Reducing MYC's transcriptional footprint unveils a good prognostic gene signature in melanoma.

MYC's key role in oncogenesis and tumor progression has long been established for most human cancers. In melanoma, its deregulated activity by amplification of 8q24 chromosome or by upstream signaling coming from activating mutations in the RAS/RAF/MAPK pathway-the most predominantly mutated pathway in this disease-turns MYC into not only a driver but also a facilitator of melanoma progression, with documented effects leading to an aggressive clinical course and resistance to targeted therapy. Here, by making use of Omomyc, the most characterized MYC inhibitor to date that has just successfully completed a phase I clinical trial, we show for the first time that MYC inhibition in melanoma induces remarkable transcriptional modulation, resulting in severely compromised tumor growth and a clear abrogation of metastatic capacity independently of the driver mutation. By reducing MYC's transcriptional footprint in melanoma, Omomyc elicits gene expression profiles remarkably similar to those of patients with good prognosis, underlining the therapeutic potential that such an approach could eventually have in the clinic in this dismal disease.

Integrated requirement of non-specific and sequence-specific DNA binding in Myc-driven transcription.

Eukaryotic transcription factors recognize specific DNA sequence motifs, but are also endowed with generic, non-specific DNA-binding activity. How these binding modes are integrated to determine select transcriptional outputs remains unresolved. We addressed this question by site-directed mutagenesis of the Myc transcription factor. Impairment of non-specific DNA backbone contacts caused pervasive loss of genome interactions and gene regulation, associated with increased intra-nuclear mobility of the Myc protein in murine cells. In contrast, a mutant lacking base-specific contacts retained DNA-binding and mobility profiles comparable to those of the wild-type protein, but failed to recognize its consensus binding motif (E-box) and could not activate Myc-target genes. Incidentally, this mutant gained weak affinity for an alternative motif, driving aberrant activation of different genes. Altogether, our data show that non-specific DNA binding is required to engage onto genomic regulatory regions; sequence recognition in turn contributes to transcriptional activation, acting at distinct levels: stabilization and positioning of Myc onto DNA, and-unexpectedly-promotion of its transcriptional activity. Hence, seemingly pervasive genome interaction profiles, as detected by ChIP-seq, actually encompass diverse DNA-binding modalities, driving defined, sequence-dependent transcriptional responses.

Pratiquer la responsabilité sociale en santé : de la théorie à la pratique. Une étude Delphi internationale.

INTRODUCTION: Health professionals’ social responsibility in health resists translation into skills that can be taught and implemented concretely in professional practice. PURPOSE OF THE RESEARCH: This study, conducted by the Réseau International Francophone pour la Responsabilité Sociale en Santé (RIFRESS), aims to develop a consensus on the components of doctors’ social responsibility in health from the perspective of experts in medical education. Its findings are intended to inform the creation of a skills profile. A three-round Delphi consensus method was used, with an open first round and closed second and third rounds. Mesydel software was used to organize the process and to do the qualitative analysis of the first round. SPSS was used for consensus analysis for rounds 2 and 3. RESULTS: Thirty-four experts responded to the study. During the first round, 62 codes emerged, grouped into 13 themes. From the initial analysis, 40 items were submitted for the Delphi round 2. Of these 40 items, 23 came out consensual after the second round, as did 13 of the 18 resubmitted items after the third. Examples of items that emerged as consensual are eco-responsibility, advocacy, defense of the common good, critical analysis of practice, and collaborative leadership. CONCLUSIONS: The present study represents a much-needed effort to concretely define the components of doctors’ social responsibility in health. Local context must be taken into account when using these findings. They can help to train tomorrow’s doctors to better meet the priority health needs of society in a profoundly changing world.

Neutrophils and IL-1α Regulate Surfactant Homeostasis during Cigarette Smoking.

Cigarette smoke exposure induces inflammation marked by rapid and sustained neutrophil infiltration, IL-1α, release and altered surfactant homeostasis. However, the extent to which neutrophils and IL-1α contribute to the maintenance of pulmonary surfactant homeostasis is not well understood. We sought to investigate whether neutrophils play a role in surfactant clearance as well as the effect of neutrophil depletion and IL-1α blockade on the response to cigarette smoke exposure. In vitro and in vivo administration of fluorescently labeled surfactant phosphatidylcholine was used to assess internalization of surfactant by lung neutrophils and macrophages during or following cigarette smoke exposure in mice. We also depleted neutrophils using anti-Ly-6G or anti-Gr-1 Abs, or we neutralized IL-1α using a blocking Ab to determine their respective roles in regulating surfactant homeostasis during cigarette smoke exposure. We observed that neutrophils actively internalize labeled surfactant both in vitro and in vivo and that IL-1α is required for smoke-induced elevation of surfactant protein (SP)-A and SP-D levels. Neutrophil depletion during cigarette smoke exposure led to a further increase in SP-A levels in the bronchoalveolar lavage and increased IL-1α, CCL2, GM-CSF, and G-CSF release. Finally, macrophage expression of Mmp12, a protease linked to emphysema, was increased in neutrophil-depleted groups and decreased following IL-1α blockade. Taken together, our results indicate that neutrophils and IL-1α signaling are actively involved in surfactant homeostasis and that the absence of neutrophils in the lungs during cigarette smoke exposure leads to an IL-1α-dependent exacerbation of the inflammatory response.

Practices countering resident-to-resident aggression and promoting wellness care for older adults in congregate residential facilities: results from a systematic review.

Resident-to-resident aggression (RRA) is an important issue in congregate residential facilities (CRFs) for older adults and has devastating effects. This study aimed to provide an inventory and content analysis of the practices used to counter RRA and promote wellness care for older adults in CRFs. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, original, peer-reviewed research and systematic reviews published in 14 electronic databases and two gray literature sources were examined. Of the 6196 articles identified, 28 met the inclusion criteria. Practices aimed to prevent, track or intervene in RRA, mostly in long-term care centers, but few were evidence-based and ready for widespread implementation. It emerges that continuous training of staff is necessary and that it should prioritize a person-centered approach. CRFs' managers must promote a culture of wellness care and policymakers should consider the prevention practices to improve the quality of life of older adults in CRFs.

Which interventions with youths counter ageism toward older adults? Results from a realist review.

Age-related social biases - ageism - are developed at an early age. Interventions to counter ageism have been identified but little is known about their mechanisms, particularly in children. This study aimed to provide a comprehensive understanding of which interventions in youths are most effective, under which circumstances, how, and with what outcomes. Using 46 keywords in 6 databases, a realist review identified 24 studies published between 2000 and 2022 targeting youths under 18. A content analysis of these studies led to the construction of a Context-Mechanisms-Outcomes explanatory model. Contextual facilitators triggering mechanisms for changing stereotypes, prejudices and discrimination were: 1) enhancing knowledge about aging and older adults by providing nuanced information, 2) improving the quality of intergenerational contacts, 3) increasing opportunities to apply previously acquired knowledge in intergenerational interactions, and 4) promoting reflective thinking about experiences with older adults. However, stereotypes and prejudices appeared to be resistant and changes difficult to generalize. Insufficiently advanced cognitive development in children or viewing healthy and socially engaged older adults as unrepresentative of their age group were obstacles that reduced intervention effectiveness. Future studies should explore how advancing age influences interventions as well as the characteristics of older adults involved.

Recombinant human ß-defensin 2 delivery improves smoking-induced lung neutrophilia and bacterial exacerbation.

Treatment of the cigarette smoke-associated lung diseases, such as chronic obstructive pulmonary disease (COPD), has largely focused on broad-spectrum anti-inflammatory therapies. However, these therapies, such as high-dose inhaled corticosteroids, enhance patient susceptibility to lung infection and exacerbation. Our objective was to assess whether the cationic host defense peptide, human ß-defensin 2 (hBD-2), can simultaneously reduce pulmonary inflammation in cigarette smoke-exposed mice while maintaining immune competence during bacterial exacerbation. Mice were exposed to cigarette smoke acutely (4 days) or chronically (5 days/wk for 7 wk) and administered hBD-2 intranasally or by gavage. In a separate model of acute exacerbation, chronically exposed mice treated with hBD-2 were infected with nontypeable Haemophilus influenzae before euthanasia. In the acute exposure model, cigarette smoke-associated pulmonary neutrophilia was significantly blunted by both local and systemic hBD-2 administration. Similarly, chronically exposed mice administered hBD-2 therapeutically exhibited reduced pulmonary neutrophil infiltration and downregulated proinflammatory signaling in the lungs compared with vehicle-treated mice. Finally, in a model of acute bacterial exacerbation, hBD-2 administration effectively limited neutrophil infiltration in the lungs while markedly reducing pulmonary bacterial load. This study shows that hBD-2 treatment can significantly attenuate lung neutrophilia induced by cigarette smoke exposure while preserving immune competence and promoting an appropriate host-defense response to bacterial stimuli.

Sexual Activity and Physical Tenderness in Older Adults: Prevalence and Associated Characteristics From a Belgian Study.

BACKGROUND: Despite the World Health Organization calling for sexuality to be recognized as an aspect of well-being, no studies have explored sexual activity and physical tenderness in older adults aged ≥ 75 years in Belgium or those aged ≥ 85 years worldwide. AIM: To assess the prevalence and predictors of sexual activity and physical tenderness in a sample of older adults. METHODS: Using data from a Belgian cross-sectional study on sexual violence (UN-MENAMAIS), information on sexual activity, physical tenderness, and associated characteristics was collected during structured face-to-face interviews with older adults living in the community, assisted living facilities, or nursing homes. Cluster random probability sampling with a random route-finding approach was used to select the participants. OUTCOMES: Current sexual activity and physical tenderness in the previous 12 months, sociodemographic characteristics, chronological age, subjective age, number of sexual partners, sexual satisfaction, attitudes toward sexuality in later life, quality of life, and lifetime sexual victimisation. RESULTS: Among the 511 participants included, 50.3% were in a relationship, mainly living with their partner; 31.3% indicated they were sexually active; and 47.3% of sexually inactive participants reported having experienced forms of physical tenderness in the previous 12 months. Sexual activity was associated with the presence of a partner, satisfaction with sexual life, permissive attitudes regarding sexuality in later life, a younger age, and a lack of disability. Physical tenderness was associated with the presence of a partner, community residency, and permissive attitudes regarding sexuality in later life. CLINICAL IMPLICATIONS: Raising awareness among the general population, healthcare professionals, and older adults about sexuality in later life could contribute to ending this taboo and should therefore be a priority for society. STRENGTHS AND LIMITATIONS: Our study fills a gap in the literature regarding sexual activity and physical tenderness in older adults aged ≥ 70 years, including respondents aged up to 99 years. Additionally, we explored different forms of sexual expression beyond intercourse, and face-to-face interviews contributed to the quality of the collected data. The main limitation of this study was the sample size, although the findings were similar to recent statistical indicators in Belgium. CONCLUSION: One in 3 older adults aged ≥ 70 years living in Belgium are sexually active. These findings provide an opportunity to inform the general public and older adults about later life sexuality and to educate healthcare professionals about aging sexuality to increase discussions and avoid assumptions of asexuality in later life. Cismaru-Inescu A, Hahaut B, Adam S et al. Sexual Activity and Physical Tenderness in Older Adults: Prevalence and Associated Characteristics From a Belgian Study. J Sex Med 2022;19:569-580.

Does spaced education improve clinical knowledge among Family Medicine residents? A cluster randomized controlled trial.

Spaced education is a learning strategy to improve knowledge acquisition and retention. To date, no robust evidence exists to support the utility of spaced education in the Family Medicine residency. We aimed to test whether alerts to encourage spaced education can improve clinical knowledge as measured by scores on the Canadian Family Medicine certification examination. METHOD: We conducted a cluster randomized controlled trial to empirically and pragmatically test spaced education using two versions of the Family Medicine Study Guide mobile app. 12 residency training programs in Canada agreed to participate. At six intervention sites, we consented 335 of the 654 (51%) eligible residents. Residents in the intervention group were sent alerts through the app to encourage the answering of questions linked to clinical cases. At six control sites, 299 of 586 (51%) residents consented. Residents in the control group received the same app but with no alerts. Incidence rates of case completion between trial arms were compared using repeated measures analysis. We linked residents in both trial arms to their knowledge scores on the certification examination of the College of Family Physicians of Canada. RESULTS: Over 67 weeks, there was no statistically significant difference in the completion of clinical cases by participants. The difference in mean exam scores and the associated confidence interval did not exceed the pre-defined limit of 4 percentage points. CONCLUSION: Further research is recommended before deploying spaced educational interventions in the Family Medicine residency to improve knowledge.

Sexual violence in older adults: a Belgian prevalence study.

BACKGROUND: Sexual violence (SV) is an important public health problem which may cause long-lasting health problems. SV in older adults remains neglected in research, policies and practices. Valid SV prevalence estimates and associated risk factors in older adults are currently unavailable. In this study we measured lifetime and past 12-months sexual victimisation in older adults living in Belgium, its correlates, assailant characteristics and the way that victims framed their SV experiences. METHODS: SV was measured using behaviourally specific questions based on a broad definition of SV. Participants were selected via a cluster random probability sampling with a random route finding approach. Information on sexual victimisation, correlates, assailant characteristics and framing was collected via structured face-to-face interviews with adults aged 70 years and older living in Belgium (community-dwelling, assisted living and nursing homes). RESULTS: Among the 513 participants, the lifetime SV prevalence was 44% (55% F, 29% M). Past 12-months prevalence was 8% (9% F, 8% M). Female sex and a higher number of sexual partners were associated with lifetime SV (p < .05), non-heterosexual sexual orientation with past 12-months SV (p < .05). Correlates identified to be linked to elder abuse and neglect in previous studies were not linked with SV in our sample. 'Someone unknown' was identified as most common assailant. CONCLUSIONS: Sexual victimisation appears to be common in older adults in Belgium. Both correlates and assailant characteristics seem to differ from previous studies on elder abuse and neglect. Recognizing older adults as a risk group for sexual victimisation in research, policies and practices is of the utmost importance.

Patient and family views of team functioning in primary healthcare teams with nurse practitioners: a survey of patient-reported experience and outcomes.

BACKGROUND: Nurse practitioners (NPs) have been added to primary healthcare teams to improve access to care. Team processes, including communication and decision-making, explicate how patients and families view team functioning. Yet, important gaps exist in our understanding of patient-reported experience and outcomes at the level of the healthcare team. We aimed to examine the influence of individual, team, and organizational characteristics, and role clarity on outcomes of care mediated by team processes in primary healthcare teams that include NPs. METHODS: A cross-sectional survey across six sites representing practices with NPs in Québec, Canada, was conducted between March 2018 and April 2019 as part of a multiple-case study. Patients and families (n = 485; response rate: 53%) completed a validated questionnaire, which included a patient-reported experience measure (PREM) and a patient-reported outcome measure (PROM) of team functioning (Cronbach alpha: 0.771 (PROM) to 0.877 (PREM)). We performed logistic regression and mediation analyses to examine relationships between the individual, team, and organizational characteristics, role clarity, and outcomes of care mediated by team processes. RESULTS: Patients and families expressed positive perceptions of team functioning (mean 4.97/6 [SD 0.68]) and outcomes of care (5.08/6 [0.74]). Also, high team processes (adjusted odds ratio [AOR] 14.92 [95% CI 8.11 to 27.44]) was a significant predictor of high outcomes of care. Role clarity (indirect effect coefficient ab = 6.48 [95% CI 3.79 to 9.56]), living in an urban area (-1.32 [-2.59 to -0.13]), patient as respondent (-1.43 [-2.80 to -0.14]), and income (1.73 [0.14 to 3.45]) were significant predictors of outcomes of care mediated by team processes. CONCLUSIONS: This study provides key insights on how primary healthcare teams with NPs contribute to team functioning, using a validated instrument consistent with a conceptual framework. Results highlight that high role clarity, living in a non urban area, family as respondent, and adequate income were significant predictors of high outcomes of care mediated by high team processes. Additional research is needed to compare teams with and without NPs in different settings, to further explicate the relationships identified in our study.

'I care a lot' a commentary on the depiction of elder abuse in the film.

In I Care a Lot, we follow Marla Grayson, a self-proclaimed "Professional Carer" who makes a living by financially abusing older adults. Elder abuse, financial or otherwise, is seldom explored in cinema and must be handled with care. Cinema can help raise awareness on this social problem and play an important role in the de-stigmatization of older adults. Unfortunately, in our opinion, I Care a Lot fails to do so.

Exposure to nicotine-free and flavor-free e-cigarette vapors modifies the pulmonary response to tobacco cigarette smoke in female mice.

Most of electronic cigarette (e-cigarette) users are also smoking tobacco cigarettes. Because of the relative novelty of this habit, very little is known on the impact of vaping on pulmonary health, even less on the potential interactions of dual e-cigarette and tobacco cigarette use. Therefore, we used well-established mouse models to investigate the impact of dual exposure to e-cigarette vapors and tobacco cigarette smoke on lung homeostasis. Groups of female BALB/c mice were exposed to room air, tobacco smoke only, nicotine-free flavor-free e-cigarette vapors only or both tobacco smoke and e-cigarette vapors. Moreover, since tobacco smoke and electronic cigarette vapors both affect circadian processes in the lungs, groups of mice were euthanized at two different time points during the day. We found that dual-exposed mice had altered lung circadian gene expression compared with mice exposed to tobacco smoke alone. Dual-exposed mice also had different frequencies of dendritic cells, macrophages, and neutrophils in the lung tissue compared with mice exposed to tobacco smoke alone, an observation also valid for B-lymphocytes and CD4+ and CD8+ T lymphocytes. Exposure to e-cigarette vapors also impacted the levels of immunoglobulins in the bronchoalveolar lavage and serum. Finally, e-cigarette and dual exposures increased airway resistance compared with mice exposed to room air or tobacco smoke alone, respectively. Taken together, these data suggest that e-cigarette vapors, even without nicotine or flavors, could affect how the lungs react to tobacco cigarette smoke exposure in dual users, potentially altering the pathological course triggered by smoking.

Critical importance of dietary methionine and choline in the maintenance of lung homeostasis during normal and cigarette smoke exposure conditions.

Genetic predispositions and environmental exposures are regarded as the main predictors of respiratory disease development. Although the impact of dietary essential nutrient deficiencies on cardiovascular disease, obesity, and type II diabetes has been widely studied, it remains poorly explored in chronic respiratory diseases. Dietary choline and methionine deficiencies are common in the population, and their impact on pulmonary homeostasis is currently unknown. Mice were fed choline- and/or methionine-deficient diets while being exposed to room-air or cigarette smoke for up to 4 wk. Lung functions were assessed using the FlexiVent. Pulmonary transcriptional activity was assessed using gene expression microarrays and quantitative PCR. Immune cells, cytokines, and phosphatidylcholine were quantified in the bronchoalveolar lavage. In this study, we found that short-term dietary choline and/or methionine deficiencies significantly affect lung function in mice in a reversible manner. It also reduced transcriptional levels of collagens and elastin as well as pulmonary surfactant phosphatidylcholine levels. We also found that dietary choline and/or methionine deficiencies markedly interfered with the pulmonary response to cigarette smoke exposure, modulating lung function and dampening inflammation. These findings clearly show that dietary choline and/or methionine deficiencies can have dramatic pathophysiological effects on the lungs and can also affect the pathobiology of cigarette smoke-induced pulmonary alterations. Expanding our knowledge in the field of "nutri-respiratory research" may reveal a crucial role for essential nutrients in pulmonary health and disease, which may prove to be as relevant as genetic predispositions and environmental exposures.

Ageism and COVID-19: what does our society's response say about us?

The goal of this commentary is to highlight the ageism that has emerged during the COVID-19 pandemic. Over 20 international researchers in the field of ageing have contributed to this document. This commentary discusses how older people are misrepresented and undervalued in the current public discourse surrounding the pandemic. It points to issues in documenting the deaths of older adults, the lack of preparation for such a crisis in long-term care homes, how some 'protective' policies can be considered patronising and how the initial perception of the public was that the virus was really an older adult problem. This commentary also calls attention to important intergenerational solidarity that has occurred during this crisis to ensure support and social-inclusion of older adults, even at a distance. Our hope is that with this commentary we can contribute to the discourse on older adults during this pandemic and diminish the ageist attitudes that have circulated.

Non-Contrast CT and CT-Angiogram for Late Window Ischemic Stroke Treatment Selection.

INTRODUCTION: The benefit of late window endovascular treatment (EVT) for anterior circulation ischemic stroke has been demonstrated using perfusion-based neuroimaging. We evaluated whether non-contrast CT (NCCT) and CT-angiogram (CTA) alone can select late-presenting patients for EVT. METHODS: We performed a retrospective comparison of all patients undergoing EVT at a single comprehensive stroke center from January 2016 to April 2017. Patients planned for EVT were divided into early (<6 hours from onset) and late (≥6 hours from onset or last time seen normal) window groups. Incidence of symptomatic hemorrhagic transformations (sHTs) at 24 hours and 3-month modified Rankin scores (mRSs) were compared. RESULTS: During the study period, 204 (82%) patients underwent EVT in the early and 44 (18%) in the late window. Median (interquartile range) NIH Stroke Scale Score was similar between groups (early: 18 [15-23] vs. late: 17 [13-21]), as were median ASPECT scores (early: 9 [8-10] vs. late: 9 [7-9]). In the late window, 42 (95%) strokes were of unknown onset. Similar proportions of sHT occurred at 24 hours (early: 12 [6%] vs. late: 4 [9%], p = 0.43). At 3 months, the proportion of patients achieving functional independence (mRS 0-2) were comparable in the early (80/192 [42%]) and late (16/41 [39%]) windows (p = 0.76). CONCLUSION: NCCT- and CTA-based patient selection led to similar functional independence outcomes and low proportions of sHT in the early and late windows. In centers without access to perfusion-based neuroimaging, this pragmatic approach could be safe, particularly for strokes of unknown onset.

Implementing a fracture follow-up liaison service: perspective of key stakeholders.

Fracture liaison services (FLS) have been shown to prevent efficiently subsequent fragility fractures (FF). However, very few studies have examined their implementation in depth. The purpose of this research was to identify factors influencing the implementation of a FLS at three sites in Quebec, Canada. From 2013 to 2015, individual and group interviews focused on experiences of FLS stakeholders, including implementation committee members, coordinators, and orthopaedic surgeons and their teams. Emerging key implementation factors were triangulated with the FLS patients' clinico-administrative data. The Consolidated Framework for Implementation Research guided the analysis of perceived factors influencing four intervention outputs: investigation of FF risk (using the FRAX score), communication with the participant primary care provider, initiation of anti-osteoporosis medications (when relevant), and referral to organized fall prevention activities (either governmental or community based). Among the 454 FLS patients recruited to the intervention group, 83% were investigated for FF risk, communication with the primary care provider was established for 98% of the participants, 54% initiated medication, and 35% were referred to organized fall prevention activities. Challenges related to restricted rights to prescribe medication and access to organized fall prevention activities were reported. FLS coordinator characteristics to overcome those challenges included self-efficacy beliefs, knowledge of community resources, and professional background. This study highlighted the importance of enabling access to services for subsequent FF prevention, consolidating the coordinator's role to facilitate a more integrated intervention, and involving local leaders to promote the successful implementation of the FLS.

Evaluation of the implementation and associated effects of advanced access in university family medicine groups: a study protocol.

BACKGROUND: Timely access in primary health care is one of the key issues facing health systems. Among many interventions developed around the world, advanced access is the most highly recommended intervention designed specifically to improve timely access in primary care settings. Based on greater accessibility linked with patients' relational continuity and informational continuity with a primary care professional or team, this organizational model aims to ensure that patients obtain access to healthcare services at a time and date convenient for them when needed regardless of urgency of demand. Its implementation requires a major organizational change based on reorganizing the practices of all the administrative staff and health professionals. In recent years, advanced access has largely been implemented in primary care organizations. However, despite its wide dissemination, we observe considerable variation in the implementation of the five guiding principles of this model across organizations, as well as among professionals working within the same organization. The main objective of this study is to assess the variation in the implementation of the five guiding principles of advanced access in teaching primary healthcare clinics across Quebec and to better understand the influence of the contextual factors on this variation and on outcomes. METHODS: This study will be based on an explanatory sequential design that includes 1) a quantitative survey conducted in 47 teaching primary healthcare clinics, and 2) a multiple case study using mixed data, contrasted cases (n = 4), representing various implementation profiles and geographical contexts. For each case, semi-structured interviews and focus group will be conducted with professionals and patients. Impact analyses will also be conducted in the four selected clinics using data retrieved from the electronic medical records. DISCUSSION: This study is important in social and political context marked by accessibility issues to primary care services. This research is highly relevant in a context of massive media coverage on timely access to primary healthcare and a large-scale implementation of advanced access across Quebec. This study will likely generate useful lessons and support evidence-based practices to refine and adapt the advanced access model to ensure successful implementation in various clinical contexts facing different challenges.

Pharmacological activation of liver X receptor during cigarette smoke exposure adversely affects alveolar macrophages and pulmonary surfactant homeostasis.

Smoking alters pulmonary reverse lipid transport and leads to intracellular lipid accumulation in alveolar macrophages. We investigated whether stimulating reverse lipid transport with an agonist of the liver X receptor (LXR) would help alveolar macrophages limit lipid accumulation and dampen lung inflammation in response to cigarette smoke. Mice were exposed to cigarette smoke and treated intraperitoneally with the LXR agonist T0901317. Expression of lipid capture and lipid export genes was assessed in lung tissue and alveolar macrophages. Pulmonary inflammation was assessed in the bronchoalveolar lavage (BAL). Finally, cholesterol efflux capacity and pulmonary surfactant levels were determined. In room air-exposed mice, T0901317 increased the expression of lipid export genes in macrophages and the whole lung and increased cholesterol efflux capacity without inducing inflammation or affecting the pulmonary surfactant. However, cigarette smoke-exposed mice treated with T0901317 showed a marked increase in BAL neutrophils, IL-1α, C-C motif chemokine ligand 2, and granulocyte-colony-stimulating factor levels. T0901317 treatment in cigarette smoke-exposed mice failed to increase the ability of alveolar macrophages to export cholesterol and markedly exacerbated IL-1α release. Finally, T0901317 led to pulmonary surfactant depletion only in cigarette smoke-exposed mice. This study shows that hyperactivation of LXR and the associated lipid capture/export mechanisms only have minor pulmonary effects on the normal lung. However, in the context of cigarette smoke exposure, where the pulmonary surfactant is constantly oxidized, hyperactivation of LXR has dramatic adverse effects, once again showing the central role of lipid homeostasis in the pulmonary response to cigarette smoke exposure.

CD34 regulates the skeletal muscle response to hypoxia.

Chronic obstructive pulmonary disease (COPD) can sometimes be associated with skeletal muscle atrophy. Hypoxemic episodes, which occur during disease exacerbation and daily physical activity, are frequent in COPD patients. However, the link between hypoxemia and muscle atrophy remains unclear, along with mechanisms of muscle hypoxic stress response. Myogenic progenitors (MPs) and fibro/adipogenic progenitors (FAPs) express CD34 and participate to muscle mass maintenance. Although there is evidence linking CD34 expression and muscle repair, the link between CD34 expression, muscle wasting and the hypoxic stress observed in COPD has never been studied. Using a 2-day model of exposure to hypoxic conditions, we investigated the impact of hypoxia on skeletal muscle wasting and function, and elucidated the importance of CD34 expression in that response. A 2-day exposure to hypoxic conditions induces muscle atrophy, which was significantly worse in Cd34-/- mice compared to wild type (WT). Moreover, the lack of CD34 expression negatively impacts the maximal strength of the extensor digitorum longus muscle in response to hypoxia. Following exposure to hypoxic conditions, FAPs (which support MPs differentiation and myogenesis) are significantly lower in Cd34-/- mice compared to WT animals while the expression of myogenic regulatory factors and degradation factors (Atrogin) are similar. CD34 expression is important in the maintenance of muscle mass and function in response to hypoxic stress. These results highlight a new potential role for CD34 in muscle mass maintenance in hypoxic stress such as observed in COPD.