In vivo activity of the dual PI3Kδ and PI3Kγ inhibitor duvelisib against pediatric acute lymphoblastic leukemia xenografts

Background: Acute lymphoblastic leukemia (ALL) remains one of the most common causes of cancer-related mortality in children. Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases, and aberrations in the PI3K pathway are associated with several hematological malignancies, including ALL. Duvelisib (Copiktra) is an orally available, small molecule dual inhibitor of PI3Kδ and PI3Kγ, that is Food and Drug Administration (FDA) approved for the treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Here, we report the efficacy of duvelisib against a panel of pediatric ALL patient-derived xenografts (PDXs). Procedures: Thirty PDXs were selected for a single mouse trial based on PI3Kδ (PIK3CD) and PI3Kγ (PIK3CG) expression and mutational status. PDXs were grown orthotopically in NSG (NOD.Cg-PrkdcscidIL2rgtm1Wjl/SzJAusb) mice, and engraftment was evaluated by enumerating the proportion of human versus mouse CD45+ cells (%huCD45+) in the peripheral blood. Treatment commenced when the %huCD45+ reached greater than or equal to 1%, and events were predefined as %huCD45+ greater than or equal to 25% or leukemia-related morbidity. Duvelisib was administered per oral (50 mg/kg, twice daily for 28 days). Drug efficacy was assessed by event-free survival and stringent objective response measures. Results: PI3Kδ and PI3Kγ mRNA expression was significantly higher in B-lineage than T-lineage ALL PDXs (p-values <.0001). Duvelisib was well-tolerated and reduced leukemia cells in the peripheral blood in four PDXs, but with only one objective response. There was no obvious relationship between duvelisib efficacy and PI3Kδ or PI3Kγ expression or mutation status, nor was the in vivo response to duvelisib subtype dependent. Conclusions: Duvelisib demonstrated limited in vivo activity against ALL PDXs

Responsibility modelling for civil emergency planning

This paper presents a new approach to analysing and understanding civil emergency planning based on the notion of responsibility modelling combined with HAZOPS-style analysis of information requirements. Our goal is to represent complex contingency plans so that they can be more readily understood, so that inconsistencies can be highlighted and vulnerabilities discovered. In this paper, we outline the framework for contingency planning in the United Kingdom and introduce the notion of responsibility models as a means of representing the key features of contingency plans. Using a case study of a flooding emergency, we illustrate our approach to responsibility modelling and suggest how it adds value to current textual contingency plans

In vivo activity of the dual SYK/FLT3 inhibitor TAK-659 against pediatric acute lymphoblastic leukemia xenografts

Background: While children with acute lymphoblastic leukemia (ALL) experience close to a 90% likelihood of cure, the outcome for certain high-risk pediatric ALL subtypes remains dismal. Spleen tyrosine kinase (SYK) is a prominent cytosolic nonreceptor tyrosine kinase in pediatric B-lineage ALL (B-ALL). Activating mutations or overexpression of Fms-related receptor tyrosine kinase 3 (FLT3) are associated with poor outcome in hematological malignancies. TAK-659 (mivavotinib) is a dual SYK/FLT3 reversible inhibitor, which has been clinically evaluated in several other hematological malignancies. Here, we investigate the in vivo efficacy of TAK-659 against pediatric ALL patient-derived xenografts (PDXs). Methods: SYK and FLT3 mRNA expression was quantified by RNA-seq. PDX engraftment and drug responses in NSG mice were evaluated by enumerating the proportion of human CD45+ cells (%huCD45+) in the peripheral blood. TAK-659 was administered per oral at 60 mg/kg daily for 21 days. Events were defined as %huCD45+ ≥ 25%. In addition, mice were humanely killed to assess leukemia infiltration in the spleen and bone marrow (BM). Drug efficacy was assessed by event-free survival and stringent objective response measures. Results: FLT3 and SYK mRNA expression was significantly higher in B-lineage compared with T-lineage PDXs. TAK-659 was well tolerated and significantly prolonged the time to event in six out of eight PDXs tested. However, only one PDX achieved an objective response. The minimum mean %huCD45+ was significantly reduced in five out of eight PDXs in TAK-659-treated mice compared with vehicle controls. Conclusions: TAK-659 exhibited low to moderate single-agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes

Effectiveness of psychosocial interventions in eating disorders: an overview of Cochrane systematic reviews

ABSTRACT Eating disorders are psychiatric conditions originated from and perpetuated by individual, family and sociocultural factors. The psychosocial approach to treatment and prevention of relapse is crucial. To present an overview of the scientific evidence on effectiveness of psychosocial interventions in treatment of eating disorders. All systematic reviews published by the Cochrane Database of Systematic Reviews - Cochrane Library on the topic were included. Afterwards, as from the least recent date of these reviews (2001), an additional search was conducted at PubMed with sensitive search strategy and with the same keywords used. A total of 101 primary studies and 30 systematic reviews (5 Cochrane systematic reviews), meta-analysis, guidelines or narrative reviews of literature were included. The main outcomes were: symptomatic remission, body image, cognitive distortion, psychiatric comorbidity, psychosocial functioning and patient satisfaction. The cognitive behavioral approach was the most effective treatment, especially for bulimia nervosa, binge eating disorder and the night eating syndrome. For anorexia nervosa, the family approach showed greater effectiveness. Other effective approaches were interpersonal psychotherapy, dialectic behavioral therapy, support therapy and self-help manuals. Moreover, there was an increasing number of preventive and promotional approaches that addressed individual, family and social risk factors, being promising for the development of positive self-image and self-efficacy. Further studies are required to evaluate the impact of multidisciplinary approaches on all eating disorders, as well as the cost-effectiveness of some effective modalities, such as the cognitive behavioral therapy

A Pan-African Convection-Permitting Regional Climate Simulation with the Met Office Unified Model: CP4-Africa

This is the final version. Available on open access from the American Meteorological Society via the DOI in this recordA convection-permitting multiyear regional climate simulation using the Met Office Unified Model has been run for the first time on an Africa-wide domain. The model has been run as part of the Future Climate for Africa (FCFA) Improving Model Processes for African Climate (IMPALA) project, and its configuration, domain, and forcing data are described here in detail. The model [Pan-African Convection-Permitting Regional Climate Simulation with the Met Office UM (CP4-Africa)] uses a 4.5-km horizontal grid spacing at the equator and is run without a convection parameterization, nested within a global atmospheric model driven by observations at the sea surface, which does include a convection scheme. An additional regional simulation, with identical resolution and physical parameterizations to the global model, but with the domain, land surface, and aerosol climatologies of CP4-Africa, has been run to aid in the understanding of the differences between the CP4-Africa and global model, in particular to isolate the impact of the convection parameterization and resolution. The effect of enforcing moisture conservation in CP4-Africa is described and its impact on reducing extreme precipitation values is assessed. Preliminary results from the first five years of the CP4-Africa simulation show substantial improvements in JJA average rainfall compared to the parameterized convection models, with most notably a reduction in the persistent dry bias in West Africa, giving an indication of the benefits to be gained from running a convection-permitting simulation over the whole African continent.Natural Environment Research Council (NERC

Disparities in the frequency of fruit and vegetable consumption by socio-demographic and lifestyle characteristics in Canada

<p>Abstract</p> <p>Background</p> <p>The health benefits of adequate fruit and vegetable (F&V) consumption are significant and widely documented. However, many individuals self-report low F&V consumption frequency per day. This paper examines the disparities in the frequency of F&V consumption by socio-demographic and lifestyle characteristics.</p> <p>Method</p> <p>This study uses a representative sample of 93,719 individuals from the Canadian Community Health Survey (2007). A quantile regression model is estimated in order to capture the differential effects of F&V determinants across the conditional distribution of F&V consumption.</p> <p>Results</p> <p>The conditional and unconditional analyses reveal the existence of a socioeconomic gradient in F&V consumption frequency, in which the low income-education groups consume F&V less frequently than the high income-education groups. We also find significant disparities in F&V consumption frequency by demographic and lifestyle characteristics. The frequency of F&V consumption is relatively lower among: males, those in middle age, singles, smokers, individuals with weak social interaction and households with no children. The quantile regression results show that the association between F&V consumption frequency, and socio-demographic and lifestyle factors varies significantly along the conditional F&V consumption distribution. In particular, individual educational attainment is positively and significantly associated with F&V consumption frequency across different parts of the F&V distribution, while the income level matters only over the lower half of the distribution. F&V consumption follows a U-shaped pattern across the age categories. Those aged 30-39, 40-49 and 50-59 years consume F&V less frequently than those aged 18-29 years. The smallest F&V consumption is among the middle aged adults (40-49).</p> <p>Conclusions</p> <p>Understanding the socio-demographic and lifestyle characteristics of individuals with low F&V consumption frequency could increase the effectiveness of policies aimed at promoting F&V consumption. The differential effects of individual characteristics along the F&V consumption distribution suggest the need for a multifaceted approach to address the variation in F&V consumption frequency.</p

Active Chromatin Marks Are Retained on X Chromosomes Lacking Gene or Repeat Silencing Despite XIST/Xist Expression in Somatic Cell Hybrids

X-chromosome inactivation occurs early in mammalian development and results in the inactive X chromosome acquiring numerous hallmarks of heterochromatin. While XIST is a key player in the inactivation process, the method of action of this ncRNA is yet to be determined.To assess which features of heterochromatin may be directly recruited by the expression and localization of the XIST RNA we have analyzed a mouse/human somatic cell hybrid in which expression of human and mouse XIST/Xist has been induced from the active X by demethylation. Such hybrids had previously been demonstrated to disconnect XIST/Xist expression from gene silencing and we confirm maintenance of X-linked gene expression, even close to the Xist locus, despite the localized expression of mouse Xist.Loss of the active chromatin marks H3 acetylation and H3 lysine 4 methylation was not observed upon XIST/Xist expression, nor was there a gain of DNA methylation; thus these marks of facultative heterochromatin are not solely dependent upon Xist expression. Cot-1 holes, regions of depleted RNA hybridization with a Cot-1 probe, were observed upon Xist expression; however, these were at reduced frequency and intensity in these somatic cells. Domains of human Cot-1 transcription were observed corresponding to the human chromosomes in the somatic cell hybrids. The Cot-1 domain of the X was not reduced with the expression of XIST, which fails to localize to the human X chromosome in a mouse somatic cell background. The human inactive X in a mouse/human hybrid cell also shows delocalized XIST expression and an ongoing Cot-1 domain, despite X-linked gene silencing. These results are consistent with recent reports separating Cot-1 silencing from genic silencing, but also demonstrate repetitive element expression from an otherwise silent X chromosome in these hybrid cells

Effect of Smoke-Free Legislation on Adult Smoking Behaviour in England in the 18 Months following Implementation

Comprehensive smoke-free legislation covering all enclosed public places and workplaces was implemented in England on 1 July 2007. This study examines the impact of this legislation on smoking prevalence, number of cigarettes smoked and location of smoking, controlling for secular trends through the end of 2008.Repeat cross sectional survey using nationally representative data from the Health Survey for England (HSE). In total there are 54,333 respondents from 2003-2008. Logit and linear regression models were used to examine the effect of the legislation on smoking prevalence and the number of cigarettes smoked daily among continuing smokers which took the underlying trend into account. Our finding suggest that smoking prevalence (current smoker) decreased from 25% in 2003 to 21% in 2008 (AOR = 0.96 per year, 95% CI = 0.95-0.98, P<0.01) and the mean number of cigarettes consumed daily by smokers decreased from 14.1 in 2003 to 13.1 in 2008 (coefficient for time trend = -0.28±0.06 SE cig/day per year, P<0.01). After adjusting for these trends the introduction of smoke-free legislation was not associated with additional reductions in smoking prevalence (AOR = 1.02, 95% CI = 0.94-1.11, P = 0.596) or daily cigarette use in smokers (0.42±0.28 SE; P = 0.142). The percentage of respondents reporting smoking 'at work' and 'inside pubs or bars' decreased significantly from 14% to 2% (p<0.001) and from 34% to 2% (p<0.001), respectively, after the legislation. The percentage reporting smoking 'inside restaurants, cafes, or canteens' decreased significantly from 9% to 1% (p<0.001) and 'inside their home' decreased significantly from 65% to 55% (p<0.01).There is widespread compliance with the smoke-free legislation in England, which has led to large drops in indoor smoking in all venues, including at home. Declines in smoking prevalence and consumption continued along existing trends; they did not accelerate during the 18 months immediately following implementation

Patterns and predictors of place of cancer death for the oldest old

BACKGROUND: Cancer patients increasingly are among older age groups, but to date little work has examined the trends in cancer among older people, particularly in relation to end of life care and death. This study describes the older population who die of cancer and the factors which may affect their place of death. METHODS: A Cross-sectional analysis of national data was performed. The study included all people aged 75 and over dying of cancer in England and Wales between 1995 and 1999. The population was divided into exclusive 5 year age cohorts, up to 100 years and over. Descriptive analysis explored demographic characteristics, cancer type and place of death. RESULTS: Between 1995 and 1999, 315,462 people aged 75 and over were registered as dying from cancer. The number who died increased each year slightly over the 5 year period (1.2%). In the 75–79 age group, 55 % were men, in those aged 100 and over this fell to 16%. On reaching their hundreds, the most common cause of death for men was malignancies of the genital organs; and for women it was breast cancer. The most frequent place of death for women in their hundreds was the care home; for men it was hospitals. Those dying from lymphatic and haematopoietic malignancies were most likely to die in hospitals, those with head and neck malignancies in hospices and breast cancer patients in a care home. CONCLUSION: The finding of rising proportions of cancer deaths in institutions with increasing age suggests a need to ensure that appropriate high quality care is available to this growing section of the population

Impact Factor: outdated artefact or stepping-stone to journal certification?

A review of Garfield's journal impact factor and its specific implementation as the Thomson Reuters Impact Factor reveals several weaknesses in this commonly-used indicator of journal standing. Key limitations include the mismatch between citing and cited documents, the deceptive display of three decimals that belies the real precision, and the absence of confidence intervals. These are minor issues that are easily amended and should be corrected, but more substantive improvements are needed. There are indications that the scientific community seeks and needs better certification of journal procedures to improve the quality of published science. Comprehensive certification of editorial and review procedures could help ensure adequate procedures to detect duplicate and fraudulent submissions.Comment: 25 pages, 12 figures, 6 table