The built environment and its impact on health outcomes and experiences of patients, significant others and staff-A protocol for a systematic review.

Aim: This review will identify, evaluate and synthesize the literature related to evidence-based design of healthcare environments and to identify impacts of the built environment on the outcomes and experiences of patients, significant others and staff. Design: A mixed-method systematic review of literature 2010-2018. Methods: Database searches for evidence in peer-reviewed journals will be conducted electronically using CINAHL, Medline, SCOPUS and Web of Science. Abstract, full-text screening and data extraction will be completed independently by the reviewers. Quality assessment will follow Swedish Agency for Health Technology Assessment and Social Services Assessment. Results: This review will offer knowledge for informed decisions about the design of the healthcare environment. The review is comprehensive, includes a large volume of literature various research designs and will highlight the knowledge gap in evidence-based design and provide a breadth of knowledge about the built environments and its impact on health and well-being.

ICU Patient Family Stress Recovery During Breaks in a Hospital Garden and Indoor Environments.

OBJECTIVES: Measure the immediate change in intensive care unit (ICU) family members' state stress levels from the beginning to the end of a person's visit to a hospital garden and compare the changes produced by the garden with those associated with spending time in indoor hospital environments intended for respite and relaxation. BACKGROUND: No previous research has compared the efficacy of different physical environments as interventions to foster stress reduction in family members of ICU patients, a group of hospital visitors known to experience high levels of distress. METHOD: A convenience sample of 42 ICU patient family (from 42 different families) completed the Present Functioning Visual Analogue Scales (PFVAS) before and after each visit (128 total visits) to a garden, an atrium/café, or ICU waiting room. RESULTS: Stress scores significantly declined (i.e., improved) from the start to the end of a break on all PFVAS subscales (p < .0001) in both the garden and indoors locations. However, it is noteworthy that garden breaks resulted in significantly greater improvement in the "sadness" scale than breaks in indoor locations (p = .03), and changes in all five other PFVAS scores showed somewhat more reduction of stress for breaks spent in the garden than indoors, although these differences were not statistically significant. CONCLUSION: Creating an unlocked garden with abundant nature located close to an ICU can be an effective intervention for significantly mitigating state stress in family members of ICU patients and can be somewhat more effective than indoor areas expressly designed for family respite and relaxation.

Room for improvement: a randomised controlled trial with nested qualitative interviews on space, place and treatment delivery.

OBJECTIVE: Healthcare-oriented design in hospitals can promote better clinical outcomes. Creating optimal facilities may increase treatment effects. We investigated the influence of the treatment room on effects of exercise therapy. METHODS: In a mixed-method randomised controlled double-blind trial, middle-aged individuals reporting knee or hip pain performed 8 weeks of exercise therapy in (1) a newly built physically enhanced environment, (2) a standard environment or (3) were waitlisted, receiving no intervention. Participants and therapists were blind to study aim. Primary outcome was participants' Global Perceived Effect (GPE; seven-point Likert scale). Six nested focus group interviews with participants (n=25) and individual interviews with therapists (n=2) explored experiences of the environments. RESULTS: 42 people exercised in the physically enhanced environment, 40 in the standard environment, 21 were waitlisted. Contrary to our hypothesis, the treatment response seemed greater in the standard environment for GPE (0.98, 95% CI0.5 to 1.4) than for the physically enhanced environment (0.37, 95% CI -0.2 to 0.9), between-group difference (0.61, 95% CI -0.1 to 1.3) did not reach statistical significance (p=0.07). Waitlist group reported no improvement (-0.05 95% CI -0.5 to 0.4). In interviews, participants from the standard environment expressed greater social cohesion and feeling at home. Qualitative themes identified; reflection, sense of fellowship and transition. Secondary patient-reported outcomes and qualitative findings supported the primary finding, while improvements in muscle strength and aerobic capacity did not differ between exercise groups. CONCLUSION: Results suggest that the physical environment contributes to treatment response. Matching patients' preferences to treatment rooms may improve patient-reported outcomes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02043613.

Impact of Nurses Taking Daily Work Breaks in a Hospital Garden on Burnout.

BACKGROUND: Nurses working in hospital environments are at risk for burnout. Exposure to nature has psychological benefits, but the effect of hospital gardens on nurse burnout is less understood. OBJECTIVE: To compare the effect on nurse burnout of taking daily work breaks in a hospital-integrated garden with the effect of indoor-only breaks. METHODS: A prospective crossover trial was conducted of nurses assigned to either 6 weeks of a work break in an outdoor hospital garden or 6 weeks of indoor-only breaks. After a 1-week washout period, break assignments were switched for a subsequent 6 weeks. The Maslach Burnout Inventory was administered at the beginning and end of each 6-week period, and a Present Functioning Visual Analogue Scale was completed at the start and end of each break to capture immediate psychological symptoms. Change scores were analyzed by using generalized estimating equations. RESULTS: For 29 nurses, for garden compared with indoor breaks, significant improvement was apparent in scores on the Maslach Burnout Inventory subscales for emotional exhaustion (4.5 vs -0.2; P < .001) and depersonalization (1.8 vs 0.0; P = .02) but not for personal accomplishment (-0.6 vs -0.0; P = .55). Compared with indoor breaks, total symptom scores on the Present Functioning Visual Analog Scale improved significantly when nurses took a break in the garden (garden vs indoor breaks, 4.0 vs 2.4; P = .04). CONCLUSIONS: Taking daily work breaks in an outdoor garden may be beneficial in mitigating burnout for nurses working in hospital environments.

Solar Sources of Interplanetary Magnetic Clouds Leading to Helicity Prediction.

This study identifies the solar origins of magnetic clouds that are observed at 1 AU and predicts the helical handedness of these clouds from the solar surface magnetic fields. We started with the magnetic clouds listed by the Magnetic Field Investigation (MFI) team supporting NASA's Wind spacecraft in what is known as the MFI table and worked backward in time to identify solar events that produced these clouds. Our methods utilize magnetograms from the Helioseismic and Magnetic Imager instrument on the Solar Dynamics Observatory spacecraft so that we could only analyze MFI entries after the beginning of 2011. This start date and the end date of the MFI table gave us 37 cases to study. Of these we were able to associate only eight surface events with clouds detected by Wind at 1 AU. We developed a simple algorithm for predicting the cloud helicity that gave the correct handedness in all eight cases. The algorithm is based on the conceptual model that an ejected flux tube has two magnetic origination points at the positions of the strongest radial magnetic field regions of opposite polarity near the places where the ejected arches end at the solar surface. We were unable to find events for the remaining 29 cases: lack of a halo or partial halo coronal mass ejection in an appropriate time window, lack of magnetic and/or filament activity in the proper part of the solar disk, or the event was too far from disk center. The occurrence of a flare was not a requirement for making the identification but in fact flares, often weak, did occur for seven of the eight cases.

Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile.

Several small-molecule Bruton tyrosine kinase (BTK) inhibitors are in development for B cell malignancies and autoimmune disorders, each characterized by distinct potency and selectivity patterns. Herein we describe the pharmacologic characterization of BTK inhibitor acalabrutinib [compound 1, ACP-196 (4-[8-amino-3-[(2S)-1-but-2-ynoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-(2-pyridyl)benzamide)]. Acalabrutinib possesses a reactive butynamide group that binds covalently to Cys481 in BTK. Relative to the other BTK inhibitors described here, the reduced intrinsic reactivity of acalabrutinib helps to limit inhibition of off-target kinases having cysteine-mediated covalent binding potential. Acalabrutinib demonstrated higher biochemical and cellular selectivity than ibrutinib and spebrutinib (compounds 2 and 3, respectively). Importantly, off-target kinases, such as epidermal growth factor receptor (EGFR) and interleukin 2-inducible T cell kinase (ITK), were not inhibited. Determination of the inhibitory potential of anti-immunoglobulin M-induced CD69 expression in human peripheral blood mononuclear cells and whole blood demonstrated that acalabrutinib is a potent functional BTK inhibitor. In vivo evaluation in mice revealed that acalabrutinib is more potent than ibrutinib and spebrutinib. Preclinical and clinical studies showed that the level and duration of BTK occupancy correlates with in vivo efficacy. Evaluation of the pharmacokinetic properties of acalabrutinib in healthy adult volunteers demonstrated rapid absorption and fast elimination. In these healthy individuals, a single oral dose of 100 mg showed approximately 99% median target coverage at 3 and 12 hours and around 90% at 24 hours in peripheral B cells. In conclusion, acalabrutinib is a BTK inhibitor with key pharmacologic differentiators versus ibrutinib and spebrutinib and is currently being evaluated in clinical trials.

Combined BTK and PI3Kδ Inhibition with Acalabrutinib and ACP-319 Improves Survival and Tumor Control in CLL Mouse Model.

Purpose: Targeting the B-cell receptor (BCR) pathway with inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ is highly effective for the treatment of chronic lymphocytic leukemia (CLL). However, deep remissions are uncommon, and drug resistance with single-agent therapy can occur. In vitro studies support the effectiveness of combing PI3Kδ and BTK inhibitors.Experimental Design: As CLL proliferation and survival depends on the microenvironment, we used murine models to assess the efficacy of the BTK inhibitor acalabrutinib combined with the PI3Kδ inhibitor ACP-319 in vivo We compared single-agent with combination therapy in TCL1-192 cell-injected mice, a model of aggressive CLL.Results: We found significantly larger reductions in tumor burden in the peripheral blood and spleen of combination-treated mice. Although single-agent therapy improved survival compared with control mice by a few days, combination therapy extended survival by over 2 weeks compared with either single agent. The combination reduced tumor proliferation, NF-κB signaling, and expression of BCL-xL and MCL-1 more potently than single-agent therapy.Conclusions: The combination of acalabrutinib and ACP-319 was superior to single-agent treatment in a murine CLL model, warranting further investigation of this combination in clinical studies. Clin Cancer Res; 23(19); 5814-23. ©2017 AACR.

Drug-induced corneal epithelial changes.

Drugs across many pharmacologic classes induce corneal epithelial changes. Many of these drugs have cationic amphiphilic structures, with a hydrophobic ring and hydrophilic cationic amine side chain that allow them to cross cell membranes. These drugs lead to intracellular phospholipid accumulation, often manifested in the cornea by vortex keratopathy, with no effect on visual acuity and few ocular symptoms. Other drugs, notably antineoplastic agents, produce a fine diffuse corneal haze, sometimes accompanied by decreased vision that can be dose limiting. Still other medications cause crystalline epithelial precipitation that might require debridement for resolution. An understanding of the variety of drugs involved, the multiple mechanisms responsible, and the systemic diseases that produce similar changes can lead to improved management strategies for patients with corneal epithelial deposits. In most cases, drug therapy need not be modified or discontinued, but if visual acuity is affected, close collaboration with the prescribing physician can result in determining an optimized dose that treats systemic disease and minimizes these deposits. Additionally, close monitoring might be required if the drug is also associated with other ocular findings, such as optic neuropathy or retinopathy.

The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia.

Purpose: Acalabrutinib (ACP-196) is a novel, potent, and highly selective Bruton tyrosine kinase (BTK) inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the antitumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL).Experimental Design: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eµ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model. Mice received either vehicle or acalabrutinib formulated into the drinking water.Results: Utilizing biochemical assays, we demonstrate that acalabrutinib is a highly selective BTK inhibitor as compared with ibrutinib. In the human CLL NSG xenograft model, treatment with acalabrutinib demonstrated on-target effects, including decreased phosphorylation of PLCγ2, ERK, and significant inhibition of CLL cell proliferation. Furthermore, tumor burden in the spleen of the mice treated with acalabrutinib was significantly decreased compared with vehicle-treated mice. Similarly, in the TCL1 adoptive transfer model, decreased phosphorylation of BTK, PLCγ2, and S6 was observed. Most notably, treatment with acalabrutinib resulted in a significant increase in survival compared with mice receiving vehicle.Conclusions: Treatment with acalabrutinib potently inhibits BTK in vivo, leading to on-target decreases in the activation of key signaling molecules (including BTK, PLCγ2, S6, and ERK). In two complementary mouse models of CLL, acalabrutinib significantly reduced tumor burden and increased survival compared with vehicle treatment. Overall, acalabrutinib showed increased BTK selectivity compared with ibrutinib while demonstrating significant antitumor efficacy in vivo on par with ibrutinib. Clin Cancer Res; 23(11); 2831-41. ©2016 AACR.

The solar magnetic activity band interaction and instabilities that shape quasi-periodic variability.

Solar magnetism displays a host of variational timescales of which the enigmatic 11-year sunspot cycle is most prominent. Recent work has demonstrated that the sunspot cycle can be explained in terms of the intra- and extra-hemispheric interaction between the overlapping activity bands of the 22-year magnetic polarity cycle. Those activity bands appear to be driven by the rotation of the Sun's deep interior. Here we deduce that activity band interaction can qualitatively explain the 'Gnevyshev Gap'­a well-established feature of flare and sunspot occurrence. Strong quasi-annual variability in the number of flares, coronal mass ejections, the radiative and particulate environment of the heliosphere is also observed. We infer that this secondary variability is driven by surges of magnetism from the activity bands. Understanding the formation, interaction and instability of these activity bands will considerably improve forecast capability in space weather and solar activity over a range of timescales.

Exploring the effect of space and place on response to exercise therapy for knee and hip pain--a protocol for a double-blind randomised controlled clinical trial: the CONEX trial.

INTRODUCTION: Context effects are described as effects of a given treatment, not directly caused by the treatment itself, but rather caused by the context in which treatment is delivered. Exercise is a recommended core treatment in clinical guidelines for musculoskeletal disorders. Although moderately effective overall, variation is seen in size of response to exercise across randomised controlled trial (RCT) studies. Part of this variation may be related to the fact that exercise interventions are performed in different physical environments, which may affect participants differently. The study aims to investigate the effect of exercising in a contextually enhanced physical environment for 8 weeks in people with knee or hip pain. METHODS AND ANALYSIS: The study is a double-blind RCT. Eligible participants are 35 years or older with persisting knee and/or hip pain for 3 months. Participants are randomised to one of three groups: (1) exercise in a contextually enhanced environment, (2) exercise in a standard environment and (3) waiting list. The contextually enhanced environment is located in a newly built facility, has large windows providing abundant daylight and overlooks a recreational park. The standard environment is in a basement, has artificial lighting and is marked by years of use; that is, resembling many clinical environments. The primary outcome is the participant's global perceived effect rated on a seven-point Likert scale after 8 weeks exercise. Patient-reported and objective secondary outcomes are included. ETHICS AND DISSEMINATION: The Regional Scientific Ethical Committee for Southern Denmark has approved the study. Study findings will be disseminated in peer-reviewed publications and presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT02043613.

Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma.

Idelalisib (GS-1101, CAL-101), an oral inhibitor of phosphatidylinositol 3-kinase-δ, was evaluated in a phase I study in 64 patients with relapsed indolent non-Hodgkin lymphoma (iNHL). Patients had a median (range) age of 64 (32-91) years, 34 (53%) had bulky disease (≥1 lymph nodes ≥5 cm), and 37 (58%) had refractory disease. Patients had received a median (range) of 4 (1-10) prior therapies. Eight dose regimens of idelalisib were evaluated; idelalisib was taken once or twice daily continuously at doses ranging from 50 to 350 mg. After 48 weeks, patients still benefitting (n = 19; 30%) enrolled into an extension study. Adverse events (AEs) occurring in 20% or more patients (total%/grade ≥3%) included diarrhea (36/8), fatigue (36/3), nausea (25/3), rash (25/3), pyrexia (20/3), and chills (20/0). Laboratory abnormalities included neutropenia (44/23), anemia (31/5), thrombocytopenia (25/11), and serum transaminase elevations (48/25). Twelve (19%) patients discontinued therapy due to AEs. Idelalisib induced disease regression in 46/54 (85%) of evaluable patients achieving an overall response rate of 30/64 (47%), with 1 patient having a complete response (1.6%). Median duration of response was 18.4 months, median progression-free survival was 7.6 months. Idelalisib is well tolerated and active in heavily pretreated, relapsed/refractory patients with iNHL. These trials were registered at clinicaltrials.gov as NCT00710528 and NCT01090414.

Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia.

In a phase 1 trial, idelalisib (GS-1101, CAL-101), a selective inhibitor of the lipid kinase PI3Kδ, was evaluated in 54 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) with adverse characteristics including bulky lymphadenopathy (80%), extensive prior therapy (median 5 [range 2-14] prior regimens), treatment-refractory disease (70%), unmutated IGHV (91%), and del17p and/or TP53 mutations (24%). Patients were treated at 6 dose levels of oral idelalisib (range 50-350 mg once or twice daily) and remained on continuous therapy while deriving clinical benefit. Idelalisib-mediated inhibition of PI3Kδ led to abrogation of Akt phosphorylation in patient CLL cells and significantly reduced serum levels of CLL-related chemokines. The most commonly observed grade ≥3 adverse events were pneumonia (20%), neutropenic fever (11%), and diarrhea (6%). Idelalisib treatment resulted in nodal responses in 81% of patients. The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 and 33% meeting the recently updated criteria of PR with treatment-induced lymphocytosis.(1,2) The median progression-free survival for all patients was 15.8 months. This study demonstrates the clinical utility of inhibiting the PI3Kδ pathway with idelalisib. Our findings support the further development of idelalisib in patients with CLL. These trials were registered at clinicaltrials.gov as #NCT00710528 and #NCT01090414.

Chronic immune activation is a distinguishing feature of liver and PBMC gene signatures from HCV/HIV coinfected patients and may contribute to hepatic fibrogenesis.

Hepatitis C virus/human immunodeficiency virus (HCV/HIV) coinfected patients demonstrate accelerated progression to severe liver injury in comparison to HCV monoinfected patients, although the underlying mechanisms are unclear owing to infection of separate tissue compartments with two distinct viral pathogens. Microarray analysis of paired liver biopsy and peripheral blood mononuclear cell (PBMC) specimens from HCV/HIV coinfected and HCV monoinfected patients identified a gene expression signature associated with increased inflammation and immune activation that was present only in liver and PBMC samples from coinfected patients. We also identified in these samples liver- and PBMC-specific signatures enriched with fibrogenic/hepatic stellate activation and proinflammatory genes, respectively. Finally, Bayesian networks were constructed by assimilating these data with existing data from liver and PBMC samples from other cohorts, augmenting enrichment of biologically important pathways and further indicating that chronic immune activation in HCV/HIV coinfection may exacerbate liver disease progression in coinfected patients.

CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability.

Phosphatidylinositol-3-kinase p110δ serves as a central integration point for signaling from cell surface receptors known to promote malignant B-cell proliferation and survival. This provides a rationale for the development of small molecule inhibitors that selectively target p110δ as a treatment approach for patients with B-cell malignancies. We thus identified 5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one (CAL-101), a highly selective and potent p110δ small molecule inhibitor (half-maximal effective concentration [EC(50)] = 8nM). Using tumor cell lines and primary patient samples representing multiple B-cell malignancies, we have demonstrated that constitutive phosphatidylinositol-3-kinase pathway activation is p110δ-dependent. CAL-101 blocked constitutive phosphatidylinositol-3-kinase signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis. These effects have been observed across a broad range of immature and mature B-cell malignancies, thereby providing a rationale for the ongoing clinical evaluation of CAL-101.

A conceptual framework for the domain of evidence-based design.

The physical facilities in which healthcare services are performed play an important role in the healing process. Evidence-based design in healthcare is a developing field of study that holds great promise for benefiting key stakeholders: patients, families, physicians, and nurses, as well as other healthcare staff and organizations. In this paper, the authors present and discuss a conceptual framework intended to capture the current domain of evidence-based design in healthcare. In this framework, the built environment is represented by nine design variable categories: audio environment, visual environment, safety enhancement, wayfinding system, sustainability, patient room, family support spaces, staff support spaces, and physician support spaces. Furthermore, a series of matrices is presented that indicates knowledge gaps concerning the relationship between specific healthcare facility design variable categories and participant and organizational outcomes. From this analysis, the authors identify fertile research opportunities from the perspectives of key stakeholders.

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver.

Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1. The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s.

Potential biomarkers of muscle injury after eccentric exercise.

Proteomics was utilized to identify novel potential plasma biomarkers of exercise-induced muscle injury. Muscle injury was induced in nine human volunteers by eccentric upper extremity exercise. Liquid chromatography-mass spectrometry identified 30 peptides derived from nine proteins which showed significant change in abundance post-exercise. Four of these proteins, haemoglobin alpha chain, haemoglobin beta chain, alpha1-antichymotrypsin (ACT) and plasma C-1 protease inhibitor (C1 Inh), met the criterion for inclusion based on changes in at least two distinct peptides. ACT and C1 Inh peptides peaked earlier post-exercise than creatine kinase, and thus appear to provide new information on muscle response to injury.

Temporal pattern of skeletal muscle gene expression following endurance exercise in Alaskan sled dogs.

Muscle responses to exercise are complex and include acute responses to exercise-induced injury, as well as longer term adaptive training responses. Using Alaskan sled dogs as an experimental model, changes in muscle gene expression were analyzed to test the hypotheses that important regulatory elements of the muscle's adaptation to exercise could be identified based on the temporal pattern of gene expression. Dogs were randomly assigned to undertake a 160-km run (n=9), or to remain at rest (n=4). Biceps femoris muscle was obtained from the unexercised dogs and two dogs at each of 2, 6, and 12 h after the exercise, and from three dogs 24 h after exercise. RNA was extracted and microarray analysis used to define gene transcriptional changes. The changes in gene expression after exercise occurred in a temporal pattern. Overall, 569, 469, 316, and 223 transcripts were differentially expressed at 2, 6, 12, and 24 h postexercise, respectively, compared with unexercised dogs (based on Por=1.5). Increases in a number of known transcriptional regulators, including peroxisome proliferator-activated receptor-alpha, cAMP-responsive element modulator, and CCAAT enhancer binding protein-delta, and potential signaling molecules, including brain-derived neurotrophic factor, dermokine, and suprabasin, were observed 2 h after exercise. Biological functional analysis suggested changes in expression of genes with known functional relationships, including genes involved in muscle remodeling and growth, intermediary metabolism, and immune regulation. Sustained endurance exercise by Alaskan sled dogs induces coordinated changes in gene expression with a clear temporal pattern. RNA expression profiling has the potential to identify novel regulatory mechanisms and responses to exercise stimuli.