Effects of Combined Bevacizumab and Paclitaxel on Tumor Interstitial Fluid Pressure in a Preclinical Breast Cancer Model

Effects of Combined Bevacizumab and Paclitaxel on Tumor Interstitial Fluid Pressure in a Preclinical Breast Cancer Model by Ricardo H. Alvarez Several mechanisms of cell resistance are often accountable for unsuccessful chemotherapy against cancer. Another reason, which has received increased attention, is the inefficient transport of anticancer drugs into tumor tissue. These impaired transports of chemotherapy into the tumor have been attributed to abnormal microvasculature and to pathologically increased tumor hypertension also called: interstitial fluid pressure (IFP). The pathophysiological processes leading to elevated tumor IFP are poorly understood. Here, in a preclinical breast cancer model, it is argued that a condition of raised IFP is a major factor in preventing optimal access of systemically administered chemotherapy agents. In our experimental model, we used a GILM2 human breast cancer in xenografts; mice were treated with different doses of paclitaxel –a widely used antimicrotubular agent, and bevacizumab –monoclonal antibody against vascular endothelial growth factor (VEGF). The proposed research project is designed to test the hypothesis that paclitaxel in combination with bevacizumab decreases the tumor IPF by restoring tumor permeability and increasing chemotherapy delivery. We demonstrated that the combination of paclitaxel and bevacizumab produced greater tumor control than either agent given alone and this combination reduced the IFP, producing an increment of 75% of apoptosis compared with the control arm. In addition, the intra-tumor paclitaxel quantification by liquid chromatography/Mass Spectrometry (LC/MS) demonstrated that lower dose of both agents showed a synergistic effect compared with high dose of treatment, where there is no significantly increase of paclitaxel into the tumor. These preclinical results are likely to have broad implications for the utility of anti-angiogenic therapies alone and in combination with chemotherapeutic agents.

Genes to blood pressure: The effects of variation in genes of the renin-angiotensin system on the hormonal and renal control of blood pressure

Objective. Essential hypertension affects 25% of the US adult population and is a leading contributor to morbidity and mortality. Because BP is a multifactorial phenotype that resists simple genetic analysis, intermediate phenotypes within the complex network of BP regulatory systems may be more accessible to genetic dissection. The Renin-Angiotensin System (RAS) is known to influence intermediate and long-term blood pressure regulation through alterations in vascular tone and renal sodium and fluid resorption. This dissertation examines associations between renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT1) gene variation and interindividual differences in plasma hormone levels, renal hemodynamics, and BP homeostasis.^ Methods. A total of 150 unrelated men and 150 unrelated women, between 20.0 and 49.9 years of age and free of acute or chronic illness except for a history of hypertension (11 men and 7 women, all off medications), were studied after one week on a controlled sodium diet. RAS plasma hormone levels, renal hemodynamics and BP were determined prior to and during angiotensin II (Ang II) infusion. Individuals were genotyped by PCR for a variable number tandem repeat (VNTR) polymorphism in REN, and for the following restriction fragment length polymorphisms (RFLP): AGT M235T, ACE I/D, and AT1 A1166C. Associations between clinical measurements and allelic variation were examined using multiple linear regression statistical models.^ Results. Women homozygous for the AT1 1166C allele demonstrated higher intracellular levels of sodium (p = 0.044). Men homozygous for the AGT T235 allele demonstrated a blunted decrement in renal plasma flow in response to Ang II infusion (p = 0.0002). There were no significant associations between RAS gene variation and interindividual variation in RAS plasma hormone levels or BP.^ Conclusions. Rather than identifying new BP controlling genes or alleles, the study paradigm employed in this thesis (i.e., measured genes, controlled environments and interventions) may provide mechanistic insight into how candidate genes affect BP homeostasis. ^

Contribution of the genes of the renin-angiotensin system to interindividual differences in blood pressure levels in Caucasians from Rochester, Minnesota

The Renin-Angiotensin system (RAS) regulates blood pressure through its effects on vascular tone, renal hemodynamics, and renal sodium and fluid balance. The genes encoding the four major components of the RAS, angiotensinogen, renin, angiotensin I-converting enzyme (ACE), and angiotensin II receptor type 1 (AT1), have been investigated as candidate genes in the pathogenesis of essential hypertension. However, studies have primarily focused on small samples of diseased individuals, and, therefore, have provided little information about the determinants of interindividual variation in blood pressure (BP) in the general population.^ Using data from a large population-based sample from Rochester, MN, I have evaluated the contribution of variation in the region of the RAS genes to interindividual variation in systolic, diastolic, and mean arterial pressure in the population-at-large. Marker genotype data from four polymorphisms located within or very near these genes were first collected on 3,974 individuals from 583 randomly ascertained three-generation pedigrees. Haseman-Elston regression and variance component methods of linkage analysis were then carried out to estimate the proportion of interindividual variance in BP attributable to the effects of variation at these four measured loci.^ A significant effect of the ACE locus on interindividual variation in mean arterial pressure (MAP) was detected in a sample of siblings belonging to the youngest generation. After allowing for measured covariates, this effect accounted for 15-25% of the interindividual variance in MAP, and was even greater in a subset with a positive family history of hypertension. When gender-specific analyses were carried out, this effect was significant in males but not in females. Extended pedigree analyses also provided evidence for an effect of the ACE locus on interindividual variation in MAP, but no difference between males and females was observed. Circumstantial evidence suggests that the ACE gene itself may be responsible for the observed effects on BP, although the possibility that other genes in the region may be at play cannot be excluded.^ No definitive evidence for an effect of the renin, angiotensinogen, or AT1 loci on interindividual variation in BP was obtained in this study, suggesting that the impact of these genes on BP may not be great in the Caucasian population-at-large. However, this does not preclude a larger effect of these genes in some subsets of individuals, especially among those with clinically manifest hypertension or coronary heart disease, or in other populations. ^

The influence of contact pressure, moisture, and compression time on the performance of cotton anti-contamination clothing

The objectives of this research were (1) to study the effect of contact pressure, compression time, and liquid (moisture content of the fabric) on the transfer by sliding contact of non-fixed surface contamination to protective clothing constructed from uncoated, woven fabrics, (2) to study the effect of contact pressure, compression time, and liquid content on the subsequent penetration through the fabric, and (3) to determine if varying the type of contaminant changes the effect of contact pressure, compression time, and liquid content on the transfer by sliding contact and penetration of non-fixed surface contamination. ^ It was found that the combined influence of the liquid (moisture content of the fabric), load (contact pressure), compression time, and their interactions significantly influenced the penetration of all three test agents, sucrose- 14C, triolein-3H, and starch-14C through 100% cotton fabric. The combined influence of the statistically significant main effects and their interactions increased the penetration of triolein- 3H by 32,548%, sucrose-14C by 7,006%, and starch- 14C by 1,900%. ^

Blood-oxygen-level-dependent (BOLD) signal changes in total cortex and subcortex, pain, reward, and vigilance regions during mechanical pressure pain after morphine administration

Morphine is the most common clinical choice in the management of severe pain. Although the molecular mechanisms of morphine have already been characterized, the cerebral circuits by which it attenuates the sensation of pain have not yet been studied in humans. The objective of this two-arm (morphine versus placebo), between-subjects study was to examine whether morphine affects pain via pain-related cortical circuits, but also via reward regions that relate to the motivational state, as well as prefrontal regions that relate to vigilance as a result of morphine's sedative effects. Cortical activity was measured by the blood-oxygen-level-dependent (BOLD) signal changes using functional magnetic resonance imaging (fMRI). ^ The novelty of this study is at three levels: (i) to develop a methodology that will assess the average BOLD signal across subjects for the pain, reward, and vigilance cortical systems; (ii) to examine whether the reward and/or sedative effects of morphine are contributing factors to cortical regions associated with the motivational state and vigilance; and (iii) to propose a neuroanatomical model related to the opioid-sensitive effects of reward and sedation as a function of cortical activity related to pain in an effort to assess future analgesics. ^ Consistent with our hypotheses, our findings showed that the decrease in total pain-related volume activated between the post- and the pre-treatment morphine group was about 78%, while the post-treatment placebo group displayed only a 5% decrease when compared to pre-treatment levels of activation. The volume increase in reward regions was 451% in the post-treatment compared to the pre-treatment morphine condition. Finally, the volumetric decrease in vigilance regions was 63% in the posttreatment compared to the pre-treatment morphine condition. ^ These findings imply that changes in the blood flow of the reward and vigilance regions may be contributing factors in producing the analgesic effect under morphine administration. Future studies need to replicate this study in a higher resolution fMRI environment and to assess the proposed neuroanatomical model in patient populations. The necessity of pain research is apparent, since pain cuts across different diseases especially chronic ones, and thus, is recognized as a vital public health developing area. ^

A review of the effects of Transcendental Meditation on cardiovascular disease

Cardiovascular disease (CVD) is the single greatest cause of death in the United States, accounting for nearly 2400 deaths each day. It is estimated that 79.4 million American adults have some form of the disease, and CVD mortality rates are greater than those of cancer, chronic lower respiratory diseases, accidents and diabetes mellitus combined. Psychosocial stress is a nontraditional risk factor for CVD, and can contribute to the clustering of traditional risk factors as well as to vascular manifestations of the disease. The Transcendental Meditation (TM) technique has been researched as a cost effective intervention aimed at decreasing psychosocial stress. This literature review attempts to analyze randomized controlled clinical trials of TM on cardiovascular disease outcomes. Eleven studies met inclusion criteria and are described below, with statistically significant positive outcomes observed in each study. Studies are grouped by primary outcome reported in the categories of cardiovascular function, blood pressure, and exercise tolerance. The TM intervention significantly decreased insulin resistance, heart rate variability, and carotid intima media thickness and improved exercise tolerance compared to control groups. Seven studies also reported significant decreases in blood pressure among hypertensive and normotensive subjects. Five studies focused solely on African American subjects, a population that has disproportionately higher rates of CVD and hypertension, and found significant improvements in CVD outcomes. Further research is recommended to establish the efficacy of TM on CVD outcomes. Future trials should include larger sample populations, wider ethnic distributions of subjects, and longer follow-up to ascertain the impact of this particular stress reduction technique on cardiovascular disease.^

Effectiveness of dietary intervention in children and adolescents with elevated blood pressure

Hypertension is a known risk factor for cardiovascular disease in adults. Essential hypertension in children and adolescents is increasing in prevalence in the United States, and hypertension in children may track into adulthood. This increasing prevalence is attributed to the trends of increasing overweight and obese children and adolescents. Family history and being of African-American/black descent may predispose youth to elevated blood pressure. Interventions targeted to reduce and treat hypertension in youth include non-pharmaceutical interventions such as weight reduction, increased physical activity, and dietary changes and pharmaceutical treatment when indicated. The effectiveness of non-pharmaceutical interventions is well documented in adults, but there are limited studies with regards to children and adolescents, specifically in the arena of dietary interventions. Lifestyle modifications such as dietary interventions are the mainstay of recommended treatment for those children and adolescents with prehypertension or stage 1 hypertension. Given the association of being overweight and hypertension, efficacy of dietary interventions are of interest because of reduced cost, easy implementation and potential for multiple beneficial outcomes such as reduced weight and reduction of other metabolic or cardiovascular derangements. Barriers to dietary interventions often include socioeconomic status, ethnicity, personal, and external factors. The goal of this systematic review of the literature is to identify interventions targeted to children and adolescents that focus on recommended dietary changes related to blood pressure. Dietary interventions found for this review mostly focused on a particular nutrient or food group with the one notable exception that focused on the DASH pattern of eating. The effects of the interventions on blood pressure varied, but overall dietary modifications can be achieved in youth and can serve a role in producing positive outcomes on blood pressure. Increasing potassium and following a DASH diet seemed to provide the most clinically significant results. Further studies are still needed to evaluate long-term effectiveness and to contribute more supporting evidence for particular modifications in these age cohorts.^

Epidemiologic and methodological issues in serial measurements of blood pressure: The blood pressure study in Mexican children

The Blood Pressure Study in Mexican Children (BPSMC) is a short term longitudinal study of serial blood pressure collected in three observation periods by standardized examinations of 233 female children, 10 to 12 years of age, enrolled in public and private primary schools in Tlalpan, Mexico. Study objectives were: (1) to describe from baseline information the distribution and relationship of blood pressure to age and selected anthropometric factors, as well as to compare the BPSMC results with other blood pressure studies, (2) to examine the sources and amount of variation present in serial blood pressure of 123 children, and (3) to evaluate observer performance by means of intra- and inter-observer variability.^ Stepwise regression results from baseline revealed that of all anthropometric factors and age, weight was the best predictor for blood pressure.^ The results of serial blood pressure measurements show that, besides the known sources of blood pressure variability (subject, day, reading), the physiologic event of menarche has an important bearing upon the variability and characterization of blood pressure in young girls. The assessment of the effects of blood pressure variability and reliability upon the design and analysis of epidemiologic studies, became apparent among post-menarcheal girls; where blood pressure measurements taken from them have low reliability. Research is needed to propose alternatives for assessing blood pressure during puberty.^ Finally, observer performance of blood pressure and anthropometry were evaluated. Anthropometric measurements had reliabilities in excess of R = 0.96. Acceptable reliabilities (R = 0.88 to 0.95) were obtained for systolic and diastolic (phase 4 and 5) blood pressures. The BPSMC showed a 50 percent decrease in measurement error from the first to the third observation periods. ^

FEMALE SEXUAL MATURATION AND BLOOD PRESSURE (SECONDARY-SEX CHARACTERISTICS, GROWTH, DEVELOPMENT)

This study described the relationship of sexual maturation and blood pressure in a sample (n = 361) of white females, ages seven through 18, attending public schools in a defined area of Central Texas during October through December, 1984. Other correlates of blood pressure were also described for this sample.^ A survey was performed to obtain the data on height, weight, body mass, pulse rate, upper arm circumference and length, and blood pressure. Each subject self-assessed her secondary sex characteristics (breast and pubic hair) according to drawings of the Tanner stages of maturation. The subjects were interviewed to obtain data on personal health habits and menstrual status. Student age, ethnic group and place of residence were abstracted from school records. Parents or guardians of the subjects responded to a questionnaire pertaining to parental and subject health history and parents' occupation and educational attainment.^ In the simple linear regression analysis, sexual maturation and variables of body size were significantly (p < 0.001) and positively associated with systolic and fourth- and fifth-phase diastolic blood pressure. The demographic and socioeconomic variables were not sufficiently variant in this population to have differential effects on the relation between blood pressure and maturation. Stepwise multiple regression was used to assess the contribution of sexual maturation to the variance of blood pressure after accounting for the variables of body size. Sexual maturation (breast stage) along with weight, height and body mass remained in the multiple regression models for fourth- and fifth-phase diastolic blood pressure. Only height and body mass remained in the regression model for systolic blood pressure; sexual maturation did not contribute more to the explanation of the systolic blood pressure variance.^ The association of sexual maturation with blood pressure level was established in this sample of young white females. More research is needed first, to determine if this relationship prevails in other populations of young females, and second, to determine the relationship of sexual maturation sequence and change with the change of blood pressure during childhood and adolescence. ^

Patient-centered medical home technology effects on hypertension and diabetes control

Background: Hypertension and Diabetes is a public health and economic concern in the United States. The utilization of medical home concepts increases the receipt of preventive services, however, do they also increase adherence to treatments? This study examined the effect of patient-centered medical home technologies such as the electronic health record, clinical support system, and web-based care management in improving health outcomes related to hypertension and diabetes. Methods: A systematic review of the literature used a best evidence synthesis approach to address the general question " Do patient-centered medical home technologies have an effect of diabetes and hypertension treatment?" This was followed by an evaluation of specific examples of the technologies utilized such as computer-assisted recommendations and web-based care management provided by the patient's electronic health record. Ebsco host, Ovid host, and Google Scholar were the databases used to conduct the literature search. Results: The initial search identified over 25 studies based on content and quality that implemented technology interventions to improve communication between provider and patient. After further assessing the articles for risk of bias and study design, 13 randomized controlled studies were chosen. All of the studies chosen were conducted in various primary care settings in both private practices and hospitals between the years 2000 and 2007. The sample sizes of the studies ranged from 42 to 2924 participants. The mean age for all of the studies ranged from 56 to 71 years. The percent women in the studies ranged from one to 78 percent. Over one-third of the studies did not provide the racial composition of the participants. For the seven studies that did provide information about the ethnic composition, 64% of the intervention participants were White. All of the studies utilized some type of web-based or computer-based communication to manage hypertension or diabetes care. Findings on outcomes were mixed, with nine out of 13 studies showing no significant effect on outcomes examined, and four of the studies showing significant and positive impact on health outcomes related to hypertension or diabetes Conclusion: Although the technologies improved patient and provider satisfaction, the outcomes measures such as blood pressure control and glucose control were inconclusive. Further research is needed with diverse ethnic and SES population to investigate the role of patient-centered technologies on hypertension and diabetes control. Also, further research is needed to investigate the effects of innovative medical home technologies that can be used by both patients and providers to increase quality of communication concerning adherence to treatments.^

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.^

Booster Breaks in the workplace: Effects on employee stress

The current study examined the effects of a 15-minute daily physical activity break on the stress levels of white collar employees. An innovative group physical activity program, the Booster Break, was implemented in two worksites, both located in a large metropolitan area. One hundred sixteen participants were randomly assigned to one of three conditions; 43 participants were assigned to the Booster Break condition, 40 participants were assigned to an individual, computer-based physical activity condition, and 32 were assigned to a no-physical activity control condition. Self-report and objective measures were taken at baseline and after the completion of the intervention. There were no significant differences among conditions in perceived stress or blood pressure after the intervention. However, the data showed trends in the direction predicted with a decrease in perceived stress among Booster Break (change in perceived stress = -0.1) and computer prompt participants (change in perceived stress = -0.2) and an increase in perceived stress among the control group (change in perceived stress = 0.2). More research is recommended to fully understand the effects of worksite physical activity on stress.^