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Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs—particularly palmitic acid—induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.

Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5–7in the immune system only. We show that Vav-iCre+/−;Ercc1−/flmice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8–10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/−;Ercc1−/flor aged wild-type mice into young mice induced senescence intrans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/−;Ercc1−/flmice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.

Introduction: Older adults with hematologic malignancy (HM) are a growing demographic with wide-ranging therapeutic options. With aging, patient health and treatment decision-making are heterogenous. Treatment decisions are impacted by chronological age, performance status, and comorbidities. An approach to treating older adults based on objective measures of health may better personalize therapy by focusing on physiologic parameters. Here we examined the relationship of a blood-based aging biomarker, p16 INK4a(p16), with clinical frailty.

Early childhood care and development has increasingly become a part of the global development agenda. Fueled by a threefold rationale, rooted in development psychology, social economy, and human rights, the arguments for investing in early childhood care and development are virtually unassailable. However, this rationale is somehow at odds with insights developed within the sociology of childhood, emphasizing childhood as a social construction amendable to context and children’s own agency. Inspired by the methodological approach known as institutional ethnography, we explore how development aid workers respond to and enact the early childhood care and development mission. Building on interviews with development aid workers in Phnom Penh, Cambodia, we describe how their actions, when justified, enter into institutional circuits where the demand for evidence is striking. By exploring development aid workers’ own work knowledge, including how they strive to be compliant with the early childhood care and development rationale, yet also oppose it, our contribution points to the importance of re-negotiating evidence in order to discover the blind spots that may be concealed within what we refer to as a “justification loop.”

La réforme de la médecine légale (2011) a permis le développement d’unités médicojudicaires (UMJ) dédiées à l’accueil spécialisé pluridisciplinaire des victimes d’infractions pénales. Si le ministère de la Justice assure le financement des actes à finalité judiciaire au moyen d’une dotation budgétaire annuelle, les établissements de santé supportent le financement du volet médico-psycho-social. L’objectif de cette étude a été de déterminer les coûts directs de la prise en charge initiale d’une victime de viol afin de voir comment son financement pourrait être repensé dans le but de limiter les dépenses supplémentaires que pourrait générer une prise en charge insuffisante.

Les mesures pénalement ordonnées représentent un ensemble de soins prononcés par la justice à l’encontre d’un auteur d’infraction pénale souvent rattachable à des actes de violences ou d’usage de substances illicites. Dans le cadre des consommations de toxiques, hors contexte d’hospitalisation, on dénombre quatre mesures : l’obligation de soin, l’injonction thérapeutique, l’injonction de soins et le stage de sensibilisation aux dangers de l’usage de produits stupéfiants. Ces dispositifs, au-delà de la finalité répressive, revêtent un intérêt particulier grâce à l’interaction qu’ils créent entre le consommateur et le système de soins, par la sanction pénale. De nombreuses difficultés persistent dans la mise en place de ces soins, malgré plusieurs tentatives d’amélioration via de multiples modifications législatives. Ces difficultés concernent notamment l’injonction thérapeutique qui semble être la réponse la plus adaptée à la problématique addictive. De surcroît, les données de la littérature disponibles soulignent l’existence d’inadéquations entre ces mesures prononcées par la justice et les modalités d’usage de toxiques des personnes. Les mesures de courte durée, comme le stage de sensibilisation, sont adaptées aux usagers simples, dans un cadre de prévention et de sensibilisation, mais sont trop souvent prononcées pour une problématique de dépendance nécessitant une prise en charge au long cours.

AbstractA strong focus on early intervention involves broad categories by which to assess children at risk of social marginalisation. Most of these categories relate to family characteristics and qualities. In this article, we explore social vulnerability from children’s perspectives and consider whether their self-esteem provides evidence for risk of social marginalisation, here understood as exclusion from social, academic, and cultural communities. The data are derived from a survey of 10-year-old children in the south of Norway on their everyday life and well-being (N = 1360). We have constructed an index of global self-esteem. First, we find a significant correlation between low global self-esteem and personal social vulnerability. Next, we quite surprisingly find no significant correlation between children’s global self-esteem and their family characteristics. The final analysis reveals a correlation between children’s global self-esteem and their social networks. These results prompt us to question some of the common assumptions about the association between family characteristics and social vulnerability. Our results show that more attention should be paid to children’s social networks, regardless of family characteristics. More importantly, the results show that global self-esteem – including self-evaluations of academic skills, athletic skills, feelings of self-worth, and sociability – is a fruitful approach to expanding our categorical understanding of children at risk.

Le but de cette étude était d’établir un descriptif des violences exercées à l’égard des hommes dans le cadre familial.

Les mesures pénalement ordonnées correspondent à des soins initiés sur décision judiciaire. Il existe quatre mesures prononcées par la justice dans le cadre de la consommation de substances : l’obligation de soins, l’injonction thérapeutique, l’injonction de soins ainsi que le stage de sensibilisation aux dangers de l’usage de produits stupéfiants.

Conditional expression of the most common somatic gain-of-function Ezh2mutation in mouse models of melanoma and lymphoma reveals insight into its cooperation with other oncogenic events and its effects on the epigenome.

Le Flash-Ball®est couramment utilisé par les unités de police et de gendarmerie en France depuis 1995. Bien que la dangerosité des lanceurs sub-létaux de balles de défense soit connue, les traumatismes imputables au Flash-Ball®sont régulièrement relayés dans les médias mais restent peu décrits dans la littérature. Les auteurs rapportent le cas d’un jeune homme âgé de 34ans, victime d’un impact de projectile type balle caoutchouc de Flash-Ball®en marge d’une manifestation sportive, à l’origine d’un traumatisme crânio-encéphalique sévère avec persistance d’un tableau sequellaire. Ce cas, associé à une revue de la littérature, illustre le fait que bien que le Flash-Ball®soit qualifié d’arme sub-létale, ce dernier peut être à l’origine de tableaux traumatiques graves, particulièrement en cas d’impact au niveau de l’extrémité céphalique, et également de décès.

In this article, we address the question of how boys whose fathers are absent construct an image of fatherhood. Drawing on the stories told by three boys whose fathers are absent, we explore how the boys, in the relation with their mothers, siblings and others, construct and negotiate an image of fatherhood, including how they envisage themselves to be as fathers in the future. The data material consists of life-mode interviews with the boys and their mothers. Theoretically, we are inspired by social constructionism and cultural psychology. We find that the boys aspire to become fathers who engage in close and mutual relations within the family, who are emotionally and practically available, who are consistent and predictable, and who participate in activities with their children. This image of fatherhood is in line with the contemporary expectations to fathers in our culture. In developing this notion of fatherhood, the role of the mothers is crucial, and we find that they – in their repertoire of motherhood – propose to their sons a cultural orientation that affirms their sons’ identity as men and future fathers.

Using a novel approach to identify exonic circular RNAs (ecircRNAs), the authors show widespread production of circular RNAs from a significant fraction of expressed genes in murine and human cells. They demonstrate that several of these noncoding transcripts are stable and abundant and can be targeted by siRNA. Bioinformatic analysis of the entire ecircRNA complement revealed gene features associated with RNA circularization.

Androgen receptor regulation is pivotal for prostate growth and development. Activation of the receptor is dictated by association with androgen (ligand) and through interaction with co-activators and co-repressors. We have shown previously that cyclin D1 functions as a co-repressor to inhibit ligand-dependent androgen receptor activation. We demonstrate that cyclin D1 directly binds the N terminus of the androgen receptor and that this interaction is independent of ligand. Furthermore, we show that the interaction occurs in the nucleus and does not require the LXXLL motif of cyclin D1. Although two distinct transactivation domains exist in the N terminus (AF-1 and AF-5), the data shown support the hypothesis that cyclin D1 targets the AF-1 transactivation function. The constitutively active AF-5 domain was refractory to cyclin D1 inhibition. By contrast, cyclin D1 completely abolished androgen receptor activity, even in the presence of potent androgen receptor co-activators. This action of cyclin D1 at least partially required de-acetylase activity. Finally, we show that transient, ectopic expression of cyclin D1 results in reduced cell cycle progression in androgen-dependent LNCaP cells independent of CDK4 association. Collectively, our data support a model wherein cyclin D1 has a mitogenic (CDK4-dependent) function and an anti-mitogenic function (dependent on regulation of the AF-1 domain) that can collectively control the rate of androgen-dependent cellular proliferation. These findings provide insight into the non-cell cycle functions of cyclin D1 and provide the impetus to study its pleiotropic effects in androgen-dependent cells, especially prostatic adenocarcinomas.

Previous research has shown that relatively localized acoustic information, such as voice pitch, f0 perturbation, and hoarseness are cues to age perception. The present studies examined the potential role of sentence‐level prosodic information in the perception of age. Sixteen different six‐word sentences were recorded from eight different males in each of three age groups (middle school students, college students, and senior citizens). Several acoustic measurements were made of each sentence, including mean frequency, slope of intonation contour across entire sentence, slope of terminal fall, and amount of inflection (i.e., absolute frequency change summed across the sentence). A second set of sentences was constructed by randomly reordering the words in each sentence. Original sentences and their scrambled counterparts were presented to 19 listeners who rated the age in years of the speaker of each sentence. Analyses of variance revealed that age judgments were less extreme for scrambled sentences as compared to the regular sentences, particularly for the college‐aged and elder voices. These results suggest that the scrambling altered sentence‐level vocal information. Preliminary regression analyses also indicate that perceived age is related to some relatively global acoustic measures, such as amount of inflection.

UVR promotes skin cancer through multiple mechanisms, including induction of inflammation, oxidative stress, and DNA damage such as 8-oxoguanine and cyclobutane pyrimidine dimers. We investigated whether the anti-inflammatory activities of aspirin (acetylsalicylic acid [ASA]) could protect against UVB-induced DNA damage and skin carcinogenesis. ASA reduced UVB-induced 8-oxoguanine and cyclobutane pyrimidine dimers in Melan-A melanocytes and HaCaT keratinocytes. Skin from UVB-irradiated C57BL/6 mice receiving 0.4 mg ASA daily by gavage exhibited less inflammation, fewer sunburn cells, and reduced 8-oxoguanine lesions than skin from irradiated control animals. ASA similarly reduced UVB-induced sunburn cells, 8-oxoguanine, and cyclobutane pyrimidine dimer lesions in skin of melanoma-prone TN61Rmice, and this was associated with decreased prostaglandin E2in plasma and skin. These effects of ASA, however, did not delay melanoma onset in TN61Rmice exposed to a single neonatal dose of UVB. In SKH1-E mice prone to squamous cell carcinoma, ASA reduced plasma and skin prostaglandin E2levels and indices of UVB-induced DNA damage and delayed squamous cell carcinoma onset induced by chronic UVB. These results indicate that ASA can protect against UVB-induced inflammation in skin and reduce UVB-induced DNA damage in both melanocytes and keratinocytes. These effects translated into greater chemopreventive efficacy for UVB-induced squamous cell carcinoma than melanoma mouse models.

L’Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM) a mis en place, depuis le 1erjuillet 2003, un dispositif d’observation prospectif pour recenser tous les cas enregistrés de soumission chimique (SC) avec identification et dosage des substances en cause. À cette occasion, une classification a été mise en place (SC vraisemblable, possible, et « vulnérabilité chimique »). Le CAUVA est une unité de médecine légale du vivant du CHU de Bordeaux dont l’objectif est d’améliorer la prise en charge des victimes d’agression.

No relevant conflicts of interest to declare.

Background:Multiple Myeloma (MM) is associated with T-cell dysfunction. MM-related T-cell deficiencies are reported as both quantitative and qualitative defects with variable functional abnormalities. The clinical significance of these T-cell abnormalities in MM is not fully characterized. Furthermore, the impact of Autologous Stem Cell Transplant (ASCT) on T-cell subsets and immune checkpoint molecules, including PD-L1, PD-1, BLIMP-1, CTLA-4/CD28, TIM-3, and LAG-3, is being explored. Here we examined these features along with other mRNA markers of cellular senescence, immunosenescence, and exhaustion in MM patients pre- and post-ASCT. These studies aimed to improve understanding of the immunologic changes in MM and relationship to disease progression. Evaluating T-cell immune reconstitution post-transplant is invaluable for future therapies to identify targets or stimulate T-cell response to mitigate relapse.

Le 5-APB ou 5-(2-Aminopropyl)benzofuran de la classe des phénéthylamines est un nouveau produit de synthèse (NPS), non classé stupéfiant et obtenu sur Internet sous le nom de « BenzoFury ». Nous rapportons le cas d’un patient de 36ans, pris en charge par le Smur sur appel de 2 amies, comateux, en mydriase bilatérale, tachycarde à 150, hypotendu à 80/60, hyperthermique à 41°C, ayant consommé 2 doses rapprochées de 5-APB. Devant ce toxidrome sérotoninergique, le patient était intubé (induction à séquence rapide). Un ECG était réalisé montrant des signes d’hyperkaliémie. Au cours du transport, le patient présentait une bradycardie, puis une tachycardie ventriculaire. À l’admission à l’hôpital, il présentait une fibrillation ventriculaire conduisant au décès malgré les manœuvres de réanimation. Une autopsie et des analyses toxicologiques étaient requises par le Parquet. Ses 2 amies, dont les urines seront analysées, ont également consommées ces substances achetées sur Internet.

Jaglowski: Immunomedics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Seattle Genetics: Consultancy.

A geriatric assessment (GA) is a global approach to improve healthy aging, wherein occult problems are assessed and intervened upon using a multidisciplinary method. A GA is feasible and can predict chemotherapy-induced toxicity and overall survival in cancer patients. Biomarkers of aging are also being explored as objective and reproducible measures of health and fitness. p16INK4a(p16) is a marker of cellular senescence that rises exponentially with chronologic age and is influenced by factors such as physical activity, smoking, and solid tumor chemotherapy. Here, we investigated the relationship of both the GA and molecular (i.e. p16) metrics in pre-bone marrow transplant (BMT) multiple myeloma (MM) patients. We selected this group for our studies as BMT patients are a vulnerable cohort in which transplant eligibility is subjective and age related. BMT patients are also at high risk for adverse events and treatment toxicity. In this preliminary analysis, we explored the predictive value of GA metrics and p16 with inpatient length of stay (LOS) during autologous BMT.