Development of an Oral Form of Azacytidine: 2′3′5′Triacetyl-5-Azacytidine

Myelodysplastic syndromes (MDSs) represent a group of incurable stem-cell malignancies which are predominantly treated by supportive care. Epigenetic silencing through promoter methylation of a number of genes is present in poor-risk subtypes of MDS and often predicts transformation to acute myelogenous leukemia (AML). Azacitidine and decitabine, two FDA-approved DNA methyltransferase (DNMT) inhibitors, are able to improve overall response although their oral bioavailability complicates their clinical use. This study evaluated 2′, 3′, 5′-triacetyl-5-azacitidine (TAC) as a potential prodrug for azacitidine. The prodrug demonstrated significant pharmacokinetic improvements in bioavailability, solubility, and stability over the parent compound. In vivo analyses indicated a lack of general toxicity coupled with significantly improved survival. Pharmacodynamic analyses confirmed its ability to suppress global methylation in vivo. These data indicate that esterified nucleoside derivatives may be effective prodrugs for azacitidine and encourages further investigation of TAC into its metabolism, activity, and possible clinical evaluation

Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors.

Chemotherapies active in preclinical studies frequently fail in the clinic due to lack of efficacy, which limits progress for rare cancers since only small numbers of patients are available for clinical trials. Thus, a preclinical drug development pipeline was developed to prioritize potentially active regimens for pediatric brain tumors spanning from in vitro drug screening, through intracranial and intra-tumoral pharmacokinetics to in vivo efficacy studies. Here, as an example of the pipeline, data are presented for the combination of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in three pediatric brain tumor models. The in vitro activity of nine novel therapies was tested against tumor spheres derived from faithful mouse models of Group 3 medulloblastoma, ependymoma, and choroid plexus carcinoma. Agents with the greatest in vitro potency were then subjected to a comprehensive series of in vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies culminating in preclinical efficacy trials in mice harboring brain tumors. The nucleoside analog 5-fluoro-2'-deoxycytidine (FdCyd) markedly reduced the proliferation in vitro of all three brain tumor cell types at nanomolar concentrations. Detailed intracranial PK studies confirmed that systemically administered FdCyd exceeded concentrations in brain tumors necessary to inhibit tumor cell proliferation, but no tumor displayed a significant in vivo therapeutic response. Despite promising in vitro activity and in vivo PK properties, FdCyd is unlikely to be an effective treatment of pediatric brain tumors, and therefore was deprioritized for the clinic. Our comprehensive and integrated preclinical drug development pipeline should reduce the attrition of drugs in clinical trials

X-ray view of IC348 in the light of an updated cluster census

We study the properties of the coronae of the low-mass stars in the young (~2-3Myr), nearby (~310pc) open cluster IC348 combining X-ray and optical/infrared data. The four existing Chandra observations of IC348 are merged, thus providing a deeper and spatially more complete X-ray view than previous X-ray studies of the cluster. We have compiled a comprehensive catalog of IC348 members taking into account recent updates to the cluster census. Our data collection comprises fundamental stellar parameters, infrared excess indicating the presence of disks, Halpha emission as a tracer of chromospheric emission or accretion and mass accretion rates. We have detected 290 X-ray sources in four merged Chandra exposures, of which 187 are associated with known cluster members. Only four of the X-ray sources are brown dwarfs (spectral type M6 and later). The detection rate is highest for diskless Class III stars and increases with stellar mass. This may be explained with higher X-ray luminosities for higher mass and later evolutionary stage that is evident in the X-ray luminosity functions. In particular, we find that for the lowest examined masses (0.1-0.25 Msun) there is a difference between the X-ray luminosity functions of accreting and non-accreting stars (classified on the basis of their Halpha emission strength) as well as those of disk-bearing and diskless stars (classified on the basis of the slope of the spectral energy distribution). These differences disappear for higher masses. This is related to our finding that the L_x/L_bol ratio is non-constant across the mass/luminosity sequence of IC348 with a decrease towards lower luminosity stars. Our analysis of an analogous stellar sample in the Orion Nebula Cluster suggests that the decline of L_x/L_ bol for young stars at the low-mass end of the stellar sequence is likely universal.Comment: Accepted for publication in Astronomy & Astrophysic

A qualitative study of stakeholders' perspectives on the social network service environment

Over two billion people are using the Internet at present, assisted by the mediating activities of software agents which deal with the diversity and complexity of information. There are, however, ethical issues due to the monitoring-and-surveillance, data mining and autonomous nature of software agents. Considering the context, this study aims to comprehend stakeholders' perspectives on the social network service environment in order to identify the main considerations for the design of software agents in social network services in the near future. Twenty-one stakeholders, belonging to three key stakeholder groups, were recruited using a purposive sampling strategy for unstandardised semi-structured e-mail interviews. The interview data were analysed using a qualitative content analysis method. It was possible to identify three main considerations for the design of software agents in social network services, which were classified into the following categories: comprehensive understanding of users' perception of privacy, user type recognition algorithms for software agent development and existing software agents enhancement

Were Adolescent Sexual Offenders Children with Sexual Behavior Problems?

This article compares responses of three groups of incarcerated adolescents who admitted to sexual offending in an anonymous survey project on measures of trauma, sexual offending, the relationship between trauma and perpetration, and adjudication status. The first group admitted to sexual offending before the age of 12 only ( n = 48), the second after the age of 12 only ( n = 130), and the third before and after the age of 12 ( n = 65). More than 46% of the sexually aggressive adolescents began their deviant behaviors before the age of 12. Level and complexity of perpetration acts were more severe for the continuous offenders than for the other groups. Victimization and perpetration were significantly correlated for all three groups. This study supports a social learning hypothesis for the development of sexual offending by adolescents. Implications for research and clinical practice are drawn.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45557/1/11194_2004_Article_220864.pd

The assessment and rehabilitation of prospective memory problems in people with neurological disorders: A review

People with neurological disorders often report difficulty with prospective memory (PM), that is, remembering to do things they had intended to do. This paper briefly reviews the literature regarding the neuropsychology of PM function, concluding that from the clinical perspective, PM is best considered in terms of its separable but interacting mnemonic and executive components. Next, the strengths and limitations in the current clinical assessment of PM, including the assessment of component processes, desktop analogues of PM tasks, and naturalistic PM tasks, are outlined. The evidence base for the rehabilitation of PM is then considered, focusing on retraining PM, using retrospective memory strategies, problem-solving training, and finally, electronic memory aids. It is proposed that further research should focus on establishing the predictive validity of PM assessment, and refining promising rehabilitation techniques

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

The Development of Risk Politics in the UK: Thatcher’s ‘Remarkable’ but Forgotten ‘Don’t Die of Ignorance’ AIDS Campaign

Thirty years on from the dramatic and unprecedented AIDS advertising campaign organised by the Conservative administration of the late 1980s, this article reassesses the experience drawing upon subsequent memoirs and interviews. It does so in the context of an emergence of risk politics in the UK in the 1980s, situated within an historical perspective on the development of risk within modernity. Emphasis is placed upon the forgotten pragmatic, amoral core of the campaign which challenged the illiberal climate of the times, and how it was possible for an administration defined by high moralism to challenge it. The range of pressures that led to the campaign are outlined, including a conscious attempt to limit stigmatisation amidst the mood of wartime emergency that prevailed in late 1986/early 1987. Its emergency character meant little direct legacy of harm reduction has endured, but the article argues for a wider significance of the campaign as a key moment in the emergence of risk politics in the UK and beyond

Influence of obesity-related risk factors in the aetiology of glioma

BACKGROUND: Obesity and related factors have been implicated as possible aetiological factors for the development of glioma in epidemiological observation studies. We used genetic markers in a Mendelian randomisation framework to examine whether obesity-related traits influence glioma risk. This methodology reduces bias from confounding and is not affected by reverse causation. METHODS: Genetic instruments were identified for 10 key obesity-related risk factors, and their association with glioma risk was evaluated using data from a genome-wide association study of 12,488 glioma patients and 18,169 controls. The estimated odds ratio of glioma associated with each of the genetically defined obesity-related traits was used to infer evidence for a causal relationship. RESULTS: No convincing association with glioma risk was seen for genetic instruments for body mass index, waist-to-hip ratio, lipids, type-2 diabetes, hyperglycaemia or insulin resistance. Similarly, we found no evidence to support a relationship between obesity-related traits with subtypes of glioma-glioblastoma (GBM) or non-GBM tumours. CONCLUSIONS: This study provides no evidence to implicate obesity-related factors as causes of glioma

Cooperation of Sumoylated Chromosomal Proteins in rDNA Maintenance

SUMO is a posttranslational modifier that can modulate protein activities, interactions, and localizations. As the GFP-Smt3p fusion protein has a preference for subnucleolar localization, especially when deconjugation is impaired, the nucleolar role of SUMO can be the key to its biological functions. Using conditional triple SUMO E3 mutants, we show that defects in sumoylation impair rDNA maintenance, i.e., the rDNA segregation is defective and the rDNA copy number decreases in these mutants. Upon characterization of sumoylated proteins involved in rDNA maintenance, we established that Top1p and Top2p, which are sumoylated by Siz1p/Siz2p, most likely collaborate with substrates of Mms21p to maintain rDNA integrity. Cohesin and condensin subunits, which both play important roles in rDNA stability and structures, are potential substrates of Mms21, as their sumoylation depends on Mms21p, but not Siz1p and Siz2p. In addition, binding of cohesin and condensin to rDNA is altered in the mms21-CH E3-deficient mutant