or tamoxifen inhibit proliferation of the cells more effectively than the individual compounds. This synergism may be due to the fact that the compounds are exerting their inhibitory effects by different mechanisms.

Objectives: To determine whether, in individuals with hypercholesterolemia, substituting dietary soybean products for cows' milk products improves the plasma lipid profile and whether any change in the profile is due partially to soy oil., Design: Randomized 3-treatment crossover trial., Setting: Family practice clinics and an outpatient clinic in London, Ont., Participants: Seventeen healthy men and 17 healthy women with elevated plasma levels of total and low-density-lipoprotein (LDL) cholesterol and with normal plasma levels of triglycerides., Interventions: Participants incorporated into their normal diet either 2% cows' milk products, soybean products or a combination of skim milk products and soy oil, each over period of 4 weeks, with 22-week wash-out periods. Plasma lipid profile, blood pressure and body weight were assessed after each dietary and wash-out period., Outcome Measures: Plasma levels of total and lipoprotein cholesterol, plasma levels of triglycerides, apolipoprotein B and A1 levels, blood pressure and plasma lipid peroxidation., Results: The change in diet had no effect on body mass index, levels of apolipoproteins B and A1 and most plasma lipids. During the soybean period, the subjects' mean level of high-density-lipoprotein (HDL) cholesterol increased 9% (p < 0.04) and their mean LDL/HDL cholesterol ratio decreased 14% (p < 0.007). These effects were less pronounced during the skim milk/soy oil period. In the 24 subjects with the highest initial LDL cholesterol level and LDL/HDL cholesterol ratio, the mean LDL cholesterol level decreased 11% after the soybean period. In all subjects, changes in the LDL/HDL cholesterol ratio induced by a soybean diet were negatively correlated with the initial LDL/HDL cholesterol ratio and positively correlated with the initial HDL cholesterol level., Conclusions: In people with hypercholesterolemia, the plasma lipid profile improved after treatment with a soybean-product diet, and this improvement was partially due to soy oil. The degree of responsiveness was associated with initial risk factors for coronary artery disease.

Palm oil, unlike many other dietary oils, does not increase the yield of chemically-induced mammary tumors in rats when fed at high levels in the diet. This difference appears to be due to the vitamin E fraction of palm oil, which is rich in tocotrienols, since palm oil stripped of this fraction does increase tumor yields. Experiments in our laboratory have shown that tocotrienols inhibit proliferation and growth of both MDA-MB-435 and MCF-7 cells in culture much more effectively than a-tocopherol. In addition, it was found that combinations of tocotrienols with Tamoxifen, a drug widely used for treatment of breast cancer, inhibit these cells more effectively than either tocotrienols or Tamoxifen alone. The present studies have now shown synergistic effects between tocotrienols and a number of other flavonoids from various plant sources, including citrus fruits, in the inhibition of both MDA-MB-435 and MCF-7 cells (IC50s 0.05-25 and 0.02-5 μg/mL respectively). In the MCF-7 cells, 1:1:1 combinations of tocotrienols, flavonoids and Tamoxifen were even more effective, with the best combination being d-tocotrienol, hesperetin and Tamoxifen (IC50 0.0005 μg/mL). These results suggest that diets containing palm oil may reduce the risk of breast cancer, particularly when eaten with other plant foods containing flavonoids, and may also enhance the effectiveness of Tamoxifen for treatment of breast cancer.

Tocotrienols are a form of vitamin E, having an unsaturated isoprenoid side-chain rather than the saturated side-chain of tocopherols. The tocotrienol-rich fraction (TRF) from palm oil contains alpha-tocopherol and a mixture of alpha-, gamma- and delta-tocotrienols. Earlier studies have shown that tocotrienols display anticancer activity. We previously reported that TRF, alpha-, gamma- and delta-tocotrienols inhibited proliferation of estrogen receptor-negative MDA-MB-435 human breast cancer cells with 50% inhibitory concentrations (IC50) of 180, 90, 30 and 90 microg/mL, respectively, whereas alpha-tocopherol had no effect at concentrations up to 500 microg/mL. Further experiments with estrogen receptor-positive MCF-7 cells showed that tocotrienols also inhibited their proliferation, as measured by [3H] thymidine incorporation. The IC50s for TRF, alpha-tocopherol, alpha-, gamma- and delta-tocotrienols were 4, 125, 6, 2 and 2 microg/mL, respectively. Tamoxifen, a widely used synthetic antiestrogen inhibits the growth of MCF-7 cells with an IC50 of 0.04 microg/mL. We tested 1:1 combinations of TRF, alpha-tocopherol and the individual tocotrienols with tamoxifen in both cell lines. In the MDA-MB-435 cells, all of the combinations were found to be synergistic. In the MCF-7 cells, only 1:1 combinations of gamma- or delta-tocotrienol with tamoxifen showed a synergistic inhibitory effect on the proliferative rate and growth of the cells. The inhibition by tocotrienols was not overcome by addition of excess estradiol to the medium. These results suggest that tocotrienols are effective inhibitors of both estrogen receptor-negative and -positive cells and that combinations with tamoxifen should be considered as a possible improvement in breast cancer therapy.

Studies on experimental animals have generally supported a role for dietary fat in mammary cancer, but epidemiological studies have given conflicting results. The effects of dietary fat in animals may be due to its high energy density or to other specific effects, and may have relevance for human breast cancer.

The flavonoids are a group of naturally-occurring, low molecular weight compounds that are widespread in plants. Representatives of several different classes of flavonoids were tested for their effects on the proliferation of an estrogen receptor-positive human breast cancer cell line, MCF-7. The IC50S (concentration at which cell proliferation was inhibited by 50%), based on [3H]thymidine incorporation, ranged from 4.2 to 18.0 micrograms/mL. The cells were viable at these concentrations. The possibility that flavonoids may block cell proliferation by binding to the estrogen receptor was explored. The cells were depleted of endogenous steroids and incubated with individual flavonoids at their IC50 concentration. Half of the cells were exposed to an excess concentration of 17 beta-estradiol to see if this affected antiproliferation by the flavonoids. Of the flavonoids tested, only the inhibition of cell proliferation by genistein was reversed with the addition of excess, competing estrogen. Baicalein, galangin, hesperetin, naringenin and quercetin apparently exert their antiproliferative activity via some other mechanism.

Two citrus flavonoids, hesperetin and naringenin, found in oranges and grapefruit, respectively, and four noncitrus flavonoids, baicalein, galangin, genistein, and quercetin, were tested singly and in one-to-one combinations for their effects on proliferation and growth of a human breast carcinoma cell line, MDA-MB-435. The concentration at which cell proliferation was inhibited by 50% (IC50), based on incorporation of [3H]thymidine, varied from 5.9 to 140 micrograms/ml for the single flavonoids, with the most potent being baicalein. IC50 values for the one-to-one combinations ranged from 4.7 micrograms/ml (quercetin + hesperetin, quercetin + naringenin) to 22.5 micrograms/ml (naringenin + hesperetin). All the flavonoids showed low cytotoxicity (> 500 micrograms/ml for 50% cell death). Naringenin is present in grapefruit mainly as its glycosylated form, naringin. These compounds, as well as grapefruit and orange juice concentrates, were tested for their ability to inhibit development of mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female Sprague-Dawley rats. Two experiments were conducted in which groups of 21 rats were fed a semipurified diet containing 5% corn oil and were given a 5-mg dose of DMBA intragastrically at approximately 50 days of age while in diestrus. One week later, individual groups were given double-strength grapefruit juice or orange juice or fed naringin or naringenin at levels comparable to that provided by the grapefruit juice; in the second experiment, the rats were fed a semipurified diet containing 20% corn oil at that time. As expected, rats fed the high-fat diet developed more tumors than rats fed the low-fat diet, but in both experiments tumor development was delayed in the groups given orange juice or fed the naringin-supplemented diet compared with the other three groups. Although tumor incidence and tumor burden (grams of tumor/rat) were somewhat variable in the different groups, rats given orange juice had a smaller tumor burden than controls, although they grew better than any of the other groups. These experiments provide evidence of anticancer properties of orange juice and indicate that citrus flavonoids are effective inhibitors of human breast cancer cell proliferation in vitro, especially when paired with quercetin, which is widely distributed in other foods.

The tocotrienol-rich fraction (TRF) of palm oil consists of tocotrienols and some alpha-tocopherol (alpha-T). Tocotrienols are a form of vitamin E having an unsaturated side-chain, rather than the saturated side-chain of the more common tocopherols. Because palm oil has been shown not to promote chemically-induced mammary carcinogenesis, we tested effects of TRF and alpha-T on the proliferation, growth, and plating efficiency (PE) of the MDA-MB-435 estrogen-receptor-negative human breast cancer cells. TRF inhibited the proliferation of these cells with a concentration required to inhibit cell proliferation by 50% of 180 microgram/mL whereas alpha-T had no effect at concentrations up to 1000 microgram/mL as measured by incorporation of [3H]thymidine. The effects of TRF and alpha-T also were tested in longer-term growth experiments, using concentrations of 180 and 500 microgram/mL. We found that TRF inhibited the growth of these cells by 50%, whereas alpha-T did not. Their effect on the ability of these cells to form colonies also was studied, and it was found that TRF inhibited PE, whereas alpha T had no effect. These results suggest that the inhibition is due to the presence of tocotrienols in TRF rather than alpha T.

Animal proteins such as casein are more hypercholesterolemic than soy protein or other plant proteins when fed to rabbits in low-fat, cholesterol-free, semipurified diets. A casein-amino acid mixture produces a hypercholesterolemia similar to that of casein. This appears to be mainly due to lysine and methionine, although other essential amino acids probably contribute to the effect. Arginine appeared to counteract the hypercholesterolemic effects of other essential amino acids. Soy protein gave a lower level of serum cholesterol in rabbits than did a soy protein-amino acid mixture, suggesting the presence of factors in soy protein that counteract the effects of hypercholesterolemic amino acids. Soy protein is also less hypercholesterolemic than casein in other animal species, particularly when the diet contains cholesterol, and substitution of soy protein for animal protein in the diet reduces the concentration of serum cholesterol in humans. This effect is somewhat variable but is generally greater in hypercholesterolemic than in normocholesterolemic subjects. The differing effects of dietary proteins on serum cholesterol concentrations in humans and in rabbits are primarily due to changes in LDL cholesterol, and the hypercholesterolemia produced by dietary casein is associated with down-regulation of hepatic LDL receptors.

The initial endothelial morphological alterations and the development of raised, lipid-containing lesions in rabbit aortas were examined after 1 and 3 months on a casein-enriched, semipurified, cholesterol-free diet. The alterations were compared with those in rabbits fed soy-protein in the place of casein and with age-matched, chow-fed, control animals. Using immunohistochemistry macrophages, T-lymphocytes, and smooth muscle cells were identified in the lesions, and an expression of leukocyte adhesion molecules, VCAM-1, ICAM-1 and, occasionally, E-selectin was seen in sections of the aortas of casein-fed rabbits. The initial alterations in the endothelium appear to include evidence of endothelial injury and white blood cell adhesion. No evidence of extracellular liposome formation was observed. This model of atherogenesis is consistent with endothelial injury being an important component of diet-induced atherogenesis and has similarities to human atherosclerosis.

A number of aliphatic primary amines were tested for their effects on the growth of ras-transformed NIH 3T3 cells (PAP2 cells), as measured by incorporation of tritiated thymidine into DNA. Long-chain, saturated amines (C12 to C18) were growth inhibitory, whereas short-chain amines (C6, C8) were not. Farnesylamine, a branched-chain, unsaturated amine (C15), had an IC50 of 6.9 microM compared to IC50 values of 13.1 to 45.8 microM for straight-chain, saturated amines. Oleylamine, with an IC50 of 0.1 microM, was the most potent inhibitor. The long-chain amines, but not the short-chain amines, were also effective inhibitors of protein kinase C, assayed in vitro in a cell-free system. In addition, studies with indo-1-loaded PAP2 cells showed that long-chain amines induced a reversible rise in intracellular free Ca2+ concentration. Growth inhibition by the amines was positively correlated with this effect, suggesting that factors other than protein kinase C may be involved in the inhibition of growth of PAP2 cells by long-chain amines.

In rabbits, elevation of LDL cholesterol is produced by feeding a cholesterol-free, semipurified diet containing 30% casein amino acid mixture, but not by feeding the same diet containing 14.7% of the casein amino acid mixture, corresponding to a normal level of dietary protein. The hypercholesterolemic response was greater when all essential amino acids except arginine or all ketogenic essential amino acids (lysine, leucine, isoleucine, threonine, phenylalanine, tryptophan and glycine) were selectively fed at three times the normal level. In the present experiments, the same high levels of lysine, leucine and methionine produced a substantial hypercholesterolemia, addition of either isoleucine + threonine or isoleucine + valine did not enhance the effect, and a mixture of threonine, histidine, phenylalanine, tryptophan and glycine gave only a moderate response. A combination of lysine and methionine produced a greater effect than either lysine and leucine or leucine and methionine. Hypercholesterolemic diets containing high levels of lysine and leucine did not cause significantly greater plasma ketone bodies or free fatty acids. Differences in growth rates and ketogenic responses were not generally correlated with hypercholesterolemia.

Nonsaponifiable lipids of human atherosclerotic plaques obtained at autopsy from patients ranging in age from 45 to 85 years were analyzed by high pressure liquid chromatography. All plaques contained dolichol, ranging from 125 to 460 micrograms/g wet weight. Dolichol was also present in normal aortic tissue, but the amounts were generally less than in plaques. To investigate the source of the dolichol in plaques, blood serum was analyzed from both volunteer subjects and hypercholesterolemic patients. The levels of dolichol were generally higher in hypercholesterolemic compared with normal subjects, but were not correlated with levels of total or lipoprotein cholesterol. The homologue pattern of dolichol in atherosclerotic plaques differed from that of aorta and blood. The source of dolichol in plaques and its significance remains to be established.

Farnesylamine, an analogue of farnesol, was shown to inhibit growth of PAP2 cells (ras-transformed NIH 3T3 cells) in a dose-dependent manner. This inhibition was overcome by adding farnesol to the culture medium, but not by adding geranylgeraniol, squalene, cholesterol, dolichol, myristic acid or palmitic acid. Farnesylamine inhibited both farnesyl/protein transferase and geranylgeranyl/protein transferase in whole cell extracts and also inhibited the prenylation of proteins, particularly ras p21, in PAP2 cells. Inhibition of prenylation was associated with increased biosynthesis of other products of the mevalonate biosynthetic pathway. These observations suggest that inhibition of the growth of PAP2 cells by farnesylamine may be due to blocking of ras-mediated signal transduction. This offers a means of investigating mechanisms involved in ras action and raises the possibility of developing novel strategies for anticancer therapy.

High-fat diets are thought to increase the risk of breast cancer because animals develop mammary cancer more readily when they are fed high-fat compared to low-fat diets, and breast cancer incidence and mortality are higher in countries with high-fat as compared to those with low-fat diets. Prospective cohort studies and case-control studies have failed to provide much support for this theory, but such studies are less capable of showing the relationship because of smaller differences in dietary fat intakes of the study populations; difficulties in assessing the diets of individuals over a period of time; and possible differences in genetic susceptibility of cases and controls to breast cancer. Studies on migrants have shown that breast cancer incidence and mortality increase in populations who move from countries with low-fat to those with high-fat diets, indicating that observed geographical differences in breast cancer are due to environmental rather than genetic factors. This is supported by time-trend studies showing that breast cancer increases in countries as the level of fat in the diet rises. Controlled, long-term dietary trials are needed to determine whether the converse is true: namely, that reduction of dietary fat can reduce the risk of breast cancer. Large groups are required to achieve statistical significance, but smaller numbers may be adequate for studies on high-risk individuals. Preliminary experiments already have demonstrated the feasibility of carrying out such dietary trials.

Earlier studies showed that the elevation of serum total and low density lipoprotein (LDL) cholesterol levels produced in rabbits by feeding high levels of a casein amino acid mixture in a cholesterol-free, semipurified diet was due primarily to the essential amino acids (EAA) in the mixture. Replacing all of the non-essential amino acids in the mixture by glutamic acid (45% EAA+Glu) had little effect on the hypercholesterolemia produced by the EAA. Experiments designed to identify the hypercholesterolemic EAA showed that (i) feeding high levels of ketogenic EAA only (45% EketoAA) gave a substantial but variable elevation of serum total and LDL cholesterol and (ii) feeding high levels of all EAA except arginine (45% EAA-Arg) gave a particularly strong hypercholesterolemic response. In rabbits fed the 45% EAA-Arg diet and to a lesser extent, in those fed the 45% EAA+Glu diet, EDTA-sensitive binding of 125I-LDL to hepatic membranes in vitro was reduced compared to a control, low-cholesterolemic group fed all essential and non-essential amino acids at a level corresponding to 14.7% casein, indicating that the hypercholesterolemia was associated with down-regulation of hepatic LDL receptors.

Dolichol kinase activity in microsomes from etiolated rye seedlings had a pH optimum at 8 with a shoulder at pH 6.5. Triton X-100 (0.4%) was required for optimum activity. Exogenous divalent cations did not enhance activity, although Mg+2 was added routinely. Rye microsomes were found to contain dolichol and polyprenol in a ratio of 3 to 2. Rye, soybean embryo, and rat liver microsomes catalyzed the synthesis of 78, 52, and 516 nmol [14C]dolichyl phosphate/(mg microsomal protein.h) compared with 21, 22, and 49 nmol [3H]polyprenyl phosphate/(mg microsomal protein.h), respectively. It is clear that microsomes from plant systems can catalyze the phosphorylation of polyprenol better than rat liver when compared with their abilities to catalyze the phosphorylation of dolichol. It is not known whether one or more kinases is responsible for catalyzing the phosphorylation of these two closely related groups of compounds.

Dolichol, a homologous series of alpha-saturated polyisoprenoid alcohols containing 14-24 isoprene units, was first isolated and characterized about 30 years ago. The phosphorylated form, dolichyl phosphate, is required for the biosynthesis of biologically important N-linked glycoproteins. Dolichol itself is synthesized by a common isoprenoid pathway from acetate and synthesis can be inhibited by some of the factors that inhibit cholesterol biosynthesis. It is metabolized very slowly and accumulates in tissues during aging and in certain lipid storage diseases. Dolichyl phosphate and cholesterol also accumulate in tissues during aging, but to a lesser extent than dolichol. Although dolichol and cholesterol have important metabolic functions, their accumulation in tissues can have deleterious effects.

Reports that protein kinase C is inhibited by sphingosine and other long-chain amines and the suggestion that promotion of mammary carcinogenesis by dietary fat is mediated by protein kinase C prompted us to investigate the effects of a long-chain amine, 1-octadecylamine, on mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene in rats fed a high-fat diet. Rats fed the amine sulfate at a level of 0.01% in a semipurified diet containing 20% corn oil developed more tumors than those fed the high-fat diet alone, although body weight gain was inhibited slightly. Rats fed the amine sulfate at 0.1% of the diet developed very few tumors compared with those fed either the high-fat diet or a low-fat diet containing 5% corn oil. At the higher level, the C18 amine also caused a marked inhibition of body weight gain.

Experiments on animals have shown that soybean protein has hypocholesterolemic and antiatherogenic properties. In human beings, substitution of soy protein for dietary animal protein or addition of soy protein to the diet lowers total and low-density-lipoprotein cholesterol levels in individuals with hypercholesterolemia. Reductions of 20% or more have been obtained with diets high in protein (about 20% of total energy) and relatively low in fat. Triglycerides are also decreased, particularly in subjects with hypertriglyceridemia, but soy-protein diets appear to have little effect on high-density-lipoprotein cholesterol levels. Responses are similar in men and women, but may be greater in younger than in older subjects. The hypocholesterolemic effect is thought to be mainly attributable to the protein itself rather than to nonprotein components of soy-protein preparations. The mechanism of action is not known, and it may not be possible to explain the observed effects in human beings and in experimental animal models by the same mechanism. Although the hypocholesterolemic response to dietary soy protein has been observed by a number of European research groups, substitution of soy protein for animal protein in North American diets has generally had little effect, for reasons that are still not clear.

Growth and development of mammary glandular parenchyma appear to be strongly influenced by the associated adipose tissue. Because fat is the major form of energy storage in the body, any changes in energy balance will be reflected in the weight of adipose tissue to a greater extent than in body weight as a whole. High-fat diets tend to encourage energy storage and may promote mammary cancer by increasing the amount of adipose tissue in the gland. The intimate association of adipose and glandular tissue would facilitate the transfer of any growth-promoting substances, such as polyunsaturated fatty acids, eicosanoids, estrogens, or other growth factors, from the adipose to the glandular tissue. Conversely, low-fat diets or restriction of food intake may decrease the risk of mammary cancer by reducing the amount of adipose tissue and thus reducing exposure of the glandular tissue to such growth-promoting substances.

Changes in the concentration and composition of serum VLDL, LDL, and HDL were studied in rabbits transferred from Chow diets to cholesterol-free, semipurified diets containing casein or isolated soy protein. During the first week on the casein diet, there was a marked increase in LDL-cholesterol and these higher levels were maintained during the subsequent 3 weeks of the study. Similar but less marked changes were obtained with the soy protein diet. When the percent composition of the particles was determined, both VLDL and LDL had a higher proportion of cholesterol. Turnover studies indicated that the FCRs for radiolabelled VLDL and LDL were reduced in casein-fed animals compared to those fed soy protein. The elevated LDL levels in casein-fed rabbits were primarily due to a reduction in receptor-mediated catabolism of LDL-apo B. Receptor-independent removal in the two groups was similar. These studies show that the hypercholesterolemia in casein-fed rabbits, compared to those fed soy protein, is associated with cholesterol enrichment of LDL and impaired receptor-dependent removal of LDL-apo B.

Rabbits fed a cholesterol-free, semi-purified diet containing 25% casein amino acids (25% AA) for 2 wk had significantly higher serum total and low density lipoprotein (LDL) cholesterol levels than animals fed the same diet containing 11.2% casein amino acids (11.2% AA). These results were similar to those obtained by feeding diets containing 27% and 12% casein, respectively. When rabbits were fed the 11.2% AA diet supplemented with essential amino acids to the 25% level (11.2% AA + essential AA), their LDL cholesterol level was significantly higher than that in animals fed the 11.2% AA diet supplemented with nonessential amino acids to the 25% level (11.2% AA + nonessential AA). LDL protein and phospholipid levels were significantly higher in rabbits fed the 25% AA diet than in those fed 11.2% AA and tended to be elevated in animals fed 11.2% AA + essential AA compared to those fed 11.2% AA + nonessential AA. Fecal excretion of bile acids and cholesterol was similar with all dietary regimens, and the level of liver lipids showed no correlation with the degree of hypercholesterolemia produced by dietary amino acid mixtures.

Rabbits were fed semipurified casein diets containing either 4% or 2.5% mineral mix for 8 weeks. Both groups maintained weight throughout the experimental period. The plasma total cholesterol concentration was significantly higher after 4 weeks on diet and slightly higher after 8 weeks in animals fed the lower level of minerals. Plasma IDL- and LDL-cholesterol concentrations after 4 weeks and HDL-cholesterol concentrations after 8 weeks were significantly higher in animals fed the 2.5% compared to those fed the 4% mineral mix. Kinetic experiments showed that in rabbits fed the lower level, the fractional catabolic and production rates of VLDL-apo B were lower and a greater proportion of IDL-apo B was derived from sources other than VLDL compared to the animals fed the higher level. LDL-apo B kinetics were not significantly different between the 2 groups. These data suggest that a reduction in dietary minerals enhances casein-induced hypercholesterolemia.

The aim of this study was to investigate the underlying causes of elevated levels of intermediate density lipoprotein (IDL) in rabbits fed casein compared to soy protein in a cholesterol-free, semipurified diet. Kinetic studies were carried out in which homologous, radiolabelled IDL was injected into casein- and soy protein-fed animals after a period of 7 months on diet. Total plasma cholesterol and IDL cholesterol and protein were significantly higher in animals fed casein compared to those fed soy protein. The fractional catabolic rate of IDL-apolipoprotein B was significantly lower in casein-fed animals but the difference in mean values for the production rate did not reach statistical significance. The effect of feeding casein on IDL can be attributed to its reduced efficiency of removal from the plasma.

Plasma cholesterol levels in kittens and puppies were low at birth, rose during the suckling period, and then decreased at about the time of weaning. The increase during the suckling period was much greater in puppies than in kittens. No significant differences in plasma cholesterol levels were observed in puppies fed two different types of diet, horse meat or dog chow, after weaning. Guinea pigs had lower plasma cholesterols than either kittens or puppies. The level was highest on the first day after birth, decreased during the next 3 wk, and then remained fairly constant after the animals were weaned.