Cancer invasion and the microenvironment: plasticity and reciprocity.

Cancer invasion is a cell- and tissue-driven process for which the physical, cellular, and molecular determinants adapt and react throughout the progression of the disease. Cancer invasion is initiated and maintained by signaling pathways that control cytoskeletal dynamics in tumor cells and the turnover of cell-matrix and cell-cell junctions, followed by cell migration into the adjacent tissue. Here, we describe the cell-matrix and cell-cell adhesion, protease, and cytokine systems that underlie tissue invasion by cancer cells. We explain how the reciprocal reprogramming of both the tumor cells and the surrounding tissue structures not only guides invasion, but also generates diverse modes of dissemination. The resulting "plasticity" contributes to the generation of diverse cancer invasion routes and programs, enhanced tumor heterogeneity, and ultimately sustained metastatic dissemination.

Experimental and computational framework for a dynamic protein atlas of human cell division.

Essential biological functions, such as mitosis, require tight coordination of hundreds of proteins in space and time. Localization, the timing of interactions and changes in cellular structure are all crucial to ensure the correct assembly, function and regulation of protein complexes1-4. Imaging of live cells can reveal protein distributions and dynamics but experimental and theoretical challenges have prevented the collection of quantitative data, which are necessary for the formulation of a model of mitosis that comprehensively integrates information and enables the analysis of the dynamic interactions between the molecular parts of the mitotic machinery within changing cellular boundaries. Here we generate a canonical model of the morphological changes during the mitotic progression of human cells on the basis of four-dimensional image data. We use this model to integrate dynamic three-dimensional concentration data of many fluorescently knocked-in mitotic proteins, imaged by fluorescence correlation spectroscopy-calibrated microscopy5. The approach taken here to generate a dynamic protein atlas of human cell division is generic; it can be applied to systematically map and mine dynamic protein localization networks that drive cell division in different cell types, and can be conceptually transferred to other cellular functions.

Health behaviours of teachers and other education professionals in France: can we do better?

Education professionals play a critical role in health education, both as knowledge providers and as role-models. Drawing on the CONSTANCES French cohort (baseline 2012-19) and adjusting for important confounders, we compared education professionals (n = 14 730) with a random sample of non-education sector employees (n = 34 244) on three indicators of high-risk behaviour (at-risk drinking, current smoking, past-year cannabis use) and three indicators of unhealthy lifestyle (low physical activity, poor adherence to nutritional guidelines, overweight/obesity). Among education professionals, we distinguished between teachers (n = 12 820), school principals (n = 372), senior education advisers (n = 189), school health professionals (n = 128) and school service staff (n = 1221). Compared with non-education sector employees with similar demographic and socioeconomic profiles, teachers were less likely to be at-risk drinkers, to smoke, to have used cannabis in the past year and to be overweight/obese. Other non-teaching education professionals were also less involved in high-risk behaviours than non-education employees, but results were more mixed concerning some lifestyle indicators, with certain non-teaching education professional groups showing a higher likelihood of being physically inactive or overweight/obese. In this nationwide French study, our results suggest a window of opportunity to promote school staff health but also indirectly, that of the youth with whom they interact daily. We suggest that school staff should be supported in health matters not only through the provision of health information but also most importantly, through the development of a favourable and supportive environment enabling them to put health knowledge into practice.

Education professionals play a crucial role in health education, notably as role-models, since they come into contact with students on a daily basis. Therefore, examining their health behaviours may be instructive. In this nationwide French study, teachers appeared to behave more healthily compared with non-education sector employees in important domains such as alcohol consumption or tobacco use. However, certain non-teaching education professional groups were more likely to be physically inactive or overweight/obese. Our results highlight opportunities for interventions aimed at raising health awareness and empowerment among school staff. A comprehensive health promotion approach integrating our findings would draw less on a vertical or top-down transfer of knowledge and depend more on participation and exchange among school staff, on teachers leading by example, as well as on the development of a supportive school environment.

Widening the gap? Unintended consequences of health promotion measures for young people during COVID-19 lockdown.

During the first wave of the COVID-19 pandemic, global measures preventing the spread of the new coronavirus required most of the population to lockdown at home. This sudden halt to collective life meant that non-essential services were closed and many health promoting activities (i.e. physical activity, school) were stopped in their tracks. To curb the negative health impacts of lockdown measures, activities adapting to this new reality were urgently developed. One form of activity promoted indoor physical activity to prevent the adverse physical and psychological effects of the lockdown. Another form of activity included the rapid development of online learning tools to keep children and youth engaged academically while not attending school. While these health promoting efforts were meant to benefit the general population, we argue that these interventions may have unintended consequences and inadvertently increase health inequalities affecting marginalized youth in particular, as they may not reap the same benefits, both social and physical, from the interventions promoting at-home physical activities or distance learning measures. We elaborate on several interventions and their possible unintended consequences for marginalized youth and suggest several strategies that may mitigate their impact.

Reflexivity in Health Promotion: A Typology for Training.

Reflexivity has emerged as a key concept in the field of health promotion (HP). Yet it remains unclear how diverse forms of reflexivity are specifically relevant to HP concerns, and how these "reflexivities" are interconnected. We argue that frameworks are needed to support more systematic integration of reflexivity in HP training and practice. In this article, we propose a typology of reflexivity in HP to facilitate the understanding of reflexivity in professional training. Drawing from key theories and models of reflexivity, this typology proposes three reflexive positions (ideal-types) with specific purposes for HP: reflexivity in, on, and underlying action. This article illustrates our typology's ideal-types with vignettes collected from HP actors working with reflexivity in North America and Europe. We suggest that our typology constitutes a conceptual device to organize and discuss a variety of experiences of engaging with reflexivity for HP. We propose the typology may support integrating reflexivity as a key feature in training a future cadre of health promoters and as a means for building a responsible HP practice.

ChromoTrace: Computational reconstruction of 3D chromosome configurations for super-resolution microscopy.

The 3D structure of chromatin plays a key role in genome function, including gene expression, DNA replication, chromosome segregation, and DNA repair. Furthermore the location of genomic loci within the nucleus, especially relative to each other and nuclear structures such as the nuclear envelope and nuclear bodies strongly correlates with aspects of function such as gene expression. Therefore, determining the 3D position of the 6 billion DNA base pairs in each of the 23 chromosomes inside the nucleus of a human cell is a central challenge of biology. Recent advances of super-resolution microscopy in principle enable the mapping of specific molecular features with nanometer precision inside cells. Combined with highly specific, sensitive and multiplexed fluorescence labeling of DNA sequences this opens up the possibility of mapping the 3D path of the genome sequence in situ. Here we develop computational methodologies to reconstruct the sequence configuration of all human chromosomes in the nucleus from a super-resolution image of a set of fluorescent in situ probes hybridized to the genome in a cell. To test our approach, we develop a method for the simulation of DNA in an idealized human nucleus. Our reconstruction method, ChromoTrace, uses suffix trees to assign a known linear ordering of in situ probes on the genome to an unknown set of 3D in-situ probe positions in the nucleus from super-resolved images using the known genomic probe spacing as a set of physical distance constraints between probes. We find that ChromoTrace can assign the 3D positions of the majority of loci with high accuracy and reasonable sensitivity to specific genome sequences. By simulating appropriate spatial resolution, label multiplexing and noise scenarios we assess our algorithms performance. Our study shows that it is feasible to achieve genome-wide reconstruction of the 3D DNA path based on super-resolution microscopy images.

'You have to do 60 minutes of physical activity per day I saw it on TV': children's constructions of play in the context of Canadian public health discourse of playing for health.

Public health institutions in many industrialised countries have been launching calls to address childhood obesity. As part of these efforts, Canadian physical activity campaigns have recently introduced children's play as a critical component of obesity prevention strategies. We consider this approach problematic as it may reshape the meanings and affective experiences of play for children. Drawing on the analytical concept of biopedagogies, we place Canadian public health discourse on play in dialogue with children's constructions of play to examine first, how play is promoted within obesity prevention strategies and second, whether children take up this public health discourse. Our findings suggest that: (i) the public health discourse on active play is taken up and reproduced by some children. However, for other children sedentary play is important for their social and emotional wellbeing; (ii) while active play is deemed to be a solution to the risk of obesity, it also embodies contradictions over risk in play, which children have to negotiate. We argue that the active play discourse, which valorises some representations of play (that is, active) while obscuring others (that is, sedentary), is reshaping meanings of play for children, and that this may have unintended consequences for children's wellbeing.

'Active play may be lots of fun, but it's certainly not frivolous': the emergence of active play as a health practice in Canadian public health.

In the context of what has been termed a childhood obesity epidemic, public health institutions have recently begun to promote active play as a means of addressing childhood obesity, thus advancing play for health. Drawing on Foucault, this article problematises the way that children's play is being taken up as a health practice and further considers some of the effects this may have for children. Six Canadian public health websites were examined, from which 150 documents addressing children's health, physical activity, obesity, leisure activities and play were selected and coded deductively (theoretical themes) and inductively (emerging themes). Bacchi's () question-posing approach to critical discourse analysis deepened our analysis of dominant narratives. Our findings suggest that several taken-for-granted assumptions and practices underlie this discourse: (i) play is viewed as a productive activity legitimises it as a health practice; (ii) tropes of 'fun' and 'pleasure' are drawn on to promote physical activity; (iii) children are encouraged to self-govern their leisure time to promote health. We underscore the need to recognise this discourse as contingent and as only one of many ways of conceptualising children's leisure activities and their health and social lives more generally.

Playing for health? Revisiting health promotion to examine the emerging public health position on children's play.

Concerns over dwindling play opportunities for children have recently become a preoccupation for health promotion in western industrialized countries. The emerging discussions of play seem to be shaped by the urgency to address the children's obesity epidemic and by societal concerns around risk. Accordingly, the promotion of play from within the field appears to have adopted the following principles: (i) particular forms of play are critical for increasing children's levels of physical activity; and (ii) play should be limited to activities that are not risky. In this article, we argue that these emerging principles may begin to re-shape children's play: play is predominantly instrumentalized as a means to promote children's physical health, which may result in a reduction of possibilities for children to play freely and a restriction of the kinds of play designated as appropriate for physical health. We argue that within this context some of the social and emotional elements of health and well-being that children gain through diverse forms of playing are neglected. This has implications for health promotion because it suggests a narrowing of the conception of health that was originally advocated for within the field. Additionally, this reveals a curious paradox; despite the urgency to promote physical activity through play, this position may limit the range of opportunities for children to freely engage in play, in effect reducing their activity levels. We propose an example that promotes play for children and better aligns with the conception of health as outlined in the Ottawa Charter.

Problematizing "play-for-health" discourses through children's photo-elicited narratives.

There are growing concerns in many industrialized Western societies about declining opportunities for children to play, and fears that this will have adverse health consequences for them. Informed by anti-obesity efforts, public health institutions have recently begun to advance active forms of play as a way of improving children's physical health; however, promoting play for physical health might reshape meanings of play for children. We conducted photography and interview sessions with 25 Canadian children aged 7 to 11 years to examine their representations of play. Our findings suggest that for children, (a) play is an end in itself, (b) play involves but is more than active play, (c) there is ambivalence about scheduled play, and (d) risk is considered a pleasurable component of play. These findings point to a dissonance between children's play promoted for physical health and the meaning of play for children as emotionally contingent, intrinsically motivated, and purposeless.

What Levers to Promote Teachers' Wellbeing during the COVID-19 Pandemic and Beyond: Lessons Learned from a 2021 Online Study in Six Countries.

To highlight effective levers to promote teachers' wellbeing worldwide, particularly during difficult times such as the COVID-19 pandemic, we investigated work-related factors associated with teacher wellbeing, across borders and cultures. In six countries/territories, we examined the factors that were most consistently and strongly associated with two indicators of wellbeing at work: (i) job satisfaction; and (ii) work/life balance, and three indicators of general wellbeing: (i) subjective health; (ii) mental health; and (iii) life satisfaction. Between May and July 2021, after 18 months of the pandemic, 8000 teachers answered the first edition of the International Barometer of Education Personnel's Health and Wellbeing (I-BEST): 3646 teachers from France, 2349 from Québec, 1268 from Belgium, 302 from Morocco, 222 from The Gambia, and 215 from Mexico. For each country/territory and each wellbeing indicator, we used a forward stepwise regression procedure to identify important determinants among a carefully selected set of 31 sociodemographic, private, and professional life factors. Aside from healthcare access, the factors most consistently and strongly associated with teacher wellbeing in France, Québec and Belgium (samples whose size were ≥1000) were related to the psychosocial and the organizational dimensions of work, namely: feeling of safety at school, autonomy at work, and the quality of relationships with superiors and quality of relationships with students. In the smaller samples of teachers from the three remaining countries (Morocco, The Gambia and Mexico), exploratory analyses showed that the feeling of safety and autonomy at work were, there too, consistently associated with wellbeing indicators. During the COVID-19 pandemic, the factors most consistently associated with teachers' wellbeing across countries were related to security and autonomy at work, supporting the importance to consider these aspects in a continuous, structural way at school. Factors associated with teachers' wellbeing in very different contexts require further cross-cultural study.

Teachers' Health: How General, Mental and Functional Health Indicators Compare to Other Employees? A Large French Population-Based Study.

Teachers' health is a key factor of any successful education system, but available data are conflicting. To evaluate to what extent teachers' health could be at risk, we used pre-pandemic data from the CONSTANCES population-based French cohort (inclusion phase: 2012-2019) and compared teachers (n = 12,839) included in the cohort with a random subsample selected among all other employees (n = 32,837) on four self-reported health indicators: perceived general health, depressive symptoms (CES-D scale), functional limitations in the last six months, and persistent neck/back troubles (Nordic questionnaire). We further restricted our comparison group to the State employees (n = 3583), who share more occupational similarities with teachers. Lastly, we focused on teachers and evaluated how their health status might differ across teaching levels (primary, secondary, and higher education). As compared to non-teacher employees, and even after adjusting for important demographic, socioeconomic, lifestyle, and occupational confounders, teachers were less likely to report bad perceived health and depressive symptoms but were more likely to present functional limitations. Trends were similar in the analyses restricted to State employees. Within the teaching population, secondary school teachers were more likely to report depressive symptoms but less frequently declared persistent neck/back troubles than primary school teachers. Our descriptive cross-sectional study based on a probability sampling procedure (secondary use of CONSTANCES inclusion data) did not support the idea that teachers' health in France was particularly at risk in the pre-pandemic period. Both cross-cultural and longitudinal studies are needed to further gain information on the topic of teachers' health around the world and to monitor its evolution over time, particularly during crises impacting the education system such as the COVID-19 pandemic.

Collagen-based cell migration models in vitro and in vivo.

Fibrillar collagen is the most abundant extracellular matrix (ECM) constituent which maintains the structure of most interstitial tissues and organs, including skin, gut, and breast. Density and spatial alignments of the three-dimensional (3D) collagen architecture define mechanical tissue properties, i.e. stiffness and porosity, which guide or oppose cell migration and positioning in different contexts, such as morphogenesis, regeneration, immune response, and cancer progression. To reproduce interstitial cell movement in vitro with high in vivo fidelity, 3D collagen lattices are being reconstituted from extracted collagen monomers, resulting in the re-assembly of a fibrillar meshwork of defined porosity and stiffness. With a focus on tumor invasion studies, we here evaluate different in vitro collagen-based cell invasion models, employing either pepsinized or non-pepsinized collagen extracts, and compare their structure to connective tissue in vivo, including mouse dermis and mammary gland, chick chorioallantoic membrane (CAM), and human dermis. Using confocal reflection and two-photon-excited second harmonic generation (SHG) microscopy, we here show that, depending on the collagen source, in vitro models yield homogeneous fibrillar texture with a quite narrow range of pore size variation, whereas all in vivo scaffolds comprise a range from low- to high-density fibrillar networks and heterogeneous pore sizes within the same tissue. Future in-depth comparison of structure and physical properties between 3D ECM-based models in vitro and in vivo are mandatory to better understand the mechanisms and limits of interstitial cell movements in distinct tissue environments.

Telling the data story the right way.

Effective data-driven analyses of service-line performance require: Buy-in and agreement at the outset from all parties (hospital and physicians) on the validity of the data used to evaluate service-line performance, Actionable data and metrics relevant to physicians, with financial goals tangibly linked to clinical improvement, Transparent sharing of data with physicians to build their trust and support the case for change, A physician champion who can help validate findings and guide how data are presented, Willingness of physicians to acknowledge that the opportunity for improved margin depends largely on the variable costs that they control as individuals.

In-situ at a distance? challenges and opportunities for health and place research methods in a post-COVID-19 world.

In-situ methodologies, including go-along and photo-elicited interviews, are ideal for harnessing people's lived experiences of place and their meanings for health and health equity. Their immersive nature means that the COVID-19 pandemic has impacted their use. Physical distancing measures combined to anxiety over the sharing of physical space have created ethical and practical challenges to the conduct of in-person in-situ methodologies. However, in-situ methodologies are precisely needed to gain deeper understandings of people's changing relationships to place post-COVID-19. In this commentary we discuss emerging challenges, highlight questions researchers should ask before engaging in these methods in the future, and explore adaptations and alternatives to traditional in-person in-situ methodologies.

Children's understanding and production of verbal irony in family conversations.

This study examined how children use and understand various forms of irony (sarcasm, hyperbole, understatement, and rhetorical questions) in the context of naturalistic positive and negative family conversations in the home. Instances of ironic language in conversations between mothers, fathers, and their two children (M(ages) = 6.33and4.39years) were recorded during six 90-min observations for each of 39 families. Children's responses to others' ironic utterances were coded for their understanding of meaning and conversational function. Mothers were especially likely to ask rhetorical questions and to use ironic language in conflictual contexts. In contrast, fathers used hyperbole and understatement as frequently as rhetorical questions, and employed ironic language in both positive and conflictual contexts. Children also showed evidence of a nascent ability to use ironic language, especially hyperbole and rhetorical questions. Family members used rhetorical questions and understatement proportionately more often in a negative interaction context. Finally, older siblings understood irony better than younger siblings, and both children's responses revealed some understanding of ironic language, particularly sarcasm and rhetorical questions. Overall, the results suggest that family conversations in the home may be one important context for the development of children's use and understanding of ironic language.

Collective cancer invasion forms an integrin-dependent radioresistant niche.

Cancer fatalities result from metastatic dissemination and therapy resistance, both processes that depend on signals from the tumor microenvironment. To identify how invasion and resistance programs cooperate, we used intravital microscopy of orthotopic sarcoma and melanoma xenografts. We demonstrate that these tumors invade collectively and that, specifically, cells within the invasion zone acquire increased resistance to radiotherapy, rapidly normalize DNA damage, and preferentially survive. Using a candidate-based approach to identify effectors of invasion-associated resistance, we targeted ß1 and αVß3/ß5 integrins, essential extracellular matrix receptors in mesenchymal tumors, which mediate cancer progression and resistance. Combining radiotherapy with ß1 or αV integrin monotargeting in invading tumors led to relapse and metastasis in 40-60% of the cohort, in line with recently failed clinical trials individually targeting integrins. However, when combined, anti-ß1/αV integrin dual targeting achieved relapse-free radiosensitization and prevented metastatic escape. Collectively, invading cancer cells thus withstand radiotherapy and DNA damage by ß1/αVß3/ß5 integrin cross-talk, but efficient radiosensitization can be achieved by multiple integrin targeting.

Genomic instability of micronucleated cells revealed by single-cell comparative genomic hybridization.

Nuclear variation in size and shape and genomic instability are hallmarks of dedifferentiated cancer cells. Although micronuclei are a typical long-term consequence of DNA damage, their contribution to chromosomal instability and clonal diversity in cancer disease is unclear. We isolated cancer cells with or without micronuclei to perform genomic analysis. Cell suspensions of HT1080 fibrosarcoma cells from either 2D culture or after isolation from 3D collagen matrix culture were stained with Hoechst 33342 and after classification for presence or absence of a micronucleus via bright-field and epifluorescence microscopy, cells were individually aspirated with a micropipette. Subsequently, whole-genome amplification and single-cell comparative genomic hybridization (CGH) were applied to detect genomic aberrations. The data show a high-fidelity isolation and genome amplification that lacks adverse effects by prior Hoechst 33342 staining. HT1080 cells showed a high degree of divergent amplifications, but neither location nor frequency of aberrations was dependent on 2D or 3D culture conditions or micronucleation. Thus, single-cell selection of defined nuclear states is amenable to single-cell CGH and here provides first insight into the aberration drift and genomic diversity in cancer cells with and without micronuclei.

Prospective Associations Between Play Environments and Pediatric Obesity.

PURPOSE: To identify school typologies based on the availability of play equipment and installations. We also examined the associations between availability of play items and child adiposity. DESIGN: Secondary analysis of longitudinal data. SETTING: Elementary schools in Montreal, Canada. PARTICIPANTS: We used data from the Quebec Adipose and Lifestyle Investigation in Youth study (QUALITY), an ongoing investigation of the natural history of obesity and type 2 diabetes in Quebec children of Caucasian descent. MEASURES: The presence of play items was assessed in each child's school. A trained nurse directly assessed child anthropometric measurements to derive body mass index and waist circumference. Body fat composition was measured using DEXA Prodigy Bone Densitometer System. ANALYSES: The final analytic sample comprised 512 students clustered in 296 schools (81% response). We used K-cluster analyses to identify school typologies based on the variety of play items on school grounds. Generalized estimation equations were used to estimate associations between school clusters and outcomes. RESULTS: We identified 4 distinct school typologies. Children in schools with the most varied indoor play environments had lower overall body fat, B = -1.26 cm (95% confidence interval [CI], -2.28 to -0.24 cm), and smaller waist circumference, B = -4.42 cm (95% CI, -7.88 to -0.96 cm), compared to children with the least varied indoor play environment. CONCLUSION: Our results suggest that policies regulating the availability of play items in schools may enrich comprehensive school-based obesity prevention strategies. Extending research in this area to diverse populations is warranted.