The retinoid anticancer signal: mechanisms of target gene regulation

Retinoids induce growth arrest, differentiation, and cell death in many cancer cell types. One factor determining the sensitivity or resistance to the retinoid anticancer signal is the transcriptional response of retinoid-regulated target genes in cancer cells. We used cDNA microarray to identify 31 retinoid-regulated target genes shared by two retinoid-sensitive neuroblastoma cell lines, and then sought to determine the relevance of the target gene responses to the retinoid anticancer signal. The pattern of retinoid responsiveness for six of 13 target genes (RARβ2, CYP26A1, CRBP1, RGS16, DUSP6, EGR1) correlated with phenotypic retinoid sensitivity, across a panel of retinoid-sensitive or -resistant lung and breast cancer cell lines. Retinoid treatment of MYCN transgenic mice bearing neuroblastoma altered the expression of five of nine target genes examined (RARβ2, CYP26A1, CRBP1, DUSP6, PLAT) in neuroblastoma tumour tissue in vivo. In retinoid-sensitive neuroblastoma, lung and breast cancer cell lines, direct inhibition of retinoid-induced RARβ2 expression blocked induction of only one of eight retinoid target genes (CYP26A1). DNA demethylation, histone acetylation, and exogenous overexpression of RARβ2 partially restored retinoid-responsive CYP26A1 expression in RA-resistant MDA-MB-231 breast, but not SK-MES-1 lung, cancer cells. Combined, rather than individual, inhibition of DUSP6 and RGS16 was required to block retinoid-induced growth inhibition in neuroblastoma cells, through phosphorylation of extracellular-signal-regulated kinase. In conclusion, sensitivity to the retinoid anticancer signal is determined in part by the transcriptional response of key retinoid-regulated target genes, such as RARβ2, DUSP6, and RGS16

Regulation of MYCN expression in human neuroblastoma cells

Contains fulltext : 81722.pdf (publisher's version ) (Open Access)BACKGROUND: Amplification of the MYCN gene in neuroblastoma (NB) is associated with a poor prognosis. However, MYCN-amplification does not automatically result in higher expression of MYCN in children with NB. We hypothesized that the discrepancy between MYCN gene expression and prognosis in these children might be explained by the expression of either MYCN-opposite strand (MYCNOS) or the shortened MYCN-isoform (DeltaMYCN) that was recently identified in fetal tissues. Both MYCNOS and DeltaMYCN are potential inhibitors of MYCN either at the mRNA or at the protein level. METHODS: Expression of MYCN, MYCNOS and DeltaMYCN was measured in human NB tissues of different stages. Transcript levels were quantified using a real-time reverse transcriptase polymerase chain reaction assay (QPCR). In addition, relative expression of these three transcripts was compared to the number of MYCN copies, which was determined by genomic real-time PCR (gQPCR). RESULTS: Both DeltaMYCN and MYCNOS are expressed in all NBs examined. In NBs with MYCN-amplification, these transcripts are significantly higher expressed. The ratio of MYCN:DeltaMYCN expression was identical in all tested NBs. This indicates that DeltaMYCN and MYCN are co-regulated, which suggests that DeltaMYCN is not a regulator of MYCN in NB. However, the ratio of MYCNOS:MYCN expression is directly correlated with NB disease stage (p = 0.007). In the more advanced NB stages and NBs with MYCN-amplification, relatively more MYCNOS is present as compared to MYCN. Expression of the antisense gene MYCNOS might be relevant to the progression of NB, potentially by directly inhibiting MYCN transcription by transcriptional interference at the DNA level. CONCLUSION: The MYCNOS:MYCN-ratio in NBs is significantly correlated with both MYCN-amplification and NB-stage. Our data indicate that in NB, MYCN expression levels might be influenced by MYCNOS but not by DeltaMYCN

Estresse pós-traumático: uma abordagem baseada em evidências Posttraumatic stress disorder: an evidence-based approach

As intervenções usadas no manejo do transtorno do estresse pós-traumático (TEPT) focalizam-se em: (1) prevenção do desenvolvimento da doença após um evento traumático, (2) tratamento do quadro já estabelecido e (3) manutenção do funcionamento e da qualidade de vida em longo prazo. Uma variedade de tratamentos psicoterápicos e farmacológicos tem sido proposta para o tratamentos do TEPT. Entretanto, nem todas as modalidades de tratamento apresentam comprovação científica. No presente artigo, os autores apresentam as modalidades de tratamentos do TEPT amparadas em evidências e discutem sua aplicabilidade e limitações.<br>The interventions used in the clinical management of posttraumatic stress disorder (PTSD) focus on: 1. Prevention of the development of the disorder, after a traumatic event 2. Treatment of the disorder, once it is already established, 3. Maintenance of long term functioning and quality of life. A variety of psychotherapies and pharmacological treatments have been proposed as therapeutic options in the treatment of PTSD. However, many of these treatment modalities lack scientific background. In this article authors present the treatment modalities of PTSD which are supported by scientific evidence and discuss its applications and drawbacks

Articulating practice through Provenance

Professional practice literature acknowledges the value for practitioners inquiring into and critically reflecting on their professional practice (Brookfield, 1998; Kemmis, 2010). This approach to professional practice inquiry, initiated and undertaken by the professionals themselves, has been labelled ‘practitioner research’ (Stenhouse, 1981) in educational literature and ‘first-person action research’ (Reason & Bradbury, 2001) in research literature. The approach can also be seen as a response to Nicolini’s (2009) call for broader than ethnographic methodologies within the ‘practice-turn’ (Schatzki, Knorr-Cetina & von Savigny, 2001). The paradigm dialogue’s people-centred inquiry approach (Guba & Lincoln, 1982) generated multiple alternative investigative methodologies to the scientific method, an approach which until that time had dominated research practices. Several of the alternate approaches were relevant for professional practice investigation. The propositions within this paper are contextualised within one of the posited alternate methodologies, ‘practice-led inquiry’ (Gray, 1996), distinguished from other forms of practitioner research by its starting or initiating point within the inquirer’s own practice. This defining feature is problematic for some practitioners who have difficulty describing their practice, and specifically describing it in ways that open the practices to interrogation and inquiry and generate new knowledge and theory. This paper posits Provenance as a strategy/process within practice-led inquiry to enable practitioners to recognise knowledge about practice arising from their own experiences and utilise that in their theory building. The term Provenance describes the history and ownership of a given artefact, and the artisans who have informed its making. We discuss professional’s utilisation of Provenance’s within practice-led inquiry (Gray, 1996) to identify origins of their practice through nominating critical incidents and literature that have informed development of their practice (Finlay, 2002; Davies, 2008; Hill, 2014; Hill & Lloyd, 2015). Provenance thus creates a starting point and scaffold for practice-led inquiry, enabling a professional to interrogate their practice to build meaning about how a given professional practice can be understood and undertaken. This stands to contribute to the growing discourse about professional practice. Provenance can also support extended inquiry into a practice by scaffolding solicitation of other professional stories about a given professional practice. Provenance resonates with action inquiry, both in iterative cycles of action and reflection (Hill, 2014) and in the use of ‘first person action inquiry’ (Reason & Bradbury, 2001). It allows professionals to connect back and identify turning points in their own professional development. It affirms the practitioner/inquirer’s own understanding and knowledge of their practice. The narrative that evolves from initial consideration of critical events, and sometimes literature that have informed development of professional practice, can be repeatedly revisited to remember, reflect and change more and more detail, generating new knowledge about the practice

I complicati rapporti fra la Chiesa cattolica statunitense e la Santa Sede, 1880-1918

Relationship betwen the American Catholic Church and the Holy Seeversione world prima delle bozz