La naissance prématurée peut être la cause de modifications neurophysiologiques. En effet, être soumis, de manière répétée, à des situations particulièrement difficiles très tôt au cours du ...développement influe sur la manière dont l’individu répondra ultérieurement à des événements stressants mêmes modérés. L’axe hypothalamo-hypophysaire-surrénalien (HPA) est un système complexe, impliqué dans la régulation des réponses neuroendocriniennes au stress. Son activation déclenche notamment la production de « l’hormone de stress » – le cortisol. Cependant, la régulation de la réponse physiologique au stress est soumise à des facteurs psychologiques liés aux représentations que l’individu développe à l’égard de ses relations privilégiées – l’attachement. Les représentations d’attachement semblent à leur tour être associées à une hormone impliquée à la fois dans la réduction de la réponse de stress et dans l’engagement de comportements sociaux positifs – l’ocytocine. L’objectif de cette étude est d’examiner, chez des adultes nés grands prématurés, la concentration plasmatique de l’OT au cours d’une situation expérimentale de stress psychosocial, le Trial Social Stress Test (TSST), en lien avec les patterns d’attachement.
Methods
Soixante sujets âgés de 20 à 25 ans ont été soumis au TSST. Le plasma a été recueilli à plusieurs reprises afin de mesurer les réponses neuroendocriniennes (OT périphérique, ACTH et cortisol).
Résultats
Les résultats préliminaires semblent indiquer que le taux d’OT ne diffère pas en fonction des groupes (prématurés vs témoins) mais en lien avec les patterns d’attachement. Ces résultats doivent être confirmés par des analyses ultérieures.
Discussion et conclusions
L’analyse de la sécrétion d’OT en situation de stress suggère l’existence de régulations sous-jacentes liées à des mécanismes psychologiques « de protection ». Étudier les réponses spécifiques de l’OT au cours d’une situation socialement stressante souligne l’effet paradoxal de cette hormone impliquée, à la fois, dans les réponses de stress et dans l’engagement de comportement pro-sociaux.
HMGB1, a non‐histone nuclear factor, acts extracellularly as a mediator of delayed endotoxin lethality, which raises the question of how a nuclear protein can reach the extracellular space. We show ...that activation of monocytes results in the redistribution of HMGB1 from the nucleus to cytoplasmic organelles, which display ultrastructural features of endolysosomes. HMGB1 secretion is induced by stimuli triggering lysosome exocytosis. The early mediator of inflammation interleukin (IL)‐1β is also secreted by monocytes through a non‐classical pathway involving exocytosis of secretory lysosomes. However, in keeping with their respective role of early and late inflammatory factors, IL‐1β and HMGB1 respond at different times to different stimuli: IL‐1β secretion is induced earlier by ATP, autocrinally released by monocytes soon after activation; HMGB1 secretion is triggered by lysophosphatidylcholine, generated later in the inflammation site. Thus, in monocytes, non‐classical secretion can occur through vescicle compartments that are at least partially distinct.
Blocking the activity of IL-1β has entered the clinical arena of treating autoimmune diseases. However, a successful outcome of this approach requires a clear definition of the mechanisms controlling ...IL-1β release. These are still unclear as IL-1β, lacking a secretory signal peptide, follows a nonclassical pathway of secretion. Here, we analyze the molecular mechanism(s) undergoing IL-1β processing and release in human monocytes and provide a unifying model for the regulated secretion of the cytokine. Our data show that in a first step, pro-caspase-1 and endotoxin-induced pro-IL-1β are targeted in part to specialized secretory lysosomes, where they colocalize with other lysosomal proteins. Externalization of mature IL-1β and caspase-1 together with lysosomal proteins is then facilitated by extracellular ATP. ATP triggers the efflux of K + from the cell, followed by Ca 2+ influx and activation of three phospholipases: phosphatidylcholine-specific phospholipase C and calcium-independent and -dependent phospholipase A 2 . Whereas calcium-independent phospholipase A 2 is involved in processing, phosphatidylcholine-specific phospholipase C and calcium-dependent phospholipase A 2 are required for secretion. Dissection of the events that follow ATP triggering allowed to demonstrate that K + efflux is responsible for phosphatidylcholine-specific phospholipase C induction, which in turn allows the rise in intracellular free calcium concentration required for activation of phospholipase A 2 . This activation is ultimately responsible for lysosome exocytosis and IL-1β secretion.
Background: There is limited knowledge about prognosis of selected breast cancer subtypes among very young women.
Patients and methods: We explored patterns of recurrence by age according to four ...immunohistochemically defined tumor subtypes: Luminal A and Luminal B (estrogen receptor positive and/or progesterone receptor positive and either human epidermal growth factor receptor 2 (HER2) positive and/or high Ki-67), HER2-positive (and) endocrine receptor absent and Triple Negative, in 2970 premenopausal patients with pT1-3, pN0-3 and M0 breast cancer.
Results: Patients <35 years of age (315, 11%) presented a significantly increased risk of recurrence and death hazards ratio (HR) = 1.65, 95% confidence interval (CI) 1.30–2.10 and HR = 1.78, 95% CI 1.12–2.85, respectively when compared with older patients (2655, 89%) with similar characteristics of disease. This was true considering patients with Luminal B HR = 1.62, 95% CI 1.21–2.18 for disease-free survival (DFS) and HR = 2.09, 95% CI 0.96–4.53 for overall survival (OS) and with Triple Negative (HR = 2.04, 95% CI 1.11–3.72 for DFS and HR = 2.20, 95% CI 1.10–4.41 for OS) breast cancer, observing the highest risk of recurrence in the younger patients with HER2-positive breast cancer (HR = 2.37, 95% CI 1.12–5.02) when compared with older patients.
Conclusions: Very young patients with Triple Negative, Luminal B or HER2-positive breast cancer have a worse prognosis when compared with older patients with similar characteristics of disease.
Summary
Background Cutaneous pigmentation is regulated by a complex melanogenic network in which both keratinocytes and fibroblasts synthesize growth factors and cytokines. Solar lentigo (SL) is ...characterized by hyperpigmented lesions occurring on photodamaged skin areas. Despite the association of SL to ultraviolet (UV) exposure, the mechanisms underlying the development of these spots are not completely defined.
Objectives To analyse the involvement of the fibroblast‐derived growth factors, hepatocyte growth factor (HGF), keratinocyte growth factor (KGF) and stem cell factor (SCF) in SL hyperpigmentation; to evaluate whether the photoageing process occurring in fibroblasts could be responsible for the altered expression of these cytokines; and to investigate a new possible role of KGF in regulating pigmentation through the specific induction of melanogenic cytokines by keratinocytes.
Methods We performed immunohistochemical analysis of HGF, KGF and SCF on SL biopsies. We analysed the mRNA expression of these cytokines using an in vitro model of photoageing induced on fibroblasts. Finally, we evaluated the effects of KGF on the expression of melanogenic cytokines at the mRNA and protein levels on keratinocytes.
Results We found positive staining for HGF, KGF and SCF in the upper dermis of SL lesions and a significant induction of the three cytokines in photoaged fibroblasts. We also demonstrated the contribution of KGF to pigmentation, showing its ability specifically to modulate the expression of SCF in keratinocytes.
Conclusions Fibroblasts may be persistently activated by UV exposure to release melanogenic growth factors; this inducible cytokine network acts both directly and indirectly through keratinocytes and may contribute to the hyperpigmentation of SL.
Abstract Long-term implications of the exposure to traumatizing experiences during childhood or adolescence, such as sexual abuse, or cancer, have been documented, namely the subjects' response to an ...acute stress in adulthood. Several indicators of the stress response have been considered (e.g. cortisol, heart rate). Oxytocin (OT) response to an acute stress of individuals exposed to trauma has not been documented. Eighty subjects ( n =26 women who had experienced episodes of child abuse, n =25 men and women healthy survivors of cancer in childhood or adolescence, and 29 controls) have been submitted to a laboratory session involving an experimental stress challenge, the Trier social stress test. Overall, there was a clear OT response to the psychosocial challenge. Subjects having experienced a childhood/adolescence life-threatening illness had higher mean levels of OT than both abused and control subjects. There was a moderate negative relationship between OT and salivary cortisol. It is suggested that an acute stress stimulates OT secretion, and that the exposure to enduring life-threatening experiences in childhood/adolescence has long-lasting consequences regarding the stress system and connected functions, namely the activation of OT secretion. Better knowledge of such long-term implications is important so that to prevent dysregulations of the stress responses, which have been shown to be associated to the individual's mental health.
Purpose
Trabecular bone score (TBS) is a gray-level textural metric that has shown to correlate with risk of fractures in several forms of osteoporosis. The value of TBS in predicting fractures and ...the effects of bone-active drugs on TBS in aromatase inhibitors (AIs)-induced osteoporosis are still largely unknown. The primary objective of this retrospective study was to assess the effects of denosumab and bisphosphonates (BPs) on TBS and vertebral fractures (VFs) in women exposed to AIs.
Methods
241 consecutive women (median age 58 years) with early breast cancer undergoing treatment with AIs were evaluated for TBS, bone mineral density (BMD) and morphometric VFs at baseline and after 18–24 months of follow-up. During the study period, 139 women (57.7%) received denosumab 60 mg every 6 months, 53 (22.0%) BPs, whereas 49 women (20.3%) were not treated with bone-active drugs.
Results
Denosumab significantly increased TBS values (from 1.270 to 1.323;
P
< 0.001) accompanied by a significant decrease in risk of VFs (odds ratio 0.282;
P
= 0.021). During treatment with BPs, TBS did not significantly change (
P
= 0.849) and incidence of VFs was not significantly different from women untreated with bone-active drugs (
P
= 0.427). In the whole population, women with incident VFs showed higher decrease in TBS vs. non-fractured women (
P
= 0.003), without significant differences in changes of BMD at any skeletal site.
Conclusions
TBS variation predicts fracture risk in AIs treated women. Denosumab is effective to induce early increase of TBS and reduction in risk of VFs.
To identify the role of estrogen (ER), progesterone (PgR), epidermal growth factor 1 (HER1), and HER2 receptors in predicting response to preoperative chemotherapy.
We reviewed the pretreatment ...biopsies of 485 patients with locally advanced breast cancer (cT2-T4, N0-2, M0) treated with preoperative chemotherapy. The incidence of pathological complete remission (pCR) and outcome were assessed with respect to clinical and pathological findings including ER/PgR status (absent versus expressed), HER1 (absent versus expressed) and HER2 (overexpressed versus none) expression.
Patients with ER/PgR-absent tumors were 12.0 times 95% confidence interval (CI) 4.93–29.28 more likely to achieve a pCR (P<0.0001). Predictors of disease-free survival (DFS) at the univariate analysis included HER1 hazards ratio (HR) 1.6, 95% CI 1.04–2.32, P=0.03 and HER2 (HR 1.6, 95% CI 1.08–2.38, P=0.02) expression. A statistically significant difference in DFS was confirmed at the multivariate analysis for patients with ER/PgR-absent disease (HR 2.1, 95% CI 1.41–2.99, P=0.0002).
The pCR rate is higher and outcome worse for patients with ER/PgR-absent tumors. HER1 and HER2 expression may have a prognostic role in locally advanced breast cancer and warrant further studies.
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