SOCIAL, ATTITUDINAL AND BEHAVIORAL CORRELATES OF WEIGHT CHANGE AMONG MEXICAN AMERICAN WOMEN (OBESITY, DIET, TEXAS)

In industrialized countries the prevalence of obesity among women decreases with increasing socioeconomic status. While this relation has been amply documented, its explanation and implications for other causal factors of obesity has received much less attention. Differences in childbearing patterns, norms and attitudes about fatness, dietary behaviors and physical activity are some of the factors that have been proposed to explain the inverse relation.^ The objectives of this investigation were to (1) examine the associations among social characteristics and weight-related attitudes and behaviors, and (2) examine the relations of these factors to weight change and obesity. Information on social characteristics, weight-related attitudes, dietary behaviors, physical activity and childbearing were collected from 304 Mexican American women aged 19 to 50 living in Starr County, Texas, who were at high risk for developing diabetes. Their weights were recorded both at an initial physical examination and at a follow-up interview one to two and one-half years later, permitting the computation of current Body Mass Index (weight/height('2)) and weight change during the interval for each subject. Path analysis was used to examine direct and indirect relations among the variables.^ The major findings were: (1) After controlling for age, childbearing was not an independent predictor of weight change or Body Mass Index. (2) Neither planned exercise nor total daily physical activity were independent predictors of weight change. (3) Women with higher social characteristics scores reported less frequent meals and less use of calorically dense foods, factors associated with lower risk for weight gain. (4) Dietary intake measures were not significantly related to Body Mass Index. However, dietary behaviors (frequency of meals and snacks, use of high and low caloric density foods, eating restraint and disinhibition of restraint) did explain a significant portion (17.4 percent) of the variance in weight change, indicating the importance of using dynamic measures of weight status in studies of the development of obesity. This study highlights factors amenable to intervention to reverse or to prevent weight gain in this population, and thereby reduce the prevalence of diabetes and its sequelae. ^

Symmetric inverse consistent nonlinear registration driven by mutual information.

A nonlinear viscoelastic image registration algorithm based on the demons paradigm and incorporating inverse consistent constraint (ICC) is implemented. An inverse consistent and symmetric cost function using mutual information (MI) as a similarity measure is employed. The cost function also includes regularization of transformation and inverse consistent error (ICE). The uncertainties in balancing various terms in the cost function are avoided by alternatively minimizing the similarity measure, the regularization of the transformation, and the ICE terms. The diffeomorphism of registration for preventing folding and/or tearing in the deformation is achieved by the composition scheme. The quality of image registration is first demonstrated by constructing brain atlas from 20 adult brains (age range 30-60). It is shown that with this registration technique: (1) the Jacobian determinant is positive for all voxels and (2) the average ICE is around 0.004 voxels with a maximum value below 0.1 voxels. Further, the deformation-based segmentation on Internet Brain Segmentation Repository, a publicly available dataset, has yielded high Dice similarity index (DSI) of 94.7% for the cerebellum and 74.7% for the hippocampus, attesting to the quality of our registration method.

Dissecting the Interaction between p53 and TRIM24

Dissecting the Interaction of p53 and TRIM24 Aundrietta DeVan Duncan Supervisory Professor, Michelle Barton, Ph.D. p53, the “guardian of the genome”, plays an important role in multiple biological processes including cell cycle, angiogenesis, DNA repair and apoptosis. Because it is mutated in over 50% of cancers, p53 has been widely studied in established cancer cell lines. However, little is known about the function of p53 in a normal cell. We focused on characterizing p53 in normal cells and during differentiation. Our lab recently identified a novel binding partner of p53, Tripartite Motif 24 protein (TRIM24). TRIM24 is a member of the TRIM family of proteins, defined by their conserved RING, B-box, and coiled coil domains. Specifically, TRIM24 is a member of the TIF1 subfamily, which is characterized by PHD and Bromo domains in the C-terminus. Between the Coiled-coil and PHD domain is a linker region, 437 amino acids in length. This linker region houses important functions of TRIM24 including it’s site of interaction with nuclear receptors. TRIM24 is an E3-ubiquitin ligase, recently discovered to negatively regulate p53 by targeting it for degradation. Though it is known that Trim24 and p53 interact, it is not known if the interaction is direct and what effect this interaction has on the function of TRIM24 and p53. My study aims to elucidate the specific interaction domains of p53 and TRIM24. To determine the specific domains of p53 required for interaction with TRIM24, we performed co-immuoprecipitation (Co-IP) with recombinant full-length Flag-tagged TRIM24 protein and various deletion constructs of in vitro translated GST-p53, as well as the reverse. I found that TRIM24 binds both the carboxy terminus and DNA binding domain of p53. Furthermore, my results show that binding is altered when post-translational modifications of p53 are present, suggesting that the interaction between p53 and TRIM24 may be affected by these post-translational modifications. To determine the specific domains of TRIM24 required for p53 interaction, we performed GST pull-downs with in vitro translated, Flag-TRIM24 protein constructs and recombinant GST-p53 protein purified from E. coli. We found that the Linker region is sufficient for interaction of p53 and TRIM24. Taken together, these data indicate that the interaction between p53 and TRIM24 does occur in vitro and that interaction may be influenced by post-translational modifications of the proteins.

TH and XFKBP12 interact and regulate proliferation and differentiation in neural ectoderm through the TOR signaling pathway

During development, embryos must carefully integrate the processes of cell proliferation and differentiation. TH has been identified in Xenopus laevis as a gene product that functions in regulating differentiation of the neural ectoderm through its effect on cell proliferation. However, the mechanism and molecular pathway through which TH functions are not known. We identified the Xenopus FK506 binding protein homolog (XFKBP12) as a protein that interacted with TH in a yeast two-hybrid screen with TH as the bait. The direct and specific interaction between TH and XFKBP12 was supported by several tests including CO-IP, drug competence assay and mutagenesis analysis. To investigate the function of XFKBP12 during embryogenesis, we created an XFKBP12 loss of function embryo using antisense morpholino oligonucleotides (MO). XFKBP12 MO injected embryos displayed similar phenotypes as TH depleted embryos. We also demonstrated that both TH and XFKBP12 functioned through the TOR signaling pathway which is a target for cancer therapies. The interaction between TH and XFKBP 12 was required to regulate the proliferation of neural cells. Therefore, our study indicates that TH represents the endogenous ligand of XFKBP12 and together they coordinate neural cell proliferation and differentiation through the conserved rapamycin sensitive TOR pathway. Thus, understanding how this pathway functions in development will not only provide us important insights into the relationship between proliferation and differentiation, but help design rational cancer therapies targeting this pathway. ^

Psychosocial and environmental predictors of calcium intake, physical activity and bone health among adolescent girls

Objectives. The purpose of this study was to identify the psychosocial and environmental predictors and the pathways they use to influence calcium intake, physical activity and bone health among adolescent girls. Methods. A secondary data analysis using a cross-sectional and longitudinal study design was implemented to examine the associations of interest. Data from the Incorporating More Physical Activity and Calcium in Teens (IMPACT) study collected in 2001-2003 were utilized for the analyses. IMPACT was a 1½ year nutrition and physical activity intervention study conducted among 718 middle-school girls in central Texas. Hierarchical regression modeling and Structural Equation Modeling (SEM) were used to determine the psychosocial predictors of calcium intake, physical activity and bone health at baseline. Hierarchical regression was used to determine if psychosocial factors at baseline were significant predictors of calcium intake and physical activity at follow-up. Data was adjusted for included BMI, lactose intolerance, ethnicity, menarchal status, intervention and participation in 7th grade PE/athletics. Results. Results of the baseline regression analysis revealed that calcium self-efficacy and milk availability at home were the strongest predictors of calcium intake. Friend engagement in physical activity, physical activity self-efficacy and participation in sports teams were the strongest predictors of physical activity. Finally, physical activity outcome expectations, social support and participation in sports teams were significant predictors of stiffness index at baseline. Results of the baseline SEM path analysis found that outcome expectations and milk availability at home directly influenced calcium intake. Knowledge and calcium self-efficacy indirectly influenced calcium intake with outcome expectations as the mediator. Physical activity self-efficacy and social support had significant direct and indirect influence on physical activity with participation in sports teams as the mediator. Participation in sports teams had a direct effect on both physical activity and stiffness index. Results of regression analysis for baseline predicting follow-up showed that participation in sports teams, self-efficacy, outcome expectations and social support at baseline were significant predictors of physical activity at follow-up. Conclusion. Results of this study reinforce the relevance of addressing both, psychosocial and environmental factors which are critical when developing interventions to improve bone health among adolescent girls. ^

Crack and powder cocaine federal legislation: A sentencing disparity and potential for policy improvement

Since its introduction into the United States in the 1980s, crack cocaine has been a harsh epidemic that has taken its toll on a countless number of people. This highly addictive, cheap and readily available drug of abuse has permeated many demographic sectors, mostly in low income, lesser educated, and urban communities. This epidemic of crack cocaine use in inner city areas across the Unites States has been described as an expression of economic marginality and “social suffering” coupled with the local and international forces of drug market economies (Agar 2003). As crack cocaine is a derivative of cocaine, it utilizes the psychoactive component of the drug, but delivers it in a much stronger, quicker, and more addictive fashion. This, coupled with its ready availability and cheap price has allowed for users to not only become very addicted very quickly, but to be subject to the stringent and sometimes unequal or inconsistent punishments for possession and distribution of crack-cocaine. ^ There are many public health and social ramifications from the abuse of crack-cocaine, and these epidemics appear to target low income and minority groups. Public health issues relating to the physical, mental, and economic strain will be addressed, as well as the direct and indirect effects of the punishments that come as a result of the disparity in penalties for cocaine and crack-cocaine possession and distribution. ^ Three new policies have recently been introduced into the United Stated Congress that actively address the disparity in sentencing for drug and criminal activities. They are, (1) Powder-Crack Cocaine Penalty Equalization Act of 2009, (HR 18, 111th Cong. 2009), (2) The Drug Sentencing Reform and Cocaine Kingpin Trafficking Act of 2009, (HR 265, 111th Cong. 2009) and (3) The Justice Integrity Act of 2009, (111th Cong. 2009). ^ Although they have only been initiated, if passed, they have potential to not only eliminate the crack-cocaine disparity, but to enact laws that help those affected by this epidemic. The final and overarching goal of this paper is to analyze and ultimately choose the ideal policy that would not only eliminate the cocaine and crack disparity regardless of current or future state statutes, but will provide the best method of rehabilitation, prevention, and justice. ^

Delays in diagnosis and referral and treatment for hematologic malignancies

The purpose of this thesis project was to identify factors that may contribute to a delay in the diagnosis, referral or treatment of the hematologic malignancies. This thesis is a secondary data analysis of both qualitative and quantitative data collected during a pilot study for a parent CDC study to determine factors related to time to diagnosis, referral, and treatment of chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma (MM), and myelodisplastic syndrome (MDS). To identify patterns for referral, as well as explore referral, treatment, and follow-up patterns, MDACC performed a pathways analysis, and conducted semi-structured interviews with hematologic cancer patients to help identify factors related to delays. Interviews were also conducted with primary care physicians and community hematologists/oncologists to help identify factors associated with optimal and sub-optimal patterns of diagnosis and referral. The results of these analyses suggest a set of factors that may be related to a fairly smooth and rapid trajectory to treatment, and factors that may be related to a slower, more disrupted trajectory. Factors that may be especially important to facilitating rapid treatment include the presence of cues to seek diagnosis in the patient's environment and the patient recognizing and acting upon these cues to seek immediate medical attention. Furthermore, providers who perform behaviors including recognizing cues as indicators of hematologic malignancies and conducting appropriate diagnostic testing effectively and efficiently indicate that these behaviors may also contribute to shorter times to diagnosis. In regards to referrals, direct and effective communication between providers and patients, as well between providers themselves helped facilitate speedier referrals. A patient's insurance status as well as the presence or absence of social support in his environment served as factors that may increase or decrease time to diagnosis, referral, and treatment for a hematologic malignancy. Further research is needed to define delay to diagnosis, referral and treatment in order to improve early diagnosis, referral, and treatment of hematologic malignancies.^

ENVIRONMENTAL EXPOSURES AND LUNG CANCER RISK AMONG WOMEN IN HARRIS COUNTY, TEXAS, 1977-1980 (OCCUPATION, SMOKING, BYSTANDER)

Excessively high, accelerating lung cancer rates among women in Harris County, Texas, prompted this case-comparison study. Objectives were to compare patterns of employment, indirect exposures, and sociodemographic variables of lung cancer cases with comparison subjects (compeers) after standardizing for possible confounders, such as age and cigarette smoking. Lung cancer cases were microscopically confirmed, white, Harris County residents. Compeers, chosen from Medicare records and Texas Department of Public Safety records, were matched on gender, race, age, resident and vital status. Personal interviews were conducted with study subjects or next-of-kin. Industries and occupations were categorized as high risk, based on previous studies.^ Almost all cases (95.0%) and 60.0% of compeers smoked cigarettes. The odds ratio for lung cancer and smoking is 13.9. Stopping smoking between ages 30-50 years carries a lower risk than stopping at age 58 or more years. Women's employment in a high risk industry or occupation results in consistently elevated, smoking-adjusted odds ratios. Frequency and duration of employment demonstrate a moderate dose-response effect. A temporal association exists with employment in a high risk occupation during 1940-1949.^ No increased risk appeared with passive smoking. Husband's employment in a construction industry or a structural occupation significantly increased the smoking-adjusted odds ratios among cases and compeers (O.R. = 2.9, 2.2). Smoking-adjusted odds ratios increased significantly when women had resided with persons employed in cement (O.R. = 3.2) or insulation (O.R. = 5.5) manufacturing, or a high rise construction industry (O.R. = 2.4). A family history of lung cancer resulted in a two-fold increase in smoking-adjusted odds ratios. Vital status of compeers affected the odds ratios.^ Work-related exposures appear to increase the risk of lung cancer in women although cigarette smoking has the single highest odds ratio. Indirect exposure to certain employment also plays a significant role in lung cancer in women. Investigations of specific direct and indirect hazardous exposures in the workplace and home are needed. Cigarette smoking is as hazardous for women as for men. Smoking should be prevented and eliminated. ^

MicroRNA Regulation of Prostate Cancer Stem/Progenitor Cells and Prostate Cancer Development

Most human tumors contain a population of cells with stem cell properties, called cancer stem cells (CSCs), which are believed to be responsible for tumor establishment, metastasis, and resistance to clinical therapy. It’s crucial to understand the regulatory mechanisms unique to CSCs, so that we may design CSC-specific therapeutics. Recent discoveries of microRNA (miRNA) have provided a new avenue in understanding the regulatory mechanisms of cancer. However, how miRNAs may regulate CSCs is still poorly understood. Here, we present miRNA expression profiling in six populations of prostate cancer (PCa) stem/progenitor cells that possess distinct tumorigenic properties. Six miRNAs were identified to be commonly and differentially expressed, namely, four miRNAs (miR-34a, let-7b, miR-106a and miR-141) were under-expressed, and two miRNAs (miR-301 and miR-452) were over-expressed in the tumorigenic subsets compared to the corresponding marker-negative subpopulations. Among them, the expression patterns of miR-34, let-7b, miR-141 and miR-301 were further confirmed in the CD44+ human primary prostate cancer (HPCa) samples. We then showed that miR-34a functioned as a critical negative regulator in prostate CSCs and PCa development and metastasis. Over-expression of miR-34a in either bulk or CD44+ PCa cells significantly suppressed clonal expansion, tumor development and metastasis. Systemic delivery of miR-34a in tumor-bearing mice demonstrated a potent therapeutic effect again tumor progression and metastasis, leading to extended animal survival. Of great interest, we identified CD44 itself as a direct and relevant downstream target of miR-34a in mediating its tumor-inhibitory effects. Like miR-34a, let-7 manifests similar tumor suppressive effects in PCa cells. In addition, we observed differential mechanisms between let-7 and miR-34a on cell cycle, with miR-34a mainly inducing G1 cell-cycle arrest followed by cell senescence and let-7 inducing G2/M arrest. MiR-301, on the other hand, exerted a cell type dependent effect in regulating prostate CSC properties and PCa development. In summary, our work reveals that the prostate CSC populations display unique miRNA expression signatures and different miRNAs distinctively and coordinately regulate various aspects of CSC properties. Altogether, our results lay a scientific foundation for developing miRNA-based anti-cancer therapy.

The role of cardiorespiratory fitness and weight status on 24-hr ambulatory blood pressure among adolescents

BACKGROUND: This observational research study investigated the association of cardiorespiratory fitness and weight status with repeated measures of 24-hr ambulatory blood pressure (24-hr ABP). Little is known about these associations and few data exist examining the interaction between cardiorespiratory fitness and weight status and the contributions of each on 24-hr ABP in youth. ^ METHODS: This research study used secondary analysis data from the "Adolescent Blood Pressure and Anger: Ethnic Differences" study. This current study sample included 374 African-American, Anglo-American, and Mexican-American adolescents 11-16 years of age. Mixed-effects models were used for testing the relationship between weight status and cardiorespiratory fitness and repeated measures of ambulatory blood pressure over 24 hours (24-hr ABP). Weight status was categorized into "normal weight" (BMI<85th percentile), "overweight" (85th≤BMI<95th), and "obese" (BMI≥95th). Cardiorespiratory fitness, determined by heart rate recovery (HRR), was defined as the difference between heart rate at peak exercise and heart rate at two minutes post-exercise, as measured by a height-adjusted step test and stratified into two groups: low and high fitness, using a median split. Ambulatory blood pressure (ABP) was monitored for a 24-hr period on a school day using the Spacelabs ambulatory monitor (Model 90207). Blood pressure and heart rate were recorded at 30 minute intervals throughout the day of recording and at 60 minute intervals during sleep. ^ RESULTS: No significant associations were found between weight status and mean 24-hr systolic blood pressure (SBP) or mean arterial pressure (MAP). A significant and inverse association between weight status and mean 24-hr diastolic blood pressure (DBP) was revealed. Cardiorespiratory fitness was significantly and inversely associated with mean 24-hr ABP. High fitness adolescents had significantly lower mean 24-hr SPB, DBP, and MAP measurements than low fitness adolescents. Compared to low fitness adolescents, high fitness adolescents had 1.90 mmHg, 1.16 mmHg, and 1.68 mmHg lower mean 24-hr SBP, DBP, and MAP, respectively. Additionally, high fitness appeared to afford protection from higher mean 24-hr SBP and MAP, irrespective of weight status. Among normal weight adolescents, low fitness resulted in higher mean 24-hr SBP and MAP, compared to their fit counterparts. Among adolescents categorized as high fitness, increasing weight status did not appear to result in higher mean 24-hr SBP or MAP. Cardiorespiratory fitness, rather than weight status, appeared to be a more dominant predictor of mean 24-hr SBP and MAP. ^ CONCLUSIONS: To our knowledge, this research is the first study to investigate the independent and combined contributions of cardiorespiratory fitness and weight status on 24-hr ABP, all objectively measured. The results of this study may potentially guide and inform future research. It appears that early cardiovascular disease (CVD) prevention should focus on improving cardiorespiratory fitness levels among all adolescents, particularly those adolescents least fit, regardless of their weight status, while obesity prevention efforts continue.^

Potential roles for bcl-2 in the pathogenesis, progression, and treatment of prostate cancer

The most common molecular alterations observed in prostate cancer are increased bcl-2 protein expression and mutations in p53. Understanding the molecular alterations associated with prostate cancer are critical for successful treatment and designing new therapeutic interventions. Hormone-ablation therapy remains the most effective nonsurgical treatment; however, most patients will relapse with hormone-independent, refractory disease. This study addresses how hormone-ablation therapy may increase bcl-2, develops a transgenic model to elucidate the role of bcl-2 multistep prostate carcinogenesis, and assesses how bcl-2 may confer resistance to cell death induction using adenoviral wild-type p53 gene therapy. ^ Two potential androgen response elements were identified in the bcl-2 promoter. Bcl-2 promoter luciferase constructs were transfected into the hormone- sensitive LNCaP prostate cell line. In the presence of dihydrotestosterone, the activity of one bcl-2 promoter luciferase construct was repressed 40% compared to control cells grown in charcoal-stripped serum. Additionally, it was demonstrated that both bcl-2 mRNA and protein were downregulated in the LNCaP cells grown in the presence DHT. This suggests that DHT represses bcl-2 expression through possible direct and indirect mechanisms and that hormone-ablation therapy may actually increases bcl-2 protein. ^ To determine the role of bcl-2 in prostate cancer progression in vivo, probasin-bcl-2 mice were generated where human bcl-2 was targeted to the prostate. Increased bcl-2 expression rendered the ventral prostate more resistant to apoptosis induction following castration. When the probasin-bcl-2 mice were crossed with TRAMP mice, the latency to tumor formation was decreased. The expression of bcl-2 in the double transgenic mice did not affect the incidence of metastases. The double transgenic model will facilitate the study of in vivo effects of specific genetic lesions during the pathogenesis of prostate cancer. ^ The effects of increased bcl-2 protein on wild-type adenoviral p53-mediated cell death were determined in prostatic cell lines. Increased bcl-2 protected PC3 and DU145 cell lines, which possess mutant p53, from p53-mediated cell death and reductions in cell viability. Bcl-2 did not provide the same protective effect in LNCaP cell line, which expresses wild-type p53. This suggests that the ability of bcl-2 to protect against p53-mediated cell death is dependent upon the endogenous status of p53. ^