The heart challenge: The effect of regular aerobic exercise on body fat distribution in third and fourth grade school children: A randomized clinical trial

The pattern of body fat distribution known as "centralized", and characterized by a predominance of subcutaneous fat on the trunk and a "pot belly", has been associated with an increased risk of chronic disease. These patterns of fat distribution, as well as the lifestyle habit variables associated with adult fatness and chronic morbidity clearly begin to develop during childhood, indicating the need for intervention and primary prevention of obesity, particularly the centralized form, during childhood or adolescence. The purpose of this study was to determine whether regular aerobic exercise could beneficially alter the distribution of body fat in 8 and 9 year old children. One hundred and eighty-eight participants were randomized into either a regular aerobic exercise treatment group or a standard physical education program control group. A variety of aerobic activities was used for intervention 5 days per week during physical education class for a period of 12 weeks. Fat distribution was measured by a number of the most commonly used indices, including ratios of body circumferences and skinfolds and indices derived from a principal components analysis. Change over time in average pulse rate was used to determine if intervention actually occurred. Approximately 10% of the students were remeasured, allowing the calculation of intra- and interexaminer measurement reliability estimates for all indices.^ This study group was comparable to the U.S. population, though the study children were slightly larger for certain measures. No effect of the exercise intervention was found. The most likely explanation for this was inadequacy of the intervention, as indicated by the lack of any change in average pulse rate with treatment. The results of the measurement reliability analysis are reported and indicate that body circumference ratios are more precise than skinfold ratios, particularly when multiple observers are used. Reliability estimates for the principal component indices were also high.^ It remains unclear whether the distribution of body fat can be altered with exercise. It is likely that this issue will remain undecided until one highly reliable, valid, and sensitive measure of fat distribution can be found. ^

Upregulation of VEGF through p70S6K in ErbB2 -mediated angiogenesis and inhibition by combined herceptin plus taxol therapy

ErbB2 overexpression in breast tumors increases metastasis, angiogenesis, and reduces survival. To study ErbB2 signaling mechanisms in metastasis and angiogenesis, a spontaneous metastasis assay was performed using human breast cancer cells transfected with constitutively active ErbB2 kinase (V659E), an ErbB2 kinase-dead mutant (K753M), or vector control. Mice injected with V659E had increased metastasis and tumor microvessel density; and the increased angiogenesis in vivo from the V659E transfectants paralleled increased angiogenic potential in vitro, which resulted from increased VEGF by increased protein synthesis. This appeared to be mediated through a PI3K, Akt, mTOR, p70S6K-signaling pathway. Furthermore, V659E xenografts had significantly increased phosphorylated Akt, phosphorylated p70S6K, and VEGF compared with control. To validate the clinical relevance of these findings, human breast tumor samples were examined. Tumors overexpressing ErbB2 correlated with p70S6K phosphorylation and VEGF expression, which significantly correlated with higher levels of Akt and mTOR phosphorylation. Additionally, patients with tumors having increased p70S6K phosphorylation showed a trend for worse disease-free survival and increased metastasis. Together, ErbB2 increases VEGF expression by activating the p70S6K signaling pathway, which may serve as targets for antiangiogenic and antimetastatic therapies. ^ Herceptin is an anti-ErbB2 antibody that demonstrated anti-tumor function, especially in combination with other chemotherapies such as Taxol, in patients with ErbB2-overexpressing tumors. Since the repeated administration of low-dose chemotherapy endorsed an antiangiogenic effect in vitro, and Herceptin was shown to inhibit angiogenesis in tumor xenografts, I investigated whether combined Taxol plus Herceptin treatment inhibits ErbB2-mediated angiogenic responses more effectively. Mice with ErbB2-overexpressing xenografts were treated with control, Herceptin, Taxol, or combination Herceptin plus Taxol. Mice treated with the combination exhibited reduced tumor volumes, tumor microvessel densities, and lung metastasis; and ErbB2-overexpressing cells treated with the combination secreted less VEGF, and stimulated less endothelial cell migration. Furthermore, Akt phosphorylation contributed to VEGF upregulation and was most effectively reduced by combination treatment. ^ In summary, ErbB2 activates signaling to Akt and p70S6K leading to increased VEGF and angiogenesis. Combination Herceptin plus Taxol treatment most effectively inhibited ErbB2-mediated angiogenesis, resulting in pronounced tumoricidal effects, and may be mediated through reduction of phosphorylated Akt, a positive regulator in the p70S6K pathway. ^

THE CHLOREX TREATABILITY STUDY: ENVIRONMENTAL FATE IN FACULTATIVE ANAEROBIC AND AEROBIC WASTE STABILIZATION PONDS (BIODEGRADATION, VOLATILIZATION, SORPTION, PRIORITY POLLUTANTS)

The efficacy of waste stabilization lagoons for the treatment of five priority pollutants and two widely used commercial compounds was evaluated in laboratory model ponds. Three ponds were designed to simulate a primary anaerobic lagoon, a secondary facultative lagoon, and a tertiary aerobic lagoon. Biodegradation, volatilization, and sorption losses were quantified for bis(2-chloroethyl) ether, benzene, toluene, naphthalene, phenanthrene, ethylene glycol, and ethylene glycol monoethyl ether. A statistical model using a log normal transformation indicated biodegradation of bis(2-chloroethyl) ether followed first-order kinetics. Additionally, multiple regression analysis indicated biochemical oxygen demand was the water quality variable most highly correlated with bis(2-chloroethyl) ether effluent concentration. ^

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.

Using Acceptance and Commitment Therapy during Methadone Dose Reduction: Rationale, Treatment Description, and a Case Report.

Many clients who undergo methadone maintenance (MM) treatment for heroin and other opiate dependence prefer abstinence from methadone. Attempts at methadone detoxification are often unsuccessful, however, due to distressing physical as well as psychological symptoms. Outcomes from a MM client who voluntarily participated in an Acceptance and Commitment Therapy (ACT) - based methadone detoxification program are presented. The program consisted of a 1-month stabilization and 5-month gradual methadone dose reduction period, combined with weekly individual ACT sessions. Urine samples were collected twice weekly to assess for use of illicit drugs. The participant successfully completed the program and had favorable drug use outcomes during the course of treatment, and at the one-month and one-year follow-ups. Innovative behavior therapies, such as ACT, that focus on acceptance of the inevitable distress associated with opiate withdrawal may improve methadone detoxification outcomes.

Predictors of weight stability in women and men: The aerobic center longitudinal study, 1987--1995

It is estimated that more than half the U.S. adult population is overweight or obese as classified by a body mass index of 25.0–29.9 or ≥30 kg/m 2, respectively. Since the current treatment approaches for long-term maintenance of weight loss are lacking, the National Institutes of Health state that an effective approach may be to focus on weight gain prevention. There is a limited body of literature describing how adults maintain a stable weight as they age. It is hypothesized that weight stability is the result of a balance between energy consumption and energy expenditure as influenced by diet, lifestyle, behavior, genetics and environment. The purpose of this research was to examine the dietary intake and behaviors, lifestyle habits, and risk factors for weight change that predict weight stability in a cohort of 2101 men and 389 women aged 20 to 8 7 years in the Aerobic Center Longitudinal Study regardless of body weight at baseline. At baseline, participants completed a maximal exercise treadmill test to determine cardiorespiratory fitness, a medical history questionnaire, which included self-reported measures of weight, dietary behaviors, lifestyle habits, and risk factors for weight change, a three-day diet record, and a mail-back version of the medical history questionnaire in 1990 or 1995. All analyses were performed separately for men and women. Results from multivariate regression analyses indicated that the strongest predictor of follow-up weight for men and women was previous weight, accounting for 87.0% and 81.9% of the variance, respectively. Age, length of follow-up and eating habits were also significant predictors of follow-up weight in men, though these variables only explained 3% of the variance. For women, length of follow-up and currently being on a diet were significantly associated with follow-up weight but these variables explained only an additional 2% of the variance. Understanding the factors that influence weight change has tremendous public health importance for developing effective methods to prevent weight gain. Since current weight was the strongest predictor of previous weight, preventing initial weight gain by maintaining a stable weight may be the most effective method to combat the increasing prevalence of overweight and obesity. ^

A new combined endpoint using U-statistic in analysis in clinical trials

Common endpoints can be divided into two categories. One is dichotomous endpoints which take only fixed values (most of the time two values). The other is continuous endpoints which can be any real number between two specified values. Choices of primary endpoints are critical in clinical trials. If we only use dichotomous endpoints, the power could be underestimated. If only continuous endpoints are chosen, we may not obtain expected sample size due to occurrence of some significant clinical events. Combined endpoints are used in clinical trials to give additional power. However, current combined endpoints or composite endpoints in cardiovascular disease clinical trials or most clinical trials are endpoints that combine either dichotomous endpoints (total mortality + total hospitalization), or continuous endpoints (risk score). Our present work applied U-statistic to combine one dichotomous endpoint and one continuous endpoint, which has three different assessments and to calculate the sample size and test the hypothesis to see if there is any treatment effect. It is especially useful when some patients cannot provide the most precise measurement due to medical contraindication or some personal reasons. Results show that this method has greater power then the analysis using continuous endpoints alone. ^

Performance enhancement of large industrial wastewater stabilization ponds

A 6-month-long, bench-scale simulation of an industrial wastewater stabilization pond (WSP) system was conducted to evaluate responses to several potential performance-enhancing treatments. The industrial WSP system consists of an anaerobic primary (1ry) WSP treating high-strength wastewater, followed by facultative secondary (2ry) and aerobic tertiary (3ry) WSPs in series treating lower-strength wastewater. The 1ry WSP was simulated with four glass aquaria which were fed with wastewater from the actual WSP system. The treatments examined were phosphorus supplementation (PHOS), phosphorus supplementation with pH control (PHOS+ALK), and phosphorus supplementation with pH control and effluent recycle (PHOS+ALK+RCY). The supplementary phosphorus treatment alone did not yield any significant change versus the CONTROL 1ry model pond. The average carbon to phosphorus ratio of the feed wastewater received from the WSP system was already 100:0.019 (i.e., 2,100 mg/l: 0.4 mg/l). The pH-control treatments (PHOS+ALK and PHOS+ALK+RCY) produced significant results, with 9 to 12 percent more total organic carbon (TOC) removal, 43 percent more volatile organic acid (VOA) generation, 78 percent more 2-ethoxyethanol and 14 percent more bis(2-chloroethyl)ether removal, and from 100- to 10,000-fold increases in bacterial enzyme activity and heterotrophic bacterial numbers. Recycling a 10-percent portion of the effluent yielded less variability for certain physicochemical parameters in the PHOS+ALK+RCY 1ry model pond, but overall there was no statistically-detectable improvement in performance versus no recycle. The 2ry and 3ry WSPs were also simulated in the laboratory to monitor the effect and fate of increased phosphorus loadings, as might occur if supplemental phosphorus were added to the 1ry WSP. Noticeable increases in algal growth were observed at feed phosphorus concentrations of 0.5 mg/l; however, there were no significant changes in the monitored physicochemical parameters. The effluent phosphorus concentrations from both the 2ry and 3ry model ponds did increase notably when feed phosphorus concentrations were increased from 0.5 to 1.0 mg/l. ^

Simultaneous induction of NKG2D and NKG2D ligand for promoting immune surveillance by IL-12 plus doxorubicin treatment

NKG2D (natural killer group 2, member D) and its ligands interaction in tumor microenvironment directs tumor infiltrating immune cells to recognize tumor cells, stimulate cytotoxic effector immune cells, and therefore eradicate tumor cells. IL-12, a cytokine produced by antigen presenting cells, has remarkable antitumor effect by activating innate and adaptive immunity. Doxorubicin, a commonly used chemotherapeutic agent also boosts the host antitumor immune response to cause tumor cell death. Our previous publication suggests that IL-12 plus doxorubicin enhances NKG2D function-dependent inhibition of tumor progression and promotes CD8+T cells infiltrating into tumors. The purpose of this study is to determine the underlying mechanism. Our study reveals a novel function of doxorubicin, which is to augment IL-12–induced NKG2D expression in CD8+T cells but not in NK or CD4+T cells. This observation was further validated by NK and CD8+T cell-depletion studies, in which only depletion of CD8+T cells abolished the expression of NKG2D in lymphocytes. The induced NKG2D expression in CD8+T cells is tightly associated with tumor-specific localization of CD8+T cells and improved antitumor efficacy. The IL-12 plus doxorubicin treatment-induced antitumor efficacy is also due to NKG2D ligand Rae-1 induction in tumors. Rae-1 induction in tumors is a long term effect in multiple tumor models, but not in normal tissues. A novel CD8+T cell direct contact dependent mechanism accounts for Rae-1 induction in vivo and in vitro, and CD80 is the receptor through which CD8+T cells interplay with tumor cells to upregulate Rae-1 on tumor cells. In summary, increased NKG2D expression in CD8+T cells in response to IL-12 plus doxorubicin was closely associated with tumor-specific localization of CD8+T cells and greater antitumor efficacy of the combined regimen than either agent alone. NKG2D ligand Rae-1 induction is triggered by the interaction of CD80 on tumor cells with tumor infiltrating CD+8 T cells.

A hybrid method in combining treatment effects from matched and unmatched studies

In the biomedical studies, the general data structures have been the matched (paired) and unmatched designs. Recently, many researchers are interested in Meta-Analysis to obtain a better understanding from several clinical data of a medical treatment. The hybrid design, which is combined two data structures, may create the fundamental question for statistical methods and the challenges for statistical inferences. The applied methods are depending on the underlying distribution. If the outcomes are normally distributed, we would use the classic paired and two independent sample T-tests on the matched and unmatched cases. If not, we can apply Wilcoxon signed rank and rank sum test on each case. ^ To assess an overall treatment effect on a hybrid design, we can apply the inverse variance weight method used in Meta-Analysis. On the nonparametric case, we can use a test statistic which is combined on two Wilcoxon test statistics. However, these two test statistics are not in same scale. We propose the Hybrid Test Statistic based on the Hodges-Lehmann estimates of the treatment effects, which are medians in the same scale.^ To compare the proposed method, we use the classic meta-analysis T-test statistic on the combined the estimates of the treatment effects from two T-test statistics. Theoretically, the efficiency of two unbiased estimators of a parameter is the ratio of their variances. With the concept of Asymptotic Relative Efficiency (ARE) developed by Pitman, we show ARE of the hybrid test statistic relative to classic meta-analysis T-test statistic using the Hodges-Lemann estimators associated with two test statistics.^ From several simulation studies, we calculate the empirical type I error rate and power of the test statistics. The proposed statistic would provide effective tool to evaluate and understand the treatment effect in various public health studies as well as clinical trials.^

Targeting Histone deacetylases (HDAC) for the treatment of soft tissue sarcoma

Targeting Histone deacetylases (HDAC) for the treatment of genetically complex soft tissue sarcoma Histone deactylase inhibitors (HDACi) are a new class of anticancer therapeutics; however, little is known about HDACi or the individual contribution of HDAC isoform activity in soft tissue sarcoma (STS). We investigated the potential efficacy of HDACi as monotherapy and in combination with chemotherapy in a panel of genetically complex STS. We found that HDACi combined with chemotherapy significantly induced anti-STS effects in vitro and in vivo. We then focused our study of HDACi in malignant peripheral nerve sheath tumor (MPNST), a subtype of highly aggressive, therapeutically resistant, and commonly fatal malignancies that occur in patients with neurofibromatosis type-1 (NF1) or sporadically. The therapeutic efficacy of HDACi was investigated in a panel of NF1-associated and sporadic MPNST cell lines. Our results demonstrate the NF1-assocaited cohort to be highly sensitive to HDACi while sporadic cell lines exhibited resistance. HDACi-induced productive autophagy was found to be a mode of resistance and inhibiting HDACi-induced autophagy significantly induced pro-apoptotic effects of HDACi in vitro and in vivo. HDACs are not a single enzyme consisting of 11 currently known isoforms. HDACis used in these studies inhibit a variety of these isoforms, namely class I HDACs which include HDAC1, 2, 3, and 8. Recently, HDAC8-specific inhibitors (HDAC8i) have been created and tested in various cancer cell lines. Lastly, the potential therapeutic efficacy of HDAC8i was investigated in human (NF1-associated and sporadic) and NF1-associated murine-derived MPNST. HDAC8i abrogated cell growth in human and murine-derived MPNST cells. Similar to the pattern noticed with pan-HDACis NF1-associated cells, especially murine-derived, were more sensitive to HDAC8i compared to human sporadic MPNST cell lines. S-phase arrest was observed in human and murine MPNST cells, independent of p53 mutational and NF1 status. HDAC8i induced apoptosis is all cell lines tested, with a more pronounced effects in human and murine-derived NF1-associated cells. Most importantly, HDAC8i abrogated murine-derived MPNST xenograft growth in vivo. Taken together, these findings support the evaluation of pan-HDACi and isoform-specific inhibitors as a novel therapy to treat MPNST, including in combination with autophagy blocking combination regimens in particular for patients with sporadic MPNST.