Epidemiological investigation to assess environmental contributions to childhood blood lead levels

Reduction in childhood blood lead levels has been one of the most successful public health efforts in history. However, there is ongoing evidence that declines in cognition and social behavior occur at levels well below 10 µg/dL and the effects of lead exposure are irreversible. This body of work will address current and continuous sources of lead in the environment and its potential impact on childhood blood lead levels. Toxic Release Inventory (TRI) lead emissions and ambient air lead estimated by the National Air Toxics Assessment (NATA) were used to assess associations between environmental lead and childhood blood lead levels (n = 3,223) measured in the National Health and Nutrition Examination Survey (1999-2006). After adjustment (gender, race, age in months, percent pre-1950 housing, reference adult’s education, poverty income ratio, region and survey cycle) a 10,000 lb/mi2 increase in TRI resulted in a 1.13% (95%CI: 0.45, 1.81) increase in blood lead. Neither TRI nor NATA estimates were significantly associated with blood lead after adjusting for cotinine and floor lead dust. Two additional studies were conducted with a specific focus on children living in Pennsylvania and New Jersey. The first study assessed if living within 3km of an airport was associated with elevated blood lead levels (n = 493,956). After adjustment for percent pre-1950 housing, poverty and race, gender, age in months, and industrial emissions, children living near an airport (n = 25,684) did not have a higher prevalence of elevated blood lead (≥ 5µg/dL) than children living further away. Finally, a geospatial regression was performed to determine the distribution of children with elevated blood lead levels (n = 855,291). Children living in large rural towns and isolated rural towns have a higher prevalence of elevated blood lead levels than urban areas after adjusting for percent male, pre-1950 housing, poverty, race, and industrial air lead emissions. Other sources such as neighborhood lead contamination and residential lead dust may contribute to childhood blood lead levels. The public health significance of these studies is to determine current sources of environmental lead so primary prevention programs can be implemented to further limit exposures in children

Practical steps toward integrating economic, social and institutional elements in fisheries policy and management

While international agreements and legislation call for incorporation of four pillars of sustainability, the social (including cultural), economic and institutional aspects (the ‘human dimension’) have been relatively neglected to date. Three key impediments have been identified: a relative lack of explicit social, economic and institutional objectives; a general lack of process (frameworks, governance) for routine integration of all four pillars of sustainability; and a bias towards biological considerations. Practical integration requires a ‘systems’ approach with explicit consideration of strategic and operational aspects of management; multidisciplinary or transdisciplinary evaluations; practical objectives for the four pillars of sustainability; appropriate participation; and a governance system that is able to integrate these diverse considerations in management. We challenge all involved in fisheries to immediately take five practical steps toward integrating ecological, economic, social and institutional aspects: (1) Adopt the perspective of the fishery as a ‘system’ with interacting natural, human and management elements; (2) Be aware of both strategic and operational aspects of fisheries assessment and management; (3) Articulate overarching objectives that incorporate all four pillars of sustainability; (4) Encourage appropriate (and diverse) disciplinary participation in all aspects of research, evaluation and management; and (5) Encourage development of (or emulate) participatory governance

The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity

Background: We characterized the biologic effects of a novel small molecule STAT3 pathway inhibitor that is derived from the natural product curcumin. We hypothesized this lead compound would specifically inhibit the STAT3 signaling pathway to induce apoptosis in melanoma cells. Results: FLLL32 specifically reduced STAT3 phosphorylation at Tyr705 (pSTAT3) and induced apoptosis at micromolar amounts in human melanoma cell lines and primary melanoma cultures as determined by annexin V/propidium iodide staining and immunoblot analysis. FLLL32 treatment reduced expression of STAT3-target genes, induced caspase-dependent apoptosis, and reduced mitochondrial membrane potential. FLLL32 displayed specificity for STAT3 over other homologous STAT proteins. In contrast to other STAT3 pathway inhibitors (WP1066, JSI-124, Stattic), FLLL32 did not abrogate IFN-γ-induced pSTAT1 or downstream STAT1-mediated gene expression as determined by Real Time PCR. In addition, FLLL32 did not adversely affect the function or viability of immune cells from normal donors. In peripheral blood mononuclear cells (PBMCs), FLLL32 inhibited IL-6-induced pSTAT3 but did not reduce signaling in response to immunostimulatory cytokines (IFN-γ, IL 2). Treatment of PBMCs or natural killer (NK) cells with FLLL32 also did not decrease viability or granzyme b and IFN-γ production when cultured with K562 targets as compared to vehicle (DMSO). Conclusions: These data suggest that FLLL32 represents a lead compound that could serve as a platform for further optimization to develop improved STAT3 specific inhibitors for melanoma therapy

Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms

Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3′-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability

Genome-Wide Association Study in East Asians Identifies Novel Susceptibility Loci for Breast Cancer

Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-β activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8×10−12 in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85–0.94) and 0.80 (0.75–0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9×10−6 from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10−7), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively

Patterns of HIV-1 Protein Interaction Identify Perturbed Host-Cellular Subsystems

Human immunodeficiency virus type 1 (HIV-1) exploits a diverse array of host cell functions in order to replicate. This is mediated through a network of virus-host interactions. A variety of recent studies have catalogued this information. In particular the HIV-1, Human Protein Interaction Database (HHPID) has provided a unique depth of protein interaction detail. However, as a map of HIV-1 infection, the HHPID is problematic, as it contains curation error and redundancy; in addition, it is based on a heterogeneous set of experimental methods. Based on identifying shared patterns of HIV-host interaction, we have developed a novel methodology to delimit the core set of host-cellular functions and their associated perturbation from the HHPID. Initially, using biclustering, we identify 279 significant sets of host proteins that undergo the same types of interaction. The functional cohesiveness of these protein sets was validated using a human protein-protein interaction network, gene ontology annotation and sequence similarity. Next, using a distance measure, we group host protein sets and identify 37 distinct higher-level subsystems. We further demonstrate the biological significance of these subsystems by cross-referencing with global siRNA screens that have been used to detect host factors necessary for HIV-1 replication, and investigate the seemingly small intersect between these data sets. Our results highlight significant host-cell subsystems that are perturbed during the course of HIV-1 infection. Moreover, we characterise the patterns of interaction that contribute to these perturbations. Thus, our work disentangles the complex set of HIV-1-host protein interactions in the HHPID, reconciles these with siRNA screens and provides an accessible and interpretable map of infection

Prevention and management of adverse events of novel agents in multiple myeloma: a consensus of the European Myeloma Network

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events

Poly Economics-Capitalism, Class, and Polyamory

Academic research and popular writing on nonmonogamy and polyamory has so far paid insufficient attention to class divisions and questions of political economy. This is striking since research indicates the significance of class and race privilege within many polyamorous communities. This structure of privilege is mirrored in the exclusivist construction of these communities. The article aims to fill the gap created by the silence on class by suggesting a research agenda which is attentive to class and socioeconomic inequality. The paper addresses relevant research questions in the areas of intimacy and care, household formation, and spaces and institutions and advances an intersectional perspective which incorporates class as nondispensable core category. The author suggests that critical research in the field can stimulate critical self-reflexive practice on the level of community relations and activism. He further points to the critical relevance of Marxist and Postmarxist theories as important resources for the study of polyamory and calls for the study of the contradictions within poly culture from a materialist point of view. © 2013 Springer Science+Business Media New York

LGBTQ parenting post heterosexual relationship dissolution

The chapter examines parenting among sexual and gender minorities post heterosexual relationship dissolution (PHRD). Reviewing the literature around intersecting identities of LGBTQ parents, we consider how religion, race, and socioeconomic status are associated with routes into and out of heterosexual relationships and variation in the lived experience of sexual and gender identity minorities, in particular how LGBTQ parents PHRD feel about being out. Further consideration is given to examining how family relationships change and develop as parental sexual and/or gender identity changes. We also explore the impact of PHRD identity and parenthood on new partnerships and stepfamily experiences. The chapter addresses the reciprocal relationship between research on LGBTQ parenting and policy and legal influences that impact upon the experience of LGBTQ parenting PHRD when custody and access are disputed. Finally, the chapter includes future research directions and implications for practice in an area that has been revitalized in recent years