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1.  Dynamics of telomerase activity in response to acute psychological stress 
Brain, behavior, and immunity  2009;24(4):531-539.
Telomerase activity plays an essential role in cel0l survival, by lengthening telomeres and promoting cell growth and longevity. It is now possible to quantify the low levels of telomerase activity in human leukocytes. Low basal telomerase activity has been related to chronic stress in people and to chronic glucocorticoid exposure in vitro. Here we test whether leukocyte telomerase activity changes under acute psychological stress. We exposed 44 elderly women, including 22 high stress dementia caregivers and 22 matched low stress controls, to a brief laboratory psychological stressor, while examining changes in telomerase activity of peripheral blood mononuclear cells (PBMC). At baseline, caregivers had lower telomerase activity levels than controls, but during stress telomerase activity increased similarly in both groups. Across the entire sample, subsequent telomerase activity increased by 18% one hour after the end of the stressor (p<0.01). The increase in telomerase activity was independent of changes in numbers or percentages of monocytes, lymphocytes, and specific T cell types, although we cannot fully rule out some potential contribution from immune cell redistribution in the change in telomerase activity. Telomerase activity increases were associated with greater cortisol increases in response to the stressor. Lastly, psychological response to the tasks (greater threat perception) was also related to greater telomerase activity increases in controls. These findings uncover novel relationships of dynamic telomerase activity with exposure to an acute stressor, and with two classic aspects of the stress response -- perceived psychological stress and neuroendocrine (cortisol) responses to the stressor.
doi:10.1016/j.bbi.2009.11.018
PMCID: PMC2856774  PMID: 20018236
stress; telomerase activity; cortisol; caregiving; immune cell trafficking
2.  Effect of a qigong intervention program on telomerase activity and psychological stress in abused Chinese women: a randomized, wait-list controlled trial 
Background
Abused women, who suffer from chronic psychological stress, have been shown to have shorter telomeres than never abused women. Telomere shortening is associated with increased risk of cell death, and it is believed that adopting health-promoting behaviors can help to increase the activity of telomerase, an enzyme that counters telomere shortening. Qigong is an ancient Chinese mind-body integration, health-oriented practice designed to enhance the function of qi, an energy that sustains well-being. Therefore, an assessor-blind, randomized, wait-list controlled trial was developed to evaluate the effect of a qigong intervention on telomerase activity (primary objective) and proinflammatory cytokines, perceived stress, perceived coping, and depressive symptoms (secondary objectives) in abused Chinese women.
Methods/Design
A total of 240 Chinese women, aged ≥18 years, who have been abused by an intimate partner within the past three years will be recruited from a community setting in Hong Kong and randomized to receive either a qigong intervention or wait-list control condition as follows: the qigong intervention will comprise (i) a 2-hour group qigong training session twice a week for 6 weeks, (ii) a 1-hour follow-up group qigong exercise session once a week for 4 months, and (iii) a 30-minute self-practice qigong exercise session once a day for 5.5 months. The wait-list control group will receive qigong training after the intervention group completes the program. Upon completion of the qigong intervention program, it is expected that abused Chinese women in the intervention group will have higher levels of telomerase activity and perceived coping and lower levels of proinflammatory cytokines, perceived stress, and depressive symptoms than will abused Chinese women in the wait-list control group.
Discussion
This study will provide information about the effect of qigong exercise on telomerase activity and chronic psychological stress in abused Chinese women. The findings will inform the design of interventions to relieve the effects of IPV-related psychological stress on health. Also, the concept that health-promoting behaviors could slow down cellular aging might even motivate abused women to change their lifestyles.
Trial registration
Current Controlled Trials NCT02060123. Registered February 6, 2014.
doi:10.1186/1472-6882-14-300
PMCID: PMC4138386  PMID: 25127878
Qigong; Violence; Telomerase; Perceived stress; Abused women; Intimate partner violence (IPV); Intervention; Depression; Chinese; Randomized controlled trial (RCT)
3.  Mindfulness Intervention for Stress Eating to Reduce Cortisol and Abdominal Fat among Overweight and Obese Women: An Exploratory Randomized Controlled Study 
Journal of Obesity  2011;2011:651936.
Psychological distress and elevated cortisol secretion promote abdominal fat, a feature of the Metabolic Syndrome. Effects of stress reduction interventions on abdominal fat are unknown. Forty-seven overweight/obese women (mean BMI = 31.2) were randomly assigned to a 4-month intervention or waitlist group to explore effects of a mindfulness program for stress eating. We assessed mindfulness, psychological distress, eating behavior, weight, cortisol awakening response (CAR), and abdominal fat (by dual-energy X-ray absorptiometry) pre- and posttreatment. Treatment participants improved in mindfulness, anxiety, and external-based eating compared to control participants. Groups did not differ on average CAR, weight, or abdominal fat over time. However, obese treatment participants showed significant reductions in CAR and maintained body weight, while obese control participants had stable CAR and gained weight. Improvements in mindfulness, chronic stress, and CAR were associated with reductions in abdominal fat. This proof of concept study suggests that mindfulness training shows promise for improving eating patterns and the CAR, which may reduce abdominal fat over time.
doi:10.1155/2011/651936
PMCID: PMC3184496  PMID: 21977314
4.  Imagine HEALTH: results from a randomized pilot lifestyle intervention for obese Latino adolescents using Interactive Guided ImagerySM 
Background
There is an urgent need for innovative and developmentally appropriate lifestyle interventions to promote healthy lifestyle behaviors and to prevent the early onset of type 2 diabetes and cardiovascular disease risk in obese Latino adolescents. Guided imagery offers promise to reduce stress and promote lifestyle behavior change to reduce disease risk in obese adolescents. Our objectives were: 1) To pilot test a new 12-wk lifestyle intervention using a randomized trial design in obese Latino adolescents, in order to determine the effects of the mind-body modality of Interactive Guided ImagerySM (IGI), over and above those of a didactic lifestyle education, on insulin resistance, eating and physical activity behaviors, stress and stress biomarkers; and 2) To explore the role of intervention-related changes in stress and stress biomarkers on changes in metabolic outcomes, particularly insulin resistance.
Methods
Obese (BMI > 95th percentile), Latino adolescents (n = 35, age 14-17) were randomized to receive either 12 weekly sessions of a lifestyle education plus guided imagery program (GI), or lifestyle education plus a digital storytelling computer program (DS). Between-group differences in behavioral, biological, and psychological outcomes were assessed using unpaired T-tests and ANCOVA in the 29 subjects who completed the intervention.
Results
The GI group demonstrated significant reductions in leisure sedentary behavior (p < .05) and increases in moderate physical activity (p < .05) compared to DS group, and a trend toward reduced caloric intake in GI vs DS (p = .09). Salivary cortisol was acutely reduced by stress-reduction guided imagery (p < .01). There were no group differences in adiposity, insulin resistance, perceived stress, or stress biomarkers across the 12-week intervention, though decrease in serum cortisol over the course of the intervention was associated with improved insulin sensitivity (p = .03) independent of intervention group and other relevant co-variates.
Conclusions
The improvements in physical activity and stress biomarkers following this pilot intervention support the role of guided imagery in promoting healthy lifestyle behavior change and reducing metabolic disease risk in obese Latino adolescent populations. Future investigations will be needed to determine the full effects of the Imagine HEALTH intervention on insulin resistance, stress, and stress biomarkers.
Trial registration
Clinicaltrials.gov Registry #: NCT01895595
doi:10.1186/1472-6882-14-28
PMCID: PMC3931490  PMID: 24433565
Guided imagery; Obesity; Childhood; Latino; Adolescents; Lifestyle; Diabetes
5.  Effect of a prescriptive dietary intervention on psychological dimensions of eating behavior in obese adolescents 
Background
Overweight adolescents are more likely to have dysfunctional eating behaviours compared to normal weight adolescents. Little is known about the effects of obesity treatment on the psychological dimensions of eating behavior in this population.
Objective
To examine the effects of a prescriptive dietary intervention on external eating (eating in response to food cues, regardless of hunger and satiety), emotional eating and dietary restraint and their relation to weight loss. Parental acceptability was also examined.
Method
This is a secondary study of a 12-month randomized trial, the RESIST study, which examined the effects of two diets on insulin sensitivity. Participants were 109 obese 10- to 17-year-olds with clinical features of insulin resistance. The program commenced with a 3-month dietary intervention using a structured meal plan, with the addition of an exercise intervention in the next 3 months and followed by a 6 month maintenance period.This paper presents changes in eating behaviors measured by the Eating Pattern Inventory for Children and parent rated diet acceptability during the first 6 months of the trial. As there was no difference between the diets on outcome of interest, both diet groups were combined for analyses.
Results
After 6 months, the proportion of participants who reported consuming more in response to external eating cues decreased from 17% to 5% (P = 0.003), whereas non- emotional eating increased from 48% to 65% (p = 0.014). Dietary restraint and parental pressure to eat remained unchanged. A reduction in external eating (rho = 0.36, P < 0.001) and a reduction in dietary restraint (r = 0.26, P = 0.013) were associated with greater weight loss at 3 and 6 months, respectively. Overall this approach was well accepted by parents with 72% of parents considered that their child would be able to follow the meal plan for the longer term.
Conclusions
In the short to medium term, a prescriptive dietary intervention approach is a well-accepted and suitable option for obese adolescents with clinical features of insulin resistance. It may reduce external and emotional eating, led to modest weight loss and did not cause any adverse effect on dietary restraint.
Trial registration
Australian New Zealand Clinical Trial Registration Number (ACTRN) 12608000416392 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=83071
doi:10.1186/1479-5868-10-119
PMCID: PMC3842818  PMID: 24156290
Eating behavior; Structured meal plan; Dietary intervention; Obesity; Adolescent
6.  The effectiveness and applicability of different lifestyle interventions for enhancing wellbeing: the study design for a randomized controlled trial for persons with metabolic syndrome risk factors and psychological distress 
BMC Public Health  2014;14:310.
Background
Obesity and stress are among the most common lifestyle-related health problems. Most of the current disease prevention and management models are not satisfactorily cost-effective and hardly reach those who need them the most. Therefore, novel evidence-based controlled interventions are necessary to evaluate models for prevention and treatment based on self-management. This randomized controlled trial examines the effectiveness, applicability, and acceptability of different lifestyle interventions with individuals having symptoms of metabolic syndrome and psychological distress. The offered interventions are based on cognitive behavioral approaches, and are designed for enhancing general well-being and supporting personalized lifestyle changes.
Methods/Design
339 obese individuals reporting stress symptoms were recruited and randomized to either (1) a minimal contact web-guided Cognitive Behavioral Therapy-based (CBT) intervention including an approach of health assessment and coaching methods, (2) a mobile-guided intervention comprising of mindfulness, acceptance and value-based exercises, (3) a face-to-face group intervention using mindfulness, acceptance and value-based approach, or (4) a control group. The participants were measured three times during the study (pre = week 0, post = week 10, and follow-up = week 36). Psychological well-being, lifestyles and habits, eating behaviors, and user experiences were measured using online surveys. Laboratory measurements for physical well-being and general health were performed including e.g. liver function, thyroid glands, kidney function, blood lipids and glucose levels and body composition analysis. In addition, a 3-day ambulatory heart rate and 7-day movement data were collected for analyzing stress, recovery, physical activity, and sleep patterns. Food intake data were collected with a 48 -hour diet recall interview via telephone. Differences in the effects of the interventions would be examined using multiple-group modeling techniques, and effect-size calculations.
Discussion
This study will provide additional knowledge about the effects of three low intensity interventions for improving general well-being among individuals with obesity and stress symptoms. The study will show effects of two technology guided self-help interventions as well as effect of an acceptance and value–based brief group intervention. Those who might benefit from the aforesaid interventions will increase knowledge base to better understand what mechanisms facilitate effects of the interventions.
Trial registration
Current Clinical Trials NCT01738256, Registered 17 August, 2012.
doi:10.1186/1471-2458-14-310
PMCID: PMC4006637  PMID: 24708617
Lifestyle; Well-being; Obesity; Stress; Acceptance and Commitment Therapy; Cognitive behavioral therapy; Mobile application; Web-based intervention; Technology-aided interventions
7.  Telomerase reverse transcriptase and telomeric-repeat binding factor protein 1 as regulators of telomerase activity in pancreatic cancer cells 
British Journal of Cancer  2001;85(5):752-757.
Telomerase adds hexameric repeats of 5′-TTAGGG-3′ termed telomeres to ends of chromosomal DNA. This enzyme has been implicated in cellular immortalization and cellular senescence. Recently, a number of relevant genes have been cloned, including these encoding three major components of human telomerase: human telomerase RNA component (hTR), human telomerase reverse transcriptase (hTERT), and telomerase-associated protein-1 (TEP1). Also important are genes encoding human telomeric-repeat binding factor protein (TRF) 1 and 2. To clarify mechanisms regulating telomerase activity, we studied telomerase activity, the telomeric restriction fragment (TRF) length and gene expression of these telomerase components and the telomeric-repeat binding factor proteins in sequential observation following X-irradiation of cultured pancreatic cancer cells. We previously reported that PANC-1 cells are better able to tolerate thermal stress, antineoplastic drugs, and exposure to tumour necrosis factor than MIAPaCa-2 cells. MIAPaCa-2 and PANC-1 cells were exposed to X-irradiation, their telomerase activity was increased at 2 days and then decreased gradually. Of the three telomerase components, only hTERT mRNA expression showed parallel changes. TRF length was stable just before and after X-irradiation. Among binding factor proteins, TRF1 mRNA showed reciprocal changes possibly directed toward maintaining a stable telomere length. In this study, our results demonstrate that not only hTERT but also TRF1 are important regulator of telomerase activity. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2001.1954
PMCID: PMC2364122  PMID: 11531263
telomerase; hTERT; hTRF1; TRF; X-irradiation; pancreatic cancer cell
8.  A New Biomarker of Hedonic Eating? A Preliminary Investigation of Cortisol and Nausea Responses to Acute Opioid Blockade 
Appetite  2013;74:92-100.
Overweight and obese individuals differ in their degree of hedonic eating. This may reflect adaptations in reward-related neural circuits, regulated in part by opioidergic activity. We examined an indirect, functional measure of central opioidergic activity by assessing cortisol and nausea responses to acute opioid blockade using the opioid antagonist naltrexone in overweight/obese women (mean BMI = 31.1 ± 4.8) prior to the start of a mindful eating intervention to reduce stress eating. In addition, we assessed indices of hedonic-related eating, including eating behaviors (binge eating, emotional eating, external eating, restraint) and intake of sweets/desserts and carbohydrates (Block Food Frequency); interoceptive awareness (which is associated with dysregulated eating behavior); and level of adiposity at baseline. Naltrexone-induced increases in cortisol were associated with greater emotional and restrained eating and lower interoceptive awareness. Naltrexone-induced nausea was associated with binge eating and higher adiposity. Furthermore, in a small exploratory analysis, naltrexone-induced nausea predicted treatment response to the mindful eating intervention, as participants with more severe nausea at baseline maintained weight whereas those without nausea responses tended to gain weight. These preliminary data suggest that naltrexone-induced cortisol release and nausea may help identify individuals who have greater underlying food reward dependence, which leads to an excessive drive to eat. Future research is needed to confirm this finding and to test if these markers of opioidergic tone might help predict success in certain types of weight management programs.
doi:10.1016/j.appet.2013.11.014
PMCID: PMC4125886  PMID: 24291355
naltrexone; hedonic eating; food addiction; cortisol; nausea; obesity
9.  Omega-3 Fatty Acids, Oxidative Stress, and Leukocyte Telomere Length: A Randomized Controlled Trial 
Shorter telomeres have been associated with poor health behaviors, age-related diseases, and early mortality. Telomere length is regulated by the enzyme telomerase, and is linked to exposure to proinflammatory cytokines and oxidative stress. In our recent randomized controlled trial, omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation lowered the concentration of serum proinflammatory cytokines. This study assessed whether n-3 PUFA supplementation also affected leukocyte telomere length, telomerase, and oxidative stress. In addition to testing for group differences, changes in the continuous n-6:n-3 PUFA ratio were assessed to account for individual differences in adherence, absorption, and metabolism. The double-blind 4-month trial included 106 healthy sedentary overweight middle-aged and older adults who received (1) 2.5 g/day n-3 PUFAs, (2) l.25 g/day n-3 PUFAs, or (3) placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Supplementation significantly lowered oxidative stress as measured by F2-isoprostanes (p=0.02). The estimated geometric mean log-F2-isoprostanes values were 15% lower in the two supplemented groups compared to placebo. Although group differences for telomerase and telomere length were nonsignificant, changes in the n-6:n-3 PUFA plasma ratios helped clarify the intervention’s impact: telomere length increased with decreasing n-6:n-3 ratios, p=0.02. The data suggest that lower n-6:n-3 PUFA ratios can impact cell aging. The triad of inflammation, oxidative stress, and immune cell aging represents important pre-disease mechanisms that may be ameliorated through nutritional interventions. This translational research broadens our understanding of the potential impact of the n-6:n-3 PUFA balance. ClinicalTrials.gov identifier: NCT00385723
doi:10.1016/j.bbi.2012.09.004
PMCID: PMC3545053  PMID: 23010452
omega-3; omega-6; telomeres; inflammation; cell aging; nutritional neuroscience; oxidative stress; F2-isoprostanes; fish oil
10.  Effects of Lifestyle Modification on Telomerase Gene Expression in Hypertensive Patients: A Pilot Trial of Stress Reduction and Health Education Programs in African Americans 
PLoS ONE  2015;10(11):e0142689.
Background
African Americans suffer from disproportionately high rates of hypertension and cardiovascular disease. Psychosocial stress, lifestyle and telomere dysfunction contribute to the pathogenesis of hypertension and cardiovascular disease. This study evaluated effects of stress reduction and lifestyle modification on blood pressure, telomerase gene expression and lifestyle factors in African Americans.
Methods
Forty-eight African American men and women with stage I hypertension who participated in a larger randomized controlled trial volunteered for this substudy. These subjects participated in either stress reduction with the Transcendental Meditation technique and a basic health education course (SR) or an extensive health education program (EHE) for 16 weeks. Primary outcomes were telomerase gene expression (hTERT and hTR) and clinic blood pressure. Secondary outcomes included lifestyle-related factors. Data were analyzed for within-group and between-group changes.
Results
Both groups showed increases in the two measures of telomerase gene expression, hTR mRNA levels (SR: p< 0.001; EHE: p< 0.001) and hTERT mRNA levels (SR: p = 0.055; EHE: p< 0.002). However, no statistically significant between-group changes were observed. Both groups showed reductions in systolic BP. Adjusted changes were SR = -5.7 mm Hg, p< 0.01; EHE = -9.0 mm Hg, p < 0.001 with no statistically significant difference between group difference. There was a significant reduction in diastolic BP in the EHE group (-5.3 mm Hg, p< 0.001) but not in SR (-1.2 mm Hg, p = 0.42); the between-group difference was significant (p = 0.04). The EHE group showed a greater number of changes in lifestyle behaviors.
Conclusion
In this pilot trial, both stress reduction (Transcendental Meditation technique plus health education) and extensive health education groups demonstrated increased telomerase gene expression and reduced BP. The association between increased telomerase gene expression and reduced BP observed in this high-risk population suggest hypotheses that telomerase gene expression may either be a biomarker for reduced BP or a mechanism by which stress reduction and lifestyle modification reduces BP.
Trial Registration
ClinicalTrials.gov NCT00681200
doi:10.1371/journal.pone.0142689
PMCID: PMC4646647  PMID: 26571023
11.  Psychological and Behavioral Correlates of Baseline BMI in the Diabetes Prevention Program (DPP) 
Diabetes care  2002;25(11):1992-1998.
OBJECTIVE
To determine psychological and behavioral correlates of baseline BMI in the Diabetes Prevention Program (DPP).
RESEARCH DESIGN AND METHODS
Of 1,079 DPP lifestyle intervention participants, 274 completed validated questionnaires at baseline assessing weight loss history, stage of change, self-efficacy, dietary restraint, emotional eating, binge eating, perceived stress, depression, and anxiety.
RESULTS
The mean age of subjects was 52.5 years, 65% were women, and their mean BMI was 33.9 kg/m2. Higher BMI correlated with more frequent weight cycling (r = 0.50, P < 0.0001) and efforts at weight loss (r = 0.34, P < 0.0001); younger age when first overweight (r = −0.42, P < 0.0001); lower exercise efficacy (r = −0.15, P = 0.015); lower weight loss efficacy (r = −0.21, P < 0.001); a less advanced stage of change for weight loss (r = −0.12, P = 0.04); more perceived stress (r = 0.14, P = 0.02); emotional eating (r = 0.19, P = 0.001); poor dietary restraint (r = −0.14, P = 0.02); binge eating frequency (r = 0.18, P = 0.004) and severity (r = 0.30, P < 0.0001); feeling deprived, angry, or upset while dieting (r = 0.27, P ≤ 0.0001); and food cravings while dieting (r = 0.31, P < 0.0001). Correlations did not differ as a function of sex; however, correlations of BMI with anxiety and low-fat diet and weight loss self-efficacy differed as a function of ethnicity. In multivariate models, binge eating severity, poor dietary restraint, and food craving were independent correlates of baseline BMI.
CONCLUSIONS
Many psychological and behavioral factors are associated with higher BMI in this ethnically diverse group of men and women. Whether strategies that help patients increase levels of dietary restraint and reduce binge eating and food craving lead to long-term weight loss maintenance needs longitudinal study.
PMCID: PMC1475806  PMID: 12401745
BES, Binge Eating Scale; DPP, Diabetes Prevention Program
12.  A Transposable Element within the Non-canonical Telomerase RNA of Arabidopsis thaliana Modulates Telomerase in Response to DNA Damage 
PLoS Genetics  2015;11(6):e1005281.
Long noncoding RNAs (lncRNAs) have emerged as critical factors in many biological processes, but little is known about how their regulatory functions evolved. One of the best-studied lncRNAs is TER, the essential RNA template for telomerase reverse transcriptase. We previously showed that Arabidopsis thaliana harbors three TER isoforms: TER1, TER2 and TER2S. TER1 serves as a canonical telomere template, while TER2 is a novel negative regulator of telomerase activity, induced in response to double-strand breaks (DSBs). TER2 contains a 529 nt intervening sequence that is removed along with 36 nt at the RNA 3’ terminus to generate TER2S, an RNA of unknown function. Here we investigate how A. thaliana TER2 acquired its regulatory function. Using data from the 1,001 Arabidopsis genomes project, we report that the intervening sequence within TER2 is derived from a transposable element termed DSB responsive element (DRE). DRE is found in the TER2 loci of most but not all A. thaliana accessions. By analyzing accessions with (TER2) and without DRE (TER2Δ) we demonstrate that this element is responsible for many of the unique properties of TER2, including its enhanced binding to TERT and telomerase inhibitory function. We show that DRE destabilizes TER2, and further that TER2 induction by DNA damage reflects increased RNA stability and not increased transcription. DRE-mediated changes in TER2 stability thus provide a rapid and sensitive switch to fine-tune telomerase enzyme activity. Altogether, our data shows that invasion of the TER2 locus by a small transposon converted this lncRNA into a DNA damage sensor that modulates telomerase enzyme activity in response to genome assault.
Author Summary
Telomerase is a highly regulated enzyme whose activity is essential for long-term cellular proliferation. In the presence of DNA double-strand breaks (DSBs), telomerase activity must be curtailed to promote faithful DNA repair. We previously showed that the flowering plant Arabidopsis thaliana rapidly down-regulates telomerase in response to DSBs, and further that this mode of regulation is dependent on TER2, a non-canonical telomerase RNA subunit. Here we demonstrate that the unique regulatory properties of TER2 are conveyed by a transposable element (TE) embedded in the TER2 gene. A comparison of A. thaliana accessions with and without the TE revealed that the element increases the binding affinity of TER2 for the telomerase catalytic subunit TERT relative to the canonical telomerase RNA subunit. The TE also increases TER2 turnover. In response to DSBs, TER2 is induced and accumulates in TERT containing complexes in vivo. Thus, invasion of a TE endows TER2 with a DNA damage sensor to rapidly and reversibly modulate enzyme activity in response to genotoxic stress. These findings provide an example of how exaptation of a TE altered the function of a long noncoding RNA. In this case, a duplicated gene (TER2) was used as the platform, and the TE as the tool to engineer a novel mode of telomerase regulation.
doi:10.1371/journal.pgen.1005281
PMCID: PMC4468102  PMID: 26075395
13.  Teaching Intuitive Eating and Acceptance and Commitment Therapy Skills Via a Web-Based Intervention: A Pilot Single-Arm Intervention Study 
JMIR Research Protocols  2016;5(4):e180.
Background
Middle-aged women are at risk of weight gain and associated comorbidities. Deliberate restriction of food intake (dieting) produces short-term weight loss but is largely unsuccessful for long-term weight management. Two promising approaches for the prevention of weight gain are intuitive eating (ie, eating in accordance with hunger and satiety signals) and the development of greater psychological flexibility (ie, the aim of acceptance and commitment therapy [ACT]).
Objectives
This pilot study investigated the usage, acceptability, and feasibility of “Mind, Body, Food,” a Web-based weight gain prevention intervention prototype that teaches intuitive eating and psychological flexibility skills.
Methods
Participants were 40 overweight women (mean age 44.8 [standard deviation, SD, 3.06] years, mean body mass index [BMI] 32.9 [SD 6.01] kg/m2, mean Intuitive Eating Scale [IES-1] total score 53.4 [SD 7.46], classified as below average) who were recruited from the general population in Dunedin, New Zealand. Module completion and study site metrics were assessed using Google Analytics. Use of an online self-monitoring tool was determined by entries saved to a secure online database. Intervention acceptability was assessed postintervention. BMI, intuitive eating, binge eating, psychological flexibility, and general mental and physical health were assessed pre- and postintervention and 3-months postintervention.
Results
Of the 40 women enrolled in the study, 12 (30%) completed all 12 modules (median 7.5 [interquartile range, IQR, 2-12] modules) and 4 (10%) used the self-monitoring tool for all 14 weeks of the intervention period (median 3 [IQR 1-9] weeks). Among 26 women who completed postintervention assessments, most women rated “Mind, Body, Food” as useful (20/26, 77%), easy to use (17/25, 68%) and liked the intervention (22/25, 88%). From pre- to postintervention, there were statistically significant within-group increases in intuitive eating (IES-2 total score P<.001; all IES-2 subscale scores: P ≤.01), psychological flexibility (P=.01), and general mental health (P<.001) as well as significant decreases in binge eating (P=.01). At the 3-month follow-up, IES-2 improvements were maintained, and there were further improvements in binge eating (P<.001) and general mental health (P=.03), and a marginal yet nonsignificant tendency for further improvement in psychological flexibility (P=.06). There were no significant within-group changes in BMI from pre- to postintervention and postintervention to 3-month follow-up (P=.46 and P=.93, respectively).
Conclusions
The “Mind, Body, Food” prototype Web-based intervention is appealing to middle-aged women and may be a useful tool to help women learn intuitive eating and ACT skills, reduce binge eating, and maintain weight over 3 months. Further work to improve the user experience and engagement is required before testing the online intervention in a randomized controlled trial.
doi:10.2196/resprot.5861
PMCID: PMC5086025  PMID: 27742602
Web-based intervention; overweight; obesity; prevention; middle-aged women; BMI; intuitive eating; acceptance and commitment therapy
14.  Short Telomeres Initiate Telomere Recombination in Primary and Tumor Cells 
PLoS Genetics  2009;5(1):e1000357.
Human tumors that lack telomerase maintain telomeres by alternative lengthening mechanisms. Tumors can also form in telomerase-deficient mice; however, the genetic mechanism responsible for tumor growth without telomerase is unknown. In yeast, several different recombination pathways maintain telomeres in the absence of telomerase—some result in telomere maintenance with minimal effects on telomere length. To examine non-telomerase mechanisms for telomere maintenance in mammalian cells, we used primary cells and lymphomas from telomerase-deficient mice (mTR−/− and Eμmyc+mTR−/−) and CAST/EiJ mouse embryonic fibroblast cells. These cells were analyzed using pq-ratio analysis, telomere length distribution outliers, CO-FISH, Q-FISH, and multicolor FISH to detect subtelomeric recombination. Telomere length was maintained during long-term growth in vivo and in vitro. Long telomeres, characteristic of human ALT cells, were not observed in either late passage or mTR−/− tumor cells; instead, we observed only minimal changes in telomere length. Telomere length variation and subtelomeric recombination were frequent in cells with short telomeres, indicating that length maintenance is due to telomeric recombination. We also detected telomere length changes in primary mTR−/− cells that had short telomeres. Using mouse mTR+/− and human hTERT+/− primary cells with short telomeres, we found frequent length changes indicative of recombination. We conclude that telomere maintenance by non-telomerase mechanisms, including recombination, occurs in primary cells and is initiated by short telomeres, even in the presence of telomerase. Most intriguing, our data indicate that some non-telomerase telomere maintenance mechanisms occur without a significant increase in telomere length.
Author Summary
Telomeres shorten with each cell division and are normally maintained by telomerase. Tumor cells typically up-regulate telomerase to maintain telomeres during rapid growth; however, some tumors lack telomerase and utilize alternative mechanisms to maintain the telomeres. Studies in yeast indicate that recombination contributes to telomere maintenance in the absence of telomerase. To examine whether recombination contributes to non-telomerase mechanisms for telomere maintenance in mouse and human cells, we utilized mouse primary and tumor cells, which were genetically deleted for telomerase. In addition, we assayed human primary cells that had short telomeres due to reduced telomerase activity. Our data indicate that cells with short telomeres have an increased level of telomere recombination, which can occur in telomeric or subtelomeric regions. We also found that, in addition to tumor cells, primary cells can utilize non-telomerase mechanisms for telomere maintenance. Lastly, we found that, unlike human telomerase negative tumors, some mechanisms of telomere maintenance do not result in dramatic telomere lengthening. Thus, mammalian cells likely utilize several different non-telomerase mechanisms for telomere maintenance. These findings will be useful for understanding the process of telomere lengthening in various types of human tumors.
doi:10.1371/journal.pgen.1000357
PMCID: PMC2627939  PMID: 19180191
15.  Correcting magnesium deficiencies may prolong life 
The International Space Station provides an extraordinary facility to study the accelerated aging process in microgravity, which could be triggered by significant reductions in magnesium (Mg) ion levels with, in turn, elevations of catecholamines and vicious cycles between the two. With space flight there are significant reductions of serum Mg (P < 0.0001) that have been shown in large studies of astronauts and cosmonauts. The loss of the functional capacity of the cardiovascular system with space flight is over ten times faster than the course of aging on Earth. Mg is an antioxidant and calcium blocker and in space there is oxidative stress, insulin resistance, and inflammatory conditions with evidence in experimental animals of significant endothelial injuries and damage to mitochondria. The aging process is associated with progressive shortening of telomeres, repetitive DNA sequences, and proteins that cap and protect the ends of chromosomes. Telomerase can elongate pre-existing telomeres to maintain length and chromosome stability. Low telomerase triggers increased catecholamines while the sensitivity of telomere synthesis to Mg ions is primarily seen for the longer elongation products. Mg stabilizes DNA and promotes DNA replication and transcription, whereas low Mg might accelerate cellular senescence by reducing DNA stability, protein synthesis, and function of mitochondria. Telomerase, in binding to short DNAs, is Mg dependent. On Earth, in humans, a year might be required to detect changes in telomeres, but in space there is a predictably much shorter duration required for detection, which is therefore more reasonable in time and cost. Before and after a space mission, telomere lengths and telomerase enzyme activity can be determined and compared with age-matched control rats on Earth. The effect of Mg supplementation, both on maintaining telomere length and extending the life span, can be evaluated. Similar studies in astronauts would be fruitful.
doi:10.2147/CIA.S28768
PMCID: PMC3287408  PMID: 22379366
magnesium; life span; telomeres; telomerase; catecholamines
16.  Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response 
Molecular Psychiatry  2011;17(2):164-172.
Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. When telomeres critically shorten, cells become susceptible to senescence and apoptosis. Telomerase, a cellular ribonucleoprotein enzyme, rebuilds the length of telomeres and promotes cellular viability. Leukocyte telomeres are reportedly shortened in major depression, but telomerase activity in depression has not been previously reported. Further, there are no published reports of the effects of antidepressants on telomerase activity or on the relationship between telomerase activity and antidepressant response. Peripheral blood mononuclear cell (PBMC) telomerase activity was assessed in 20 medication-free depressed individuals and 18 controls. In total, 16 of the depressed individuals were then treated with sertraline in an open-label manner for 8 weeks, and PBMC telomerase activity was reassessed in 15 of these individuals after treatment. Pre- and post-treatment symptom severity was rated with the Hamilton Depression Rating Scale. All analyses were corrected for age and sex. Pretreatment telomerase activity was significantly elevated in the depressed individuals compared with the controls (P = 0.007) and was directly correlated with depression ratings (P< 0.05) across all subjects. In the depressed group, individuals with relatively lower pretreatment telomerase activity and with relatively greater increase in telomerase activity during treatment, showed superior antidepressant responses (P < 0.05 and P < 0.005, respectively). This is the first report characterizing telomerase activity in depressed individuals. PBMC telomerase activity might reflect a novel aspect of depressive pathophysiology and might represent a novel biomarker of antidepressant responsiveness.
doi:10.1038/mp.2010.133
PMCID: PMC3130817  PMID: 21242992
antidepressant; cell aging; depression; leukocytes; telomeres; telomerase
17.  Evaluation of a Serious Self-Regulation Game Intervention for Overweight-Related Behaviors (“Balance It”): A Pilot Study 
Background
Serious games have the potential to promote health behavior. Because overweight is still a major issue among secondary vocational education students in the Netherlands, this study piloted the effects of “Balance It,” a serious self-regulation game intervention targeting students’ overweight-related behaviors: dietary intake and physical activity (PA).
Objective
We aimed to pilot the effects of Balance It on secondary vocational education students’ dietary intake and PA.
Methods
In total, 501 secondary vocational education students participated at baseline (intervention: n=250; control: n=251) in this pre-post cluster randomized trial. After 4 weeks, at immediate posttest, 231 students filled in the posttest questionnaire (intervention: n=105; control: n=126). The sample had a mean age of 17.28 (SD 1.26, range 15-21) years, 62.8% (145/231) were female, and 26.8% (62/231) had a non-Dutch background. Body mass index (BMI kg/m2) ranged from 14.4 to 31.1 (mean 21.1, SD 3.3). The intervention and control groups were compared on the primary (behavioral) outcomes of dietary intake (fruit and vegetable consumption, snack consumption, and soft drink consumption) and PA (moderate and vigorous). Additionally, we explored (1) differences between the intervention and control groups in determinants of dietary intake and PA, including attitude, self-efficacy, intention, barrier identification, action planning, and action control, and (2) differences between active (intervention) users and the control group in dietary intake, PA, and associated determinants.
Results
After corrections for multiple testing, we did not find significant differences between the intervention group and control group in terms of dietary intake, PA, and determinants of dietary intake and PA. Exploratory research indicated that only 27.6% (29/105) of the intervention group reported actual intervention use (ie, active users). For exploratory reasons, we compared the active users (n=29) with the control group (n=124) and corrected for multiple testing. Results showed that active users’ snack consumption decreased more strongly (active users: mean change=–0.20; control group: mean change=–0.08; beta=–0.36, P=.01, R2 change=.05), and their use of active transport had a stronger increase (active users: mean change=0.92; control group=–0.12; beta=1.58, P=.02, R2 change=.03) than the control group. Results also revealed significant differences in action planning (active users: mean change=0.42; control group: mean change=0.07; beta=0.91, P=.01, R2 change=.04) and action control (active users: mean change=0.63; control group: mean change=–0.05; beta=1.25, P=.001, R2 change=.08) in terms of unhealthy eating.
Conclusions
The Balance It intervention did not show favorable effects on dietary intake and PA compared to the control condition. However, only a small number of people in the intervention condition actually used Balance It (27.6%). Exploratory analyses did suggest that, if used as planned, Balance It could contribute to changing dietary intake and PA behaviors, albeit it remains debatable whether this would be sufficient to prevent overweight.
doi:10.2196/jmir.4964
PMCID: PMC5057062  PMID: 27670222
Balance It; effect evaluation; serious game; self-regulation; prevention and control; health promotion; dietary intake; physical activity
18.  Sensitivity of Yeast Strains with Long G-Tails to Levels of Telomere-Bound Telomerase 
PLoS Genetics  2007;3(6):e105.
The Saccharomyces cerevisiae Pif1p helicase is a negative regulator of telomere length that acts by removing telomerase from chromosome ends. The catalytic subunit of yeast telomerase, Est2p, is telomere associated throughout most of the cell cycle, with peaks of association in both G1 phase (when telomerase is not active) and late S/G2 phase (when telomerase is active). The G1 association of Est2p requires a specific interaction between Ku and telomerase RNA. In mutants lacking this interaction, telomeres were longer in the absence of Pif1p than in the presence of wild-type PIF1, indicating that endogenous Pif1p inhibits the active S/G2 form of telomerase. Pif1p abundance was cell cycle regulated, low in G1 and early S phase and peaking late in the cell cycle. Low Pif1p abundance in G1 phase was anaphase-promoting complex dependent. Thus, endogenous Pif1p is unlikely to act on G1 bound Est2p. Overexpression of Pif1p from a non-cell cycle-regulated promoter dramatically reduced viability in five strains with impaired end protection (cdc13–1, yku80Δ, yku70Δ, yku80–1, and yku80–4), all of which have longer single-strand G-tails than wild-type cells. This reduced viability was suppressed by deleting the EXO1 gene, which encodes a nuclease that acts at compromised telomeres, suggesting that the removal of telomerase by Pif1p exposed telomeres to further C-strand degradation. Consistent with this interpretation, depletion of Pif1p, which increases the amount of telomere-bound telomerase, suppressed the temperature sensitivity of yku70Δ and cdc13–1 cells. Furthermore, eliminating the pathway that recruits Est2p to telomeres in G1 phase in a cdc13–1 strain also reduced viability. These data suggest that wild-type levels of telomere-bound telomerase are critical for the viability of strains whose telomeres are already susceptible to degradation.
Author Summary
Telomeres, the ends of linear chromosomes, are essential for chromosome stability. Telomerase is the enzyme that is responsible for lengthening telomeres in most organisms, including humans. One mechanism of survival for many human cancers is increased expression of telomerase. In baker's yeast, telomerase acts only late in the cell cycle, even though the catalytic subunit of telomerase is telomere bound throughout most of the cell cycle. Pif1p is a yeast helicase that limits telomerase by removing it from DNA ends. We demonstrate that Pif1p abundance is cell cycle regulated with its highest expression at the same time when telomerase acts. Consistent with this expression pattern, Pif1p is able to remove the active form of telomerase from DNA ends. Reducing the amount of telomere-bound telomerase either by Pif1p overexpression or by mutation in strains with defective telomere end protection causes death. Moreover, reducing Pif1p levels in the same end protection mutants improves their growth. These experiments suggest that compared to wild-type cells, strains with defective end protection require more telomere-bound telomerase for the proper replication or proper protection of their chromosome ends.
doi:10.1371/journal.pgen.0030105
PMCID: PMC1892048  PMID: 17590086
19.  Telomere structure and telomerase in health and disease 
International Journal of Oncology  2012;41(5):1561-1569.
Telomerase is the enzyme responsible for maintenance of the length of telomeres by addition of guanine-rich repetitive sequences. Telomerase activity is exhibited in gametes and stem and tumor cells. In human somatic cells, proliferation potential is strictly limited and senescence follows approximately 50–70 cell divisions. In most tumor cells, on the contrary, replication potential is unlimited. The key role in this process of the system of the telomere length maintenance with involvement of telomerase is still poorly studied. Undoubtedly, DNA polymerase is not capable of completely copying DNA at the very ends of chromosomes; therefore, approximately 50 nucleotides are lost during each cell cycle, which results in gradual telomere length shortening. Critically short telomeres cause senescence, following crisis and cell death. However, in tumor cells the system of telomere length maintenance is activated. Much work has been done regarding the complex telomere/telomerase as a unique target, highly specific in cancer cells. Telomeres have additional proteins that regulate the binding of telomerase. Telomerase, also associates with a number of proteins forming the sheltering complex having a central role in telomerase activity. This review focuses on the structure and function of the telomere/telomerase complex and its altered behavior leading to disease, mainly cancer. Although telomerase therapeutics are not approved yet for clinical use, we can assume that based on the promising in vitro and in vivo results and successful clinical trials, it can be predicted that telomerase therapeutics will be utilized soon in the combat against malignancies and degenerative diseases. The active search for modulators is justified, because the telomere/telomerase system is an extremely promising target offering possibilities to decrease or increase the viability of the cell for therapeutic purposes.
doi:10.3892/ijo.2012.1611
PMCID: PMC3583695  PMID: 22941386
telomere; telomerase; tert; htr; dyskerin; cancer
20.  Herpesvirus Telomerase RNA(vTR)-Dependent Lymphoma Formation Does Not Require Interaction of vTR with Telomerase Reverse Transcriptase (TERT) 
PLoS Pathogens  2010;6(8):e1001073.
Telomerase is a ribonucleoprotein complex involved in the maintenance of telomeres, a protective structure at the distal ends of chromosomes. The enzyme complex contains two main components, telomerase reverse transcriptase (TERT), the catalytic subunit, and telomerase RNA (TR), which serves as a template for the addition of telomeric repeats (TTAGGG)n. Marek's disease virus (MDV), an oncogenic herpesvirus inducing fatal lymphoma in chickens, encodes a TR homologue, viral TR (vTR), which significantly contributes to MDV-induced lymphomagenesis. As recent studies have suggested that TRs possess functions independently of telomerase activity, we investigated if the tumor-promoting properties of MDV vTR are dependent on formation of a functional telomerase complex. The P6.1 stem-loop of TR is known to mediate TR-TERT complex formation and we show here that interaction of vTR with TERT and, consequently, telomerase activity was efficiently abrogated by the disruption of the vTR P6.1 stem-loop (P6.1mut). Recombinant MDV carrying the P6.1mut stem-loop mutation were generated and tested for their behavior in the natural host in vivo. In contrast to viruses lacking vTR, all animals infected with the P6.1mut viruses developed MDV-induced lymphomas, but onset of tumor formation was significantly delayed. P6.1mut viruses induced enhanced metastasis, indicating functionality of non-complexed vTR in tumor dissemination. We discovered that RPL22, a cellular factor involved in T-cell development and virus-induced transformation, directly interacts with wild-type and mutant vTR and is, consequently, relocalized to the nucleoplasm. Our study provides the first evidence that expression of TR, in this case encoded by a herpesvirus, is pro-oncogenic in the absence of telomerase activity.
Author Summary
The enzyme complex telomerase, with its two main components telomerase reverse transcriptase and telomerase RNA, plays an important role in telomere maintenance. Perturbation of telomere length regulation can ultimately result in cellular senescence (telomere shortening) and is also observed in tumor cells (increased telomere maintenance). Recent studies suggest telomerase RNAs can function independently of the telomerase complex and promote tumor development independently of telomere maintenance. Here we demonstrate that vTR, a herpesvirus-encoded telomerase RNA, serves two distinct functions in MDV-induced tumor formation. vTR has its first function early after infection, when it is part of the telomerase complex and contributes to the survival of rapidly dividing transformed cells. The second function of vTR is independent of telomerase action and essential for formation of solid lymphomas and metastasis. This latter function is likely a consequence of vTR-mediated gene regulation that is at least in part controlled by its interaction with and relocalization of RPL22, a cellular factor involved in T-cell development and virus-induced transformation. Taken together, our study demonstrates that telomerase RNA encoded by a herpesvirus is directly involved in tumor formation in vivo in a fashion that is largely independent of its function within an active telomerase complex.
doi:10.1371/journal.ppat.1001073
PMCID: PMC2929889  PMID: 20865127
21.  Change of the Expression of Human Telomerase Reverse Transcriptase mRNA and Human Telomerase RNA after Cisplatin and 5-Fluorouracil Exposure in Head and Neck Squamous Cell Carcinoma Cell Lines 
Journal of Korean Medical Science  2007;22(Suppl):S73-S78.
Telomerase activity appears to be associated with cell immortalization and malignant progression. Understanding how telomerase activity is regulated in vivo is important not only for understanding the molecular biology of telomerase but also for the potential clinical application of anticancer drugs. This study evaluated telomerase activity and quantified the expression of human telomerase reverse transcriptase (hTERT) mRNA and human telomerase RNA (hTR) using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) method before and after the exposure of cisplatin and 5-fluorouracil (5-FU) in two head and neck squamous cell carcinoma (HNSCC) cell lines. Two human HNSCC cell lines (PNUH-12 and SNU-899) were studied. Cell cytotoxicity, the change of telomerase activity, and hTERT mRNA and hTR expression by 5-FU and cisplatin exposure were assessed by MTT assay, TRAP assay, and real-time RT-PCR, respectively. In two cell lines, after cisplatin exposure, the telomerase activity and hTERT mRNA expression decreased, but hTR expression increased according to the concentration of drug. However, in both cell lines, the telomerase activity and hTR did not show any significant change after 5-FU treatment, but the expression of hTERT mRNA decreased. These results suggest that there may be other important regulating mechanism except hTERT mRNA as the regulation factor of telomerase activity in HNSCC cell lines.
doi:10.3346/jkms.2007.22.S.S73
PMCID: PMC2694390  PMID: 17923759
Telomerase; Telomerase Reverse Transcriptase; Telomerase RNA, Cisplatin; 5-Fluorouracil
22.  A Common Cancer Risk-Associated Allele in the hTERT Locus Encodes a Dominant Negative Inhibitor of Telomerase 
PLoS Genetics  2015;11(6):e1005286.
The TERT-CLPTM1L region of chromosome 5p15.33 is a multi-cancer susceptibility locus that encodes the reverse transcriptase subunit, hTERT, of the telomerase enzyme. Numerous cancer-associated single-nucleotide polymorphisms (SNPs), including rs10069690, have been identified within the hTERT gene. The minor allele (A) at rs10069690 creates an additional splice donor site in intron 4 of hTERT, and is associated with an elevated risk of multiple cancers including breast and ovarian carcinomas. We previously demonstrated that the presence of this allele resulted in co-production of full length (FL)-hTERT and an alternatively spliced, INS1b, transcript. INS1b does not encode the reverse transcriptase domain required for telomerase enzyme activity, but we show here that INS1b protein retains its ability to bind to the telomerase RNA subunit, hTR. We also show that INS1b expression results in decreased telomerase activity, telomere shortening, and an increased telomere-specific DNA damage response (DDR). We employed antisense oligonucleotides to manipulate endogenous transcript expression in favor of INS1b, which resulted in a decrease in telomerase activity. These data provide the first detailed mechanistic insights into a cancer risk-associated SNP in the hTERT locus, which causes cell type-specific expression of INS1b transcript from the presence of an additional alternative splice site created in intron 4 by the risk allele. We predict that INS1b expression levels cause subtle inadequacies in telomerase-mediated telomere maintenance, resulting in an increased risk of genetic instability and therefore of tumorigenesis.
Author Summary
Multiple cancer-associated single nucleotide polymorphisms (SNPs) associated with risk of a wide variety of cancers have been identified in the TERT-CLPTM1L region of 5p15.33, identifying this as a multi-cancer susceptibility locus. hTERT encodes the catalytic subunit of the enzyme telomerase, which is responsible for telomere length maintenance in the germline and in most immortalised cancer cells. To date, very little is known regarding the mechanisms by which specific hTERT SNPs predispose to cancer. In this study, we carried out detailed functional analyses on the intron 4 SNP rs10069690, which is associated with a small, but highly significant risk for many types of cancer. We show that the risk-associated minor allele of this SNP results in an hTERT mRNA splice variant, encoding a catalytically inactive protein which acts as a dominant negative inhibitor of telomerase activity and therefore decreases total telomerase activity. We propose that individuals who carry the rs10069690 minor allele have less telomerase activity in some cell types due to cell type-specific alternative splicing, which may result in slightly shorter telomeres, and hence an increased risk of genetic instability and tumorigenesis.
doi:10.1371/journal.pgen.1005286
PMCID: PMC4459975  PMID: 26053551
23.  Glucose restriction decreases telomerase activity and enhances its inhibitor response on breast cancer cells: possible extra-telomerase role of BIBR 1532 
Background
Considerable progress has been made to understand the association between lifestyle and diet in cancer initiation and promotion. Because excessive glucose consumption is a key metabolic hallmark of cancer cells, glucose restriction (GR) decreases the proliferation, and promotes the differentiation and transformation of cancer cells to quiescent cells. The immortality of cancerous cells is largely assured by telomerase, which is an interesting target for inhibition by BIBR 1532. In this study, we investigated the effect of GR on telomerase activity and on the efficacy of its inhibition by BIBR 1532.
Methods
Breast cancer MDA-MB 231 and MCF-7 cells were cultured in DMEM (Dulbecco’s modified eagle’s media) with 0, 1 or 4.5 g/l of glucose. The telomerase activity was measured via quantitative Real-Time PCR, and the two telomerase subunits were semi-quantified by RT-PCR. Proliferation test and mitochondrial metabolism were assessed via tetrazolium salt reduction and cell counts; apoptosis was assessed via caspase-3 quantification and flow cytometry.
Results
A decrease in the telomerase activity of more than 75% was associated with a significant reduction in the mRNA expression of its catalytic subunit hTERT (Reverse Transcriptase) and a decrease in the mitochondrial metabolism by more than 80% under restricted glucose conditions. In addition, GR increased the effect of BIBR 1532. Glucose deprivation induces apoptosis via BIBR 1532-mediated telomerase inhibition in triple negative breast cancer cells, as assessed by caspase-3 measurements and Annexin analysis.
Conclusions
Taken together, our results suggest that the effect of BIBR 1532 is potentiated by GR to induce triple negative breast cancer cell death.
doi:10.1186/1475-2867-14-60
PMCID: PMC4118312  PMID: 25089119
Glucose restriction; Cancer; Telomerase; Breast cancer; BIBR 1532
24.  Successful behavior change in obesity interventions in adults: a systematic review of self-regulation mediators 
BMC Medicine  2015;13:84.
Background
Relapse is high in lifestyle obesity interventions involving behavior and weight change. Identifying mediators of successful outcomes in these interventions is critical to improve effectiveness and to guide approaches to obesity treatment, including resource allocation. This article reviews the most consistent self-regulation mediators of medium- and long-term weight control, physical activity, and dietary intake in clinical and community behavior change interventions targeting overweight/obese adults.
Methods
A comprehensive search of peer-reviewed articles, published since 2000, was conducted on electronic databases (for example, MEDLINE) and journal reference lists. Experimental studies were eligible if they reported intervention effects on hypothesized mediators (self-regulatory and psychological mechanisms) and the association between these and the outcomes of interest (weight change, physical activity, and dietary intake). Quality and content of selected studies were analyzed and findings summarized. Studies with formal mediation analyses were reported separately.
Results
Thirty-five studies were included testing 42 putative mediators. Ten studies used formal mediation analyses. Twenty-eight studies were randomized controlled trials, mainly aiming at weight loss or maintenance (n = 21). Targeted participants were obese (n = 26) or overweight individuals, aged between 25 to 44 years (n = 23), and 13 studies targeted women only. In terms of study quality, 13 trials were rated as “strong”, 15 as “moderate”, and 7 studies as “weak”. In addition, methodological quality of formal mediation analyses was “medium”. Identified mediators for medium-/long-term weight control were higher levels of autonomous motivation, self-efficacy/barriers, self-regulation skills (such as self-monitoring), flexible eating restraint, and positive body image. For physical activity, significant putative mediators were high autonomous motivation, self-efficacy, and use of self-regulation skills. For dietary intake, the evidence was much less clear, and no consistent mediators were identified.
Conclusions
This is the first systematic review of mediational psychological mechanisms of successful outcomes in obesity-related lifestyle change interventions. Despite limited evidence, higher autonomous motivation, self-efficacy, and self-regulation skills emerged as the best predictors of beneficial weight and physical activity outcomes; for weight control, positive body image and flexible eating restraint may additionally improve outcomes. These variables represent possible targets for future lifestyle interventions in overweight/obese populations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0323-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-015-0323-6
PMCID: PMC4408562  PMID: 25907778
Lifestyle interventions; Obesity; Self-regulation; Weight control; Physical activity; Dietary intake; Maintenance; Behavior change; Mediation analysis
25.  Primary Prevention of Gestational Diabetes Mellitus and Large-for-Gestational-Age Newborns by Lifestyle Counseling: A Cluster-Randomized Controlled Trial 
PLoS Medicine  2011;8(5):e1001036.
In a cluster-randomized trial, Riitta Luoto and colleagues find that counseling on diet and activity can reduce the birthweight of babies born to women at risk of developing gestational diabetes mellitus (GDM), but fail to find an effect on GDM.
Background
Our objective was to examine whether gestational diabetes mellitus (GDM) or newborns' high birthweight can be prevented by lifestyle counseling in pregnant women at high risk of GDM.
Method and Findings
We conducted a cluster-randomized trial, the NELLI study, in 14 municipalities in Finland, where 2,271 women were screened by oral glucose tolerance test (OGTT) at 8–12 wk gestation. Euglycemic (n = 399) women with at least one GDM risk factor (body mass index [BMI] ≥25 kg/m2, glucose intolerance or newborn's macrosomia (≥4,500 g) in any earlier pregnancy, family history of diabetes, age ≥40 y) were included. The intervention included individual intensified counseling on physical activity and diet and weight gain at five antenatal visits. Primary outcomes were incidence of GDM as assessed by OGTT (maternal outcome) and newborns' birthweight adjusted for gestational age (neonatal outcome). Secondary outcomes were maternal weight gain and the need for insulin treatment during pregnancy. Adherence to the intervention was evaluated on the basis of changes in physical activity (weekly metabolic equivalent task (MET) minutes) and diet (intake of total fat, saturated and polyunsaturated fatty acids, saccharose, and fiber). Multilevel analyses took into account cluster, maternity clinic, and nurse level influences in addition to age, education, parity, and prepregnancy BMI. 15.8% (34/216) of women in the intervention group and 12.4% (22/179) in the usual care group developed GDM (absolute effect size 1.36, 95% confidence interval [CI] 0.71–2.62, p = 0.36). Neonatal birthweight was lower in the intervention than in the usual care group (absolute effect size −133 g, 95% CI −231 to −35, p = 0.008) as was proportion of large-for-gestational-age (LGA) newborns (26/216, 12.1% versus 34/179, 19.7%, p = 0.042). Women in the intervention group increased their intake of dietary fiber (adjusted coefficient 1.83, 95% CI 0.30–3.25, p = 0.023) and polyunsaturated fatty acids (adjusted coefficient 0.37, 95% CI 0.16–0.57, p<0.001), decreased their intake of saturated fatty acids (adjusted coefficient −0.63, 95% CI −1.12 to −0.15, p = 0.01) and intake of saccharose (adjusted coefficient −0.83, 95% CI −1.55 to −0.11, p  =  0.023), and had a tendency to a smaller decrease in MET minutes/week for at least moderate intensity activity (adjusted coefficient 91, 95% CI −37 to 219, p = 0.17) than women in the usual care group. In subgroup analysis, adherent women in the intervention group (n = 55/229) had decreased risk of GDM (27.3% versus 33.0%, p = 0.43) and LGA newborns (7.3% versus 19.5%, p = 0.03) compared to women in the usual care group.
Conclusions
The intervention was effective in controlling birthweight of the newborns, but failed to have an effect on maternal GDM.
Trial registration
Current Controlled Trials ISRCTN33885819
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Gestational diabetes mellitus (GDM) is diabetes that is first diagnosed during pregnancy. Like other types of diabetes, it is characterized by high levels of sugar (glucose) in the blood. Blood-sugar levels are normally controlled by insulin, a hormone that the pancreas releases when blood-sugar levels rise after meals. Hormonal changes during pregnancy and the baby's growth demands increase a pregnant woman's insulin needs and, if her pancreas cannot make enough insulin, GDM develops. Risk factors for GDM, which occurs in 2%–14% of pregnant women, include a high body-mass index (a measure of body fat), excessive weight gain or low physical activity during pregnancy, high dietary intake of polyunsaturated fats, glucose intolerance (an indicator of diabetes) or the birth of a large baby in a previous pregnancy, and a family history of diabetes. GDM is associated with an increased rate of cesarean sections, induced deliveries, birth complications, and large-for-gestational-age (LGA) babies (gestation is the time during which the baby develops within the mother). GDM, which can often be controlled by diet and exercise, usually disappears after pregnancy but increases a woman's subsequent risk of developing diabetes.
Why Was This Study Done?
Although lifestyle changes can be used to control GDM, it is not known whether similar changes can prevent GDM developing (“primary prevention”). In this cluster-randomized controlled trial, the researchers investigate whether individual intensified counseling on physical activity, diet, and weight gain integrated into routine maternity care visits can prevent the development of GDM and the occurrence of LGA babies among newborns. In a cluster-randomized controlled trial, groups of patients rather than individual patients are randomly assigned to receive alternative interventions, and the outcomes in different “clusters” are compared. In this trial, each cluster is a municipality in the Pirkanmaa region of Finland.
What Did the Researchers Do and Find?
The researchers enrolled 399 women, each of whom had a normal blood glucose level at 8–12 weeks gestation but at least one risk factor for GDM. Women in the intervention municipalities received intensified counseling on physical activity at 8–12 weeks' gestation, dietary counseling at 16–18 weeks' gestation, and further physical activity and dietary counseling at each subsequent antenatal visits. Women in the control municipalities received some dietary but little physical activity counseling as part of their usual care. 23.3% and 20.2% of women in the intervention and usual care groups, respectively, developed GDM, a nonstatistically significant difference (that is, a difference that could have occurred by chance). However, the average birthweight and the proportion of LGA babies were both significantly lower in the intervention group than in the usual care group. Food frequency questionnaires completed by the women indicated that, on average, those in the intervention group increased their intake of dietary fiber and polyunsaturated fatty acids and decreased their intake of saturated fatty acids and sucrose as instructed during counseling, The amount of moderate physical activity also tended to decrease less as pregnancy proceeded in the intervention group than in usual care group. Finally, compared to the usual care group, significantly fewer of the 24% of women in the intervention group who actually met dietary and physical activity targets (“adherent” women) developed GDM.
What Do These Findings Mean?
These findings indicate that intensified counseling on diet and physical activity is effective in controlling the birthweight of babies born to women at risk of developing GDM and encourages at least some of them to alter their lifestyle. However, the findings fail to show that the intervention reduces the risk of GDM because of the limited power of the study. The power of a study—the probability that it will achieve a statistically significant result—depends on the study's size and on the likely effect size of the intervention. Before starting this study, the researchers calculated that they would need 420 participants to see a statistically significant difference between the groups if their intervention reduced GDM incidence by 40%. This estimated effect size was probably optimistic and therefore the study lacked power. Nevertheless, the analyses performed among adherent women suggest that lifestyle changes might be a way to prevent GDM and so larger studies should now be undertaken to test this potential primary prevention intervention.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001036.
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information for patients on diabetes and on gestational diabetes (in English and Spanish)
The UK National Health Service Choices website also provides information for patients on diabetes and on gestational diabetes, including links to other useful resources
The MedlinePlus Encyclopedia has pages on diabetes and on gestational diabetes; MedlinePlus provides links to additional resources on diabetes and on gestational diabetes (in English and Spanish)
More information on this trial of primary prevention of GDM is available
doi:10.1371/journal.pmed.1001036
PMCID: PMC3096610  PMID: 21610860

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