The lung cancer exercise training study: a randomized trial of aerobic training, resistance training, or both in postsurgical lung cancer patients: rationale and design.

BACKGROUND: The Lung Cancer Exercise Training Study (LUNGEVITY) is a randomized trial to investigate the efficacy of different types of exercise training on cardiorespiratory fitness (VO2peak), patient-reported outcomes, and the organ components that govern VO2peak in post-operative non-small cell lung cancer (NSCLC) patients. METHODS/DESIGN: Using a single-center, randomized design, 160 subjects (40 patients/study arm) with histologically confirmed stage I-IIIA NSCLC following curative-intent complete surgical resection at Duke University Medical Center (DUMC) will be potentially eligible for this trial. Following baseline assessments, eligible participants will be randomly assigned to one of four conditions: (1) aerobic training alone, (2) resistance training alone, (3) the combination of aerobic and resistance training, or (4) attention-control (progressive stretching). The ultimate goal for all exercise training groups will be 3 supervised exercise sessions per week an intensity above 70% of the individually determined VO2peak for aerobic training and an intensity between 60 and 80% of one-repetition maximum for resistance training, for 30-45 minutes/session. Progressive stretching will be matched to the exercise groups in terms of program length (i.e., 16 weeks), social interaction (participants will receive one-on-one instruction), and duration (30-45 mins/session). The primary study endpoint is VO2peak. Secondary endpoints include: patient-reported outcomes (PROs) (e.g., quality of life, fatigue, depression, etc.) and organ components of the oxygen cascade (i.e., pulmonary function, cardiac function, skeletal muscle function). All endpoints will be assessed at baseline and postintervention (16 weeks). Substudies will include genetic studies regarding individual responses to an exercise stimulus, theoretical determinants of exercise adherence, examination of the psychological mediators of the exercise - PRO relationship, and exercise-induced changes in gene expression. DISCUSSION: VO2peak is becoming increasingly recognized as an outcome of major importance in NSCLC. LUNGEVITY will identify the optimal form of exercise training for NSCLC survivors as well as provide insight into the physiological mechanisms underlying this effect. Overall, this study will contribute to the establishment of clinical exercise therapy rehabilitation guidelines for patients across the entire NSCLC continuum. TRIAL REGISTRATION: NCT00018255.

Rationale and design of the Exercise Intensity Trial (EXCITE): A randomized trial comparing the effects of moderate versus moderate to high-intensity aerobic training in women with operable breast cancer.

BACKGROUND: The Exercise Intensity Trial (EXcITe) is a randomized trial to compare the efficacy of supervised moderate-intensity aerobic training to moderate to high-intensity aerobic training, relative to attention control, on aerobic capacity, physiologic mechanisms, patient-reported outcomes, and biomarkers in women with operable breast cancer following the completion of definitive adjuvant therapy. METHODS/DESIGN: Using a single-center, randomized design, 174 postmenopausal women (58 patients/study arm) with histologically confirmed, operable breast cancer presenting to Duke University Medical Center (DUMC) will be enrolled in this trial following completion of primary therapy (including surgery, radiation therapy, and chemotherapy). After baseline assessments, eligible participants will be randomized to one of two supervised aerobic training interventions (moderate-intensity or moderate/high-intensity aerobic training) or an attention-control group (progressive stretching). The aerobic training interventions will include 150 mins.wk⁻¹ of supervised treadmill walking per week at an intensity of 60%-70% (moderate-intensity) or 60% to 100% (moderate to high-intensity) of the individually determined peak oxygen consumption (VO₂peak) between 20-45 minutes/session for 16 weeks. The progressive stretching program will be consistent with the exercise interventions in terms of program length (16 weeks), social interaction (participants will receive one-on-one instruction), and duration (20-45 mins/session). The primary study endpoint is VO₂peak, as measured by an incremental cardiopulmonary exercise test. Secondary endpoints include physiologic determinants that govern VO₂peak, patient-reported outcomes, and biomarkers associated with breast cancer recurrence/mortality. All endpoints will be assessed at baseline and after the intervention (16 weeks). DISCUSSION: EXCITE is designed to investigate the intensity of aerobic training required to induce optimal improvements in VO₂peak and other pertinent outcomes in women who have completed definitive adjuvant therapy for operable breast cancer. Overall, this trial will inform and refine exercise guidelines to optimize recovery in breast and other cancer survivors following the completion of primary cytotoxic therapy. TRIAL REGISTRATION: NCT01186367.

Cardiorespiratory fitness and cognitive function in midlife: neuroprotection or neuroselection?

OBJECTIVE: A study was undertaken to determine whether better cognitive functioning at midlife among more physically fit individuals reflects neuroprotection, by which fitness protects against age-related cognitive decline, or neuroselection, by which children with higher cognitive functioning select more active lifestyles. METHODS: Children in the Dunedin Longitudinal Study (N = 1,037) completed the Wechsler Intelligence Scales and the Trail Making, Rey Delayed Recall, and Grooved Pegboard tasks as children and again at midlife (age = 38 years). Adult cardiorespiratory fitness was assessed using a submaximal exercise test to estimate maximum oxygen consumption adjusted for body weight in milliliters/minute/kilogram. We tested whether more fit individuals had better cognitive functioning than their less fit counterparts (which could be consistent with neuroprotection), and whether better childhood cognitive functioning predisposed to better adult cardiorespiratory fitness (neuroselection). Finally, we examined possible mechanisms of neuroselection. RESULTS: Participants with better cardiorespiratory fitness had higher cognitive test scores at midlife. However, fitness-associated advantages in cognitive functioning were already present in childhood. After accounting for childhood baseline performance on the same cognitive tests, there was no association between cardiorespiratory fitness and midlife cognitive functioning. Socioeconomic and health advantages in childhood and healthier lifestyles during young adulthood explained most of the association between childhood cognitive functioning and adult cardiorespiratory fitness. INTERPRETATION: We found no evidence for a neuroprotective effect of cardiorespiratory fitness as of midlife. Instead, children with better cognitive functioning are selecting healthier lives. Fitness interventions may enhance cognitive functioning. However, observational and experimental studies testing neuroprotective effects of physical fitness should consider confounding by neuroselection.

Later Life Consequences of Developmental Mitochondrial DNA Damage in C. elegans

Mitochondria are responsible for producing the vast majority of cellular ATP, and are therefore critical to organismal health [1]. They contain thir own genomes (mtDNA) which encode 13 proteins that are all subunits of the mitochondrial respiratory chain (MRC) and are essential for oxidative phosphorylation [2]. mtDNA is present in multiple copies per cell, usually between 103 and 104 , though this number is reduced during certain developmental stages [3, 4]. The health of the mitochondrial genome is also important to the health of the organism, as mutations in mtDNA lead to human diseases that collectively affect approximately 1 in 4000 people [5, 6]. mtDNA is more susceptible than nuclear DNA (nucDNA) to damage by many environmental pollutants, for reasons including the absence of Nucleotide Excision Repair (NER) in the mitochondria [7]. NER is a highly functionally conserved DNA repair pathway that removes bulky, helix distorting lesions such as those caused by ultraviolet C (UVC) radiation and also many environmental toxicants, including benzo[a]pyrene (BaP) [8]. While these lesions cannot be repaired, they are slowly removed through a process that involves mitochondrial dynamics and autophagy [9, 10]. However, when present during development in C. elegans, this damage reduces mtDNA copy number and ATP levels [11]. We hypothesize that this damage, when present during development, will result in mitochondrial dysfunction and increase the potential for adverse outcomes later in life.

To test this hypothesis, 1st larval stage (L1) C. elegans are exposed to 3 doses of 7.5J/m2 ultraviolet C radiation 24 hours apart, leading to the accumulation of mtDNA damage [9, 11]. After exposure, many mitochondrial endpoints are assessed at multiple time points later in life. mtDNA and nucDNA damage levels and genome copy numbers are measured via QPCR and real-time PCR , respectively, every 2 day for 10 days. Steady state ATP levels are measured via luciferase expressing reporter strains and traditional ATP extraction methods. Oxygen consumption is measured using a Seahorse XFe24 extra cellular flux analyzer. Gene expression changes are measured via real time PCR and targeted metabolomics via LC-MS are used to investigate changes in organic acid, amino acid and acyl-carnitine levels. Lastly, nematode developmental delay is assessed as growth, and measured via imaging and COPAS biosort.

I have found that despite being removed, UVC induced mtDNA damage during development leads to persistent deficits in energy production later in life. mtDNA copy number is permanently reduced, as are ATP levels, though oxygen consumption is increased, indicating inefficient or uncoupled respiration. Metabolomic data and mutant sensitivity indicate a role for NADPH and oxidative stress in these results, and exposed nematodes are more sensitive to the mitochondrial poison rotenone later in life. These results fit with the developmental origin of health and disease hypothesis, and show the potential for environmental exposures to have lasting effects on mitochondrial function.

Lastly, we are currently working to investigate the potential for irreparable mtDNA lesions to drive mutagenesis in mtDNA. Mutations in mtDNA lead to a wide range of diseases, yet we currently do not understand the environmental component of what causes them. In vitro evidence suggests that UVC induced thymine dimers can be mutagenic [12]. We are using duplex sequencing of C. elegans mtDNA to determine mutation rates in nematodes exposed to our serial UVC protocol. Furthermore, by including mutant strains deficient in mitochondrial fission and mitophagy, we hope to determine if deficiencies in these processes will further increase mtDNA mutation rates, as they are implicated in human diseases.

Cell cycle Start is coupled to entry into the yeast metabolic cycle across diverse strains and growth rates.

Cells have evolved oscillators with different frequencies to coordinate periodic processes. Here we studied the interaction of two oscillators, the cell division cycle (CDC) and the yeast metabolic cycle (YMC), in budding yeast. Previous work suggested that the CDC and YMC interact to separate high oxygen consumption (HOC) from DNA replication to prevent genetic damage. To test this hypothesis, we grew diverse strains in chemostat and measured DNA replication and oxygen consumption with high temporal resolution at different growth rates. Our data showed that HOC is not strictly separated from DNA replication; rather, cell cycle Start is coupled with the initiation of HOC and catabolism of storage carbohydrates. The logic of this YMC-CDC coupling may be to ensure that DNA replication and cell division occur only when sufficient cellular energy reserves have accumulated. Our results also uncovered a quantitative relationship between CDC period and YMC period across different strains. More generally, our approach shows how studies in genetically diverse strains efficiently identify robust phenotypes and steer the experimentalist away from strain-specific idiosyncrasies.

Cell cycle start is coupled to entry into the yeast metabolic cycle across diverse strains and growth rates

© 2016 Burnetti et al. Cells have evolved oscillators with different frequencies to coordinate periodic processes. Here we studied the interaction of two oscillators, the cell division cycle (CDC) and the yeast metabolic cycle (YMC), in budding yeast. Previous work suggested that the CDC and YMC interact to separate high oxygen consumption (HOC) from DNA replication to prevent genetic damage. To test this hypothesis, we grew diverse strains in chemostat and measured DNA replication and oxygen consumption with high temporal resolution at different growth rates. Our data showed that HOC is not strictly separated from DNA replication; rather, cell cycle Start is coupled with the initiation of HOC and catabolism of storage carbohydrates. The logic of this YMC-CDC coupling may be to ensure that DNA replication and cell division occur only when sufficient cellular energy reserves have accumulated. Our results also uncovered a quantitative relationship between CDC period and YMC period across different strains. More generally, our approach shows how studies in genetically diverse strains efficiently identify robust phenotypes and steer the experimentalist away from strain-specific idiosyncrasies.

The effects of cadence and power output upon physiological and biomechanical responses to incremental arm-crank ergometry

The aim of this study was to examine the effects of cadence and power output on physiological and biomechanical responses to incremental arm-crank ergometry (ACE). Ten male subjects (mean +/- SD age, 30.4 +/-5.4 y; height, 1.78 +/-0.07 m; mass, 86.1 +/-14.2 kg) undertook 3 incremental ACE protocols to determine peak oxygen uptake (VO2 peak; mean of 3 tests: 3.07 +/- 0.17 L.min-1) at randomly assigned cadences of 50, 70, or 90 r.min-1. Heart rate and expired air were continually monitored. Central (RPE-C) and local (RPE-L) ratings of perceived exertion were recorded at volitional exhaustion. Joint angles and trunk rotation were analysed during each exercise stage. During submaximal power outputs of 50, 70, and 90 W, oxygen consumption (VO2) was lowest for 50 r.min-1 and highest for 90 r.min-1 (p < 0.01). VO2 peak was lowest during 50 r.min-1 (2.79 +/-0.45 L.min-1; p < 0.05) when compared with both 70 r.min-1 and 90 r.min-1 (3.16 +/-0.58, 3.24 +/-0.49 L.min-1, respectively; p > 0.05). The difference between RPE-L and RPE-C at volitional exhaustion was greatest during 50 r.min-1 (2.9 +/- 1.6) when compared with 90 r.min-1 (0.9 +/- 1.9, p < 0.05). At VO2 peak, shoulder range of motion (ROM) and trunk rotation were greater for 50 and 70 r.min-1 when compared with 90 r.min-1 (p < 0.05). During submaximal power outputs, shoulder angle and trunk rotation were greatest at 50 r.min-1 when compared with 90 r.min-1 (p < 0.05). VO2 was inversely related to both trunk rotation and shoulder ROM during submaximal power outputs. The results of this study suggest that the greater forces required at lower cadences to produce a given power output resulted in greater joint angles and range of shoulder and trunk movement. Greater isometric contractions for torso stabilization and increased cost of breathing possibly from respiratory-locomotor coupling may have contributed increased oxygen consumption at higher cadences.

Reproductive Effort And Value In Different Populations Of The Marine Mussel Mytilus-Edulis-L

Fecundity, reproductive effort (estimated both from production measurements and from physiological data), the energetic costs of reproduction and the reproductive value of different size classes were measured for mussels at different sites and related to age and to tissue weight. Variability between sites was considerable and differences as great as 10 x were recorded between minimum and maximum values for egg production, reproductive effort and reproductive value. However, similarities between mussels from different sites were also apparent, as regards egg size, the estimated metabolic costs of egg production (based on measurements of oxygen consumption), the relationship (isometric) between egg production and body size, the fact of an increase in reproductive effort with increase in size, and the age at which maximum residual reproductive values was expressed. These relationships are discussed in terms of the fundamental reproductive strategy of the species and the degree of environmental stress imposed on the mussels at the different sites.

Responses Of Mytilus-Edulis On Exposure To The Water-Accommodated Fraction Of North-Sea-Oil

Individuals of Mytilus edulis L., collected from the Erme estuary (S.W. England) in 1978, were exposed to low concentrations (7 to 68 μg l-1) of the water-accommodated fraction (WAF) of North Sea crude oil. The pattern of accumulation of petroleum hydrocarbons in the body tissues was affected by the presence of algal food cells, the period of exposure, the hydrocarbon concentration in seawater, the type of body tissue and the nature of the hydrocarbon. Many physiological responses (e.g. rates of oxygen consumption, feeding, excretion, and scope for growth), cellular responses (e.g. lysosomal latency and digestive cell size) and biochemical responses (e.g. specific activities of several enzymes) were significantly altered by short-term (4 wk) and/or long-term (5 mo) exposure to WAF. Stress indices such as scope for growth and lysosomal latency were negatively correlated with tissue aromatic hydrocarbons.

Some Practical Considerations In The Measurement Of Pollution Effects On Bivalve Mollusks And Some Possible Ecological Consequences

A consideration of some physiological (rates of oxygen consumption, the scope for growth) and cellular (the cytochemical latency of a lysosomal enzyme) processes in bivalve molluscs suggests that animal size and seasonal changes related to the gametogenic cycle are important sources of natural variability. Correcting for size using regression techniques, and limiting measurements to one part of the gametogenic cycle, reduces observed natural variability considerably. Differences between populations are then still apparent, but the results of laboratory experiments with hydrocarbons from crude oil suggest that it should be possible to detect sub-lethal effects due to pollution (the ‘signal’) in the presence of the remaining natural variability (the ‘noise’). Statistical considerations, taken together with results from current studies on Mytilus edulis and Scobicularia plana, indicate that sample sizes of 10–15 individuals should suffice for the detection of possible pollution effects. The physiological effects to be expected in the presence of sub-lethal levels of polluting hydrocarbons are on a scaie that can cause significant ecological damage to a population through a reduction in fecundity and the residual reproductive value of the individuals.

Seasonal-Changes In The Physiology Reproductive Condition And Carbohydrate Content Of The Cockle Cardium (=Cerastoderma) Edule (Bivalvia Cardiidae)

Pronounced seasonal cycles in the rates of oxygen consumption and feeding were found for Cardium (=Cerastoderma) edule L. measured in the field under ambient conditions. The cockles had a maximum rate of oxygen consumption (0.89 ml O2 g-1 h-1) in April which declined to a minimum of 0.35 ml O2 g-1 h-1 in March. Their feeding rate was variable but had a maximum value (3.91 l g-1 h-1) in April and a minimum value (0.73 l g-1 h-1) in October. There was no apparent seasonal variation in absorption efficiency, with a mean value of 67.6%. Gametogenesis was initiated in January and the population reached a peak in reproductive condition in April/May, followed by a 3 month spawning period. Carbohydrate reserves were synthesised during spawning, and were then utilised during the winter and early spring. An adaptive function for a reduction in time spent feeding is postulated, and correlations between the rates of certain physiological processes and some exogenous and endogenous variables are discussed.

Physiological And Biochemical Responses Of Bivalve Mollusks To Exposure To Air

1. Aerial rate of oxygen consumption by Mytilus edulis and M. galloprovincialis is 4–17% of the aquatic rate. 2. For Cardium edule and Modiolus demissus the aerial rate of oxygen uptake is between 28 and 78% of the aquatic rate. 3. These species differences are related to the degree of shell gape during air exposure. 4. All species show an apparent oxygen debt after exposure to air, the extent of which is not simply related to either the level of aerobic respiration or the degree of anaerobiosis during exposure. 5. Anaerobic end-products accumulate in the tissues of Mytilus during aerial exposure, but not in Cardium. 6. The relative energy yields by aerobic and anaerobic means in M. edulis are discussed.

Relationships Between Seston Available Food And Feeding-Activity In The Common Mussel Mytilus-Edulis

The feeding and metabolic rates of Mytilus edulis L. of different body sizes were measured in response to changes in particle concentrations ranging from 2 to 350 mg l-1. Rates of oxygen consumption were not significantly affected by changes in seston concentration, whereas clearance rates gradually declined with increasing particle concentration. Pseudofaeces production was initiated at relatively low seston concentrations (<5 mg l-1). Marked seasonal changes were recorded in the composition of suspended particulates (seston) in an estuary in south-west England. Total seston was sampled at frequent intervals throughout an annual cycle and analysed in terms of: particle size-frequency distributions, total dry weight (mg l-1), inorganic content, chlorophyll a, carbohydrate, protein and lipid. The particulate carbohydrate, protein and lipid content provided an estimate of the food content of the seston. The results are discussed in terms of the “food available” to a nonselective suspension feeder, such as M. edulis, during a seasonal cycle. The effect of inorganic silt in suspension was mainly to limit by “dilution” the amount of food material ingested rather than to reduce the amount of material filtered by the mussel. In winter, the food content of the material ingested was 5%, and this increased to 25% during the spring and summer.

Physiological-Responses Of Mytilus-Edulis L To Parasitic Infestation By Mytilicola-Intestinalis

Various levels of infestation by Mytilicola had no effect on the rates of oxygen consumption by Mytilus edulis in laboratory experiments. However, high levels of infestation (> 10 parasites per mussel) caused a depression in the feeding rate of the host at high temperatures (22° or 23° C) and low ration (maintenance or sub-maintenance). This depression of feeding resulted in a decline in the scope for growth, which would result in time in a decline in the “condition” of the host. It is concluded that similar effects may occur in the field when large numbers of small parasites are present at a time of high metabolic demand and low food availability.

Combined Effects Of Body Size Food Concentration And Season On Physiology Of Mytilus-Edulis

Multivariate experiments are used to study the effects of body size, food concentration, and season on the oxygen consumption, ammonia excretion, food assimilation efficiency and filtration rate of Mytilus edulis adults. Food concentrations and season affect both the intercept and the slope of the allometric equation describing oxygen uptake as a function of body size. Multiple regression and response surface techniques are used to describe and illustrate the complex relationship between metabolic rate, ration, season and the body size of M. edulis. Filtration rate has a relatively low weight exponent Q> = 038) and the intercept for the allometric equation is not significantly affected by food concentration, season or acclimation temperatures between 5 and 20 °C. Food assimilation efficiency declines exponentially with increasing food concentration and is dependent on body size at high food levels. The rate of ammonia excretion shows a similar seasonal cycle to that of oxygen consumption. They are both minimal in the autumn/winter and reach a maximum in the spring /summer.