HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network

Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies.

Tumor suppressor Ras-association domain family 1 isoform A is a novel regulator of cardiac hypertrophy

BACKGROUND: Ras signaling regulates a number of important processes in the heart, including cell growth and hypertrophy. Although it is known that defective Ras signaling is associated with Noonan, Costello, and other syndromes that are characterized by tumor formation and cardiac hypertrophy, little is known about factors that may control it. Here we investigate the role of Ras effector Ras-association domain family 1 isoform A (RASSF1A) in regulating myocardial hypertrophy.

METHODS AND RESULTS: A significant downregulation of RASSF1A expression was observed in hypertrophic mouse hearts, as well as in failing human hearts. To further investigate the role of RASSF1A in cardiac (patho)physiology, we used RASSF1A knock-out (RASSF1A(-)(/)(-)) mice and neonatal rat cardiomyocytes with adenoviral overexpression of RASSF1A. Ablation of RASSF1A in mice significantly enhanced the hypertrophic response to transverse aortic constriction (64.2% increase in heart weight/body weight ratio in RASSF1A(-)(/)(-) mice compared with 32.4% in wild type). Consistent with the in vivo data, overexpression of RASSF1A in cardiomyocytes markedly reduced the cellular hypertrophic response to phenylephrine stimulation. Analysis of molecular signaling events in isolated cardiomyocytes indicated that RASSF1A inhibited extracellular regulated kinase 1/2 activation, likely by blocking the binding of Raf1 to active Ras.

CONCLUSIONS: Our data establish RASSF1A as a novel inhibitor of cardiac hypertrophy by modulating the extracellular regulated kinase 1/2 pathway.

Bereavement outcomes: a quantitative survey identifying risk factors in family carers bereaved through cancer.

Background: Enabling patients to die in their preferred place is important but achieving preferred place of death may increase the informal carer’s risk into bereavement. Aim: to determine risk factors of family carers bereaved through cancer in Northern Ireland. Design: These results form part of a larger QUALYCARE-NI study which used postal questionnaires to capture quantitative data on carer’s bereavement scores using the Texas Revised Inventory of Grief. Setting/participants: Participants were individuals who: registered the death of a person between 1st December 2011 and 31st May 2012; where cancer (defined by ICD10 codes C00-D48) was the primary cause; where the deceased was over 18 years of age and death occurred at home, hospice, nursing home or hospital in Northern Ireland. Participants were approached in confidence by the Demography and Methodology Branch of the Northern Ireland Statistics and Research Agency. Those wishing to decline participation were invited to return the reply slip. Non-responders received a second questionnaire six weeks after initial invitation. Results indicated that risk factors positively influencing bereavement outcomes included patients having no preference for place of death and carers remaining in employment pre or post bereavement. In contrast, patients dying in hospital, carers stopping work, being of lower socio-economic status and close kinship to the deceased negatively impacted on bereavement scores. Family carers should be adequately supported to continue in employment; priority should be given to assessing the financial needs of families from lower socio-economic areas; and bereavement support should focus on close relatives of the deceased.

Seasons, Family and Nation in American Horror Story

Arguably, the title of American Horror Story sets out an agenda for the program: this is not just a horror story, but it is a particularly American one. This chapter examines the way that the program uses seasonal celebrations as a way of expressing that national identity, with special emphasis on the importance of family to those celebrations. The particular seasonal celebrations focused on are those of Halloween and Christmas, each of which has associations with the supernatural. However, the use of the supernatural at those seasons is one which is particularly associated with the US, presenting Halloween as a time of supernatural incursion and horror, and of disruption to society and the normal order of things, while Christmas is presented more as a time of unity for the family. Where the supernatural emerges in American Christmas television, it is typically as a force to encourage togetherness and reconciliation, rather than as a dark reminder of the past. While these interpretations of these festivals have been broadcast abroad by American cultural products, not least American television, they have different associations and implications elsewhere, as will be shown. So the particular uses of these festivals is part of what marks American Horror Story out as American, as is the way that the program's narratives have been structured to fit in with US television scheduling. This chapter, then, argues that the structures of the narratives combines with their use of the festivals of Halloween and Christmas in order to enhance the sense of this series as a particularly American horror story.

Impact de la monoparentalité et de la pauvreté combinées sur l'évolution des familles bénéficiant d'une intervention brève intensive de crise

L'objectif de la présente étude vise à documenter l'évolution de familles confrontées à la monoparentalité et la pauvreté suite à une intervention brève et intensive de crise. Pour atteindre cet objectif, nous avons procédé à la comparaison de l'évolution de deux sous-groupes de familles soit des familles monoparentales bénéficiant d'un revenu familial annuel faible (moins de $40,000/année) (familles défavorisées) (n=10) et des familles biparentales bénéficiant d'un revenu familial annuel plus favorable (plus de $40,000/année) (familles favorisées) (n=50). Les caractéristiques des familles ont été évaluées à 2 reprises, soit après la deuxième semaine suivant le début du suivi et 12 mois plus tard. Les questionnaires qui ont été retenus dans la présente étude visaient à évaluer différentes dimensions du fonctionnement familial notamment la résolution de problème, la communication, les rôles, l'investissement affectif, l'expression affective, le contrôle des comportements et le fonctionnement familial général ( Family Assessment Device de Epstein et al. , 1983) et certaines caractéristiques des pratiques éducatives des parents soit l'engagement parental, les comportements parentaux positifs, la supervision parentale et la discipline inconsistante (Alabama Parenting Questionnaire de Shelton et al ., 1995). Les premières analyses comparatives ont permis de constater que globalement, du point de vue des adolescents, l'ensemble des familles ont connu en moyenne une évolution positive sur la plupart des dimensions évaluées concernant le fonctionnement familial sauf en ce qui concerne l'investissement affectif et le contrôle des comportements. De même, les adolescents rapportent que les pratiques éducatives ont évolué positivement sur les plans de l'engagement des parents et des pratiques parentales positives. De plus, selon le point de vue des parents répondants, il apparaît que les familles ont connu une évolution positive sur l'ensemble des dimensions mesurées concernant le fonctionnement de la famille. En outre, il ressort que les familles ne connaissent pas d'évolution significative suite à l'intervention sur la presque totalité des dimensions mesurées concernant les pratiques éducatives sauf en ce qui concerne la discipline inconsistante. D'autres analyses comparatives concernant l'évolution des familles défavorisées comparativement aux familles favorisées suite à l'intervention ont permis de constater que les familles défavorisées connaissent une évolution positive plus importante sur les plans de la distribution des rôles, de l'investissement affectif, du contrôle des comportements et de la discipline inconsistante selon le point de vue des parents répondants. Par ailleurs, on note, selon le point de vue des adolescents, une évolution négative plus importante des familles défavorisées sur les plans du contrôle des comportements comparativement aux familles favorisées.

Factoring in family freight forwarder company: case study

Each freight forwarder company must independently determine whether factoring is the right choice for them and if will pay off. If the factoring as a financial method would not be economically viable, it certainly would not exist. There are several different financing methods, which are more or less useful. However, not all of them are appropriate for every company, just like all buyers do not represent equal risks for the suppliers. The same buyer can pay one supplier within the agreed period, and not pay the other supplier at all. Still, the most important elements are the agreement made with the customer, the method of insuring ourselves and the method of monitoring the implementation of the agreements. Problems rarely occur overnight and that is why we have to constantly supervise our buyers; otherwise account receivables can occur. My thesis contributes to the ongoing research into how the use of factoring within the Slovenian economic environment can help a small freight forwarder company to grow. In effect, the specific characteristics of the Slovenian economic, legal and institutional environment make such an analysis an interesting one to explore. I used data from a family freight forwarder company TOP Hrvatin in drugi d.n.o. in order to establish future company growth by applying factoring as a right choice of financing. After applying all the data and preparing the company's financial plan, my results suggest that factoring is not the right choice for financing future investments for this particular freight forwarder business. Furthermore, the results even show that factoring is an extremely undeveloped financing method in Slovenia and that practically there is no legal base for its use.