The Wnt-dependent signaling pathways as target in oncology drug discovery

Our current understanding of the Wnt-dependent signaling pathways is mainly based on studies performed in a number of model organisms including, Xenopus, Drosophila melanogaster, Caenorhabditis elegans and mammals. These studies clearly indicate that the Wnt-dependent signaling pathways are conserved through evolution and control many events during embryonic development. Wnt pathways have been shown to regulate cell proliferation, morphology, motility as well as cell fate. The increasing interest of the scientific community, over the last decade, in the Wnt-dependent signaling pathways is supported by the documented importance of these pathways in a broad range of physiological conditions and disease states. For instance, it has been shown that inappropriate regulation and activation of these pathways is associated with several pathological disorders including cancer, retinopathy, tetra-amelia and bone and cartilage disease such as arthritis. In addition, several components of the Wnt-dependent signaling pathways appear to play important roles in diseases such as Alzheimer’s disease, schizophrenia, bipolar disorder and in the emerging field of stem cell research. In this review, we wish to present a focused overview of the function of the Wnt-dependent signaling pathways and their role in oncogenesis and cancer development. We also want to provide information on a selection of potential drug targets within these pathways for oncology drug discovery, and summarize current data on approaches, including the development of small-molecule inhibitors, that have shown relevant effects on the Wnt-dependent signaling pathways

Affective technologies of welfare deterrence in Australia and the United Kingdom

Across the political spectrum of different historical periods, welfare deterrence has shaped social security and immigration policy in both Australia and the United Kingdom. Deterrence discourages access to state welfare through the production and mobilization of negative affect to deter specific groups from claiming state support, and by crafting public affect (of fear and disgust) about these target populations in order to garner consent for punitive policies. In this paper, we argue that deterrence works as a human technology where the crafting of negative affect operates as a technology of statecraft. Through critical juxtaposition and multiple genealogies of deterrence, this paper meshes time and space, and colony/colonizer and metropole, to show the historical and contemporary connectivity of the affective nature of deterrence. We identify five main operations that produce the ‘feel’ of deterrence: stigmatization by design, destitution by design, deterrent architecture, the control of movement, and the centrality of labour; as well as tracing the political economy of deterrence

Harvests of shame: enduring unfree labour in twentieth century United States, 1933-1964

This article reframes the discussion on vulnerable and exploited agricultural labour in twentieth-century United States using the overarching category of unfree labour. In order to do so, it bridges two usually distinct historiographies by linking the phenomenon of ‘peonage’ during the New Deal, with the one of immigrant contract labour southern Florida, under the H2 visa. Archival research on the practices at the US Sugar Corporation in southern Florida exemplifies this link. This article draws on federal archives, government proceedings, papers of political activists and legal and labour scholarship to argue: firstly, that unfree labour has been an enduring feature of agricultural labour relations at regional level during the twentieth century, through both a transmission and a transformation of practice that had their origin in the control of black emancipated labour; secondly, that the introduction of guest workers under the H2 and Bracero programme meant a modernization in the practices of unfree labour, pivoting on the lack of citizenship rights, racial discrimination, debt at home, and threat of deportation; and, finally, that the failure to recognise forms of legal and economic deprivation and coercion as unfree labour has hurt the ability of the United States to enforce protection of human rights at home

Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo

The influence of short stature on psychological adaptation in childhood and adolescence is controversial. GH is currently used to treat children with idiopathic short stature (ISS, also known as non-GH-deficient short stature). This study represents the first double-blind, placebo-controlled trial of the effects of GH on the psychological adaptation of children and adolescents with ISS, treated with GH until adult height was attained. Sixty-eight children (53 males, 15 females), 9-16 yr old, with marked ISS (measured height or predicted adult height -2.5 SD or less) received either GH 0.074 mg/kg or placebo sc three times per week until height velocity decreased to less than 1.5 cm/yr. Parents completed the Child Behavior Checklist (CBCL) and children the Self-Perception Profile (SPP) and Silhouette Apperception Technique at baseline and annually thereafter. Baseline behavioral/emotional adjustment (CBCL) and self-concept (SPP) scores for children with ISS were within the normative ra

Testicular adrenal rest tumors and Leydig and Sertoli cell function in boys with classical congenital adrenal hyperplasia

Context: Infertility observed in adult males with congenital adrenal hyperplasia (CAH) has been associated with testicular adrenal rest tumors (TART) that may originate during childhood. Objective: Our objective was to describe the prevalence of TART and Sertoli and Leydig cell function in a group of boys aged 2-10 yr with CAH and to compare prevalence with that of a control group. Design: From August 2005 to January 2007, 19 patients with classical CAH (CAH group) were referred from seven endocrinology centers. Methods: We studied 19 subjects in the CAH group and, as a control group, 13 boys from the community that did not have testicular diseases. A complete physical exam was performed. High-resolution ultrasound was used to determine TART prevalence. Inhibin B and anti-Müllerian hormone were used as Sertoli cell markers. The ratio between basal testosterone levels and testosterone levels 72 h after β-human chorionic gonadotropin (5000 U/m2) treatment [(T72- T 0)/T0] was used to eva

Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature: A randomized, double-blind, placebo-controlled trial

GH is often used to treat children with idiopathic short stature despite the lack of definitive, long-term studies of efficacy. We performed a randomized, double-blind, placebo-controlled trial to determine the effect of GH on adult height in peripubertal children. Subjects (n = 68; 53 males and 15 females), 9-16 yr old, with marked, idiopathic short stature [height or predicted height ≤ -2.5 SD score (SDS)] received either GH (0.074 mg/kg) or placebo sc three times per week until they were near adult height. At study termination, adult height measurements were available for 33 patients after mean treatment duration of 4.4 yr. Adult height was greater in the GH-treated group (-1.81 ± 0.11 SDS, least squares mean ± SEM) than in the placebo-treated group (-2.32 ± 0.17 SDS) by 0.51 SDS (3.7 cm; P < 0.02; 95% confidence interval, 0.10-0.92 SDS). A similar GH effect was demonstrated in terms of adult height SDS minus baseline height SDS and adult height SDS minus baseline predicted height