Purpose: Data from epidemiological and experimental studies suggest that dietary protein intake may play a role in inhibiting prostate and breast cancer by modulating the IGF/AKT/mTOR pathway. In this study we investigated the effects of diets with different protein content or quality on prostate and breast cancer.Experimental Design: To test our hypothesis we assessed the inhibitory effect of protein diet restriction on prostate and breast cancer growth, serum PSA and IGF-1 concentrations, mTOR activity and epigenetic markers, by using human xenograft cancer models.Results: Our results showed a 70% inhibition of tumor growth in the castrate-resistant LuCaP23.1 prostate cancer model and a 56% inhibition in the WHIM16 breast cancer model fed with a 7% protein diet when compared to an isocaloric 21% protein diet. Inhibition of tumor growth correlated, in the LuCaP23.1 model, with decreased serum PSA and IGF-1 levels, down-regulation of mTORC1 activity, decreased cell proliferation as indicated by Ki67 staining, and reduction in epigenetic markers of prostate cancer progression, including the histone methyltransferase EZH2 and the associated histone mark H3K27me3. In addition, we observed that modifications of dietary protein quality, independently of protein quantity, decreased tumor growth. A diet containing 20% plant protein inhibited tumor weight by 37% as compared to a 20% animal dairy protein diet.Conclusions: Our findings suggest that a reduction in dietary protein intake is highly effective in inhibiting tumor growth in human xenograft prostate and breast cancer models, possibly through the inhibition of the IGF/AKT/mTOR pathway and epigenetic modifications.

A double-blind placebo-controlled randomized phase II trial was performed to determine whether High Dose Vitamin D2 supplementation (HDD) in women receiving adjuvant anastrozole improves aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) and bone loss. Patients with early breast cancer and AIMSS were stratified according to their baseline 25-hydroxy vitamin D (25OHD) level. Stratum A (20-29 ng/ml) received either HDD 50,000 IU capsules weekly for 8 weeks then monthly for 4 months or placebo. Stratum B (10-19 ng/ml) received either HDD for 16 weeks and then monthly for 2 months, or placebo. AIMSS was assessed by the Brief Pain Inventory-Short Form (BPI-SF), the Fibromyalgia Impact Questionnaire (FIQ), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at baseline, 2, 4, and 6 months. Bone Mineral Density (BMD) was measured at baseline and at 6 months. The primary endpoint of the study was the change-from-baseline musculoskeletal pain. The secondary endpoint was the percent change in BMD at 6 months. Sixty women were enrolled. Baseline characteristics were comparable between the groups. At 2 months, FIQ pain (P = 0.0045), BPI worst-pain (P = 0.04), BPI average-pain (P = 0.0067), BPI pain-severity (P = 0.04), and BPI interference (P = 0.034) scores were better in the HDD than placebo group. The positive effect of HDD on AIMSS was stronger across all time points in Stratum B than Stratum A (FIQ pain, P = 0.04; BPI average, P = 0.03; BPI severity, P = 0.03; BPI interference, P = 0.04). BMD at the femoral neck decreased in the placebo and did not change in the HDD group (P = 0.06). Weekly HDD improves AIMSS and may have a positive effect on bone health. Vitamin D supplementation strategies for breast cancer patients on AI should be further investigated.

Purpose Polymorphisms in the CYP19A1 (aromatase) gene have been reported to influence disease-free survival and the incidence of musculoskeletal complaints in patients taking aromatase inhibitors (AIs) for estrogen receptor positive (ER+) breast cancer. Bone loss and fractures are wellrecognized complications from AI therapy. The objective of this study is to determine the influence of polymorphisms in the CYP19A1 gene on bone loss among patients taking aromatase inhibitors for ER+ breast cancer. Patients and Methods The subjects consisted of 97 postmenopausal women with ER+ breast cancer who were initiated on third-generation AIs. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry at baseline and at 6 and 12 months. Twenty-four hour urine N-telopeptide (NTX) was measured by Elisa and serum estradiol was measured by ultrasensitive radioimmunoassay at baseline, and at 6 months. Genotyping was done by Taqman SNP allelic discrimination assay. Results Women with the AA genotype for the rs700518 (G/A at Val80) developed significant bone loss at the lumbar spine and the total hip at 12 months relative to patients carrying the G allele (GA/GG); both p=0.03. There was a borderline greater increase in urinary NTX in those with the AA genotype compared to patients with the G allele, p=0.05; but no significant difference in changes in estradiol levels among the genotypes. Conclusion Patients with the AA genotype for the rs700518 polymorphism in the CYP19A1 gene are at risk for AI-associated bone loss and deserve close follow-up during long-term AI therapy.

Reduced dietary protein intake and intermittent fasting (IF) are both linked to healthy longevity in rodents, and are effective in inhibiting cancer growth. The molecular mechanisms underlying the beneficial effects of chronic protein restriction (PR) and IF are unclear, but may be mediated in part by a down-regulation of the IGF/mTOR pathway. In this study we compared the effects of PR and IF on tumor growth in a xenograft mouse model of breast cancer. We also investigated the effects of PR and IF on the mechanistic Target Of Rapamycin (mTOR) pathway, inhibition of which extends lifespan in model organisms including mice. The mTOR protein kinase is found in two distinct complexes, of which mTOR complex 1 (mTORC1) is responsive to acute treatment with amino acids in cell culture and in vivo. We found that both PR and IF inhibit tumor growth and mTORC1 phosphorylation in tumor xenografts. In somatic tissues, we found that PR, but not IF, selectively inhibits the activity of the amino acid sensitive mTORC1, while the activity of the second mTOR complex, mTORC2, was relatively unaffected by PR. In contrast, IF resulted in increased S6 phosphorylation in multiple metabolic tissues. Our work represents the first finding that PR may reduce mTORC1 activity in tumors and multiple somatic tissues, and suggest that PR may represent a highly translatable option for the treatment not only of cancer, but also other age-related diseases.

Background and aims Reduced vitamin D levels may play a significant role in the development of fractures and musculoskeletal pains reported in patients on aromatase inhibitors (AIs) for breast cancer. In this study, we evaluated the vitamin D status in postmenopausal women with non-metastatic breast cancer who were about to start AI therapy. Methods This study was conducted on community dwelling postmenopausal subjects, aged 35–80 years, with early non-metastatic breast cancer (up to stage IIIA), who were about to start therapy using third generation AIs. Symptoms of joint and muscle pains were obtained using a modified Leuven menopausal questionnaire. 25-hydroxyvitamin D [25(OH)D] was evaluated by radioimmunoassy while bone mineral density (BMD) of the lumbar spine and the proximal femur by dual energy X-ray absorptiometry (DXA) Results Of the 145 participants (mean age = 60.96 ± 0.88 years), 63/145 (43.5%) had baseline levels of 25(OH)D of < 20 ng/ml (deficient), 50/145 (34.5%) had levels between 20–29 ng/ml (insufficient), and only 32/145 (22%) had > 30 ng/ml (sufficient); thus, 113/145 (78%) had low 25(OH)D levels (i.e. < 30ng/ml). Arthralgias and myalgias were found in 61.3% and 43% of patients, respectively; and of those, 83.3% and 88.1% had 25(OH)D of < 30ng/ml, respectively. Conclusions Prevalence of vitamin D deficiency is high in breast cancer women and this may increase the risk of bone loss and fractures in those who are going to start AIs. Moreover, musculoskeletal pains are common in breast cancer women, even before the initiation of AIs and in association with low vitamin D in the majority. Future studies may be needed to establish the contribution of low vitamin D, if any, on the prevalence of musculoskeletal pains in women on AIs.

Purpose Polymorphisms in the CYP19A1 (aromatase) gene influence disease-free survival and bone loss in patients taking aromatase inhibitors (AIs) for estrogen receptor positive (ER+) breast cancers. Because AI use results in profound estrogen deficiency which may lead to changes in body composition, the objective of this study was to determine the effect of the rs700518 polymorphism in the CYP19A1 gene, on the changes in body composition among postmenopausal women who were treated with AIs for ER+ breast cancer. Methods This is a 1-year prospective study of changes in body composition in postmenopausal women who were initiated on third-generation AIs for ER+ breast cancer. Body composition was measured by dual energy absorptiometry at 6 and 12 months, serum estradiol by radioimmunoassay and genotyping by Taqman SNP allelic discrimination assay. Results Eighty-two women were able to provide at least one follow-up body composition measurement. Women with the GG genotype for the rs700518 (G/A at Val80) developed a significant increase in Truncal fat mass index (p=0.03) and a significant decrease in fat-free mass index (p=0.01) at 12 months relative to patients carrying the A allele (GA/AA). There was no significant difference in the changes in estradiol levels among the genotypes. Conclusion Patients with the GG genotype for the rs700518 polymorphism in the CYP19A1 gene are at risk for significant loss of fat-free mass and increase in truncal fat with AI therapy. Whether there are associated metabolic abnormalities and whether changes would persist with long-term AI therapy, need to be confirmed in a larger study with a longer duration of follow-up.

Objectives The study was designed to determine which histological lesions produce cellular atypia in lavage specimens and whether ductoscopy adds useful information for the evaluation of high-risk patients with atypical lavage cytology. Methods We prospectively recruited women ≥35 years at high risk for developing breast cancer. All underwent ductal lavage. Women found to have atypia underwent ductoscopy-directed duct excision (group 1). Women without atypia were observed (group 2). Data included patient demographics, risk assessment, cytologic and histologic findings, and outcomes. Descriptive statistics were utilized for data summary and were compared using Fisher’s exact test. Results We enrolled 102 women; 93 (91%) were Caucasian. Their median age was 49 (range 34–73) years with a median follow-up of 80 (range 5–90) months. Overall, 27 (26%) had atypical lavage cytology (group 1), and 75 (74%) had benign cytology (group 2). Subsequent duct excision in group 1 revealed benign histology in 11 (44%), papillomas in 9 (36%), atypical hyperplasia (AH) in 4 (16%), and ductal carcinoma in situ (DCIS) in 1 (4%). At follow-up, three patients developed breast cancer, including one group 1 patient and two group 2 patients. There were no differences between groups 1 and 2 according to patient demographics, Gail scores, or risk for subsequent breast cancer (P >0.05). Conclusions Although 20% of high-risk women with ductal lavage atypia have AH or malignancy on subsequent excision, the majority do not. Atypia identified by ductal lavage is not associated with a higher risk of developing subsequent breast cancer, even in this high-risk population.

SUMMARY Motion perception was tested by requiring adult subjects to view gratings that remained stationary but reversed in contrast several times per second. Subjects viewed monocularly and judged whether the gratings were stationary, or moving in one direction, in successive 3s trials. Subjects who had early‐onset strabismus most frequently perceived vertically oriented gratings to be moving nasalward, and horizontally oriented gratings to be moving up or down. Norma! subjects and subjects who had late‐onset strabismus most frequently perceived the gratings to be stationary. The asymmetries of motion perception in early‐onset strabismus imply that the visual motion neurons of cerebral cortex develop properly only if they receive normal binocular input during infancy. RÉSUMÉ Biais de la perception du mouvement révilés par des grilles‐inverses chez les sujets avec un strabisme à début précoce La perception du mouvement a été exploréc en demandant à des sujets adultes d'observer des grilles demeurant stationnaires mais inversées en contraste plusieurs fois par seconde. Les sujets en vision monoculaire jugeaient si les grilles étaient stationnaires ou se déplaçaient dans une direction, dans essais successifs de trois secondes. Les sujets présentant un strabisme à début precoce percevaient plus fréquemment un déplacement nasal des grilles à orientation verticale et un désplacement vers le haut ou le bas des grilles horizontales. Les sujets normaux ou à strabisme tardif percevaient plus fréquemment les grilles commc stationnaires. Les asymétries de la perception du mouvement dans le strabisme á début précoce impliquent que les neurones visuocorticaux de la perception du mouvement ne se développent correctement que s'ils bénéficient d'une entreé binoculaire normale durant la petite enfance. ZUSAMMENFASSUNG Störungen der Bewegungswahrnelmumg, nachgewiesen durch Rasterumkehr, bei Patienlen mil früh beginnendem Nystagmus Zur Beurteilung der Bewegungswahrnehmung wurden erwachsene Probanden aufgefordert. Raster, die stationär blieben, sich aber mehrere Male pro Sekunde umkehrten, zu bcobachten. Die Probanden sahen mit einem Auge und beurteilten in aufeinanderfolgenden 3s Versuchen, ob das Raster stationär blieb oder sich in einer Richtung bewegte. Patienten mit früh beginnendem Strabismus sahen sehr haüfig vertikal ausgerichtete Raster sich nasalwärts bewegen und horizontal ausgerichtcte Raster sich auf‐ oder abbewegen. Gesunde Personen und Probanden mit spät beginnendem Strabismus sahen die Raster fast immer stationär. Die Asymmetrien der Bewegungswahrnehmung beim früh beginneden Nystagmus besagen, daß die visuellen Motoneurone des cerebralen Cortex sich nur normal entwickeln, wenn sie im Kindesalter normale binokuläre Stimulationen crhalten. RESUMEN Sesos de percepción motora revelados por medio de parrillas reversibles en personas que tenian un estrabismo desde la infancia Se exploró la percepción de movimiento, pidiendo a adultos que observaran emparrillados que permanecían estacionarios, pero revertidos varias veces po...