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In a recent publication in Nature , Fane et al. establish WNT5A as a central, age-sensitive regulator of the dormancy-to-reactivation axis of melanoma. They show that aged fibroblasts in the lungs suppress WNT5A signaling induced at the primary tumor site to awaken dormant melanoma cells and promote the outgrowth of metastases. In a recent publication in Nature , Fane et al. establish WNT5A as a central, age-sensitive regulator of the dormancy-to-reactivation axis of melanoma. They show that aged fibroblasts in the lungs suppress WNT5A signaling induced at the primary tumor site and thus awaken dormant melanoma cells and promote the outgrowth of metastases. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a disease of aging adults and autologous stem cell transplant (ASCT) is considered the standard of care. As the population ages a growing number of older adults will undergo ASCT and an objective approach to estimate physiologic reserve and transplant morbidity risk is warranted. Here, we evaluate assess p16 INK4a (p16), a molecular aging biomarker, along with geriatric metrics to determine risk of transplant toxicity. We prospectively evaluated 100 MM patients for frailty before and after ASCT using a Geriatric Assessment (GA) and collected T-cells for analysis of p16 using a custom nanostring codeset. Pre-transplant physical function was predicative of hospital length of stay (LOS). Each one-unit increase in physical function score, the average LOS decreased by 0.52 days (95% CI, −1.03–0.02); p =.04). Similarly, higher self-report of ADL/IADL (Human Activity Profile was associated with shorter LOS (0.65 less days (95% CI −1.15 to −0.15), p =.01). Patients with anxiety/depression (OR = 1.10 (95% CI 1.00–1.22), p =.056), lower handgrip strength (OR = 0.90 (95% CI 0.82–0.98), p =.02), falls (OR = 1.60 (95% CI 1.07–2.38), p =.02), or weight loss (OR = 5.65 (95% CI 1.17–25.24), p =.03) were more likely to be re-admitted. The estimated EFS at 1-year was 85% (95% CI, 75–91) with median follow-up of 15.7 months. Weight loss was a significant predictor of EFS (HR = 3.13 (95% CI 1.15–8.50), p =.03). Frailty assessment by self-reported fatigue minimally correlated with T-cell p16 expression (r = 0.28; p =.02). Age, Karnofsky Performance Status (KPS), or Hematopoietic cell transplantation-specific Co-Morbidity Index (HCT-CI) did not predict hospital LOS or readmissions. Our data illustrate that a GA can identify individuals with MM who are at greater risk for morbidity following ASCT. [ABSTRACT FROM AUTHOR]

Résumé Introduction La maltraitance des enfants constitue une problématique complexe qui nécessite une approche pluridisciplinaire encore non systématique en France. Le centre d’accueil en urgence des victimes d’agression (CAUVA) du centre hospitalier universitaire (CHU) de Bordeaux a pu rassembler dès création différents acteurs médicaux, paramédicaux et sociaux. Il a ainsi été établi une procédure d’évaluation psychosociale standardisée, qui est systématiquement diligentée en cas de suspicion de maltraitance sur mineurs. Méthode Nous avons étudié les 74 dossiers non judiciarisés de sujets mineurs (45 filles) ayant bénéficié d’une évaluation pour suspicion de violences entre le 1 er juillet 2014 et le 30 juin 2015. Résultats Ils étaient âgés en moyenne de 7 ans, nous avaient été adressés par des partenaires internes ( n = 15) ou externes au CHU ( n = 37), 22 s’étant présentés spontanément et alléguaient principalement (75 %) des faits de violences sexuelles. Trente-cinq ont pu rentrer au domicile, 17 fait l’objet d’un dépôt de plainte, 19 d’un signalement au Procureur de la République et 3 d’une information préoccupante au Conseil départemental. Conclusion En l’absence de consensus national sur la méthodologie d’évaluation des cas de suspicion de violences sur mineur, nous proposons une évaluation psychosociale comportant un regard collégial qui permet non seulement de faciliter le travail des professionnels mais également le dépistage et la judiciarisation des cas de maltraitance. Summary Introduction Maltreatment is a complex issue and therefore, requires a multidisciplinary approach, which has been commonly used in North America since the 1980s but remains unsystematic in France. Since 1999, the Centre d’Accueil en Urgence des Victimes d’Agression (emergency unit for victims of assault) of the Bordeaux University Hospital has brought together various medical, paramedical, and social actors on this issue. A standardized psychosocial assessment procedure has been introduced and is detailed in this paper, and was consistently conducted in all cases of suspicion of abuse on a minor. Method The authors studied 74 cases of minors having undergone a psychosocial assessment following suspicions of maltreatment between 1 July 2014 and 30 June 2015 that were not referred to the courts. Results Forty-five girls and 29 boys, mean age 7 years, claiming mainly (75 %) to have been subjected to sexual violence, were addressed to us by internal partners ( n = 15) and external partners ( n = 37) and 22 who came to our unit by self-referral. Following our assessment, 35 returned to their home and 36 went to court following a police complaint ( n = 17) and a report filed to the public prosecutor of the Republic ( n = 19). Three of these cases were subjected to a report on matters of concern sent to the departmental council. Conclusion Given the absence of a national consensus on the methodology used for assessing suspicions of maltreatment on minors, our psychosocial assessment can facilitate the task with its peer review as well as the detection and judicialization of the maltreatment. The authors also highlight the recent modification of article 226-14 of the Penal Code, which aims at protecting professionals reporting matters to legal authorities from any legal proceeding, except if it is established that the individual did not act in good faith. [ABSTRACT FROM AUTHOR]

Examines the Delta proteolysis and the three proteolytic cleavages in the region of the juxtamembrane and transmembrane domains. Ligand for the Notch family of receptors; Functional role of the intracellular domain of the Notch ligands; Model of bi-directional signaling through Notch-Delta interactions.

RB, p107, and p130 are highly related proteins, each capable of regulating cellular proliferation. However, only RB is frequently mutated in cancer. In this issue of Cancer Cell, Chicas et al. shed new light on this conundrum, defining a “special,” nonredundant role for RB in promoting cellular senescence. [Copyright &y& Elsevier]

The androgen receptor (AR) is a ligand-dependent transcription factor whose activity is required for prostate cancer proliferation. Because ablation of AR activity is a critical goal of prostate cancer therapy, much emphasis has been placed on understanding the accessory proteins that regulate AR function in the prostate. Several co-activators have been shown to be required for full AR activity, including histone acetyltransferases and TRAP/mediator complexes. SWI/SNF comprises a family of large, multisubunit complexes present in the cell, which contain one of two core ATPases required for nucleosome re-positioning, BRG1 or hBRM. We investigated the specific requirement of the SWI/SNF core ATPases for AR function. Using cells deficient in both BRG1 and hBRM, we show that activation of one AR target promoter, prostate-specific antigen (PSA), requires SWI/SNF chromatin remodeling for activity. A second AR target promoter, probasin, maintained a low level of activation in the absence of SWI/SNF. AR stimulation on the probasin core promoter could be partially induced with BRG1, but hBRM strongly stimulated AR activity. The PSA promoter was only induced by the restoration of hBRM. In contrast, ligand-dependent activation of the estrogen receptor was equally stimulated by BRG1 or hBRM. We demonstrate that the addition of a known enhancer region to the core PSA promoter bypasses the requirement for SWI/SNF on the PSA promoter, indicating that elements upstream of specific proximal promoters can impact the influence of the SWI/SNF complex on target gene activation. Addition of the enhancer to the probasin core promoter failed to impact the SWI/SNF requirement. In summary, SWI/SNF function potently regulates core AR target gene promoter activation, with a preference for hBRM-containing complexes. These studies highlight a role for the enhancer in altering the impact of SWI/SNF action and suggest a disparity in AR target genes for SWI/SNF requirement. [ABSTRACT FROM AUTHOR]

There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and ex vivo and in vitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies. [ABSTRACT FROM AUTHOR]

Self-inflicted stab injury to the skull, particularly in the neurocranium, is a rare method used to commit suicide. Herein is presented a case of a 26-year old woman with a temporal wound found by her partner in their home. No weapon was found in the approximate environment and the victim said that she fell. A CT scan performed at admission to the emergency room was interpreted as being compatible with injury from falls. A second CT scan in a neurosurgical unit suggested a cranio-cerebral injury from a sharp object; aggression was suspected. The discording elements led to an interview with a psychiatrist and diagnosis of attempted suicide through the action of a knife in the context of severe depression. This is a rare case that implicates a depressive woman and stabbing directly to the neurocranium. [ABSTRACT FROM AUTHOR]

• Autologous stem cell transplant (ASCT) induces global transcriptional T cell changes and altered molecular levels of markers of T cell subtypes, T cell activation, and exhaustion in patients with multiple myeloma. • High LAG3 transcript expression in T cells detectable as early as 3 months post-transplant is associated with inferior clinical outcomes in patients with myeloma. • ASCT affected soluble levels of molecules with immunomodulatory function by increasing plasma HVEM and TIM3. • ASCT promotes an exhausted immunophenotype in CD4+ cells and a senescent/anergic immunophenotype in CD8+ subsets. • Future work targeting immune defects in multiple myeloma is warranted to augment or restore T cell responses using the next generation of immune checkpoint inhibitors. Autologous stem cell transplant (ASCT) is the standard of care for patients with multiple myeloma (MM). The clinical significance of peripheral blood T lymphocyte (PBTL) immunologic changes associated with ASCT is poorly understood. Here we evaluated T cell transcriptional messenger RNA profiles and immunophenotypes to correlate immunologic senescence, exhaustion, and anergy with clinical endpoints in a cohort of patients with MM undergoing ASCT. ASCT induced global transcriptional T cell changes and altered molecular levels of markers of T cell subtypes, T cell activation, and exhaustion. These included reduced CD4/CD8 ratio, skewing toward the Th1 subset, reduced expression of costimulatory receptors CD27 and CD28, heightened T cell activation, and increased expression of immune modulatory molecules LAG3 and PD1. Multicolor flow cytometry experiments confirmed altered circulating CD4 and CD8 subsets and skewing toward differentiated effector cells. Moreover, ASCT promoted an exhausted immunophenotype in CD3+CD4+ subsets and a senescent immunophenotype in CD3+CD8+ subsets. Subset-specific altered expression was also seen for surface molecules with immunomodulatory function. ASCT affected soluble levels of molecules with immunomodulatory function by increasing plasma HVEM and TIM3. High molecular LAG3 level was associated with inferior event-free survival post-ASCT (hazard ratio = 5.44; confidence interval, 1.92 to 15.46; P =.001; adjusted P [controlling for false discovery rate] =.038). Using a comprehensive evaluation of PBTLs on a molecular and phenotypic level, we have identified that ASCT induces global T cell alterations with CD4 and CD8 subset-specific changes. Moreover, LAG3 emerged as an early biomarker of adverse events post-ASCT. These findings will support the development of treatment strategies targeting immune defects in MM to augment or restore T cell responses. [ABSTRACT FROM AUTHOR]

Résumé Introduction Si la violence au sein des établissements scolaires est bien relayée sur le plan médiatique, les données françaises dans la littérature restent parcellaires et les chiffres dont nous disposons sont issus principalement d’enquêtes de victimation. L’objectif de ce travail était double : contribuer à enrichir les données épidémiologiques nationales sur ce phénomène et mener une réflexion sur les actions susceptibles d’être menées par les praticiens susceptibles d’y être confronté. Matériel et méthodes Il s’agit d’une étude prospective descriptive monocentrique réalisée au centre d’accueil d’urgence des victimes d’agression (CAUVA) du Centre hospitalier universitaire (CHU) de Bordeaux du 1 er septembre 2014 au 30 juin 2015. Ont été incluses dans cette étude toutes personnes alléguant des faits de violence sur le trajet, en périphérie ou au sein d’un établissement d’enseignement et examinée au CAUVA dans le cadre d’une réquisition judiciaire. Résultats Quarante et un sujets ont été inclus sur dix mois, 29 garçons (70,7 %) et 12 filles (29,3 %) âgés en moyenne de 14 ans et 5 mois [7–49 ans]. Parmi eux ne figuraient qu’une très faible proportion de professionnels de l’enseignement ( n = 2), les victimes étant essentiellement des élèves ( n = 39). Le délai entre les faits et l’examen médico-légal au CAUVA avait été inférieur ou égal à 7 jours ( n = 18), entre 7 et 15 jours ( n = 14), entre 15 et 30 jours ( n = 6) ou > 30 jours ( n = 3). Vingt-six agressions (63 %) avaient eu lieu dans l’établissement dont 21 dans des collèges, 8 à proximité et 7 sur le trajet entre le domicile et l’établissement. Dans l’établissement les faits avaient eu lieu lors d’une pause ( n = 15), en classe ( n = 9) ou lors de sorties culturelles ( n = 2). Pour 25 élèves, il s’agissait du premier épisode avec récit d’actes de violences physiques ( n = 37), psychologiques ( n = 20) et sexuelles ( n = 2). Dans 6 cas l’agresseur avait été un enseignant et dans 34 cas un autre élève, de la même classe ( n = 19), d’une autre classe ( n = 14), ou ancien élève ( n = 1). Vingt-neuf des 41 patients avaient eu recours à un médecin généraliste (MG). La répartition du temps d’incapacité totale de travail (ITT) attribué par le MG ou par le CAUVA était respectivement de 14 et 13 pour 0 jour, 12 et 23 entre 1 et 8 jours ( p < 0,05) et 3 et 5 pour 8 jours ou plus. Conclusion Cette étude a permis de dresser des tendances sur lesquelles le praticien peut s’aider lors de consultations de violences. Le dépistage, la description du retentissement physique et psychologique et l’orientation vers une unité médico-judiciaire (UMJ) pour les situations complexes ou les agressions sexuelles font du médecin généraliste, de l’urgentiste ou du pédiatre des acteurs essentiels dans la prise en charge. Summary Introduction Although violence in schools is quite well conveyed in the media, the French literature data remain patchy, and the figures available arise mainly from surveys of victimization. This study had two main purposes: to add to the national epidemiological data on this phenomenon and to emphasize the actions that can be undertaken by the practitioner facing such events. Material and methods This was a prospective descriptive study that was conducted from September 1st, 2014, to June 30, 2015, in a single center, the CAUVA, an emergency center within the Bordeaux University Hospital for victims of assault. Included in the study was any person alleging acts of violence on the way to school, in the neighborhood, or within the school itself, and who was examined at the CAUVA following a judicial requisition. An anonymized questionnaire was distributed during the consultation. Results We collected 41 questionnaires over a 10-month period with 70.7% males ( n = 29) and 29.3% females ( n = 12), with a mean age of 14 years and 5 months (range, 7–49 years). The subjects included two teachers and 39 students. The time between the event and the forensic examination at CAUVA was mostly less than or equal to 7 days ( n = 18), between 7 and 15 days ( n = 14), 15 and 30 days ( n = 6), and more than 30 days ( n = 3). Twenty-six attacks (63%) took place inside the school – 21 middle schools – eight near the school, and seven between the student's home and the school. Inside the school, the events took place during a break ( n = 15), in the classroom ( n = 9), and during cultural outings ( n = 2). For one student out of two ( n = 25), the event reported was the first with acts of physical ( n = 37), psychological ( n = 20), or sexual violence ( n = 2). In 14.6% ( n = 6) of the cases, the assailant was a teacher and in almost 83% ( n = 34) of the cases it was another student, either from the same class ( n = 19) or another class ( n = 14), or a former student ( n = 1). Conclusion This study brings out trends that can assist the practitioner during consultations related to violence. Screening, the description of the physical and psychological impact, and dispatching to a medical-legal unit for complex situations or sexual assaults contribute to making the general practitioner, the emergency physician, the pediatrician, and the school doctor key players in the treatment and management of violence. [ABSTRACT FROM AUTHOR]