Rationale and design of the participant, investigator, observer, and data-analyst-blinded randomized AGENDA trial on associations between gene-polymorphisms, endophenotypes for depression and antidepressive intervention: the effect of escitalopram versus placebo on the combined dexamethasone-corticotrophine releasing hormone test and other potential endophenotypes in healthy first-degree relatives of persons with depression

<p>Abstract</p> <p>Background</p> <p>Endophenotypes are heritable markers, which are more prevalent in patients and their healthy relatives than in the general population. Recent studies point at disturbed regulation of the hypothalamic-pituitary-adrenocortical axis as a possible endophenotype for depression. We hypothesize that potential endophenotypes for depression may be affected by selective serotonin re-uptake inhibitor antidepressants in healthy first-degree relatives of depressed patients. The primary outcome measure is the change in plasma cortisol in the dexamethasone-corticotrophin releasing hormone test from baseline to the end of intervention.</p> <p>Methods</p> <p>The AGENDA trial is designed as a participant, investigator, observer, and data-analyst-blinded randomized trial. Participants are 80 healthy first-degree relatives of patients with depression. Participants are randomized to escitalopram 10 mg per day versus placebo for four weeks. Randomization is stratified by gender and age. The primary outcome measure is the change in plasma cortisol in the dexamethasone-corticotrophin releasing hormone test at entry before intervention to after four weeks of intervention. With the inclusion of 80 participants, a 60% power is obtained to detect a clinically relevant difference in the primary outcome between the intervention and the placebo group. Secondary outcome measures are changes from baseline to four weeks in scores of: 1) cognition and 2) neuroticism. Tertiary outcomes measures are changes from baseline to four weeks in scores of: 1) depression and anxiety symptoms; 2) subjective evaluations of depressive symptoms, perceived stress, quality of life, aggression, sleep, and pain; and 3) salivary cortisol at eight different timepoints during an ordinary day. Assessments are undertaken by assessors blinded to the randomization group.</p> <p>Trial registration</p> <p>Local Ethics Committee: H-KF 307413</p> <p>Danish Medicines Agency: 2612-3162.</p> <p>EudraCT: 2006-001750-28.</p> <p>Danish Data Agency: 2006-41-6737.</p> <p>ClinicalTrials.gov: NCT 00386841</p

Effect of post-implant exercise on tumour growth rate, perfusion and hypoxia in mice.

Preclinical studies have shown a larger inhibition of tumour growth when exercise begins prior to tumour implant (preventative setting) than when training begins after tumour implant (therapeutic setting). However, post-implantation exercise may alter the tumour microenvironment to make it more vulnerable to treatment by increasing tumour perfusion while reducing hypoxia. This has been shown most convincingly in breast and prostate cancer models to date and it is unclear whether other tumour types respond in a similar way. We aimed to determine whether tumour perfusion and hypoxia are altered with exercise in a melanoma model, and compared this with a breast cancer model. We hypothesised that post-implantation exercise would reduce tumour hypoxia and increase perfusion in these two models. Female, 6-10 week old C57BL/6 mice were inoculated with EO771 breast or B16-F10 melanoma tumour cells before randomisation to either exercise or non-exercising control. Exercising mice received a running wheel with a revolution counter. Mice were euthanised when tumours reached maximum ethical size and the tumours assessed for perfusion, hypoxia, blood vessel density and proliferation. We saw an increase in heart to body weight ratio in exercising compared with non-exercising mice (p = 0.0008), indicating that physiological changes occurred with this form of physical activity. However, exercise did not affect vascularity, perfusion, hypoxia or tumour growth rate in either tumour type. In addition, EO771 tumours had a more aggressive phenotype than B16-F10 tumours, as inferred from a higher rate of proliferation (p<0.0001), a higher level of tumour hypoxia (p = 0.0063) and a higher number of CD31+ vessels (p = 0.0005). Our results show that although a physiological training effect was seen with exercise, it did not affect tumour hypoxia, perfusion or growth rate. We suggest that exercise monotherapy is minimally effective and that future preclinical work should focus on the combination of exercise with standard cancer therapies

Effect of immune modulation on the skeletal muscle mitochondrial exercise response: An exploratory study in mice with cancer

Cancer causes mitochondrial alterations in skeletal muscle, which may progress to muscle wasting and, ultimately, to cancer cachexia. Understanding how exercise adaptations are altered by cancer and cancer treatment is important for the effective design of exercise interventions aimed at improving cancer outcomes. We conducted an exploratory study to investigate how tumor burden and cancer immunotherapy treatment (anti-PD-1) modify the skeletal muscle mitochondrial response to exercise training in mice with transplantable tumors (B16-F10 melanoma and EO771 breast cancer). Mice remained sedentary or were provided with running wheels for ~19 days immediately following tumor implant while receiving no treatment (Untreated), isotype control antibody (IgG2a) or anti-PD-1. Exercise and anti-PD-1 did not alter the growth rate of either tumor type, either alone or in combination therapy. Untreated mice with B16-F10 tumors showed increases in most measured markers of skeletal muscle mitochondrial content following exercise training, as did anti-PD-1-treated mice, suggesting increased mitochondrial content following exercise training in these groups. However, mice with B16-F10 tumors receiving the isotype control antibody did not exhibit increased skeletal muscle mitochondrial content following exercise. In untreated mice with EO771 tumors, only citrate synthase activity and complex IV activity were increased following exercise. In contrast, IgG2a and anti-PD-1-treated groups both showed robust increases in most measured markers following exercise. These results indicate that in mice with B16-F10 tumors, IgG2a administration prevents exercise adaptation of skeletal muscle mitochondria, but adaptation remains intact in mice receiving anti-PD-1. In mice with EO771 tumors, both IgG2a and anti-PD-1-treated mice show robust skeletal muscle mitochondrial exercise responses, while untreated mice do not. Taken together, we postulate that immune modulation may enhance skeletal muscle mitochondrial response to exercise in tumor-bearing mice, and suggest this as an exciting new avenue for future research in exercise oncology