Search

BACKGROUND: Binge drinking is associated with increased risk for cardiovascular (CV) disease. MicroRNA-21 (miR21) is upregulated in the setting of excessive alcohol consumption and CV disease. Therefore, the goal of this study was to examine the vasodilatory responses to flow and acetylcholine in the absence and presence of an anti-miR21 inhibitor in the microcirculation of young adult repeated binge drinkers. METHODS: Gluteal subcutaneous adipose tissue biopsies were obtained from young adults (18–30 yrs, n = 35 vessels from binge drinkers [BDs] and n = 28 vessels from abstainers). Resistance arteries (RAs) were isolated, incubated with anti-miR21 or a negative control to miR-21 (12 hours; 5 nM), and lumen diameters measured with video microscopy. MiRNA-21 of adipose tissues was determined by quantitative PCR (qPCR). RESULTS: Flow-induced dilation (FID) and acetylcholine (ACh)-induced dilation (AChID) were reduced in BDs as compared to abstainers. The miR-21 inhibitor but not the negative control abrogated these effects in BDs, but did not affect vasodilation in abstainers. Nitric oxide synthase inhibition with L-NAME reduced vasodilation in abstainers but not in BDs. In BDs, vasodilation was reduced by L-NAME in the presence of anti-miR-21 but not the negative control. Scavenging the reactive oxygen species hydrogen peroxide with polyethyleneglyco-catalase reduced dilation in BDs but did not affect the restored dilation by miR-21 inhibitor. Maximum dilation to papaverine (endothelium-independent) was similar between groups and unaffected by pharmacological inhibition. Finally, vascular endogenous miR-21 was increased in BDs compared to abstainers. CONCLUSIONS: Endogenous microRNA-21 is increased in RAs of young BDs, leading to reduced flow and acetylcholine-induced vasodilation in the microcirculation.

Genistein has protective effects against prostate cancer (PCa) but whether this protection involves an estrogen receptor (ER) β dependent mechanism has yet to be elucidated. ER-β has a tumor suppressor role in PCa and its levels decline with cancer progression which was linked to ER-β promoter hypermethylation. Genistein has been suggested to have demethylating activities in cancer. However, the ability of genistein to reverse ER-β promoter hypermethylation in PCa has not been studied. In addition, there are great discrepancies among studies that examined the effect of genistein on ER-β gene expression. Therefore, we sought to explore effects of genistein on ER-β promoter methylation as a mechanism of modulating ER-β expression using three PCa cell lines, LNCaP, LAPC-4 and PC-3. We also examined the role of ER-β in mediating the preventive action of genistein. Our data demonstrated that genistein at physiological ranges (0.5–10 µmol/L) reduced ER-β promoter methylation significantly with corresponding dose-dependent increases in ER-β expression in LNCaP and LAPC-4 but not in PC-3 cells, which could be attributed to the low basal levels of ER-β promoter methylation in PC-3 cell line. Genistein induced phosphorylation, nuclear translocation and transcriptional activity of ER-β in all three PCa cell lines. Inhibitory effects of genistein on LAPC-4 and PC-3 cell proliferation were diminished using a specific ER-β antagonist. In conclusion, genistein and ER-β act together to prevent PCa cell proliferation; genistein increases ER-β levels via reducing its promoter methylation and ER-β, in turn, mediates the preventive action of genistein.

In this perspective, modifiable carcinogenic factors for the prostate are summarized. This is followed by a discussion of how current knowledge about causation of prostate cancer and chemoprevention of prostate cancer can be used to develop preventive strategies. Prostate cancer is a slowly developing cancer which offers opportunities for preventive interventions. Only a few randomized clinical trials of prostate cancer prevention have been completed. The SELECT study with selenium and vitamin E did not find protective effects, but in two trials with 5α-reductase inhibitors risk was reduced about 25%, showing that chemoprevention is possible and indicating that the androgen receptor is a suitable target. Besides smoking cessation and reduction of obesity, there are no known dietary or life style interventions that will have a major impact on prostate cancer risk. Inflammation of the prostate is an attractive target and aspirin may be a promising candidate agent, but has not been addressed yet in preclinical and clinical studies. Antioxidants other than selenium and vitamin E are unlikely to be very effective and data on several dietary supplements are not encouraging. More candidate agents need to be identified and tested in relevant and adequate preclinical models and Phase II trials that have predictive value for outcome of Phase III randomized studies. Doing this will require a systematic approach comparing preclinical and clinical study outcomes to determine their predictive value of preventive efficacy.

Insulin resistance promotes vascular endothelial dysfunction and subsequent development of cardiovascular disease. Previously we found that skeletal muscle arteriolar flow-induced dilation (FID) was reduced following a hyperinsulinemic clamp in healthy adults. Therefore, we hypothesized that hyperinsulinemia, a hallmark of insulin resistance, contributes to microvascular endothelial cell dysfunction via inducing oxidative stress that is mediated by NADPH oxidase (Nox) system. We examined the effect of insulin, at levels that are comparable with human hyperinsulinemia on 1) FID of isolated arterioles from human skeletal muscle tissue in the presence and absence of Nox inhibitors and 2) human adipose microvascular endothelial cell (HAMECs) expression of nitric oxide (NO), endothelial NO synthase (eNOS), and Nox-mediated oxidative stress. In six lean healthy participants (mean age 25.5±1.6 y, BMI 21.8±0.9), reactive oxygen species (ROS) were increased while NO and arteriolar FID were reduced following 60 min of ex vivo insulin incubation. These changes were reversed after co-incubation with the Nox isoform 2 (Nox2) inhibitor, VAS2870. In HAMECs, insulin-induced time-dependent increases in Nox2 expression and P47phox phosphorylation were echoed by elevations of superoxide production. In contrast, phosphorylation of eNOS and expression of superoxide dismutase (SOD2 and SOD3) isoforms showed a biphasic response with an increased expression at earlier time points followed by a steep reduction phase. Insulin induced eNOS uncoupling that was synchronized with a drop of NO and a surge of ROS production. These effects were reversed by Tempol (SOD mimetic), Tetrahydrobiopterin (BH4; eNOS cofactor), and VAS2870. Finally, insulin induced nitrotyrosine formation which was reversed by inhibiting NO or superoxide generation. In conclusions, hyperinsulinemia may reduce FID via inducing Nox2-mediated superoxide production in microvascular endothelial cells which reduce the availability of NO and enhances peroxynitrite formation. Therefore, the Nox2 pathway should be considered as a target for the prevention of oxidative stress-associated endothelial dysfunction during hyperinsulinemia., Graphical abstract fx1, Highlights • Hyperinsulinemia impairs FID and induces ROS production in human muscle arterioles. • Insulin-induced ROS production in endotelial cells is mediated by NADPH oxidase. • Long exposure to high insulin levels reduces eNOS phosphorylation and NO production.

The non-steroidal anti-inflammatory agent, sulindac, has shown strong effects on cancer prevention in colorectal cancers, however, its anticancer activities on prostate cancer remain unclear. In the current study, human prostate cancer cell lines, LNCaP and PC-3, were treated with various concentrations of sulindac and it was found that sulindac significantly inhibits prostate cancer cell proliferation and promotes cell apoptosis in a dose- and time-dependent manner. Further studies revealed that sulindac significantly induces c-Jun NH2-terminal kinase (JNK) 1 phosphorylation and inhibits β-catenin at the transcriptional and post-transcriptional levels. In conclusion, by targeting the JNK1/β-catenin signaling pathway, sulindac may present a potential preventive or therapeutic agent for treatment of patients with prostate cancer.

Soy isoflavones are dietary components for which an association has been demonstrated with reduced risk of prostate cancer (PCa) in Asian populations. However, the exact mechanism by which these isoflavones may prevent the development or progression of PCa is not completely understood. There are a growing number of animal and in vitro studies that have attempted to elucidate these mechanisms. The predominant and most biologically active isoflavones in soy products, genistein, daidzein, equol, and glycetin, inhibit prostate carcinogenesis in some animal models. Cell-based studies show that soy isoflavones regulate genes that control cell cycle and apoptosis. In this review, we discuss the literature relevant to the molecular events that may account for the benefit of soy isoflavones in PCa prevention or treatment. These reports show that although soy isoflavone-induced growth arrest and apoptosis of PCa cells are plausible mechanisms, other chemo protective mechanisms are also worthy of consideration. These possible mechanisms include antioxidant defense, DNA repair, inhibition of angiogenesis and metastasis, potentiation of radio- and chemotherapeutic agents, and antagonism of estrogen- and androgen-mediated signaling pathways. Moreover, other cells in the cancer milieu, such as the fibroblastic stromal cells, endothelial cells, and immune cells, may be targeted by soy isoflavones, which may contribute to soy-mediated prostate cancer prevention. In this review, these mechanisms are discussed along with considerations about the doses and the preclinical models that have been used.

High blood pressure has been shown to elicit impaired dilation in the vasculature. The purpose of this investigation was to elucidate the mechanisms through which high pressure may elicit vascular dysfunction and determine the mechanisms through which regular aerobic exercise protects arteries against high pressure. Male C57BL/6J mice were subjected to 2 wk of voluntary running (~6 km/day) for comparison with sedentary controls. Hindlimb adipose resistance arteries were dissected from mice for measurements of flow-induced dilation (FID; with or without high intraluminal pressure exposure) or protein expression of NADPH oxidase II (NOX II) and superoxide dismutase (SOD). Microvascular endothelial cells were subjected to high physiological laminar shear stress (20 dyn/cm

Hyperinsulinemia is a hallmark of insulin resistance‐associated metabolic disorders. Under physiological conditions, insulin maintains a balance between nitric oxide (NO) and, the potent vasoconstrictor, endothelin‐1 (ET‐1). We tested the hypothesis that acute hyperinsulinemia will preferentially augment ET‐1 protein expression, disrupt the equilibrium between ET‐1 expression and endothelial NO synthase (eNOS) activation, and subsequently impair flow‐induced dilation (FID) in human skeletal muscle arterioles. Skeletal muscle biopsies were performed on 18 lean, healthy controls (LHCs) and 9 older, obese, type 2 diabetics (T2DM) before and during (120 min) a 40 mU/m 2 /min hyperinsulinemic‐euglycemic (5 mmol/L) clamp. Skeletal muscle protein was analyzed for ET‐1, eNOS, phosphorylated eNOS (p‐eNOS), and ET‐1 receptor type A (ETAR) and B (ETBR) expression. In a subset of T2DM ( n = 6) and LHCs ( n = 5), FID of isolated skeletal muscle arterioles was measured. Experimental hyperinsulinemia impaired FID (% of dilation at ∆60 pressure gradient) in LHCs (basal: 74.2 ± 2.0; insulin: 57.2 ± 3.3, P = 0.003) and T2DM (basal: 62.1 ± 3.6; insulin: 48.9 ± 3.6, P = 0.01). Hyperinsulinemia increased ET‐1 protein expression in LHCs (0.63 ± 0.04) and T2DM (0.86 ± 0.06) compared to basal conditions (LHCs: 0.44 ± 0.05, P = 0.007; T2DM: 0.69 ± 0.06, P = 0.02). Insulin decreased p‐eNOS (serine 1177) only in T2DM (basal: 0.28 ± 0.07; insulin: 0.17 ± 0.04, P = 0.03). In LHCs, hyperinsulinemia disturbed the balance between ETAR and ETBR receptors known to mediate vasoconstrictor and vasodilator actions of ET‐1, respectively. Moreover, hyperinsulinemia markedly impaired plasma NO concentration in both LHCs and T2DM. These data suggest that hyperinsulinemia disturbs the vasomotor balance in human skeletal muscle favoring vasoconstrictive pathways, eventually impairing arteriolar vasodilation.

SUMMARYThis paper analyses a mobile robot with independently rotating wheels travelling on uneven but smooth ground, including ascending or descending surfaces. We formulate a mathematical expression for the energy cost of the robot's movement. For our analysis, we utilise the principle of virtual work and assume that the robot moves with a fixed arrangement of wheel axes and without using a steering handle. The mathematical model reveals that the coefficient of friction and the payload distribution dominate the wheel behaviour, including slipping and skidding. We minimise the virtual work expression to determine the robot's motion complying with driven wheels. The model also enables us to estimate trajectories for different ground conditions. A hybrid robot, PEOPLER-II, is used to demonstrate the predicted motions, including turns and spins, by following angular velocity control rules. Experimental data verifies that the proposed formulation and minimisation of virtual work are valid techniques for predicting a robot's trajectory. The method described is widely applicable to wheeled robots having independently driven wheels.

One of the objectives of the paper is to describe the hybrid robot PEOPLER-II (Perpendicularly Oriented Planetary Legged Robot) with regard to switching between leg-type and wheel-type. Our robot has an easier design and control system than other hybrid robots. The software and hardware control in the process of performing five robot tasks are considered. These are the walking, rolling, switching, turning and spinning. In the switching task, we show the control method based on minimization of total energycost. Also, the hardware components and their interconnections are described. The graphical user interfaces utilized in the simulation and experiment are demonstrated. The walking, rolling and the switching without reverse rotation and arm motion are verified in simulation and with real robot, in addition to turning and spinning.

Background Breast cancer formation is associated with frequent changes in DNA methylation but the extent of very early alterations in DNA methylation and the biological significance of cancer-associated epigenetic changes need further elucidation. Methods Pyrosequencing was done on bisulfite-treated DNA from formalin-fixed, paraffin-embedded sections containing invasive tumor and paired samples of histologically normal tissue adjacent to the cancers as well as control reduction mammoplasty samples from unaffected women. The DNA regions studied were promoters (BRCA1, CD44, ESR1, GSTM2, GSTP1, MAGEA1, MSI1, NFE2L3, RASSF1A, RUNX3, SIX3 and TFF1), far-upstream regions (EN1, PAX3, PITX2, and SGK1), introns (APC, EGFR, LHX2, RFX1 and SOX9) and the LINE-1 and satellite 2 DNA repeats. These choices were based upon previous literature or publicly available DNA methylome profiles. The percent methylation was averaged across neighboring CpG sites. Results Most of the assayed gene regions displayed hypermethylation in cancer vs. adjacent tissue but the TFF1 and MAGEA1 regions were significantly hypomethylated (p ≤0.001). Importantly, six of the 16 regions examined in a large collection of patients (105 – 129) and in 15-18 reduction mammoplasty samples were already aberrantly methylated in adjacent, histologically normal tissue vs. non-cancerous mammoplasty samples (p ≤0.01). In addition, examination of transcriptome and DNA methylation databases indicated that methylation at three non-promoter regions (far-upstream EN1 and PITX2 and intronic LHX2) was associated with higher gene expression, unlike the inverse associations between cancer DNA hypermethylation and cancer-altered gene expression usually reported. These three non-promoter regions also exhibited normal tissue-specific hypermethylation positively associated with differentiation-related gene expression (in muscle progenitor cells vs. many other types of normal cells). The importance of considering the exact DNA region analyzed and the gene structure was further illustrated by bioinformatic analysis of an alternative promoter/intron gene region for APC. Conclusions We confirmed the frequent DNA methylation changes in invasive breast cancer at a variety of genome locations and found evidence for an extensive field effect in breast cancer. In addition, we illustrate the power of combining publicly available whole-genome databases with a candidate gene approach to study cancer epigenetics. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1777-9) contains supplementary material, which is available to authorized users.

The objective of this study was to establish whether alterations in the REDD1-mTOR axis underlie skeletal muscle insensitivity to insulin in Type 2 diabetic (T2D), obese individuals. Vastus lateralis muscle biopsies were obtained from lean, control and obese, T2D subjects under basal and after a 2-h hyperinsulinemic (40 mU·m−2·min−1)-euglycemic (5 mM) clamp. Muscle lysates were examined for total REDD1, and phosphorylated Akt, S6 kinase 1 (S6K1), 4E-BP1, ERK1/2, and MEK1/2 via Western blot analysis. Under basal conditions [(-) insulin], T2D muscle exhibited higher S6K1 and ERK1/2 and lower 4E-BP1 phosphorylation ( P < 0.05), as well as elevations in blood cortisol, glucose, insulin, glycosylated hemoglobin ( P < 0.05) vs. lean controls. Following insulin infusion, whole body glucose disposal rates (GDR; mg/kg/min) were lower ( P < 0.05) in the T2D vs. the control group. The basal-to-insulin percent change in REDD1 expression was higher ( P < 0.05) in muscle from the T2D vs. the control group. Whereas, the basal-to-insulin percent change in muscle Akt, S6K1, ERK1/2, and MEK1/2 phosphorylation was significantly lower ( P < 0.05) in the T2D vs. the control group. Findings from this study propose a REDD1-regulated mechanism in T2D skeletal muscle that may contribute to whole body insulin resistance and may be a target to improve insulin action in insulin-resistant individuals.

Diabetes is a serious health problem today. Most of the people are unaware that they are in risk of or may even have type-2 diabetes. Type-2 diabetes is becoming more common due to risk factors like older age, obesity, lack of exercise, family history of diabetes, heart diseases . Along with good lifestyle and healthy diet, reduces the risk of development of type 2 diabetes for treatment of elder people , proper care of diet, exercise and medication as well is more important.. The research in developing intelligence knowledge base systems in diabetic domain is important for both health industry and diabetes patients. Recently expert systems technology provides an efficient tools for diagnosing diabetes and hence providing a sufficient treatment. The main challenge in building such systems is the knowledge acquisition and developing of the knowledge base of these systems. Our research was motivated by the need of such an efficient tool. The main objective of this paper is gathering knowledge acquisition for developing the knowledge base of diabetic type-2 diet. Therefore, the paper presents the main phases of knowledge acquisition process on the development of fully automated healthy meal planner for diaptic-type-2. Key-Words: expert systems semantic network, diabetic diet, type 2 diabetes, rule-base.

Insulin is a vasoactive hormone that regulates vascular homeostasis by maintaining balance of endothelial-derived NO and ET-1. Although there is general agreement that insulin resistance and the associated hyperinsulinemia disturb this balance, the vascular consequences for hyperinsulinemia in isolation from insulin resistance are still unclear. Presently, there is no simple answer for this question, especially in a background of mixed reports examining the effects of experimental hyperinsulinemia on endothelial-mediated vasodilation. Understanding the mechanisms by which hyperinsulinemia induces vascular dysfunction is essential in advancing treatment and prevention of insulin resistance-related vascular complications. Thus, we review literature addressing the effects of hyperinsulinemia on vascular function. Furthermore, we give special attention to the vasoregulatory effects of hyperinsulinemia on skeletal muscle, the largest insulin-dependent organ in the body. This review also characterizes the differential vascular effects of hyperinsulinemia on large conduit vessels versus small resistance microvessels and the effects of metabolic variables in an effort to unravel potential sources of discrepancies in the literature. At the cellular level, we provide an overview of insulin signaling events governing vascular tone. Finally, we hypothesize a role for hyperinsulinemia and insulin resistance in the development of CVD.

Physical inactivity is a major risk factor for the development of obesity and other cardiovascular (CV) disease (CVD). Vascular endothelial dysfunction is a key event in the development of CVD and is associated with a sedentary lifestyle in otherwise healthy adults. In addition, vascular endothelial dysfunction may be exacerbated in sedentary individuals who are obese and insulin resistant, since excess body fat is associated with elevated levels of pro-atherogenic inflammatory adipokines and cytokines that reduce the nitric oxide (NO) and other upstream paracrine signaling substances which reduces vascular health. Since blood flow-related shear stress is a major stimulus to NO release from the endothelium, disturbed flow or low shear stress is the likely mechanism by which vascular endothelial function is altered with inactivity. Evidence shows that regular physical exercise has beneficial effects on CVD and the risk factors that promote peripheral arterial function and health. Both aerobic and resistance exercise training are generally believed to improve endothelial function and are commonly recommended for CV health, including the management of obesity, hypertension, and insulin resistance. However, many factors including age, disease status, and race appear to influence these outcomes. Although evidence supporting the health benefits of exercise is compelling, the optimum prescription (volume and intensity) and the exact mechanism underlying the effects of exercise training on arterial function and cardiometabolic risk has yet to be identified. The focus of this review will be on the evidence supporting exercise interventions for peripheral arterial function.

Purpose Mutations in BRCA1 are associated with familial as well as sporadic aggressive subtypes of breast cancer, but less is known about whether BRCA1 expression or subcellular localization contributes to progression in population-based settings. Methods We examined BRCA1 expression and subcellular localization in invasive breast cancer tissues from an ethnically diverse sample of 286 patients and 36 normal breast tissue controls. Two different methods were used to label breast cancer tissues for BRCA1: (1) Dual immunofluoresent staining with BRCA1 and cytokeratin 8/18 and (2) immunohistochemical staining using the previously validated MS110 mouse monoclonal antibody. Slides were visualized and quantified using the VECTRA Automated Multispectral Image Analysis System and InForm software. Results BRCA1 staining was more intense in normal than in invasive breast tissue for both cytoplasmic (p

Quadratic Assignment Problem (QAP) is an NP-hard combinatorial optimization problem, therefore, solving the QAP requires applying one or more of the meta-heuristic algorithms. This paper presents a comparative study between Meta-heuristic algorithms: Genetic Algorithm, Tabu Search, and Simulated annealing for solving a real-life (QAP) and analyze their performance in terms of both runtime efficiency and solution quality. The results show that Genetic Algorithm has a better solution quality while Tabu Search has a faster execution time in comparison with other Meta-heuristic algorithms for solving QAP., 6 pages, 3 figures

with the increased rates of the slow learners (SL) enrolled in schools nowadays; the schools realized that the traditional academic curriculum is inadequate. Some schools have developed a special curricula that are particularly suited a slow learner while others are focusing their efforts on the devising of better and more effective methods and techniques in teaching. In the other hand, knowledge discovery and data mining techniques certainly can help to understand more about these students and their educational behaviors. This paper discusses the clustering of elementary school slow learner students behavior for the discovery of optimal learning patterns that enhance their learning capabilities. The development stages of an integrated E-Learning and mining system are briefed. The results show that after applying the clustering algorithms Expectation maximization and K-Mean on the slow learner’s data, a reduced set of five optimal patterns list (RSWG, RWSG, RWGS, GRSW, and SGWR) is reached. Actually, the students followed these five patterns reached grads higher than 75%. Therefore, the proposed system is significant for slow learners, teachers and schools.

This paper presents a novel hybrid machine learning (ML)reduction approach to enhance cancer classification accuracy of microarray data based on two ML gene ranking techniques (T-test and Class Separability (CS)). The proposed approach is integrated with two ML classifiers; K-nearest neighbor (KNN) and support vector machine (SVM); for mining microarray gene expression profiles. Four public cancer microarray databases are used for evaluating the proposed approach and successfully accomplish the mining process. These are Lymphoma, Leukemia SRBCT, and Lung Cancer. The strategy to select genes only from the training samples and totally excluding the testing samples from the classifier building process is utilized for more accurate and validated results. Also, the computational experiments are illustrated in details and comprehensively presented with literature related results. The results showed that the proposed reduction approach reached promising results of the number of genes supplemented to the classifiers as well as the classification accuracy.

Blocking the androgen receptor (AR) activity is the main goal of therapies for advanced prostate cancer (PCa). However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent) activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A) mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L) stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.

This paper proposes a trajectory estimation method for a skid-steering mobile robot (SSMR) incorporating free wheels on uneven but smooth ground with different ground properties and distributed loads on wheel axes. We formulate a mathematical expression in terms of virtual work for evaluating the energy cost of all the wheel motions with skidding and slipping under the condition that each wheel is always in contact with the ground via a pivot suspension structure. Minimization of the expression for virtual work results in a unique solution for the new position of the robot after small movement of the wheels. Further, by iterating we calculate a continuous trajectory which is an important result for assigning powered wheel velocities for self-navigation. Trajectories demonstrated by a test robot confirm the validity of the method.

This paper presents an 3D algorithm to estimate the motion trajectory of a four legged sliding robot considering the ground friction coefficient and the payload distribution at leg ends during walk on a flat ground including ascending or descending slopes. We formulate mathematical expression for estimating energy cost of motion utilizing the principle of virtual work under the condition where the robot moves by alternating pivotal feet having hemispherical form at their ends. Then we minimize the sum of the virtual work for determining actual robot motion. Results of the minimization make it possible to simulate the motion behaviors for visualizing robot trajectory in different traveling environments. Additionally, we verify simulation results by demonstrating the walk with functions of turn and spin as a legged type of the hybrid robot PEOPLER-II. Hence the proposed algorithm is useful for clarifying the robot motion behaviors.

Purpose: Non-Hispanic (nH) Black and Hispanic (or minority) breast cancer patients tend to be diagnosed with more aggressive forms of breast cancer compared to their nH White counterparts. Prior research as well as analyses from the current study has identified hormonal and reproductive factors associated with breast cancer aggressiveness subtypes. We explored the potential role of hormonal and reproductive factors, and the potential contribution of DNA methylation, in explaining the racial/ethnic disparity in tumor aggressiveness in a population based study of breast cancer disparities. Methods: The breast Cancer Care in Chicago (BCCC) study included 989 recently diagnosed nH White, nH Black and Hispanic patients with first primary breast cancer. Analyses include a subset of 286 patients with available tumor immunohistochemistry (IHC) data on estrogen and progesterone receptor (ER/PR), HER2, p53 and Ki67 status. A tumor aggressiveness score (TAS) with a high internal reliability coefficient (Chronbach's alpha=0.76) was created from tumor grade and IHC data on ER, PR, HER2, p53 and Ki67. Values were standardized to have a mean of 0 and standard deviation of 1, then summed together and re-standardized to create the score. Pyrosequencing assays for DNA methylation were conducted on a set of DNA sequences identified based on prior literature, ENCODE data for DNA methylation, and transcription for normal vs. cancer cell lines from the UCSC genome browser. Of the 286 patients with tumor aggressiveness data, 214 had available methylation data for BRCA1, GSTM2, EGFR, RASSF1, Sat2 and TFF1 genes. Multivariable linear regression models were estimated with standardized aggressiveness score as the dependent variable and using nested models to conduct likelihood ratio tests for both forward (type 1) and backwards (type 3) analyses. A method of rescaled-coefficients was then used to estimate an average controlled direct effect representing the ethnic disparity in breast cancer tumor aggressiveness and the extent to which the disparity might be explained by patient reproductive factors and tumor DNA methylation. Because stage at diagnosis is downstream of, and strongly influenced by, tumor aggressiveness, it was excluded from our analyses. Results: Factors significantly associated with having a higher TAS (p< 0.05) included: nH black or Hispanic race/ethnicity; younger age at first birth; nulliparity; positive family history (FH) of breast cancer, longer use of oral contraceptives; higher pathologic stage; and higher mean BRCA1, GSTM2 and TFF2 methylation levels. In multivariable modeling, variables retained for further analysis included: FH, nulliparity, and methylation of BRCA1, GSTM2, TFF1 and Sat2. In forwards (type 1) analysis of nested models, both nulliparity (p= 0.034) and DNA methylation variables (p< 0.001) were retained. In backwards (type 3) analyses, DNA methylation variables (p< 0.001) but not nulliparity (p= 0.261) were retained. As independent domains, DNA methylation variables explained 46% of the ethnic disparity in TAS (p= 0.054), whereas nulliparity explained 38% (p= 0.058), and family history did not explain any of the disparity. Further, the combination of DNA methylation variables and nulliparity together explained 63% of the disparity (p= 0.033). Conclusions: Our findings suggest that DNA methylation of specific genes may influence breast cancer tumor aggressiveness and may help to explain the preponderance of aggressive subtypes diagnosed in ethnic minority women. DNA methylation may represent a promising avenue for biomarker development for early detection for biologically aggressive tumor types in vulnerable populations. These findings require replication and validation in other studies. Citation Format: Keith A. Dookeran, Abeer M. Mahmoud, Matthew Poulin, Liying Yan, Melanie Ehrlich, Jacob K. Kresovich, Virgilia Macias, Andre Kajdacsy-Balla, Elizabeth Wiley, Garth H. Rauscher. Exploring the role of reproductive factors and DNA methylation in ethnic disparities in breast cancer tumor aggressiveness. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B51.

Mutations in BRCA1 are associated with familial as well as sporadic aggressive subtypes of breast cancer. However, it is not clear to what extent BRCA1 expression or its subcellular localization contributes to breast cancer progression. The goal of this analysis was to examine the differential expression and subcellular localization of BRCA1 among normal breast tissue and breast cancer cases, and whether it could serve as an additional prognostic marker in an ethnically diverse sample of 287 patients (86 Non-Hispanic White, 84 Hispanic and 116 African American). Tissue microarrays (TMAs) were constructed from invasive breast cancer samples obtained from the Breast Cancer Care in Chicago study in addition to 46 age and race-matched normal breast tissue samples. In these TMAs, BRCA1 was immunolabeled with Alexa647; epithelial cytoplasm with Alexa488; and nuclei with DAPI. Slides were visualized and quantified using “VECTRA Automated Multispectral Image Analysis System” and “InForm software”. BRCA1 expression was evaluated based on the percentage of positive cells and staining intensity using the H-score. The H score is a product of the percentage of cells (0-100%) in each intensity category (0, 1+, 2+ and 3+). The final score is on a continuous scale between 0 and 300. The average nuclear score for BRCA1 (Nuc) was higher than that of the cytoplasmic score (Cyto) in normal breast tissue (Nuc: 157.7 ±6.0; Cyto: 150.7±7.5, p = 0.02) and breast cancer cells (Nuc: 140.7 ±3.3; Cyto: 118.0±3.4, p Note: This abstract was not presented at the meeting. Citation Format: Abeer Mostafa Mahmoud, Umaima Al-alem, Virgilia Macias, Ryan J. Deaton, Andre Balla, Peter Gann, Garth Rauscher. BRCA1 protein expression and subcellular localization in primary breast cancer: automated digital microscopy analysis of tissue microarrays. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-019. doi:10.1158/1538-7445.AM2015-LB-019

Androgen receptor (AR) has been demonstrated to be a prognostic marker in invasive breast cancer; higher expression levels of AR is associated with better prognosis among breast cancer patients. The goal of this analysis was to examine the extent to which AR was associated with specific breast cancer subtypes, and whether it could serve as an additional prognostic marker above and beyond breast cancer subtype, in an ethnically diverse sample of 287 patients (86 Non-Hispanic White, 84 Hispanic and 116 African American). Immunohistochemical analysis was performed on tissue microarrays constructed from invasive breast cancer samples obtained from the Breast Cancer Care in Chicago study. Tissue samples were tested for the expression of estrogen receptor (ER), progesterone receptor (PR), HER2. From these results, breast cancers were classified as Luminal A (ER+/PR+/HER2-), Luminal B (ER+/PR+/HER2+), HER2 enriched (ER-/PR-/HER2+), and triple negative (TN) (ER-/PR-/HER2-). Tumor tissues were also analyzed for the expression of other proliferative and apopototic markers (i.e. Ki67, P53 and bcl2) as well as BRCA1 protein expression. AR expression was evaluated based on the percentage of positive tumor cells and staining intensity using the H-score. The H score is a product of the percentage of cells (0-100%) in each intensity category (0, 1+, 2+ and 3+). The final score is on a continuous scale between 0 and 300. AR expression was then classified as low ( Citation Format: Abeer M. Mahmoud, Umaima Al-alem, Virgilia Macias, Jacob K. Kresovich, Andre Kajdacsy-Balla, Elizabeth L. Wiley, Garth H. Rauscher. Androgen receptor is an independent prognostic marker of breast cancer in ethnically diverse women from Chicago. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2774. doi:10.1158/1538-7445.AM2015-2774

Introduction Non-Hispanic (nH) Black and Hispanic women are disproportionately affected by early onset disease, later stage, and with more aggressive, higher grade and ER/PR negative breast cancers. The purpose of this analysis was to examine whether genetic ancestry could account for these variation in breast cancer characteristics, once data were stratified by self-reported race/ethnicity and adjusted for potential confounding by social and behavioral factors. Methods We used a panel of 100 ancestry informative markers (AIMs) to estimate individual genetic ancestry in 656 women from the “Breast Cancer Care in Chicago” study, a multi-ethnic cohort of breast cancer patients to examine the association between individual genetic ancestry and breast cancer characteristics. In addition we examined the association of individual AIMs and breast cancer to identify genes/regions that may potentially play a role in breast cancer disease disparities. Results As expected, nH Black and Hispanic patients were more likely than nH White patients to be diagnosed at later stages, with higher grade, and with ER/PR negative tumors. Higher European genetic ancestry was protective against later stage at diagnosis (OR 0.7 95%CI: 0.54–0.92) among Hispanic patients, and higher grade (OR 0.73, 95%CI: 0.56–0.95) among nH Black patients. After adjustment for multiple social and behavioral risk factors, the association with later stage remained, while the association with grade was not significant. We also found that the AIM SNP rs10954631 on chromosome 7 was associated with later stage (p = 0.02) and higher grade (p = 0.012) in nH Whites and later stage (p = 0.03) in nH Blacks. Conclusion Non-European genetic ancestry was associated with later stage at diagnosis in ethnic minorities. The relation between genetic ancestry and stage at diagnosis may be due to genetic factors and/or unmeasured environmental factors that are overrepresented within certain racial/ethnic groups.

Ki67 labeling index (LI) has been demonstrated to be a prognostic marker in invasive breast cancer; a high Ki67 LI is associated with poorer survival among breast cancer patients. The goal of these analyses was to examine the extent to which Ki67 was associated with specific breast cancer subtypes, and whether it could serve as an additional prognostic marker above and beyond breast cancer subtype, in an ethnically diverse sample of 287 patients (86 Non-Hispanic White, 84 Hispanic and 116 African American). IHC analysis was performed on tissue microarrays constructed from invasive breast cancer samples obtained from the Breast Cancer Care in Chicago study (patients diagnosed between 2005-2008). Tissue samples were tested for the expression of estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR and CK5/6. From these results, breast cancers were classified as Luminal A (ER+/PR+/HER2-), Luminal B (ER+/PR+/HER2+), HER2 enriched (ER-/PR-/HER2+), and triple negative (TN) (ER-/PR-/HER2-). TN tumors were subclassified into basal like (BL) if they expressed either EGFR or CK5/6 or otherwise classified as unspecified (US) if negative for both EGFR and CK5/6. Ki67 LI was classified as low ( In adjusted models, the proportion of tumors with a high Ki67 LI was much lower for luminal A (28%) than for luminal B, HER2, TN-US, and TN-BL subtypes (91,66, 77 and 89%, respectively, p In this multi-ethnic sample of breast cancer patients, we found that Ki67 was a significant independent predictor of more aggressive, higher grade disease, even after accounting for molecular subtype. Ki67 might serve as a useful additional marker for the classification of breast cancer into molecular subtypes. Citation Format: Abeer M. Mahmoud, Virgilia Macias, Umaima Al-alem, Jacob K. Kresovich, Galina Khramtsova, Andre Kajdacsy-Balla, Elizabeth L. Wiley, Garth H. Rauscher. Ki67 is an independent prognostic marker in breast cancer even after accounting for molecular subtype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5569. doi:10.1158/1538-7445.AM2014-5569

Screening mammography reduces breast cancer stage at diagnosis by detecting it early before symptoms develop. Nonetheless, a breast cancer can arise as a lump despite a recent prior negative screen (“missed detection”). In the Breast Cancer Care in Chicago study, Non-Hispanic (nH) Black and Hispanic women were more likely than their nH White counterparts to report a missed detection despite a recent prior screening mammogram. We examined whether breast cancer subtype and immunohistochemical (IHC) markers of tumor aggressiveness predicted missed detection and whether they could explain racial/ethnic disparities in missed detection, in a subsample of 198 patients with a recent prior screening mammogram (63 Non-Hispanic White, 78 Hispanic and 57 African American). Missed detection was defined as symptomatic awareness despite a negative screen in the prior 24 months. IHC analyses were conducted for estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR and CK5/6, Ki67 and p53 expression. Breast cancers were classified as Luminal A (ER+/PR+/HER2-), Luminal B (ER+/PR+/HER2+), HER2 enriched (ER-/PR-/HER2+), and triple negative (TN) (ER-/PR-/HER2-). Missed detection was highest for more aggressive TN and HER2 enriched subtypes (61% and 60%) and lowest for luminal A and B tumors (37% and 38%). Greater Ki67, EGFR and p53 expression were each associated with missed detection (p In this multi-ethnic sample of breast cancer patients, markers of tumor aggressiveness were strongly associated with missed detection at screening but they did not explain racial/ethnic disparities in missed detection. Citation Format: Abeer Mostafa Mahmoud, Virgilia Macias, Jacob K. Kresovich, Andre Kajdacsy-Balla, Elizabeth L. Wiley, Garth H. Rauscher. Mode of breast cancer detection: Do markers of tumor aggressiveness predict which tumors are “missed” at screening. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-274. doi:10.1158/1538-7445.AM2014-LB-274

Background: Zinc is involved in many essential cellular functions. It has been shown that the prostate contains high concentrations of zinc, but zinc levels decrease in prostate cancer tissues. Although, experimental evidence implicates zinc in the pathogenesis of prostate cancer, epidemiological data are inconsistent. We conducted a systematic review of the literature to summarize the evidence regarding the association between zinc and prostate cancer. Methods: Relevant studies were identified by searching PubMed and the Cochrane Library databases through November 2012 and reviewing reference lists of retrieved articles. Inclusion criteria were original and peer-reviewed publications reporting the association between zinc intake or status and prostate cancer outcomes (diagnosis, progression). No reviews, editorials, or comments were included. Two investigators abstracted study information and evaluated quality independently using standardized forms. Results: Sixteen studies met inclusion criteria, including 3 cohorts, 2 nested case-control, 10 case-control, and 1 randomized clinical trial, with a total of 111,288 participants and 11,681 cases of prostate cancer. All studies measured the association between zinc levels and prostate cancer. In most studies, regardless of the study design or source of zinc, the highest dose of zinc was associated with a modest elevation of odds of prostate cancer. Four studies had decreased odds of prostate cancer for the highest dose of zinc but the confidence interval crossed one. There was evidence of a dose-response relationship and subgroup analysis revealed a protective effect of high zinc intake among advanced prostate cancer cases. Conclusions: Although the level of zinc in prostate cancer tissue is reduced, studies assessing the association of zinc intake and prostate cancer have yielded inconsistent results. We performed a systematic review to assess the role of zinc in prostate cancer. As a result of this systematic review, the evidence is still insufficient to recommend zinc supplementation for cancer patients in clinical practice. Citation Format: Abeer M. Mahmoud, Umaima Al-alem, Ebony Shah, Ken Batai, Firas Dabbous, Mohamed Ali, Rick Kittles. Zinc and prostate cancer: a systematic review. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4883. doi:10.1158/1538-7445.AM2013-4883

Introduction: Prostate cancer is a solid malignancy that disproportionately affects men of African descent. Zinc, an essential dietary trace mineral, has been implicated in the pathogenesis of prostate cancer. Total zinc intake is lower in older African American men compared to European Americans (NHANES III). Despite the high prevalence of prostate cancer and decreased levels of zinc intake among African Americans, very little is known about the relationship between zinc intake and prostate cancer in this group. This is significant because dietary factors such as zinc intake are potentially modifiable risk factors. Here, we examine the association between self-reported zinc intake and prostate cancer in a hospital-based case-control study. Methods: Newly diagnosed African American men with histologically confirmed prostate cancer (n=141) were recruited from an urban academic urology clinic in Washington, DC. Controls (n=109) were unaffected volunteers. Usual dietary intake was assessed at the time of recruitment (2000 to 2004) with the use of a food-frequency questionnaire. Two tailed T-Test was used to compare characteristic means between cases and controls. Unconditional logistic regression was used to calculate the unadjusted and adjusted odds ratio (OR) and 95% confidence intervals (95%CI). Results: In this population, cases were older and had higher levels of PSA. Controls had higher zinc intake, with a mean of 13.23 mg/day (SD±13.9) versus 10.67 mg/day (SD±7.3) for cases. An increase of 1 mg/day of zinc decreased the odds of prostate cancer by 3% (OR=0.97 and 95% CI: 0.95-1.002). Controlling for age, body mass index (BMI), PSA and total food energy intake did not affect the observed association. Conclusions: Overall, these results suggest that zinc intake may have slight protective effect on prostate cancer. These analyses should be repeated in large studies to confirm these findings. Citation Format: Firas Dabbous, Umaima Al-alem, Sparkle Springfield, Abeer M. Mahmoud, Ken Batai, Ebony Shah, Chiledum Ahaghotu, Rick A. Kittles. Dietary zinc and prostate cancer: a case-control study in African Americans men. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3621. doi:10.1158/1538-7445.AM2013-3621

Prostate cancer is the most common malignancy and the second leading cause of cancer death among men in the United States. The lower incidence and mortality rates of prostate cancer in Asian population were correlated to the high dietary consumption of isoflavone-rich soy. One of the most abundant and potent isoflavones in soy is genistein which has an estradiol like structure and high affinity to estrogen receptor-α (ER-α). It has been suggested that genistein exerts its anti-cancer effects through binding to ER-α, the later has anti-proliferative and pro-apoptotic effects in prostate cancer. ER-α is mainly expressed in prostate epithelial cells and is downregulated in localized prostate cancer with increasing grade from Prostatic Intraepithelial Neoplasia (PIN) through low to high Gleason grade. This expression pattern supports the notion of a tumor suppressor role of ER-α. Therefore, ER-α agonists may be potential chemopreventive and therapeutic agents for prostate cancer. One of the mechanisms by which ER-α is suppressed in prostate cancer is promoter methylation, the extent of which correlates with the ER-α expression level which in turn may be linked to the degree of aggressiveness of prostate cancer. We examined the effects of physiological range of genistein concentrations (0.5, 1, and 10µM) on ER-α promoter methylation and ER-α expression in LNCaP, LAPC-4, and PC-3 prostate cancer cells that exhibit various basal levels of ER-α expression. We demonstrated for the first time that genistein caused a significant dose-dependent reduction in ER-α promoter methylation in LNCaP and LAPC-4 cells, using methylation specific PCR. There was a corresponding dose-related increase in ER-α mRNA and protein levels in these two cell lines assayed by quantitative RT-PCR and immunoblotting, respectively. However, ER-α expression levels and ER-α promoter methylation were not changed in PC-3 cells, which could be attributed to the low basal level of ER-α promoter methylation and the high basal level of ER-α expression in this cell line. These findings suggest that physiological concentrations of genistein is capable of reactivating tumor suppressor pathways by reversing ER-α promoter methylation with a subsequent restoration of the level of ER-α expression in prostate cancer cells that have higher basal levels of methylation. (Supported in part by Grant No. CA116195) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 583. doi:1538-7445.AM2012-583

Background and Objective: Black men develop and die from prostate cancer (PCa) more than any other racial group. According to recent United States (US) statistics, PCa incidence and mortality rates in Black men are 1.6 and 2.4 times that of their White (WH) counterparts, respectively. Various biologic, behavioral, environmental, demographic, and social-contextual factors have been shown to be components of the persisting disparities in outcomes. However, it is not clear how aspects of body composition, particularly adiposity, contribute to racial and ethnic disparities in PCa occurrence and course. Current reviews on the adiposity relationship have tended not to adequately address this. Therefore, we conducted a systematic review of the literature examining the role of adiposity in racial disparities in prostate cancer. Methods: The US National Library of Medicine National Institutes of Health PubMed database was searched for English articles published through October 1, 2011. Criteria for selection were: 1) an adiposity-related factor (BMI, WHR etc.) was an exposure of interest and related to a PCa outcome (diagnosis, progression, prostate cancer-specific mortality); 2) focused on racial disparities in an adiposity association with PCa; 3) the participant sample included men of predominant African Ancestry [AA] (e.g. Black, African American, Ghanaian etc.); 4) and race-stratified, particularly AA specific, effect estimates for PCa occurrence, mortality, or progression were reported. Adjustment for race in a multivariate model alone was not sufficient for inclusion in the review analysis. No reviews, editorials, or comments were included in the review, although they were cited for background content. Results: Many of the available reviews on adiposity and PCa racial disparities focused on disparities in screening, rather than incidence, progression, or mortality. The articles which did address occurrence and outcomes often did not present race-specific effect estimates and simply adjusted for race in multivariate models. The available evidence suggests a unique role of adiposity-related factors (i.e. body size, body fat distribution, and fatty acid intake,) in the risk of PCa occurrence, progression, differences in treatment efficacy, and PCa-specific death. Lack of studies including sufficiently large numbers of AA prohibited reporting of race-specific estimates in many studies, especially in studies involving molecular biology and genetics. Conclusions: Incidence, morbidity, and mortality are highest in Black men. Clarifying the role of adiposity in PCa disparities is of great importance. Further clinical research illuminating adiposity related targets for intervention and mechanisms is crucial in this highly affected group. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3598. doi:1538-7445.AM2012-3598

Background: Black men develop and die from prostate cancer (PCa) more than any other racial group. According to recent United States (US) statistics, PCa incidence and mortality rates in Black men are 1.6 and 2.4 times that of their White (WH) counterparts, respectively. Various biologic, behavioral, environmental, demographic, and social-contextual factors have been shown to be components of the persisting disparities in outcomes. However, it is not clear how aspects of body composition, particularly adiposity, contribute to racial and ethnic disparities in PCa occurrence and course. Current reviews on the adiposity relationship have tended not to adequately address this. Therefore, we conducted a systematic review of the literature examining the role of adiposity in racial disparities in prostate cancer. Methods: The US National Library of Medicine National Institutes of Health PubMed database was searched for English articles published through October 1, 2011. Criteria for selection were: 1) an adiposity-related factor (BMI, WHR etc.) was an exposure of interest and related to a PCa outcome (diagnosis, progression, prostate cancer-specific mortality); 2) focused on racial disparities in an adiposity association with PCa; 3) the participant sample included men of predominant African Ancestry [AA] (e.g. Black, African American, Ghanaian etc.); 4) and race-stratified, particularly AA specific, effect estimates for PCa occurrence, mortality, or progression were reported. Adjustment for race in a multivariate model alone was not sufficient for inclusion in the review analysis. No reviews, editorials, or comments were included in the review, although they were cited for background content. Results: Many of the available reviews on adiposity and PCa racial disparities focused on disparities in screening, rather than incidence, progression, or mortality. The articles which did address occurrence and outcomes often did not present race-specific effect estimates and simply adjusted for race in multivariate models. The available evidence suggests a unique role of adiposity-related factors (i.e. body size, body fat distribution, and fatty acid intake,) in the risk of PCa occurrence, progression, differences in treatment efficacy, and PCa-specific death. Lack of studies including sufficiently large numbers of AA prohibited reporting of race-specific estimates in many studies, especially in studies involving molecular biology and genetics. Conclusions: Incidence, morbidity, and mortality are highest in Black men. Clarifying the role of adiposity in PCa disparities is of great importance. Further clinical research illuminating adiposity related targets for intervention and mechanisms is crucial in this highly affected group. Citation Format: Iman K. Martin, Leslie T. Stayner, Jocelyn P. Wilder, Abeer M. Mahmoud, Adam B. Murphy, Vincent L. Freeman. The role of adiposity in racial and ethnic disparities in prostate cancer occurrence and progression: A systematic literature review [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C59.

In advanced prostate cancer, cells become androgen independent and therefore resistant to androgen ablation therapy. One mechanism by which prostate cancer bypasses androgen ablation therapy is acquisition of androgen receptor (AR) mutations some of which render it promiscuous enabling activation by a broad group of steroids such as estrogen, progesterone, and even anti-androgens. Genistein, an exogenous steroid (phytoestrogen) and isoflavone found in soy, has estrogenic activity. Most studies have shown that genistein has anti-proliferative effects on prostate cancer cells without regard for the status of the AR. It has been suggested that activation of the mutant AR (MT-AR) by genistein could lead to increased cellular proliferation. Previous studies examining genistein's effect on AR expression used prostate cell lines (i.e. LNCaP) with ARs carrying the promiscuous T877A mutation, without comparison to cells with wild type (WT) AR. Genistein does not bind WT-AR, and thus, may not have the same effect on AR expression as it does in the presence of MT-AR. We set out to compare the effects of genistein in the presence of WT-AR versus MT-AR, using human prostate cancer cell lines with WT-AR (LAPC-4) and MT-AR (LNCaP). Cells were treated with increasing concentrations (0, 0.5, 1, 10, 25, and 50 μM) of genistein. Real time PCR, Western blot analysis, PSA luciferase assay, cell counting by hemocytometer, and MTS proliferation assays were used to determine levels of AR mRNA, protein, transcriptional activity, and cell proliferation, respectively. Genistein caused an androgen-independent biphasic changes in AR mRNA, protein levels, and transcriptional activity, and in cell proliferation in LNCaP cells, which reached a maximum at 1μM of genistein (40-45% increase in AR protein and mRNA expression, 42% increase in PSA luciferase activity, and 2-fold increase in cell proliferation compared to controls). These effects reversed at a concentration of 10 μM. In contrast, in LAPC-4 cells AR mRNA and protein levels and transcriptional activity as well as cell proliferation decreased linearly with increasing dose of genistein, without showing the stimulatory bi-phasic trend observed in LNCaP cells. These decreases were significant, beginning at 1 μM genistein, at which concentration AR mRNA was reduced by 30%, protein expression by 22%, PSA luciferase activity by 40%, and cell proliferation by 56%. These results demonstrate that at physiological concentrations, genistein can exert a mitogenic effect in the presence of MT-AR. Our findings highlight the significance of promiscuous mutations such as T877A for the AR response to genistein treatment and indicate that men with advanced prostatic cancers which carry such AR mutations could be adversely affected by genistein. (Supported in part by Grant No. CA116195) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1864. doi:10.1158/1538-7445.AM2011-1864

Prostate cancer is the leading non-skin malignancy detected in US males and the second cause of death due to male cancer in the US. Androgenic hormones are generally believed to be causatively associated with prostate carcinogenesis, but human evidence, mostly epidemiological, for this is minimal. Circulating hormone levels are not associated with the risk of prostate cancer and neither are polymorphisms in various genes encoding the androgen metabolizing enzymes or androgen receptors. Evidence in support of the involvement of androgens in prostate cancer development is derived from clinical trials with 5α-reductase inhibitors, which reduced the risk by approximately 25%. Animal studies using rat models, however, provide clear evidence that testosterone can induce prostate cancer and can act as a strong tumor promoter in concert with genotoxic carcinogens. One such genotoxic factor may be 17β-estradiol, which is generated from testosterone by the aromatase enzyme. Estradiol can be converted to catecholestrogens, which through redox cycling, generate reactive metabolites that can adduct the DNA and potentially lead to mutations. Animal studies and limited human evidence suggest that estrogens can be involved in prostate carcinogenesis by such a genotoxic mechanism. However, how androgens exert their tumor-promoting effect is not clear. It is likely that hormonal and non-hormonal factors as well as genetic and non-genetic (environmental) factors interact in a highly complex and poorly understood manner to determine the risk of prostate cancer.