Insulin and IGF-1 have both overlapping and distinct effects on CD4+ T cell mitochondria, metabolism, and function.

Insulin and insulin-like growth factor 1 (IGF-1) are metabolic hormones with known effects on CD4+ T cells through insulin receptor (IR) and IGF-1 receptor (IGF-1R) signaling. Here, we describe specific and distinct roles for these hormones and receptors. We have found that IGF-1R, but not IR, expression is increased following CD4+ T cell activation or following differentiation toward Th17 cells. Although both insulin and IGF-1 increase the metabolism of CD4+ T cells, insulin has a more potent effect. However, IGF-1 has a unique role and acts specifically on Th17 cells to increase IL-17 production and Th17 cell metabolism. Furthermore, IGF-1 decreases mitochondrial membrane potential and mitochondrial reactive oxygen species (mROS) in Th17 cells, providing a cytoprotective effect. Interestingly, both IR and IGF-1R are required for this effect of IGF-1 on mitochondria, which suggests that the hybrid IR/IGF-1R may be required for mediating the effect of IGF-1 on mitochondrial membrane potential and mROS production.

Effects of T cell leptin signaling on systemic glucose tolerance and T cell responses in obesity.

BACKGROUND/OBJECTIVES: Leptin is an adipokine secreted in proportion to adipocyte mass and is therefore increased in obesity. Leptin signaling has been shown to directly promote inflammatory T helper 1 (Th1) and T helper 17 (Th17) cell number and function. Since T cells have a critical role in driving inflammation and systemic glucose intolerance in obesity, we sought to determine the role of leptin signaling in this context. METHODS: Male and female T cell-specific leptin receptor knockout mice and littermate controls were placed on low-fat diet or high-fat diet to induce obesity for 18 weeks. Weight gain, serum glucose levels, systemic glucose tolerance, T cell metabolism, and T cell differentiation and cytokine production were examined. RESULTS: In both male and female mice, T cell-specific leptin receptor deficiency did not reverse impaired glucose tolerance in obesity, although it did prevent impaired fasting glucose levels in obese mice compared to littermate controls, in a sex dependent manner. Despite these minimal effects on systemic metabolism, T cell-specific leptin signaling was required for changes in T cell metabolism, differentiation, and cytokine production observed in mice fed high-fat diet compared to low-fat diet. Specifically, we observed increased T cell oxidative metabolism, increased CD4+ T cell IFN-γ expression, and increased proportion of T regulatory (Treg) cells in control mice fed high-fat diet compared to low-fat diet, which were not observed in the leptin receptor conditional knockout mice, suggesting that leptin receptor signaling is required for some of the inflammatory changes observed in T cells in obesity. CONCLUSIONS: T cell-specific deficiency of leptin signaling alters T cell metabolism and function in obesity but has minimal effects on obesity-associated systemic metabolism. These results suggest a redundancy in cytokine receptor signaling pathways in response to inflammatory signals in obesity.

Perceived Autonomy Support in Telerehabilitation by People With Chronic Respiratory Disease: A Mixed Methods Study.

BACKGROUND: Autonomy-supportive health environments can assist patients in achieving behavior change and can influence adherence positively. Telerehabilitation may increase access to rehabilitation services, but creating an autonomy-supportive environment may be challenging. RESEARCH QUESTION: To what degree does telerehabilitation provide an autonomy-supportive environment? What is the patient experience of an 8-week telerehabilitation program? STUDY DESIGN AND METHODS: Individuals undertaking telerehabilitation or center-based pulmonary rehabilitation within a larger randomized controlled equivalence trial completed the Health Care Climate Questionnaire (HCCQ; short form) to assess perceived autonomy support. Telerehabilitation participants were invited 1:1 to undertake semistructured interviews. Interviews were transcribed verbatim and coded thematically to identify major themes and subthemes. RESULTS: One hundred thirty-six participants (n = 69 telerehabilitation) completed the HCCQ and 30 telerehabilitation participants (42%) undertook interviews. HCCQ summary scores indicated that participants strongly agreed that the telerehabilitation environment was autonomy supportive, which was similar to center-based participants (HCCQ summary score, P = .6; individual HCCQ items, P ≥ .3). Telerehabilitation interview data supported quantitative findings identifying five major themes, with subthemes, as follows: (1) making it easier to participate in pulmonary rehabilitation, because telerehabilitation was convenient, saved time and money, and offered flexibility; (2) receiving support in a variety of ways, including opportunities for peer support and receiving an individualized program guided by expert staff; (3) internal and external motivation to exercise as a consequence of being in a supervised group, seeing results for effort, and being inspired by others; (4) achieving success through provision of equipment and processes to prepare and support operation of equipment and technology; and (5) after the rehabilitation program, continuing to exercise, but dealing with feelings of loss. INTERPRETATION: Telerehabilitation was perceived as an autonomy-supportive environment, in part by making it easier to undertake pulmonary rehabilitation. Support for behavior change, understanding, and motivation were derived from clinicians and patient-peers. The extent to which autonomy support translates into ongoing self-management and behavior change is not clear. TRIAL REGISTRY: Australian and New Zealand Clinical Trials Registry; No.: ACTRN12616000360415; URL: https://anzctr.org.au/.

Web-based physical activity promotion in young people with CF: a randomised controlled trial.

BACKGROUND: Physical activity levels are known to decline following hospitalisation for people with cystic fibrosis (pwCF). However, optimal physical activity promotion strategies are unclear. This study investigated the effect of a web-based application (ActivOnline) in promoting physical activity in young pwCF. METHODS: Multicentre randomised controlled trial with assessor blinding and qualitative evaluation. People with CF (12-35 years) admitted to hospital for a respiratory cause were eligible and randomised to the 12-week ActivOnline intervention (AO) or usual care (UC). The primary outcome was change in device-based time spent in moderate-to-vigorous physical activity (MVPA) from baseline to post-intervention. Follow-up was at 6 months from hospital discharge when qualitative evaluation was undertaken. RESULTS: 107 participants were randomised to AO (n=52) or UC (n=55). Sixty-three participants (59%) contributed to the intention-to-treat analysis. Mean (SD) age was 21 (6) years (n=46, <18 years). At baseline, physical activity levels were high in both groups (AO 102 (52) vs UC 127 (73) min/day). There was no statistically significant difference in MVPA between groups at either timepoint (post-intervention mean difference (95% CI) -14 mins (-45 to 16)). Uptake of the intervention was low with only 40% (n=21) of participants accessing the web application. CONCLUSION: A web-based application, including individualised goal setting, real-time feedback and motivation for behavioural change, was no better than usual care at promoting physical activity in young pwCF following hospital discharge. High levels of baseline physical activity levels in both groups, and limited engagement with the intervention, suggest alternative strategies may be necessary to identify and support young pwCF who would benefit from enhanced physical activity. TRIAL REGISTRATION NUMBER: ACTRN12617001009303, 13 July 13 2017.

Targeting Glycolysis in Alloreactive T Cells to Prevent Acute Graft-Versus-Host Disease While Preserving Graft-Versus-Leukemia Effect.

Alloreactive donor T cells undergo extensive metabolic reprogramming to become activated and induce graft-versus-host disease (GVHD) upon alloantigen encounter. It is generally thought that glycolysis, which promotes T cell growth and clonal expansion, is employed in this process. However, conflicting data have been reported regarding the requirement of glycolysis to induce T cell-mediated GVHD due to the lack of T cell-specific treatments using glycolysis inhibitors. Importantly, previous studies have not evaluated whether graft-versus-leukemia (GVL) activity is preserved in donor T cells deficient for glycolysis. As a critical component affecting the clinical outcome, it is necessary to assess the anti-tumor activity following treatment with metabolic modulators in preclinical models. In the present study, we utilized T cells selectively deficient for glucose transporter 1 (Glut1T-KO), to examine the role of glycolysis exclusively in alloreactive T cells without off-targeting effects from antigen presenting cells and other cell types that are dependent on glycolysis. We demonstrated that transfer of Glut1T-KO T cells significantly improved acute GVHD outcomes through increased apoptotic rates, impaired expansion, and decreased proinflammatory cytokine production. In addition to impaired GVHD development, donor Glut1T-KO T cells mediated sufficient GVL activity to protect recipients from tumor development. A clinically relevant approach using donor T cells treated with a small molecule inhibitor of glycolysis, 2-Deoxy-D-glucose ex vivo, further demonstrated protection from tumor development. These findings indicate that treatment with glycolysis inhibitors prior to transplantation selectively eliminates alloreactive T cells, but spares non-alloreactive T cells including those that protect against tumor growth. The present study has established a definitive role for glycolysis in acute GVHD and demonstrated that acute GVHD can be selectively prevented through targeting glycolysis.

Irgm1 regulates metabolism and function in T cell subsets.

Immunity Related GTPases (IRG) are a family of proteins produced during infection that regulate membrane remodeling events in cells, particularly autophagy and mitophagy. The human IRGM gene has been strongly associated with Crohn's disease and other inflammatory diseases through Genome-Wide Association studies. Absence of Irgm1 in mice prompts intestinal inflammation, autoimmunity, and impaired immune control of pathogenic bacteria and protozoa. Although prior work has focused on a prominent role for IRGM/Irgm1 in regulating macrophage function, the work described here addresses a potential role of Irgm1 in regulating the function of mature T cells. Irgm1 was found to be highly expressed in T cells in a manner that varied with the particular T cell subset and increased with activation. Mice with a complete lack of Irgm1, or a conditional lack of Irgm1 specifically in T cells, displayed numerous changes in T cell numbers and function in all subsets examined, including CD4+ (Th1 and Treg) and CD8+ T cells. Related to changes in T cell number, apoptosis was found to be increased in Irgm1-deficient CD4+ and CD8+ T cells. Altered T cell metabolism appeared to be a key driver of the phenotypes: Glucose metabolism and glycolysis were increased in Irgm1-deficient CD4+ and CD8+ T cells, and muting these effects with glycolytic inhibitors partially restored T cell function and viability.

Telerehabilitation for chronic respiratory disease: a randomised controlled equivalence trial.

RATIONALE: Pulmonary rehabilitation is an effective treatment for people with chronic respiratory disease but is delivered to <5% of eligible individuals. This study investigated whether home-based telerehabilitation was equivalent to centre-based pulmonary rehabilitation in people with chronic respiratory disease. METHODS: A multicentre randomised controlled trial with assessor blinding, powered for equivalence was undertaken. Individuals with a chronic respiratory disease referred to pulmonary rehabilitation at four participating sites (one rural) were eligible and randomised using concealed allocation to pulmonary rehabilitation or telerehabilitation. Both programmes were two times per week for 8 weeks. The primary outcome was change in Chronic Respiratory Disease Questionnaire Dyspnoea (CRQ-D) domain at end-rehabilitation, with a prespecified equivalence margin of 2.5 points. Follow-up was at 12 months. Secondary outcomes included exercise capacity, health-related quality of life, symptoms, self-efficacy and psychological well-being. RESULTS: 142 participants were randomised to pulmonary rehabilitation or telerehabilitation with 96% and 97% included in the intention-to-treat analysis, respectively. There were no significant differences between groups for any outcome at either time point. Both groups achieved meaningful improvement in dyspnoea and exercise capacity at end-rehabilitation. However, we were unable to confirm equivalence of telerehabilitation for the primary outcome ΔCRQ-D at end-rehabilitation (mean difference (MD) (95% CI) -1 point (-3 to 1)), and inferiority of telerehabilitation could not be excluded at either time point (12-month follow-up: MD -1 point (95% CI -4 to 1)). At end-rehabilitation, telerehabilitation demonstrated equivalence for 6-minute walk distance (MD -6 m, 95% CI -26 to 15) with possibly superiority of telerehabilitation at 12 months (MD 14 m, 95% CI -10 to 38). CONCLUSION: telerehabilitation may not be equivalent to centre-based pulmonary rehabilitation for all outcomes, but is safe and achieves clinically meaningful benefits. When centre-based pulmonary rehabilitation is not available, telerehabilitation may provide an alternative programme model. TRIAL REGISTRATION NUMBER: ACtelerehabilitationN12616000360415.

Potential Utility of Synthetic D-Lactate Polymers in Skin Cancer.

Increased breakdown of glucose through glycolysis in both aerobic and anaerobic conditions is a hallmark feature of mammalian cancer and leads to increased production of L-lactate. The high-level lactate present within the tumor microenvironment is reused as a crucial biofuel to support rapid cancer cell proliferation, survival, and immune evasion. Inhibitors that target the glycolysis process are being developed for cancer therapy. In this study, we report an approach of using synthetic D-lactate dimers to inhibit melanoma and squamous cell carcinoma cell proliferation and survival. We also provide in vivo evidence that intratumoral injection of D-lactate dimers induced an innate immune response and inhibited subcutaneous melanoma xenograft growth in immunodeficient mice. Our findings support a potential utility of D-lactate dimers in skin cancer treatment and therefore warrant further mechanistic studies.

Home-based pulmonary rehabilitation early after hospitalisation in COPD (early HomeBase): protocol for a randomised controlled trial.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterised by exacerbations of respiratory disease, frequently requiring hospital admission. Pulmonary rehabilitation can reduce the likelihood of future hospitalisation, but programme uptake is poor. This study aims to compare hospital readmission rates, clinical outcomes and costs between people with COPD who undertake a home-based programme of pulmonary rehabilitation commenced early (within 2 weeks) of hospital discharge with usual care. METHODS: A multisite randomised controlled trial, powered for superiority, will be conducted in Australia. Eligible patients admitted to one of the participating sites for an exacerbation of COPD will be invited to participate. Participants will be randomised 1:1. Intervention group participants will undertake an 8-week programme of home-based pulmonary rehabilitation commencing within 2 weeks of hospital discharge. Control group participants will receive usual care and a weekly phone call for attention control. Outcomes will be measured by a blinded assessor at baseline, after the intervention (week 9-10 posthospital discharge), and at 12 months follow-up. The primary outcome is hospital readmission at 12 months follow-up. ETHICS AND DISSEMINATION: Human Research Ethics approval for all sites provided by Alfred Health (Project 51216). Findings will be published in peer-reviewed journals, conferences and lay publications. TRIAL REGISTRATION NUMBER: ACTRN12619001122145.

ABL allosteric inhibitors synergize with statins to enhance apoptosis of metastatic lung cancer cells.

Targeting mitochondrial metabolism has emerged as a treatment option for cancer patients. The ABL tyrosine kinases promote metastasis, and enhanced ABL signaling is associated with a poor prognosis in lung adenocarcinoma patients. Here we show that ABL kinase allosteric inhibitors impair mitochondrial integrity and decrease oxidative phosphorylation. To identify metabolic vulnerabilities that enhance this phenotype, we utilized a CRISPR/Cas9 loss-of-function screen and identified HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway and target of statin therapies, as a top-scoring sensitizer to ABL inhibition. Combination treatment with ABL allosteric inhibitors and statins decreases metastatic lung cancer cell survival in vitro in a synergistic manner. Notably, combination therapy in mouse models of lung cancer brain metastasis and therapy resistance impairs metastatic colonization with a concomitant increase in animal survival. Thus, metabolic combination therapy might be effective to decrease metastatic outgrowth, leading to increased survival for lung cancer patients with advanced disease.

Community Participation by People with Chronic Obstructive Pulmonary Disease.

Little is known regarding community participation in individuals with chronic obstructive pulmonary disease (COPD). The aim of this study was to explore community participation in individuals with COPD and to determine whether there is an association between community participation and activity-related outcome variables commonly collected during pulmonary rehabilitation assessment. We also sought to investigate which of these variables might influence community participation in people with COPD. Ninety-nine individuals with COPD were enrolled (67 ± 9 years, FEV1: 55 ± 22% predicted). We assessed community participation (Community Participation Indicator (CPI) and European Social Survey (ESS) for formal and informal community participation), daily physical activity levels (activity monitor), exercise capacity (6-minute walk test), breathlessness (Modified Medical Research Council, MMRC scale), self-efficacy (Pulmonary Rehabilitation Adapted Index of Self-Efficacy) and anxiety and depression (Hospital Anxiety and Depression Scale). Higher levels of community participation on the CPI were associated with older age and greater levels of physical activity (total, light and moderate-to-vigorous) (all rs = 0.30, p < 0.05). Older age and more moderate-to-vigorous physical activity independently predicted greater community participation measured by CPI. Higher levels of depression symptoms were associated with less formal and informal community participation on ESS (rs = -0.25). More formal community participation on ESS was weakly (rs = 0.2-0.3) associated with older age, better lung function, exercise capacity and self-efficacy, and less breathlessness. Self-efficacy, exercise capacity, and age independently predicted formal community participation in individuals with COPD. Strategies to optimize self-efficacy and improve exercise capacity may be useful to enhance community participation in people with COPD.

Undernutrition and Hypoleptinemia Modulate Alloimmunity and CMV-specific Viral Immunity in Transplantation.

BACKGROUND: Immunological mechanisms linking undernutrition to infection and the alloimmune response are poorly understood in transplantation. We aimed to determine how undernutrition and hypoleptinemia impact T-cell allospecific and cytomegalovirus (CMV) viral-specific immunity in a murine model. METHODS: Fed, fasted for 48 h (model of undernutrition), and fasted with leptin injections (leptin rescue), C57BL/6 mice received skin grafts from either C57BL/6 (syngeneic) or BALB/c (allogeneic) mice donors. Allograft rejection and survival were monitored. Fed, fasted, and leptin rescue C57BL/6 mice were inoculated with murine cytomegalovirus (mCMV). Mouse spleens were retrieved for T-cell flow cytometry analysis, mCMV DNA extraction, and quantitative polymerase chain reaction. Serum leptin levels were measured with ELISA. RESULTS: Fasted mice had prolonged rejection-free and graft survival compared with fed mice (P = 0.0002 and P = 0.043). Leptin administration did not alter rejection-free survival or allograft failure. CD8+ central memory T cell and CD8+ effector T cell proportions were significantly lower in fasted mice receiving allogeneic skin transplants compared with fed mice (P = 0.0009 and P = 0.0015). Fasted mice had higher viral loads (P = 0.0028) and impaired mCMV-specific interferon-gamma-producing CD8+ T cells (P = 0.0007), which improved with leptin rescue (P = 0.032). CONCLUSIONS: Undernutrition and its associated hypoleptinemia correlated with impaired allospecific and viral-specific immunities. Leptin administration decreased mCMV viral burden and increased mCMV-specific T-cell immunity, however, it did not increase rejection or worsen graft survival in complete major histocompatibility complex-mismatched skin allografts. Leptin may be a potential adjunctive therapy for CMV viremia in undernourished transplant recipients.

Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity.

BACKGROUND: Obesity is associated with impaired primary and secondary immune responses to influenza infection, with T cells playing a critical role. T-cell function is highly influenced by the cellular metabolic state; however, it remains unknown how altered systemic metabolism in obesity alters T-cell metabolism and function to influence immune response. Our objective was to identify the altered cellular metabolic state of T cells from obese mice so that we may target T-cell metabolism to improve immune response to infection. METHODS: Mice were fed normal chow or high-fat diet for 18-19 weeks. Changes in T-cell populations were analyzed in both adipose tissue and spleens using flow cytometry. Splenic T cells were further analyzed for nutrient uptake and extracellular metabolic flux. As changes in T-cell mitochondrial oxidation were observed in obesity, obese mice were treated with metformin for 6 weeks and compared to lean control mice or obese mice undergoing weight loss through diet switch; immunity was measured by survival to influenza infection. RESULTS: We found changes in T-cell populations in adipose tissue of high-fat diet-induced obese mice, characterized by decreased proportions of Treg cells and increased proportions of CD8+ T cells. Activated CD4+ T cells from obese mice had increased glucose uptake and oxygen consumption rate (OCR), compared to T cells from lean controls, indicating increased mitochondrial oxidation of glucose. Treatment of isolated CD4+ T cells with metformin was found to inhibit OCR in vitro and alter the expression of several activation markers. Last, treatment of obese mice with metformin, but not weight loss, was able to improve survival to influenza in obesity. CONCLUSIONS: T cells from obese mice have an altered metabolic profile characterized by increased glucose oxidation, which can be targeted to improve survival against influenza infection.

Early home-based pulmonary rehabilitation following acute exacerbation of COPD: A feasibility study using an action research approach.

OBJECTIVE: Pulmonary rehabilitation (PR) improves function, reduces symptoms and decreases healthcare usage in people with chronic obstructive pulmonary disease (COPD) following an acute exacerbation (AECOPD). However, rehabilitation uptake rates are low. This study aimed to address barriers to uptake and completion of PR following AECOPD. METHODS: An action research approach was used to reflect on study feasibility, and to plan and implement an improved protocol. Phase I tested the feasibility of home-based PR started early after AECOPD. Phase II used qualitative interviews to identified potential barriers to program uptake. Phase III re-tested the program with changes to recruitment and assessment strategies. RESULTS: Phase I: From 97 screened patients, 26 were eligible and 10 (38%) started home-based PR. Eight participants undertook ≥70% of PR sessions, achieving clinically meaningful improvement in 6-minute walk distance (mean (SD) change 76 (60) m) and chronic respiratory disease questionnaire total score (15 (21) units). Phase II: Potential barriers to uptake of home-based PR included access issues, confidence to exercise, and lack of information about PR benefits. Phase III: From 77 screened patients, 23 were eligible and 5 (22%) started the program. DISCUSSION: Home-based PR improved clinical outcomes, but program eligibility and uptake remain challenging. Efforts should be made to ensure PR program eligibility criteria are broad enough to accommodate patient needs, and new ways of engaging patients are needed to improve PR uptake after AECOPD.

The impact of home-based pulmonary rehabilitation on people with mild chronic obstructive pulmonary disease: A randomised controlled trial.

INTRODUCTION: People with mild chronic obstructive pulmonary disease (COPD) experience exercise intolerance, dyspnoea and poor quality of life. However, the role of pulmonary rehabilitation (PR) in this group is unclear. OBJECTIVES: This randomised controlled trial aimed to explore the effects of home-based PR in people with mild COPD. METHODS: People with mild COPD (FEV1 /FVC < 70%; FEV1  > 80%predicted) with a smoking history of ≥10 packet years were randomised to either 8 weeks of home-based PR (one home visit and seven once-weekly telephone calls) or standard care (weekly social telephone calls). Six minute walk distance (6MWD), and Modified Medical Research Council Dyspnoea Scale (mMRC) and Chronic Respiratory Disease Questionnaire (CRQ) scores were compared. RESULTS: A total of 58 participants (34 males, mean age 68 (SD 9) years, FEV1 %predicted 90 (7), 6MWD 496 (105) m) were included with 31 participants randomised to home-based PR. Participants attended an average of 6.8 of the 8 scheduled sessions, ranging from 3 to 8 sessions. Both groups showed improvements in exercise capacity, symptoms and health-related quality of life (HRQoL) over time, however there was no difference in 6MWD at end-intervention (mean difference -3 m, 95% confidence interval (CI) -64 to 58) or 6 months (7 m, 95% CI -59 to 72). At 6 months home-based PR participants were more likely to have clinically important improvements in CRQ emotional function (50% of home PR vs 0% control, P < 0.001) and CRQ total score (45% vs 17%, P = 0.05). CONCLUSION: For people with mild COPD, home-based PR did not improve exercise capacity more than standard care. The trial was registered at the Australia New Zealand clinical trial registry (https://www.anzctr.org.au, Trial ID: ACTRN12616000965404).

A web-based intervention to promote physical activity in adolescents and young adults with cystic fibrosis: protocol for a randomized controlled trial.

BACKGROUND: Regular participation in physical activity by people with cystic fibrosis (CF) promotes positive clinical and health outcomes including reduced rate of decline in lung function, fewer hospitalizations and greater wellbeing. However adherence to exercise and activity programs is low, in part due to the substantial daily therapy burden for young people with CF. Strict infection control requirements limit the role of group exercise programs that are commonly used in other clinical groups. Investigation of methods to promote physical activity in this group has been limited. The Active Online Physical Activity in Cystic fibrosis Trial (ActionPACT) is an assessor-blinded, multi-centre, randomized controlled trial designed to compare the efficacy of a novel web-based program (ActivOnline) compared to usual care in promoting physical activity participation in adolescents and young adults with CF. METHODS: Adolescents and young adults with CF will be recruited on discharge from hospital for a respiratory exacerbation. Participants randomized to the intervention group will have access to a web-based physical activity platform for the 12-week intervention period. ActivOnline allows users to track their physical activity, set goals, and self-monitor progress. All participants in both groups will be provided with standardised information regarding general physical activity recommendations for adolescents and young adults. Outcomes will be assessed by a blinded assessor at baseline, after completion of the intervention, and at 3-months followup. Healthcare utilization will be assessed at 12 months from intervention completion. The primary outcome is change in moderate-to-vigorous physical activity participation measured objectively by accelerometry. Secondary outcomes include aerobic fitness, health-related quality of life, anxiety and depression and sleep quality. DISCUSSION: This trial will establish whether a web-based application can improve physical activity participation more effectively than usual care in the period following hospitalization for a respiratory exacerbation. The web-based application under investigation can be made readily and widely available to all individuals with CF, to support physical activity and exercise participation at a time and location of the user's choosing, regardless of microbiological status. TRIAL REGISTRATION: Clinical trial registered on July 13, 2017 with the Australian and New Zealand Clinical Trials Register at (ACTRN12617001009303).

Systematic Dissection of the Metabolic-Apoptotic Interface in AML Reveals Heme Biosynthesis to Be a Regulator of Drug Sensitivity.

Crosstalk between metabolic and survival pathways is critical for cellular homeostasis, but the connectivity between these processes remains poorly defined. We used loss-of-function CRISPR/Cas9 knockout screening to identify metabolic genes capable of influencing cellular commitment to apoptosis, using sensitization to the BCL-2 inhibitor ABT-199 in BCL-2-dependent acute myeloid leukemia (AML) cell lines as a proxy for apoptotic disposition. This analysis revealed metabolic pathways that specifically cooperate with BCL-2 to sustain survival. In particular, our analysis singled out heme biosynthesis as an unappreciated apoptosis-modifying pathway. Although heme is broadly incorporated into the proteome, reduction of heme biosynthesis potentiates apoptosis through the loss of ETC activity, resulting in baseline depolarization of the mitochondrial membrane and an increased propensity to undergo apoptosis. Collectively, our findings chart the first apoptotic map of metabolism, motivating the design of metabolically engaged combination chemotherapies and nominating heme biosynthesis as an apoptotic modulator in AML.

Obesity-Induced Changes in T-Cell Metabolism Are Associated With Impaired Memory T-Cell Response to Influenza and Are Not Reversed With Weight Loss.

BACKGROUND: Obesity is an independent risk factor for increased influenza mortality and is associated with impaired memory T-cell response, resulting in increased risk of infection. In this study, we investigated if weight loss would restore memory T-cell response to influenza. METHODS: Male C57BL/6J mice were fed either low-fat or high-fat diet to induce obesity. Once obesity was established, all mice received primary infection with influenza X-31. Following a recovery period, we switched half of the obese group to a low-fat diet to induce weight loss. Fifteen weeks after diet switch, all mice were given a secondary infection with influenza PR8, and memory T-cell function and T-cell metabolism were measured. RESULTS: Following secondary influenza infection, memory T-cell subsets in the lungs of obese mice were decreased compared to lean mice. At the same time, T cells from obese mice were found to have altered cellular metabolism, largely characterized by an increase in oxygen consumption. Neither impaired memory T-cell response nor altered T-cell metabolism was reversed with weight loss. CONCLUSION: Obesity-associated changes in T-cell metabolism are associated with impaired T-cell response to influenza, and are not reversed with weight loss.

Telerehabilitation versus traditional centre-based pulmonary rehabilitation for people with chronic respiratory disease: protocol for a randomised controlled trial.

BACKGROUND: Pulmonary rehabilitation is an effective therapeutic intervention for people with chronic respiratory disease. However, fewer than 5% of eligible individuals receive pulmonary rehabilitation on an annual basis, largely due to limited availability of services and difficulties associated with travel and transport. The Rehabilitation Exercise At Home (REAcH) study is an assessor-blinded, multi-centre, randomised controlled equivalence trial designed to compare the efficacy of home-based telerehabilitation and traditional centre-based pulmonary rehabilitation in people with chronic respiratory disease. METHODS: Participants will undertake an 8-week group-based pulmonary rehabilitation program of twice-weekly supervised exercise training, either in-person at a centre-based pulmonary rehabilitation program or remotely from their home via the Internet. Supervised exercise training sessions will include 30 min of aerobic exercise (cycle and/or walking training). Individualised education and self-management training will be delivered. All participants will be prescribed a home exercise program of walking and strengthening activities. Outcomes will be assessed by a blinded assessor at baseline, after completion of the intervention, and 12-months post intervention. The primary outcome is change in dyspnea score as measured by the Chronic Respiratory Questionnaire - dyspnea domain (CRQ-D). Secondary outcomes will evaluate the efficacy of telerehabilitation on 6-min walk distance, endurance cycle time during a constant work rate test, physical activity and quality of life. Adherence to pulmonary rehabilitation between the two models will be compared. A full economic analysis from a societal perspective will be undertaken to determine the cost-effectiveness of telerehabilitation compared to centre-based pulmonary rehabilitation. DISCUSSION: Alternative models of pulmonary rehabilitation are required to improve both equity of access and patient-related outcomes. This trial will establish whether telerehabilitation can achieve equivalent improvement in outcomes compared to traditional centre-based pulmonary rehabilitation. If efficacious and cost-effective, the proposed telerehabilitation model is designed to be rapidly deployed into clinical practice. TRIAL REGISTRATION: Clinical trial registered with the Australian and New Zealand Clinical Trials Register at ( ACTRN12616000360415 ). Registered 21 March 2016.

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages.

The immunity-related GTPases (IRGs) are a family of proteins that are induced by interferon (IFN)-γ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear. In the studies reported here, we found that uninfected Irgm1-deficient mice displayed high levels of serum cytokines typifying profound autoinflammation. Similar increases in cytokine production were also seen in cultured, IFN-γ-primed macrophages that lacked Irgm1. A series of metabolic studies indicated that the enhanced cytokine production was associated with marked metabolic changes in the Irgm1-deficient macrophages, including increased glycolysis and an accumulation of long chain acylcarnitines. Cells were exposed to the glycolytic inhibitor, 2-deoxyglucose, or fatty acid synthase inhibitors to perturb the metabolic alterations, which resulted in dampening of the excessive cytokine production. These results suggest that Irgm1 deficiency drives metabolic dysfunction in macrophages in a manner that is cell-autonomous and independent of infectious triggers. This may be a significant contributor to excessive inflammation seen in Irgm1-deficient mice in different contexts.