Global analyses of TetR family transcriptional regulators in mycobacteria indicates conservation across species and diversity in regulated functions

BACKGROUND: Mycobacteria inhabit diverse niches and display high metabolic versatility. They can colonise both humans and animals and are also able to survive in the environment. In order to succeed, response to environmental cues via transcriptional regulation is required. In this study we focused on the TetR family of transcriptional regulators (TFTRs) in mycobacteria. RESULTS: We used InterPro to classify the entire complement of transcriptional regulators in 10 mycobacterial species and these analyses showed that TFTRs are the most abundant family of regulators in all species. We identified those TFTRs that are conserved across all species analysed and those that are unique to the pathogens included in the analysis. We examined genomic contexts of 663 of the conserved TFTRs and observed that the majority of TFTRs are separated by 200 bp or less from divergently oriented genes. Analyses of divergent genes indicated that the TFTRs control diverse biochemical functions not limited to efflux pumps. TFTRs typically bind to palindromic motifs and we identified 11 highly significant novel motifs in the upstream regions of divergently oriented TFTRs. The C-terminal ligand binding domain from the TFTR complement in M. tuberculosis showed great diversity in amino acid sequence but with an overall architecture common to other TFTRs. CONCLUSION: This study suggests that mycobacteria depend on TFTRs for the transcriptional control of a number of metabolic functions yet the physiological role of the majority of these regulators remain unknown. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-1696-9) contains supplementary material, which is available to authorized users

Eccentric exercise versus Usual-care with older cancer survivors: The impact on muscle and mobility- an exploratory pilot study

<p>Abstract</p> <p>Background</p> <p>Resistance exercise programs with high compliance are needed to counter impaired muscle and mobility in older cancer survivors. To date outcomes have focused on older prostate cancer survivors, though more heterogeneous groups of older survivors are in-need. The purpose of this exploratory pilot study is to examine whether resistance exercise via negative eccentrically-induced work (RENEW) improves muscle and mobility in a diverse sample of older cancer survivors.</p> <p>Methods</p> <p>A total of 40 individuals (25 female, 15 male) with a mean age of 74 (± 6) years who have survived (8.4 ± 8 years) since their cancer diagnosis (breast, prostate, colorectal and lymphoma) were assigned to a RENEW group or a non-exercise Usual-care group. RENEW was performed for 12 weeks and measures of muscle size, strength, power and mobility were made pre and post training.</p> <p>Results</p> <p>RENEW induced increases in quadriceps lean tissue average cross sectional area (Pre: 43.2 ± 10.8 cm²; Post: 44.9 ± 10.9 cm²), knee extension peak strength (Pre: 248.3 ± 10.8 N; Post: 275.4 ± 10.9 N), leg extension muscle power (Pre: 198.2 ± 74.7 W; Post 255.5 ± 87.3 W), six minute walk distance (Pre: 417.2 ± 127.1 m; Post 466.9 ± 125.1 m) and a decrease on the time to safely descend stairs (Pre: 6.8 ± 4.5 s; Post 5.4 ± 2.5 s). A significant (P < 0.05) group x time interaction was noted for the muscle size and mobility improvements.</p> <p>Conclusions</p> <p>This exploration of RENEW in a heterogeneous cohort of older cancer survivors demonstrates increases in muscle size, strength and power along with improved mobility. The efficacy of a high-force, low perceived exertion exercise suggests RENEW may be suited to older individuals who are survivors of cancer.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00335491">NCT00335491</a></p

The impact of physical activity on fatigue and quality of life in lung cancer patients: a randomised controlled trial protocol

Background: People with lung cancer have substantial symptom burden and more unmet needs than the general cancer population. Physical activity (PA) has been shown to positively influence quality of life (QOL), fatigue and daily functioning in the curative treatment of people with breast and colorectal cancers and lung diseases, as well as in palliative settings. A randomised controlled trial (RCT) is needed to determine if lung cancer patients benefit from structured PA intervention. The Physical Activity in Lung Cancer (PAL) trial is designed to evaluate the impact of a 2-month PA intervention on fatigue and QOL in patients with non-resectable lung cancer. Biological mechanisms will also be studied.Methods/design: A multi-centre RCT with patients randomised to usual care or a 2-month PA programme, involving supervised PA sessions including a behavioural change component and home-based PA. QOL questionnaires, disease and functional status and body composition will be assessed at baseline, 2, 4 and 6 months follow-up. The primary endpoint is comparative levels of fatigue between the 2 arms. Secondary endpoints include: QOL, functional abilities and physical function. Exploratory endpoints include: anxiety, depression, distress, dyspnoea, PA behaviour, fitness, hospitalisations, survival, cytokines and insulin-like growth factor levels.Discussion: This study will provide high-level evidence of the effect of PA programmes on cancer-related fatigue and QOL in patients with advanced lung cancer. If positive, the study has the potential to change care for people with cancer using a simple, inexpensive intervention to improve their QOL and help them maintain independent function for as long as possible.Trial registration: Australian New Zealand Clinical Trials Registry No. ACTRN12609000971235. © 2012 Dhillon et al.; licensee BioMed Central Ltd

Design of the Resistance and Endurance exercise After ChemoTherapy (REACT) study: A randomized controlled trial to evaluate the effectiveness and cost-effectiveness of exercise interventions after chemotherapy on physical fitness and fatigue

<p>Abstract</p> <p>Background</p> <p>Preliminary studies suggest that physical exercise interventions can improve physical fitness, fatigue and quality of life in cancer patients after completion of chemotherapy. Additional research is needed to rigorously test the effects of exercise programmes among cancer patients and to determine optimal training intensity accordingly. The present paper presents the design of a randomized controlled trial evaluating the effectiveness and cost-effectiveness of a high intensity exercise programme compared to a low-to-moderate intensity exercise programme and a waiting list control group on physical fitness and fatigue as primary outcomes.</p> <p>Methods</p> <p>After baseline measurements, cancer patients who completed chemotherapy are randomly assigned to either a 12-week high intensity exercise programme or a low-to-moderate intensity exercise programme. Next, patients from both groups are randomly assigned to immediate training or a waiting list (i.e. waiting list control group). After 12 weeks, patients of the waiting list control group start with the exercise programme they have been allocated to.</p> <p>Both interventions consist of equal bouts of resistance and endurance interval exercises with the same frequency and duration, but differ in training intensity. Additionally, patients of both exercise programmes are counselled to improve compliance and achieve and maintain an active lifestyle, tailored to their individual preferences and capabilities.</p> <p>Measurements will be performed at baseline (t = 0), 12 weeks after randomization (t = 1), and 64 weeks after randomization (t = 2). The primary outcome measures are cardiorespiratory fitness and muscle strength assessed by means of objective performance indicators, and self-reported fatigue. Secondary outcome measures include health-related quality of life, self-reported physical activity, daily functioning, body composition, mood and sleep disturbances, and return to work. In addition, compliance and satisfaction with the interventions will be evaluated. Potential moderation by pre- and post-illness lifestyle, health and exercise-related attitudes, beliefs and motivation will also be assessed. Finally, the cost-effectiveness of both exercise interventions will be evaluated.</p> <p>Discussion</p> <p>This randomized controlled trial will be a rigorous test of effects of exercise programmes for cancer patients after chemotherapy, aiming to contribute to evidence-based practice in cancer rehabilitation programmes.</p> <p>Trial registration</p> <p>This study is registered at the Netherlands Trial Register (NTR2153)</p

Exacerbated inflammatory cellular immune response characteristics of HAM/TSP is observed in a large proportion of HTLV-I asymptomatic carriers

BACKGROUND: A small fraction of Human T cell Leukemia Virus type-1 (HTLV-I) infected subjects develop a severe form of myelopathy. It has been established that patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) show an exaggerated immune response when compared with the immunological response observed in HTLV-I asymptomatic carriers. In this study the immunological responses in HAM/TSP patients and in HTLV-I asymptomatic carriers were compared using several immunological assays to identify immunological markers associated with progression from infection to disease. METHODS: Immunoproliferation assays, cytokine levels of unstimulated cultures, and flow cytometry analysis were used to evaluate the studied groups. Nonparametric tests (Mann-Whitney U test and Wilcoxon matched-pairs signed ranks) were used to compare the difference between the groups. RESULTS: Although both groups showed great variability, HAM/TSP patients had higher spontaneous lymphoproliferation as well as higher IFN-γ levels in unstimulated supernatants when compared with asymptomatic carriers. Flow cytometry studies demonstrated a high frequency of inflammatory cytokine (IFN-γ and TNF-α) producing lymphocytes in HAM/TSP as compared to the asymptomatic group. This difference was accounted for mainly by an increase in CD8 cell production of these cytokines. Moreover, the HAM/TSP patients also expressed an increased frequency of CD28-/CD8+ T cells. Since forty percent of the asymptomatic carriers had spontaneous lymphoproliferation and IFN-γ production similar to HAM/TSP patients, IFN-γ levels were measured eight months after the first evaluation in some of these patients to observe if this was a transient or a persistent situation. No significant difference was observed between the means of IFN-γ levels in the first and second evaluation. CONCLUSIONS: The finding that a large proportion of HTLV-I carriers present similar immunological responses to those observed in HAM/TSP, strongly argues for further studies to evaluate these parameters as markers of HAM/TSP progression

Long-Term Costs and Health Impact of Continued Global Fund Support for Antiretroviral Therapy

Background: By the end of 2011 Global Fund investments will be supporting 3.5 million people on antiretroviral therapy (ART) in 104 low- and middle-income countries. We estimated the cost and health impact of continuing treatment for these patients through 2020. Methods and Findings: Survival on first-line and second-line ART regimens is estimated based on annual retention rates reported by national AIDS programs. Costs per patient-year were calculated from country-reported ARV procurement prices, and expenditures on laboratory tests, health care utilization and end-of-life care from in-depth costing studies. Of the 3.5 million ART patients in 2011, 2.3 million will still need treatment in 2020. The annual cost of maintaining ART falls from $1.9 billion in 2011 to$1.7 billion in 2020, as a result of a declining number of surviving patients partially offset by increasing costs as more patients migrate to second-line therapy. The Global Fund is expected to continue being a major contributor to meeting this financial need, alongside other international funders and domestic resources. Costs would be $150 million less in 2020 with an annual 5$150-370 million less with a 5%-12% annual decline in second-line prices, but $200 million higher in 2020 with phase out of stavudine (d4T), or$200 million higher with increased migration to second-line regimens expected if all countries routinely adopted viral load monitoring. Deaths postponed by ART correspond to 830,000 life-years saved in 2011, increasing to around 2.3 million life-years every year between 2015 and 2020. Conclusions: Annual patient-level direct costs of supporting a patient cohort remain fairly stable over 2011-2020, if current antiretroviral prices and delivery costs are maintained. Second-line antiretroviral prices are a major cost driver, underscoring the importance of investing in treatment quality to improve retention on first-line regimens

Interpretation and Visualization of Non-Linear Data Fusion in Kernel Space: Study on Metabolomic Characterization of Progression of Multiple Sclerosis

Contains fulltext : 93904.pdf (publisher's version ) (Open Access

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

<p>Abstract</p> <p>Background</p> <p>The Lung Cancer Exercise Training Study (LUNGEVITY) is a randomized trial to investigate the efficacy of different types of exercise training on cardiorespiratory fitness (VO_2peak), patient-reported outcomes, and the organ components that govern VO_2peakin post-operative non-small cell lung cancer (NSCLC) patients.</p> <p>Methods/Design</p> <p>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 VO_2peakfor 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 VO_2peak. 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.</p> <p>Discussion</p> <p>VO_2peakis 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.</p> <p>Trial Registration</p> <p>NCT00018255</p

Randomised controlled trial of a supervised exercise rehabilitation program for colorectal cancer survivors immediately after chemotherapy: study protocol

Background Colorectal cancer (CRC) diagnosis and the ensuing treatments can have a substantial impact on the physical and psychological health of survivors. As the number of CRC survivors increases, so too does the need to develop viable rehabilitation programs to help these survivors return to good health as quickly as possible. Exercise has the potential to address many of the adverse effects of CRC treatment; however, to date, the role of exercise in the rehabilitation of cancer patients immediately after the completion of treatment has received limited research attention. This paper presents the design of a randomised controlled trial which will evaluate the feasibility and efficacy of a 12-week supervised aerobic exercise program (ImPACT Program) on the physiological and psychological markers of rehabilitation, in addition to biomarkers of standard haematological outcomes and the IGF axis. Methods/Design Forty CRC patients will be recruited through oncology clinics and randomised to an exercise group or a usual care control group. Baseline assessment will take place within 4 weeks of the patient completing adjuvant chemotherapy treatment. The exercise program for patients in the intervention group will commence a week after the baseline assessment. The program consists of three supervised moderate-intensity aerobic exercise sessions per week for 12 weeks. All participants will have assessments at baseline (0 wks), mid-intervention (6 wks), post-intervention (12 wks) and at a 6-week follow-up (18 wks). Outcome measures include cardio-respiratory fitness, biomarkers associated with health and survival, and indices of fatigue and quality of life. Process measures are participants' acceptability of, adherence to, and compliance with the exercise program, in addition to the safety of the program. Discussion The results of this study will provide valuable insight into the role of supervised exercise in improving life after CRC. Additionally, process analyses will inform the feasibility of implementing the program in a population of CRC patients immediately after completing chemotherapy