brainlife.io: a decentralized and open-source cloud platform to support neuroscience research.

Neuroscience is advancing standardization and tool development to support rigor and transparency. Consequently, data pipeline complexity has increased, hindering FAIR (findable, accessible, interoperable and reusable) access. brainlife.io was developed to democratize neuroimaging research. The platform provides data standardization, management, visualization and processing and automatically tracks the provenance history of thousands of data objects. Here, brainlife.io is described and evaluated for validity, reliability, reproducibility, replicability and scientific utility using four data modalities and 3,200 participants.

mTORC1 and BMP-Smad1/5 regulation of serum-stimulated myotube hypertrophy: a role for autophagy.

Protein synthesis regulation is critical for skeletal muscle hypertrophy, yet other established cellular processes are necessary for growth-related cellular remodeling. Autophagy has a well-acknowledged role in muscle quality control, but evidence for its role in myofiber hypertrophy remains equivocal. Both mammalian target of rapamycin complex I (mTORC1) and bone morphogenetic protein (BMP)-Smad1/5 (Sma and Mad proteins from Caenorhabditis elegans and Drosophila, respectively) signaling are reported regulators of myofiber hypertrophy; however, gaps remain in our understanding of how this regulation is integrated with growth processes and autophagy regulation. Therefore, we investigated the mTORC1 and Smad1/5 regulation of protein synthesis and autophagy flux during serum-stimulated myotube growth. Chronic serum stimulation experiments were performed on day 5 differentiated C2C12 myotubes incubated in differentiation medium [2% horse serum (HS)] or growth medium [5% fetal bovine serum (FBS)] for 48 h. Rapamycin or LDN193189 was dosed for 48 h to inhibit mTORC1 and BMP-Smad1/5 signaling, respectively. Acute serum stimulation was examined in day 7 differentiated myotubes. Protein synthesis was measured by puromycin incorporation. Bafilomycin A1 and immunoblotting for LC3B were used to assess autophagy flux. Chronic serum stimulation increased myotube diameter 22%, total protein 21%, total RNA 100%, and Smad1/5 phosphorylation 404% and suppressed autophagy flux. Rapamycin, but not LDN193189, blocked serum-induced myotube hypertrophy and the increase in total RNA. Acute serum stimulation increased protein synthesis 111%, Smad1/5 phosphorylation 559%, and rpS6 phosphorylation 117% and suppressed autophagy flux. Rapamycin increased autophagy flux during acute serum stimulation. These results provide evidence for mTORC1, but not BMP-Smad1/5, signaling being required for serum-induced myotube hypertrophy and autophagy flux by measuring LC3BII/I expression. Further investigation is warranted to examine the role of autophagy flux in myotube hypertrophy.NEW & NOTEWORTHY The present study demonstrates that myotube hypertrophy caused by chronic serum stimulation requires mammalian target of rapamycin complex 1 (mTORC1) signaling but not bone morphogenetic protein (BMP)-Smad1/5 signaling. The suppression of autophagy flux was associated with serum-induced myotube hypertrophy and mTORC1 regulation of autophagy flux by measuring LC3BII/I expression. Rapamycin is widely investigated for beneficial effects in aging skeletal muscle and sarcopenia; our results provide evidence that rapamycin can regulate autophagy-related signaling during myotube growth, which could benefit skeletal muscle functional and metabolic health.

Decreased skeletal muscle intramyocellular lipid droplet-mitochondrial contact contributes to myosteatosis in cancer cachexia.

Cancer cachexia, the unintentional loss of lean mass, contributes to functional dependency, poor treatment outcomes, and decreased survival. While its pathogenicity is multifactorial, metabolic dysfunction remains a hallmark of cachexia. However, significant knowledge gaps exist in understanding the role of skeletal muscle lipid metabolism and dynamics in this condition. We examined skeletal muscle metabolic dysfunction, intramyocellular LD content, LD morphology and subcellular distribution, and LD-mitochondrial interactions using the Lewis Lung Carcinoma (LLC) murine model of cachexia. C57/BL6 male mice (n=20) were implanted with LLC cells [106] in the right flank or underwent PBS sham injections. Skeletal muscle was excised for transmission electron microscopy (TEM; soleus), oil red o/lipid staining (tibialis anterior), and protein (gastrocnemius). LLC mice had a greater number (232%; p=0.006) and size (130%; p=0.023) of intramyocellular LDs further supported by increased oil-red O positive (87%; p=0.0109) and 'very high' oil-red O positive (178%; p=0.0002) fibers compared to controls and this was inversely correlated with fiber size (R2=0.5294; p<0.0001). Morphological analyses of LDs show increased elongation and complexity (aspect ratio: IMF: 9%, p=0.046) with decreases in circularity (circularity: SS: 6%, p=0.042) or roundness (roundness: Whole: 10%, p=0.033; IMF: 8%, p=0.038) as well as decreased LD-mitochondria touch (-15%; p=0.006), contact length (-38%; p=0.036), and relative contact (86%; p=0.004). Further, dysregulation in lipid metabolism (adiponectin, CPT-1b) and LD-associated proteins, perilipin-2 and perilipin-5, in cachectic muscle (p<0.05) were observed. Collectively, we provide evidence that skeletal muscle myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in a preclinical model of cancer cachexia.

Recovery from FOLFOX chemotherapy-induced systemic and skeletal muscle metabolic dysfunction in mice.

FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) chemotherapy is used to treat colorectal cancer and can acutely induce metabolic dysfunction. However, the lasting effects on systemic and skeletal muscle metabolism after treatment cessation are poorly understood. Therefore, we investigated the acute and lasting effects of FOLFOX chemotherapy on systemic and skeletal muscle metabolism in mice. Direct effects of FOLFOX in cultured myotubes were also investigated. Male C57BL/6J mice completed four cycles (acute) of FOLFOX or PBS. Subsets were allowed to recover for 4 wk or 10 wk. Comprehensive Laboratory Animal Monitoring System (CLAMS) metabolic measurements were performed for 5 days before study endpoint. C2C12 myotubes were treated with FOLFOX for 24 hr. Acute FOLFOX attenuated body mass and body fat accretion independent of food intake or cage activity. Acute FOLFOX decreased blood glucose, oxygen consumption (V̇o2), carbon dioxide production (V̇co2), energy expenditure, and carbohydrate (CHO) oxidation. Deficits in V̇o2 and energy expenditure remained at 10 wk. CHO oxidation remained disrupted at 4 wk but returned to control levels after 10 wk. Acute FOLFOX reduced muscle COXIV enzyme activity, AMPK(T172), ULK1(S555), and LC3BII protein expression. Muscle LC3BII/I ratio was associated with altered CHO oxidation (r = 0.75, P = 0.03). In vitro, FOLFOX suppressed myotube AMPK(T172), ULK1(S555), and autophagy flux. Recovery for 4 wk normalized skeletal muscle AMPK and ULK1 phosphorylation. Our results provide evidence that FOLFOX disrupts systemic metabolism, which is not readily recoverable after treatment cessation. FOLFOX effects on skeletal muscle metabolic signaling did recover. Further investigations are warranted to prevent and treat FOLFOX-induced metabolic toxicities that negatively impact survival and life quality of patients with cancer.NEW & NOTEWORTHY The present study demonstrates that FOLFOX chemotherapy induces long-lasting deficits in systemic metabolism. Interestingly, FOLFOX modestly suppressed skeletal muscle AMPK and autophagy signaling in vivo and in vitro. The FOLFOX-induced suppression of muscle metabolic signaling recovered after treatment cessation, independent of systemic metabolic dysfunction. Future research should investigate if activating AMPK during treatment can prevent long-term toxicities to improve health and quality of life of patients with cancer and survivors.

Online behavioural activation during the COVID-19 pandemic decreases depression and negative affective bias.

BACKGROUND: The COVID-19 pandemic highlighted the need for mental health interventions that can be easily disseminated during a crisis. Behavioural activation (BA) is a cost-effective treatment that can be administered by non-specialists; however, it is unclear whether it is still effective during a time of lockdown and social distancing, when opportunities for positive activity are significantly constrained. METHODS: Between May and October 2020, we randomised 68 UK participants with mild to moderate low mood to either a 4-week online programme of non-specialist administered BA or to a passive control group. Before and after the intervention, we collected self-report data on mood and COVID-related disruption, as well as measuring emotional cognition as an objective marker of risk for depression. RESULTS: In comparison to the control group, the BA group showed a significant decrease in depression, anxiety and anhedonia after the intervention, as well as an increase in self-reported activation and social support. Benefits persisted at 1-month follow-up. BA also decreased negative affective bias on several measures of the Facial Emotion Recognition Task and early change in bias was associated with later therapeutic gain. Participants rated the intervention as highly acceptable. CONCLUSION: This study highlights the benefits of online BA that can be administered by non-specialists after brief training. These findings can help inform the policy response towards the rising incidence of mental health problems during a crisis situation such as a pandemic. They also highlight the use of objective cognitive markers of risk across different treatment modalities.

Short duration treadmill exercise improves physical function and skeletal muscle mitochondria protein expression after recovery from FOLFOX chemotherapy in male mice.

FOLFOX (5-FU, leucovorin, oxaliplatin) is a chemotherapy treatment for colorectal cancer which induces toxic side effects involving fatigue, weakness, and skeletal muscle dysfunction. There is a limited understanding of the recovery from these toxicities after treatment cessation. Exercise training can improve chemotherapy-related toxicities. However, how exercise accelerates recovery and the dose required for these benefits are not well examined. The purpose of this study was to examine the effect of exercise duration on physical function, muscle mass, and mitochondria protein expression during the recovery from FOLFOX chemotherapy. 12-week-old male mice were administered four cycles of either PBS or FOLFOX over 8-weeks. Outcomes were assessed after the fourth cycle and after either 4 (short-term; STR) or 10 weeks (long-term; LTR) recovery. Subsets of mice performed 14 sessions (6 d/wk, 18 m/min, 5% grade) of 60 min/d (long) or 15 min/d (short duration) treadmill exercise during STR. Red and white gastrocnemius mRNA and protein expression were examined. FOLFOX treatment decreased run time (RT) (-53%) and grip strength (GS) (-9%) compared to PBS. FOLFOX also reduced muscle OXPHOS complexes, COXIV, and VDAC protein expression. At LTR, FOLFOX RT (-36%) and GS (-16%) remained reduced. Long- and short-duration treadmill exercise improved RT (+58% and +56%) without restoring GS in FOLFOX mice. Both exercise durations increased muscle VDAC and COXIV expression in FOLFOX mice. These data provide evidence that FOLFOX chemotherapy induces persistent deficits in physical function that can be partially reversed by short-duration aerobic exercise.

Proteomic Analysis of Human Lung Development.

Rationale: The current understanding of human lung development derives mostly from animal studies. Although transcript-level studies have analyzed human donor tissue to identify genes expressed during normal human lung development, protein-level analysis that would enable the generation of new hypotheses on the processes involved in pulmonary development are lacking. Objectives: To define the temporal dynamic of protein expression during human lung development. Methods: We performed proteomics analysis of human lungs at 10 distinct times from birth to 8 years to identify the molecular networks mediating postnatal lung maturation. Measurements and Main Results: We identified 8,938 proteins providing a comprehensive view of the developing human lung proteome. The analysis of the data supports the existence of distinct molecular substages of alveolar development and predicted the age of independent human lung samples, and extensive remodeling of the lung proteome occurred during postnatal development. Evidence of post-transcriptional control was identified in early postnatal development. An extensive extracellular matrix remodeling was supported by changes in the proteome during alveologenesis. The concept of maturation of the immune system as an inherent part of normal lung development was substantiated by flow cytometry and transcriptomics. Conclusions: This study provides the first in-depth characterization of the human lung proteome during development, providing a unique proteomic resource freely accessible at Lungmap.net. The data support the extensive remodeling of the lung proteome during development, the existence of molecular substages of alveologenesis, and evidence of post-transcriptional control in early postnatal development.

LungMAP Portal Ecosystem: Systems-Level Exploration of the Lung.

An improved understanding of the human lung necessitates advanced systems models informed by an ever-increasing repertoire of molecular omics, cellular, imaging, and pathological datasets. To centralize and standardize information across broad lung research efforts we expanded the LungMAP.net website into a new gateway portal. This portal connects a broad spectrum of research networks, bulk and single-cell multi-omics data and a diverse collection of image data that span mammalian lung development, and disease. The data are standardized across species and technologies using harmonized data and metadata models that leverage recent advances including those from the Human Cell Atlas, diverse ontologies, and the LungMAP CellCards initiative. To cultivate future discoveries, we have aggregated a diverse collection of single-cell atlases for multiple species (human, rhesus, mouse), to enable consistent queries across technologies, cohorts, age, disease, and drug treatment. These atlases are provided as independent and integrated queryable datasets, with an emphasis on dynamic visualization, figure generation, re-analysis, cell-type curation, and automated reference-based classification of user-provided single-cell genomics datasets (Azimuth). As this resource grows, we intend to increase the breadth of available interactive interfaces, supported data types, data portals and datasets from LungMAP and external research efforts.

Muscular contraction's therapeutic potential for cancer-induced wasting.

Skeletal muscle atrophy and dysfunction contribute to morbidity and mortality in patients with cancer. Cachexia pathophysiology is highly complex, given that perturbations to the systemic cancer environment and the interaction with diverse tissues can contribute to wasting processes. Systemic interleukin 6 (IL-6) and glycoprotein 130 (gp130) receptors signaling have established roles in some types of cancer-induced muscle wasting through disruptions to protein turnover and oxidative capacity. Although exercise has documented benefits for cancer prevention and patient survival, there are significant gaps in our understanding of muscle adaptation and plasticity during severe cachexia. Preclinical models have provided valuable insight into the adaptive potential of muscle contraction within the cancer environment. We summarize the current understanding of how resistance-type exercise impacts mechanisms involved in cancer-induced muscle atrophy and dysfunction. Specifically, the role of IL-6 and gp130 receptors in the pathophysiology of muscle wasting and the adaptive response to exercise is explained. The discussion includes current knowledge gaps and future research directions needed to improve preclinical research and accelerate clinical translation in human patients with cancer.

The pancreatic cancer immune tumor microenvironment is negatively remodeled by gemcitabine while TGF-ß receptor plus dual checkpoint inhibition maintains antitumor immune cells.

Pancreatic ductal adenocarcinoma (PDA) tumors have a highly immunosuppressive desmoplastic tumor microenvironment (TME) where immune checkpoint inhibition (ICI) therapy has been exceptionally ineffective. Transforming growth factor-ß (TGF-ß) receptor activation leads to cancer and immune cell proliferation and phenotype, and cytokine production leading to tumor progression and worse overall survival in PDA patients. We hypothesized that TGF-ß receptor inhibition may alter PDA progression and antitumor immunity in the TME. Here, we used a syngeneic preclinical murine model of PDA to explore the impact of TGF-ß pathway inhibitor galunisertib (GAL), dual checkpoint immunotherapy (anti-PD-L1 and CTLA-4), the chemotherapy gemcitabine (GEM), and their combinations on antitumor immune responses. Blockade of TGF-ß and ICI in immune-competent mice bearing orthotopically injected murine PDA cells significantly inhibited tumor growth and was accompanied by antitumor M1 macrophage infiltration. In contrast, GEM treatment resulted in increased PDA tumor growth, decreased antitumor M1 macrophages, and decreased cytotoxic CD8+ T cell subpopulation compared to control mice. Together, these findings demonstrate the ability of TGF-ß inhibition with GAL to prime antitumor immunity in the TME and the curative potential of combining GAL with dual ICI. These preclinical results indicate that targeted inhibition of TGF-ß may enhance the efficacy of dual immunotherapy in PDA. Optimal manipulation of the immune TME with non-ICI therapy may enhance therapeutic efficacy.

Barriers to and facilitators of return to learning following a sport-related concussion: Perspectives of female secondary school students.

OBJECTIVE: To identify barriers to and facilitators of return to learning (RTL) for female secondary school students following a sport-related concussion (SRC), and to identify critical junctures on the injury-to-recovery continuum that can be targeted to enhance the RTL process. DESIGN: A grounded theory approach using in-depth qualitative interviews. SETTING: Secondary schools within the York Region District School Board in Ontario. PARTICIPANTS: Ten female secondary school students who presented to a sports medicine physician with an SRC in 2015 or 2016. Five of the students received a Green Folder intervention containing an RTL strategy, while 5 students received no RTL intervention following their SRC. METHODS: In-depth interviews were conducted in person or by telephone. All interviews were audiorecorded and transcribed. The transcriptions were analyzed, coded, and examined for common themes by 2 independent reviewers. MAIN FINDINGS: Barriers to RTL included a lack of a graduated RTL process, students' own internal stress, poor communication of expectations, lack of concussion education, and inadequate support from teachers. Facilitators of RTL included academic accommodations and having a primary contact person within the school system. Owing to inconsistent implementation, the impact of the Green Folder intervention as a facilitator of RTL remains unknown. CONCLUSION: Results of this study support existing findings in the realm of concussion research. A novel finding includes the importance of a primary contact person as a facilitator of RTL. This person could help to overcome some of the identified barriers to RTL and improve outcomes by assisting with academic accommodations, providing reassurance regarding these accommodations, improving education among teachers and students, and enhancing communication between stakeholders.

Assessment of a collaborative concussion management strategy in a school-based sport program: Prospective cohort study.

OBJECTIVE: To analyze the implementation of a concussion management protocol in which a team physiotherapist is involved in the identification of concussions and return-to-play (RTP) decisions. DESIGN: A prospective injury surveillance cohort study in a school-based Canadian football program (4 teams; grades 8 to 12) over 4 years. For years 1 to 2, the team physician made all RTP decisions; over years 3 to 4, the team physiotherapist was allowed to make some RTP decisions using pre-established criteria defined in the protocol. SETTING: A high school in Québec, Que. PARTICIPANTS: Male student athletes between 11 and 17 years old. MAIN OUTCOME MEASURES: Same-season recurrence (SSR) of concussion symptoms following RTP. RESULTS: A total of 119 concussions were identified (55 during the first 2 years and 64 during the last 2 years) during 27,741 athlete-exposures in 672 athlete-years for an incidence rate of 4.3 per 1000 athlete-exposures. During years 1 to 3, no SSR was observed following RTP clearance. During year 4 there was 1 case of SSR that occurred 11 days after clearance. The overall SSR rate of concussion symptoms following RTP clearance was 0.8%. CONCLUSION: A very low rate of SSR was achieved whether the team physician made all RTP decisions or the team physiotherapist was allowed to make some of the RTP decisions through the terms of the protocol.

Relapse of concussion symptoms in the context of premature return to learn and return to play: Comparative analysis of 2006 to 2011 and 2011 to 2016.

OBJECTIVE: To determine whether the proportion of sport-related concussion (SRC) cases among student athletes that resulted in a relapse of their symptoms due to premature return to play (RTP) or premature return to learn (RTL) has changed compared with a prior (2006 to 2011) study. DESIGN: Retrospective cohort study of electronic medical record charts from a 5-year period (2011 to 2016) compared with previous data. SETTING: A sport and exercise medicine physician's office-based practice in Ontario. PARTICIPANTS: Two-hundred forty-one students who had 258 distinct cases of SRC diagnosed. MAIN OUTCOME MEASURES: Premature RTP and RTL were defined as chart records documenting the relapse, recurrence, or worsening of concussion symptoms that accompanied the patient's RTP or RTL. RESULTS: Between 2011 and 2016, premature RTP and RTL resulted in a relapse of symptoms in 26.7% and 42.6% of cases, respectively. When compared with data from the 2006 to 2011 chart review, the incidence of premature RTP decreased by 38.6%. However, the rate of the relapse of symptoms associated with premature RTL decreased by only 4.7%. There was a relapse of symptoms in 43.4% of the cases involving female students and 29.7% of the cases involving male students, indicating that female patients are more likely to experience a relapse of symptoms. Cases involving female athletes also resulted in much later RTP clearance compared with those involving male athletes, with a median duration that was almost double that of male athletes' cases (49 days vs 25 days). CONCLUSION: An important decrease in the relapse of symptoms in the context of premature RTP occurred over the 2006 to 2016 period. However, this decrease was minimal for RTL. This may reflect the fact that efforts to implement structured RTP strategies arose earlier than those to implement RTL strategies. Efforts are needed to find the best method of implementing a coordinated plan for the postconcussion athlete who is returning to school.

Exploring the value of the SCHOOLFirst return-to-school resource: Evaluating usability and satisfaction.

OBJECTIVE: To cocreate an evidence-based resource to enable educators to support students returning to school after concussion; evaluate the usability of and users' satisfaction with the resource; understand the role of the resource in supporting students' return to school; and describe changes in concussion knowledge following a concussion education and training workshop. DESIGN: Survey during a concussion education and training workshop. SETTING: Holland Bloorview Kids Rehabilitation Hospital in Toronto, Ont, and York Region District School Board in Richmond Hill, Ont. PARTICIPANTS: Fifty-six educators, of whom 64% were teachers, 11% were school administrators, 23% fulfilled other roles (eg, child and youth worker), and 2% fulfilled unspecified roles. MAIN OUTCOME MEASURES: The survey collected demographic information, usability data via the System Usability Scale, and satisfaction data. Thematic analysis was used for open-ended questions. RESULTS: Participants reported the resource to be easy to use (69.6%), not complex (62.5%), and most felt confident using this resource (83.9%). Participants indicated they were satisfied with the resource (73.2%) and would use it in the future (87.5%). Some found the resource overwhelming and recommended it be summarized in a reference guide. Participants found the links, videos, and classroom accommodations or academic supports to be helpful. CONCLUSION: SCHOOLFirst is an evidence-based, user-driven resource that was created for educators to support students returning to school following concussion. Educators, health care providers, youth, and families collaborated on developing SCHOOLFirst to improve students' successful return to school following concussion. Educators were satisfied with the resource and saw opportunities to use it to support their students.

BRAIN Initiative: Cutting-Edge Tools and Resources for the Community.

The overarching goal of the NIH BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative is to advance the understanding of healthy and diseased brain circuit function through technological innovation. Core principles for this goal include the validation and dissemination of the myriad innovative technologies, tools, methods, and resources emerging from BRAIN-funded research. Innovators, BRAIN funding agencies, and non-Federal partners are working together to develop strategies for making these products usable, available, and accessible to the scientific community. Here, we describe several early strategies for supporting the dissemination of BRAIN technologies. We aim to invigorate a dialogue with the neuroscience research and funding community, interdisciplinary collaborators, and trainees about the existing and future opportunities for cultivating groundbreaking research products into mature, integrated, and adaptable research systems. Along with the accompanying Society for Neuroscience 2019 Mini-Symposium, "BRAIN Initiative: Cutting-Edge Tools and Resources for the Community," we spotlight the work of several BRAIN investigator teams who are making progress toward providing tools, technologies, and services for the neuroscience community. These tools access neural circuits at multiple levels of analysis, from subcellular composition to brain-wide network connectivity, including the following: integrated systems for EM- and florescence-based connectomics, advances in immunolabeling capabilities, and resources for recording and analyzing functional connectivity. Investigators describe how the resources they provide to the community will contribute to achieving the goals of the NIH BRAIN Initiative. Finally, in addition to celebrating the contributions of these BRAIN-funded investigators, the Mini-Symposium will illustrate the broader diversity of BRAIN Initiative investments in cutting-edge technologies and resources.

Effects of conditioned media from murine lung cancer cells and human tumor cells on cultured myotubes.

Factors secreted from tumors/tumor cells are hypothesized to cause skeletal muscle wasting in cancer patients. We examined whether cancer cells secrete factors to promote atrophy by evaluating the effects of conditioned media (CM) from murine lung cancer cells and primary cultures of human lung tumor cells on cultured myotubes. We evaluated murine Lewis lung carcinoma (LLC) and KRASG12D cells, and primary cell lines derived from tumor biopsies from patients with lung cancer (hTCM; n = 6). In all experiments, serum content was matched across treatment groups. We hypothesized that CM from murine and human tumor cells would reduce myotube myosin content, decrease mitochondrial content, and increase mitochondrial reactive oxygen species (ROS) production. Treatment of myotubes differentiated for 7 days with CM from LLC and KRASG12D cells did not alter any of these variables. Effects of murine tumor cell CM were observed when myotubes differentiated for 4 days were treated with tumor cell CM and compared with undiluted differentiation media. However, these effects were not apparent if tumor cell CM treatments were compared with control cell CM or dilution controls. Finally, CM from human lung tumor primary cell lines did not modify myosin content or mitochondrial content or ROS production compared with either undiluted differentiated media, control cell CM, or dilution controls. Our results do not support the hypothesis that factors released from cultured lung cancer/tumor cells promote myotube wasting or mitochondrial abnormalities, but we cannot dismiss the possibility that these cells could secrete such factors in vivo within the native tumor microenvironment.

TRB3 regulates skeletal muscle mass in food deprivation-induced atrophy.

Tribbles 3 (TRB3) is a pseudokinase that has been found in multiple tissues in response to various stress stimuli, such as nutrient deprivation and endoplasmic reticulum (ER) stress. We recently found that TRB3 has the potential to regulate skeletal muscle mass at the basal state. However, it has not yet been explored whether TRB3 regulates skeletal muscle mass under atrophic conditions. Here, we report that food deprivation for 48 h in mice significantly reduces muscle mass by ∼15% and increases TRB3 expression, which is associated with increased ER stress. Interestingly, inhibition of ER stress in C2C12 myotubes reduces food deprivation-induced expression of TRB3 and muscle-specific E3-ubiquitin ligases. In further in vivo experiments, muscle-specific TRB3 transgenic mice increase food deprivation-induced muscle atrophy compared with wild-type (WT) littermates presumably by the increased proteolysis. On the other hand, TRB3 knockout mice ameliorate food deprivation-induced atrophy compared with WT littermates by preserving a higher protein synthesis rate. These results indicate that TRB3 plays a pivotal role in skeletal muscle mass regulation under food deprivation-induced muscle atrophy and TRB3 could be a pharmaceutical target to prevent skeletal muscle atrophy.-Choi, R. H., McConahay, A., Silvestre, J. G., Moriscot, A. S., Carson, J. A., Koh, H.-J. TRB3 regulates skeletal muscle mass in food deprivation-induced atrophy.

Greater mindfulness associated with lower pain, fatigue, and psychological distress in women with metastatic breast cancer.

OBJECTIVE: Women with metastatic breast cancer (MBC) report high levels of disease-related symptoms including pain, fatigue, psychological distress, and sleep disturbance. Mindfulness may be particularly relevant to women with MBC given the high symptom burden and psychological toll of this disease; however, the topic is understudied among this patient population. Therefore, we aimed to test the associations between mindfulness and patient-reported symptoms among a sample of women with MBC. METHODS: Sixty-four women with MBC completed baseline questionnaires of mindfulness (Five Facet Mindfulness Questionnaire-Short Form [FFMQ-SF]) and symptoms of pain severity and interference, fatigue, psychological distress, and sleep disturbance as part of a randomized controlled trial of a Mindful Yoga intervention. Correlational analyses of data collected at baseline tested associations between the five mindfulness facets (observing, describing, acting with awareness, nonjudging, and nonreactivity) and patient-reported measures of symptoms. RESULTS: Overall, higher mindfulness was associated with lower symptom levels including lower pain severity, pain interference, fatigue, anxiety, depression, and sleep disturbance. However, degree of association varied by mindfulness facet. Nonreactivity, nonjudging, and describing showed the most frequent associations and largest effect sizes across symptoms, while observing showed the least frequent associations and lowest effect sizes. CONCLUSIONS: Mindfulness-and in particular nonreactivity, nonjudging, and describing-may be a personal resource for women with MBC in coping with complex symptoms of this life-threatening illness. Findings are discussed relative to their implications for interventions aimed at increasing mindfulness in this vulnerable population.

Online couples mindfulness-based intervention for young breast cancer survivors and their partners: A randomized-control trial.

PURPOSE: Young breast cancer survivors (YBCS) face unique challenges in coping with disease, distress, and relationship concerns. The purposes of this study were to understand the acceptability and feasibility of an online Mindfulness-Based Intervention (MBI) for YBCS and their partners (i.e., Couples Mindfulness-Based Intervention: C-MBI) and to compare the effectiveness of the C-MBI to a closely-matched control, an online MBI for individuals (I-MBI). METHODS: YBCS and their partners were recruited. Couples were randomly assigned to an 8-week C-MBI (couples = 41) or to I-MBI (couples = 36), which included one-hour video modules, a manual, and guided-meditation audios. Both couple members participated in the C-MBI; only the YBCS participated in the control I-MBI. Participants answered surveys about individual- and couple-level functioning at baseline and post-intervention. RESULTS: Online delivery was shown to be feasible and acceptable. For YBCS and their partners, levels of perceived stress, anxiety, depression, and fatigue were lower after the intervention, in both conditions. Unexpectedly, however, participating in the C-MBI appeared to have detrimental effects on dyadic adjustment and relationship quality. CONCLUSION: Although YBCS and their partners reported online delivery was acceptable and benefited well-being, for couple-based MBIs to have benefits for relationship functioning, it may be necessary for couples to have the support of other couples and an instructor. Online delivery may be particularly acceptable and effective for clinical populations, including YBCS. Medical professionals may be more likely to recommend online-MBI programs to cancer survivors, because the programs are of little or no cost.