Differential expression of the protein kinase A subunits in normal adrenal glands and adrenocortical adenomas

Somatic mutations in protein kinase A catalytic a subunit (PRKACA) were found to be causative for 30-40% of cortisol-producing adenomas (CPA) of the adrenal gland, rendering PKA signalling constitutively active. In its resting state, PKA is a stable and inactive heterotetramer, consisting of two catalytic and two regulatory subunits with the latter inhibiting PKA activity. The human genome encodes three different PKA catalytic subunits and four different regulatory subunits that are preferentially expressed in different organs. In normal adrenal glands all regulatory subunits are expressed, while CPA exhibit reduced protein levels of the regulatory subunit II beta. In this study, we linked for the first time the loss of RII beta protein levels to the PRKACA mutation status and found the down-regulation of RII beta to arise post-transcriptionally. We further found the PKA subunit expression pattern of different tumours is also present in the zones of the normal adrenal cortex and demonstrate that the different PKA subunits have a differential expression pattern in each zone of the normal adrenal gland, indicating potential specific roles of these subunits in the regulation of different hormones secretion

Correction to: Risk of biochemical recurrence based on extent and location of positive surgical margins after robot-assisted laparoscopic radical prostatectomy

Following publication of the original article [1], we have been notified that the authors’ last names have been incorrectly tagged as first names and vice-versa. The original publication has been corrected

Risk of biochemical recurrence based on extent and location of positive surgical margins after robot-assisted laparoscopic radical prostatectomy

Abstract Background There are no published studies on the simultaneous effect of extent and location of positive surgical margins (PSMs) on biochemical recurrence (BCR) after robot-assisted laparoscopic prostatectomy (RALP). The aim was to report the incidence, extent, and location of PSMs over the inclusion period as well as the rates of BCR and cancer-related mortality, and determine if BCR is associated with PSM extent and/or location. Methods Retrospective review of 530 consecutive patients who underwent RALP between 2003 and 2012. Kaplan-Meier (KM) survival analyses and Cox regressions were performed to determine variables associated with BCR. Results For the 530 operated patients, evaluated at a median of 92 months (IQR, 87–99), PSMs were observed in 156 (29%), of which 24% were focal. Out of 172 PSMs, 126 (73%) were focal and 46 (27%) were extensive. The KM survival using BCR as endpoint was 0.81 (CI, 0.78–0.85) at 5 years and was 0.67 (CI, 0.61–0.72) at 10 years; and using cancer-related mortality as endpoint was 0.99 (CI, 0.99–1.00) at 5 years and 0.95 (CI, 0.92–0.98) at 10 years. Multi-variable analysis revealed the strongest predictors of BCR to be Gleason score ≥ 8 (HR = 7.97; CI, 4.38–14.51) and 4 + 3 (HR = 3.88; CI, 2.12–7.07), lymph nodes invasion (HR = 3.42; CI, 1.70–6.91), pT stage 3b or 4 (HR = 3.07; CI, 1.93–4.90), and extensive apical PSMs (HR = 2.62; CI, 1.40–4.90) but not focal apical PSMs (HR = 0.86; CI, 0.49–1.50; p = 0.586). Conclusion Extensive apical PSMs significantly increased the risk of BCR, independently from pT stage, Gleason score and lymph nodes invasion, while focal apical PSMs had no significant effect on BCR

Differential expression of parathyroid hormone-related protein in adrenocortical tumors: autocrine/paracrine effects on the growth and signaling pathways in H295R cells.

International audienceAdrenocortical tumors (ACT) are rare and heterogeneous, but their pathogenesis is unclear. The oncoprotein parathyroid hormone-related protein (PTHrP), found in many common tumors, can regulate their growth in an autocrine/paracrine fashion through the PTH-R1 receptor. Little is known about the role of PTHrP in ACT. We monitored the synthesis of PTHrP and PTH-R1 in a series of 25 ACT: 12 adrenocortical carcinomas (ACC) and 13 adrenocortical adenomas (ACA), and investigated the effects of PTHrP(1-34) on H295R cells derived from an ACC. PTH-R1 mRNA and proteins were detected by real-time PCR and Western blotting in all the ACT samples and in H295R cells. Their concentrations did not differ significantly from one ACT to another. PTHrP mRNA was assayed by quantitative real-time PCR. It was detected in 90% of ACC, and in 10% of ACA. There was a positive correlation with the prognostic factors, McFarlane stage and Weiss score. Tissue-specific PTHrP protein processing was shown by Western blotting. Immunohistochemical staining revealed numerous, dense foci of PTHrP-containing cells in ACC, but few positive cells in ACA or normal tissue. PTHrP stimulated the growth of H295R cells, whereas a specific anti-PTHrP antibody and a PTHrP-R1 antagonist both enhanced their apoptosis. PTHrP activated both adenylate cyclase/protein kinase A and the intracellular calcium/protein kinase C pathways via PTHrP-R1. The active synthesis of PTHrP is linked to poor prognosis in ACC, in which it may act as an autocrine/paracrine factor in tumor growth and malignancy

Impacts of Confinement on Mental Health and Health Behaviours of Individuals with Multimorbidity during Covid-19 Pandemic

Background: Confinement and its possible impact on lifestyle make people with multimorbidity more vulnerable to modifications of their mental health and health behaviours that could persist beyond confinement. Objective: To understand the mental health status and health behaviour modifications among individuals with multimorbidity during and post COVID-19 confinement. Methods: Longitudinal multinational cohort study consisting of two online questionnaires with its first wave taken place during the first COVID-19 confinement (May 2020) and its second wave post-deconfinement (November 2020). Including 559 (wave 1) and 144 (wave 2) participants with an average age of 34.30±12.35 and 36.21±13.07 years old. Mostly females living in Canada, France, India and Lebanon. Results: The prevalence of multimorbidity was 27.68%. During confinement, people with multimorbidity were 2 to 3 times more likely to experience psychological distress, depressive symptoms, increased stress or isolation, and the prevalence of stress and psychological distress increased post-deconfinement. Health behaviours were also modified during confinement with people with multimorbidity being more likely to reduce their physical activity and increased their fruit and vegetable consumption. Post-deconfinement, people with multimorbidity had increased sleep problems. Also, regardless of multimorbidity status, sexual desire continuously decreased post-deconfinement. Conclusion: Mental health and health behaviours modifications occurred during the COVID-19 confinement period and people with multimorbidity were more severely impacted on these two outcomes than those without multimorbidity, indicating a need for a more adapted approach of care to future confinement periods or pandemic for this population