Genomics has provided a detailed structural description of the cancer genome. Identifying oncogenic drivers that work primarily through dosage changes is a current challenge. Unrestrained ...proliferation is a critical hallmark of cancer. We constructed modular, barcoded libraries of human open reading frames (ORFs) and performed screens for proliferation regulators in multiple cell types. Approximately 10% of genes regulate proliferation, with most performing in an unexpectedly highly tissue-specific manner. Proliferation drivers in a given cell type showed specific enrichment in somatic copy number changes (SCNAs) from cognate tumors and helped predict aneuploidy patterns in those tumors, implying that tissue-type-specific genetic network architectures underlie SCNA and driver selection in different cancers. In vivo screening confirmed these results. We report a substantial contribution to the catalog of SCNA-associated cancer drivers, identifying 147 amplified and 107 deleted genes as potential drivers, and derive insights about the genetic network architecture of aneuploidy in tumors.
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•Barcoded genome-scale ORF expression libraries allow gain-of-function screens•Regulators of proliferation exhibit a striking degree of tissue-specificity•Proliferation driver genes help predict focal SCNAs and cancer aneuploidy patterns•Approximately 250 candidate cancer drivers identified in recurring SCNAs
The highly tissue-specific epigenetic landscape of a given cell type establishes its responsiveness to oncogenic proliferation signals and determines which drivers, somatic copy number changes, and anueploidies are selected during tumorigenesis.
Among people with physical disabilities, one of the most frequently-cited barriers to physical activity participation is a lack of basic information on what to do. Likewise, rehabilitation ...professionals often cite a lack of knowledge about what to recommend or prescribe, as their primary reason for not promoting physical activity to clients with disabilities. The development and implementation of disability-specific physical activity guidelines are important steps toward addressing informational barriers. This paper describes the reasoning behind disability-specific physical activity guidelines, the gold-standard process used to develop disability-specific guidelines for people with spinal cord injury and multiple sclerosis, and the "who, what, and how" of behavioural interventions and messaging to support people with disabilities in achieving physical activity guidelines.
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The needs, values and preferences of people with disabilities must be taken into consideration when undertaking a disability-specific guideline development process. Guidelines can play an important role in physical activity promotion, but behavioural and other interventions are required to address the myriad physical activity barriers faced by people with disabilities.
Implications for Rehabilitation
People with and without disabilities can achieve significant fitness and health benefits from activity well below the WHO's 150 minutes/week guideline.
Disability-specific physical activity guidelines can alleviate informational barriers for people who want to get active and rehabilitation professionals who want to promote physical activity.
Behavioural and other interventions are needed to support people's efforts to achieve physical activity guidelines.
A physiotherapist-delivered intervention has shown promise for increasing physical activity in adults with a physical disability.
It is unclear whether PD-L1 on tumor cells is sufficient for tumor immune evasion or simply correlates with an inflamed tumor microenvironment. We used three mouse tumor models sensitive to PD-1 ...blockade to evaluate the significance of PD-L1 on tumor versus nontumor cells. PD-L1 on nontumor cells is critical for inhibiting antitumor immunity in B16 melanoma and a genetically engineered melanoma. In contrast, PD-L1 on MC38 colorectal adenocarcinoma cells is sufficient to suppress antitumor immunity, as deletion of PD-L1 on highly immunogenic MC38 tumor cells allows effective antitumor immunity. MC38-derived PD-L1 potently inhibited CD8
T cell cytotoxicity. Wild-type MC38 cells outcompeted PD-L1-deleted MC38 cells in vivo
demonstrating tumor PD-L1 confers a selective advantage. Thus, both tumor- and host-derived PD-L1 can play critical roles in immunosuppression. Differences in tumor immunogenicity appear to underlie their relative importance. Our findings establish reduced cytotoxicity as a key mechanism by which tumor PD-L1 suppresses antitumor immunity and demonstrate that tumor PD-L1 is not just a marker of suppressed antitumor immunity.
Diabetes mellitus (DM) is a complex metabolic disorder arising from lack of insulin production or insulin resistance (Diagnosis and classification of diabetes mellitus, 2007). DM is a leading cause ...of morbidity and mortality in the developed world, particularly from vascular complications such as atherothrombosis in the coronary vessels. Aldose reductase (AR; ALR2; EC 1.1.1.21), a key enzyme in the polyol pathway, catalyzes nicotinamide adenosine dinucleotide phosphate-dependent reduction of glucose to sorbitol, leading to excessive accumulation of intracellular reactive oxygen species (ROS) in various tissues of DM including the heart, vasculature, neurons, eyes, and kidneys. As an example, hyperglycemia through such polyol pathway induced oxidative stress, may have dual heart actions, on coronary blood vessel (atherothrombosis) and myocardium (heart failure) leading to severe morbidity and mortality (reviewed in Heather and Clarke, 2011). In cells cultured under high glucose conditions, many studies have demonstrated similar AR-dependent increases in ROS production, confirming AR as an important factor for the pathogenesis of many diabetic complications. Moreover, recent studies have shown that AR inhibitors may be able to prevent or delay the onset of cardiovascular complications such as ischemia/reperfusion injury, atherosclerosis, and atherothrombosis. In this review, we will focus on describing pivotal roles of AR in the pathogenesis of cardiovascular diseases as well as other diabetic complications, and the potential use of AR inhibitors as an emerging therapeutic strategy in preventing DM complications.
Children and youth with autism spectrum disorder engage in less physical activity than neurotypically developing peers. This may be due to factors associated with autism spectrum disorder at the ...individual and environmental level that can make physical activity participation more challenging. Parent support is a known determinant of physical activity among children and youth; however, limited research has explored the relationship between parent physical activity support behaviour and child physical activity behaviour within the autism spectrum disorder population. Guided by the multi-process action control framework, this study examined the relationship between parent physical activity support behaviour and physical activity levels of children and youth with autism spectrum disorder. Parents (n = 201) of school-aged children and youth with autism spectrum disorder completed measures of parent physical activity support (intentions, behavioural regulation, support behaviour), as well as their child’s physical activity behaviour. Congruent with the multi-process action control model, intentions to provide physical activity support were significantly associated with parent physical activity support behaviour. Behavioural regulation of physical activity support mediated this relationship, which in turn significantly predicted child physical activity behaviour. Findings suggest parents play an instrumental role in the physical activity behaviour of children and youth with autism spectrum disorder. Family-level interventions targeting parents’ behavioural regulation strategies to provide physical activity support may be an effective strategy to increase physical activity in children and youth with autism spectrum disorder.
Lay abstract
Children and youth with autism spectrum disorder engage in less physical activity than neurotypically developing peers. This may be due to factors associated with autism spectrum disorder at the individual and environmental level that can make physical activity participation more challenging. Parent support is a known determinant of physical activity among children and youth; however, limited research has explored the relationship between parent physical activity support behaviour and child physical activity behaviour within the autism spectrum disorder population. The purpose of this study was to examine the relationship between parent physical activity support behaviour and physical activity levels of children and youth with autism spectrum disorder. Parents (n = 201) of school-aged children and youth with autism spectrum disorder completed measures of parent physical activity support (intentions, behavioural regulation, support behaviour), as well as their child’s physical activity behaviour. The results showed that parent’s intentions to provide physical activity support were associated with their support behaviour for their child’s physical activity (e.g. encouragement, being active together). Parents who followed through with their intentions to provide support reported using behavioural regulation strategies such as goal setting and planning more often. Finally, the results showed parent physical activity support behaviour was positively associated with child physical activity behaviour. Findings suggest parents play an instrumental role in the physical activity behaviour of children and youth with autism spectrum disorder. Family-level interventions targeting parents’ behavioural regulation strategies to provide physical activity support may be an effective strategy to increase physical activity in children and youth with autism spectrum disorder.
Deciding whether to disclose a disability to others at work is complex. Many chronic mental and physical health conditions are associated with episodic disability and include times of relative ...wellness punctuated by intermittent periods of activity limitations. This research draws on the disclosure processes model to examine approach and avoidance disclosure and non-disclosure goals and their association with perceived positive and negative workplace outcomes. Participants were 896 employed individuals (57.7% women) living with a chronic physical or mental health/cognitive condition. They were recruited from an existing national panel and completed an online, cross-sectional survey. Participants were asked about disclosure decisions, reasons for disclosure/non-disclosure, demographic, work context and perceived positive and negative disclosure decision outcomes (e.g., support, stress, lost opportunities). About half the sample (51.2%) had disclosed a disability to their supervisor. Decisions included both approach and avoidance goals. Approach goals (e.g., desire support, want to build trust, maintain the status quo at work) were significantly associated with perceived positive work outcomes regardless of whether a participant disclosed or did not disclose a disability at work, while avoidance goals (e.g., concerns about losing one’s job, feeling forced to disclose because others notice a problem) were associated with perceived negative work outcomes. The findings highlight benefits and challenges that workers perceive arise when they choose to disclose or not disclose personal health information. By better understanding disclosure decisions, we can inform organizational health privacy and support gaps to help sustain the employment of people living with disabilities.
Smooth muscle cells (SMC) are the major cell type in blood vessels. Their principal function in the body is to regulate blood flow and pressure through vessel wall contraction and relaxation. Unlike ...many other mature cell types in the adult body, SMC do not terminally differentiate but retain a remarkable plasticity. They have the unique ability to toggle between a differentiated and quiescent “contractile” state and a highly proliferative and migratory “synthetic” phenotype in response to environmental stresses.
While there have been major advances in our understanding of SMC plasticity through the identification of growth factors and signals that can influence the SMC phenotype, how these regulate SMC plasticity remains unknown. To date, several key transcription factors and regulatory cis elements have been identified that play a role in modulating SMC state. The frontier in understanding the molecular mechanisms underlying SMC plasticity has now advanced to the level of epigenetics. This review will summarize the epigenetic regulation of SMC, highlighting the role of histone modification, DNA methylation, and our most recent identification of a DNA demethylation pathway in SMC that is pivotal in the regulation of the SMC phenotypic state.
Many disorders are associated with smooth muscle dysfunction, including atherosclerosis, the major underlying cause of stroke and coronary heart disease, as well as transplant vasculopathy, aneurysm, asthma, hypertension, and cancer. An increased understanding of the major regulators of SMC plasticity will lead to the identification of novel target molecules that may, in turn, lead to novel drug discoveries for the treatment of these diseases. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity.
•We summarize the role of smooth muscle cell plasticity in disease.•We review the roles of histone and DNA methylation in smooth muscle phenotype.•We highlight the key role of TET2 and 5hmC in smooth muscle cell plasticity.
Abstract
Cognitive aging is associated with widespread neural reorganization processes in the human brain. However, the behavioral impact of such reorganization is not well understood. The current ...neuroimaging study investigated age differences in the functional network architecture during semantic word retrieval in young and older adults. Combining task-based functional connectivity, graph theory and cognitive measures of fluid and crystallized intelligence, our findings show age-accompanied large-scale network reorganization even when older adults have intact word retrieval abilities. In particular, functional networks of older adults were characterized by reduced decoupling between systems, reduced segregation and efficiency, and a larger number of hub regions relative to young adults. Exploring the predictive utility of these age-related changes in network topology revealed high, albeit less efficient, performance for older adults whose brain graphs showed stronger dedifferentiation and reduced distinctiveness. Our results extend theoretical accounts on neurocognitive aging by revealing the compensational potential of the commonly reported pattern of network dedifferentiation when older adults can rely on their prior knowledge for successful task processing. However, we also demonstrate the limitations of such compensatory reorganization and show that a youth-like network architecture in terms of balanced integration and segregation is associated with more economical processing.
The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse ...species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cellular senescence suppresses cancer by preventing cell proliferation. However, as senescent cells accumulate with age, the senescence-associated secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR inhibition suppressed the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced IL6 and other cytokine mRNA levels, but selectively suppressed translation of the membrane-bound cytokine IL1A. Reduced IL1A diminished NF-κB transcriptional activity, which controls much of the SASP; exogenous IL1A restored IL6 secretion to rapamycin-treated cells. Importantly, rapamycin suppressed the ability of senescent fibroblasts to stimulate prostate tumour growth in mice. Thus, rapamycin might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-associated inflammation.
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