Characterisation of tumor microvessel density during progression of high-grade serous ovarian cancer: clinico-pathological impact. An OCTIPS Consortium study.

Background: High-grade serous ovarian cancer (HGSOC) intratumoural vasculature evolution remains unknown. The study investigated changes in tumour microvessel density (MVD) in a large cohort of paired primary and recurrent HGSOC tissue samples and its impact on patients’ clinico-pathological outcome. Methods: A total of 222 primary (pOC) and recurrent (rOC) intra-patient paired HGSOC were assessed for immunohistochemical expression of angiogenesis-associated biomarkers (CD31, to evaluate MVD, and VEGF-A). Expression profiles were compared between pOCs and rOCs and correlated with patients' data. Results: High intratumoural MVD and VEGF-A expression were observed in 75.7% (84/111) and 20.7% (23/111) pOCs, respectively. MVDhighand VEGF(+)samples were detected in 51.4% (57/111) and 20.7% (23/111) rOCs, respectively. MVDhigh/VEGF(+)co-expression was found in 19.8% (22/111) and 8.1% (9/111) of pOCs and rOCs, respectively (p = 0.02). Pairwise analysis showed no significant change in MVD (p = 0.935) and VEGF-A (p = 0.121) levels from pOCs to rOCs. MVDhighpOCs were associated with higher CD3(+)(p = 0.029) and CD8(+)(p = 0.013) intratumoural effector TILs, while VEGF(+)samples were most frequently encountered among BRCA-mutated tumours (p = 0.019). Multivariate analysis showed VEGF and MVD were not independent prognostic factors for OS. Conclusions: HGSOC intratumoural vasculature did not undergo significant changes during disease progression. High concentration of CD31(+)vessels seems to promote recruitment of effector TILs. The study also provides preliminary evidence of the correlation between VEGF-positivity and BRCA status

Sox17 modulates Wnt3A/β-catenin-mediated transcriptional activation of the Lef-1 promoter

Wnt/β-catenin-dependent activation of lymphoid enhancer factor 1 (Lef-1) plays an important role in numerous developmental processes. In this context, transcription of the Lef-1 gene is increased by Wnt-mediated TCF4/β-catenin activation on the Lef-1 promoter through mechanisms that remain poorly defined. In mouse airway submucosal gland progenitor cells, Wnt3A transiently induces Lef-1 gene expression, and this process is required for epithelial cell proliferation and glandular morphogenesis. In the present study, we sought to identify additional candidate transcriptional regulators of the Lef-1 gene during glandular morphogenesis. To this end, we found that Sox17 expression is dramatically downregulated in early glandular progenitor cells that induce Lef-1 expression. Wnt stimulation of undifferentiated primary airway epithelial cells induced similar changes in Sox17 and Lef-1 expression. Reporter assays revealed that ectopic expression of Sox17 suppresses Wnt3A/β-catenin activation of the Lef-1 promoter in cell lines. EMSA and ChIP analyses defined several Sox17- and TCF4-binding sites that collaborate in transcriptional control of the Lef-1 promoter. More specifically, Sox17 bound to four sites in the Lef-1 promoter, either directly or indirectly through TCF complexes. The DNA- or β-catenin-binding domains of Sox17 controlled context-specific binding of Sox17/TCF complexes on the Lef-1 promoter. Combinatorial site-directed mutagenesis of Sox17- or TCF-binding sites in the Lef-1 promoter demonstrated that these sites control Wnt/β-catenin-mediated induction and/or repression. These findings demonstrate for the first time that Sox17 can directly regulate Wnt/β-catenin-dependent transcription of the Lef-1 promoter and reveal new context-dependent binding sites in the Lef-1 promoter that facilitate protein-protein interactions between Sox17 and TCF4

Adult attention deficit hyperactivity disorder (ADHD) in ASD

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by core symptoms of inattention, impulsivity, and hyperactivity. ADHD has been considered for a long time as a childhood condition, fading as children grew up. Instead, ADHD changes its clinical presentation over the lifespan, but persists in most cases in adulthood with its associated impairment. It is only since 2013, with the release of DSM-5, that it is possible to diagnose ADHD in the presence of ASD. This change was based on studies performed in children, adolescents, and adults that found high comorbidity rates between ASD and ADHD. Studies investigating the co-occurrence of such disorders at a genetic, at structural and functional neuroimaging levels indicate that they share common genetic risk factors, involve similar biological mechanisms, and affect the same brain regions. The co-existence of both disorders causes a significant burden. Individuals with ASD presenting ADHD symptomatology exhibit a more severe phenotype, with more autistic traits, greater impairment in adaptive behavior, and increased risk for developing additional psychiatric conditions. Pharmacotherapeutic treatments for ADHD, such as methylphenidate and atomoxetine, have been studied in individuals with ADHD+ASD, demonstrating efficacy in decreasing the severity of ADHD symptoms, although with lower effect sizes than in people with only ADHD. The diagnosis of ADHD is established clinically and requires the use of rating scales as well as clinical interviews for avoiding the risk of misdiagnosis. The stigma surrounding individuals with ADHD is huge, therefore it is necessary to increase awareness about this disorder among both the public and healthcare professionals, in order to reduce the barriers that patients face to get access to proper diagnosis and treatment