Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen deprivation remain poorly described, despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild-type (WT) mouse prostates a rare population of luminal progenitor cells that we called LSC according to their FACS profile (Lin /Sca-1 /CD49f ). Here, we investigated the prevalence and castration resistance of LSC in various mouse models of prostate tumourigenesis (Pb-PRL, Pten , and Hi-Myc mice). LSC prevalence is low (∼8%, similar to WT) in Hi-Myc mice, where prostatic androgen receptor signalling is unaltered, but is significantly higher in the two other models, where androgen receptor signalling is decreased, rising up to more than 80% in Pten prostates. LSC tolerate androgen deprivation and persist or are enriched 2-3 weeks after castration. The tumour-initiating properties of LSC from Pten mice were demonstrated by regeneration of tumours in vivo. Transcriptomic analysis revealed that LSC represent a unique cell entity as their gene expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signalling is markedly decreased, explaining why LSC tolerate androgen deprivation. This also illuminates why Pten tumours are castration-resistant since LSC represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSC on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSC in various mouse prostate specimens. In castrated Pten prostates, there was significant proliferation of CK4 cells, further demonstrating their key role in castration-resistant prostate cancer progression. Taken together, this study identifies LSC as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
A significant comorbidity between attention-deficit/hyperactivity disorder (ADHD) and affective disorders has been consistently reported in adults. Less data regarding the role of personality traits and the influence of ADHD co-occurrence on clinical characteristics and outcome of mood disorders are currently available. One hundred and six remitted major depressed, 102 euthymic bipolar subjects, and 120 healthy controls, homogeneous with respect to demographic characteristics, were included in the study. ADHD diagnosis was based on DSM-IV-TR criteria. Childhood and adult ADHD features were measured with the Wender Utah Rating Scale, the Adult ADHD Self-rating Scale, and the Brown Attention-Deficit Disorder Scale. The Revised NEO Personality Inventory was also administered to the clinical groups, in order to investigate personality dimensions. The occurrence of adult ADHD in subjects with bipolar disorders (BD) or major depressive disorder (MDD) was 15.7 and 7.5 %, respectively, compared to 3.3 % in healthy controls (HC). Significant associations (p < .001) between personality traits (neuroticism, conscientiousness, and extraversion) and ADHD features were observed. Logistic regression analysis of all clinical subjects (n = 208) showed that those with lower levels of neuroticism (OR = 1.031; p = .025) had a lower frequency of ADHD comorbidity. The present study emphasizes the close relationship between affective disorders, especially BD, and ADHD in adults. Our findings support the need to assess subjects with mood disorders in the clinical setting for possible coexisting ADHD and to further investigate personality traits to better understand the etiology of affective disorders and ADHD co-occurrence.
Purpose The purpose of this paper is to provide quantitative estimates on the impact of active labour market policy (ALMP) on youth unemployment in Europe based on a macroeconomic panel data set of youth unemployment, ALMP and education policy variables and further country-specific characteristics on labour market institutions and the broader demographic and macroeconomic environment for all EU-Member States. Design/methodology/approach The authors follow the design of an aggregate impact analysis, which aims to explain the impact of policy on macroeconomic variables like youth employment and unemployment (see Bellmann and Jackman, 1996). This follows the assumption that programmes, which are effective in terms of improving individual employment opportunities, are going to make a difference on the equilibrium of youth unemployment. Findings The findings show that both wage subsidies and job creation are reducing aggregate youth unemployment, which is in contrast to some of the surveys of microeconomic studies indicating that job creation schemes are not effective. This finding points towards the importance to assist young people making valuable work experience, which is a benefit from job creation, even if this experience is made outside regular employment and/or the commercial sector. Research limitations/implications In terms of the variables to model public policy intervention in the youth labour market, only few indicators exist, which are consistently available for all EU-Member States, despite much more interest and research aiming to provide an exhaustive picture of the youth labour market in Europe. The only consistently available measures are spending on ALMP as a percentage of gross domestic product (in the different programmes) and participation stocks and entries by type of intervention. Practical implications The different effects found for the 15–19 year olds, who seem to benefit from wage subsidies, compared to the effect of job creations benefitting the 20–24 year olds, might relate to the different barriers for both groups to find employment. Job creation programmes seem to offer this group an alternative mechanism to gain valuable work experience outside the commercial sector, which could help form a narrative of positive labour market experience. In this way, job creation should be looked more positively at when further developing ALMP provision, especially for young people relatively more distant to engagement in regular employment. Social implications Improving the situation of many millions of young Europeans failing to find gainful employment, and more generally suffering from deprivation and social exclusion, has been identified as a clear priority for policy both at the national level of EU-Member States and for EU-wide initiatives. With this study, the authors attempt to contribute to the debate about the effectiveness of policies which combat youth unemployment by estimating the quantitative relationship of ALMP and other institutional features and youth unemployment. Originality/value To research the relationship between youth unemployment and ALMP, the authors created a macroeconomic database with repeated observations for all EU-Member States for a time series (1998–2012). The authors include variables on country demographics and the state of the economy as well as variables describing the labour market regimes from Eurostat, i.e. the flexibility of the labour market (part-time work and fixed-term employment as a percentage of total employment) and the wage setting system (level and coordination of bargaining and government intervention in wage bargaining).
The high severity of the included patients and the significant attrition rate should limit our conclusions for a subgroup of patients. New approaches are needed to facilitate changes in the way patients assess their ideal body image.
In our study the comorbidity between ADHD and ED appeared to be frequent, particularly among patients with AN-BP. ED inpatients with higher level of anxiety and more abnormal eating attitudes and bulimic symptoms should be assessed for potentially associated ADHD.
We assessed whether re-nutrition and weight gain have an influence on comorbid depression and anxiety in patients hospitalised for chronic eating disorders (ED). Seventy-five inpatients agreed to participate by completing the Eating Attitudes Test (EAT-40), the Beck Depression Inventory (BDI-13), and the State-Trait Anxiety Inventory (STAI-Y) before, during and after three months of treatment. Patients suffering from either anorexia nervosa or bulimia nervosa successfully regained weight during treatment. This weight gain was accompanied by statistically significant reductions in ED symptoms. Anxiety and, to a lesser extent, depressive symptoms diminished, but remained at pathological levels, with between diagnostic subtype differences. Improvement of depressive (r=0.77) and anxiety (r=0.64) levels were significantly (p<0.001) and positively correlated with the reduction of eating attitudes (EAT). These results are discussed in the context of re-orienting the therapeutic strategies aimed at reducing emotional suffering in patients with ED.
The transport system b(0,+) mediates reabsorption of dibasic amino acids and cystine in the kidney. It is made up of two disulfide-linked membrane subunits: the carrier, b(0,+)AT and the helper, rBAT (related to b(0,+) amino acid transporter). rBAT mutations that impair biogenesis of the transporter cause type I cystinuria. It has been shown that upon assembly, b(0,+)AT prevents degradation and promotes folding of rBAT; then, rBAT traffics b(0,+)AT from the endoplasmic reticulum (ER) to the plasma membrane. The role of the N-glycans of rBAT and of its C-terminal loop, which has no homology to any other sequence, in biogenesis of system b(0,+) is unknown. In the present study, we studied these points. We first identified the five N-glycans of rBAT. Elimination of the N-glycan Asn(575), but not of the others, delayed transporter maturation, as measured by pulse chase experiments and endoglycosidase H assays. Moreover, a transporter with only the N-glycan Asn(575) displayed similar maturation compared with wild-type, suggesting that this N-glycan was necessary and sufficient to achieve the maximum rate of transporter maturation. Deletion of the rBAT C-terminal disulfide loop (residues 673-685) prevented maturation and prompted degradation of the transporter. Alanine-scanning mutagenesis uncovered loop residues important for stability and/or maturation of system b(0,+). Further, double-mutant cycle analysis showed partial additivity of the effects of the Asn(679) loop residue and the N-glycan Asn(575) on transporter maturation, indicating that they may interact during system b(0,+) biogenesis. These data highlight the important role of the N-glycan Asn(575) and the C-terminal disulfide loop of rBAT in biogenesis of the rBAT-b(0,+)AT heterodimer.
The canonical prolactin (PRL) Signal Transducer and Activator of Transcription (STAT) 5 pathway has been suggested to contribute to human prostate tumorigenesis via an autocrine/paracrine mechanism. The probasin (Pb)-PRL transgenic mouse models this mechanism by overexpressing PRL specifically in the prostate epithelium leading to strong STAT5 activation in luminal cells. These mice exhibit hypertrophic prostates harboring various pre-neoplastic lesions that aggravate with age and accumulation of castration-resistant stem/progenitor cells. As STAT5 signaling is largely predominant over other classical PRL-triggered pathways in Pb-PRL prostates, we reasoned that Pb-Cre recombinase-driven genetic deletion of a floxed Stat5a/b locus should prevent prostate tumorigenesis in so-called Pb-PRLSTAT5 mice. Anterior and dorsal prostate lobes displayed the highest Stat5a/b deletion efficiency with no overt compensatory activation of other PRLR signaling cascade at 6 months of age; hence the development of tumor hallmarks was markedly reduced. Stat5a/b deletion also reversed the accumulation of stem/progenitor cells, indicating that STAT5 signaling regulates prostate epithelial cell hierarchy. Interestingly, ERK1/2 and AKT, but not STAT3 and androgen signaling, emerged as escape mechanisms leading to delayed tumor development in aged Pb-PRLSTAT5 mice. Unexpectedly, we found that Pb-PRL prostates spontaneously exhibited age-dependent decline of STAT5 signaling, also to the benefit of AKT and ERK1/2 signaling. As a consequence, both Pb-PRL and Pb-PRLSTAT5 mice ultimately displayed similar pathological prostate phenotypes at 18 months of age. This preclinical study provides insight on STAT5-dependent mechanisms of PRL-induced prostate tumorigenesis and alternative pathways bypassing STAT5 signaling down-regulation upon prostate neoplasia progression.
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